EIDD-2801 works similarly to Gilead Sciences’ remdesivir, an unapproved drug that was developed for the Ebola virus and is being studied in five Phase III trials against COVID-19. Both molecules are nucleoside analogs that metabolize into an active form that blocks RNA polymerase, an essential component of viral replication.
Azithromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumonia, traveler’s diarrhea, and certain other intestinal infections. It can also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections. Along with other medications, it may also be used for malaria. It can be taken by mouth or intravenously with doses once per day.
Common side effects include nausea, vomiting, diarrhea and upset stomach. An allergic reaction, such as anaphylaxis, QT prolongation, or a type of diarrhea caused by Clostridium difficile is possible. No harm has been found with its use during pregnancy. Its safety during breastfeeding is not confirmed, but it is likely safe. Azithromycin is an azalide, a type of macrolide antibiotic. It works by decreasing the production of protein, thereby stopping bacterial growth.
Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The World Health Organization classifies it as critically important for human medicine. It is available as a generic medication and is sold under many trade names worldwide. The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose. In the United States, it is about US$4 for a course of treatment as of 2018. In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.
Azithromycin is used to treat many different infections, including:
- Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.
- Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae
- Uncomplicated skin infections due to S. aureus, S. pyogenes, or S. agalactiae
- Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.
- Trachoma due to C. trachomatis
- Genital ulcer disease (chancroid) in men due to H. ducrey
- Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.
- Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.
- Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy
Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.
A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin, but the drug is not widely used as monotherapy due to a low barrier to resistance development. Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.
Aerobic and facultative Gram-positive microorganisms
- Staphylococcus aureus (Methicillin-sensitive only)
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
Aerobic and facultative Gram-negative microorganisms
- Haemophilus ducreyi
- Haemophilus influenzae
- Moraxella catarrhalis
- Neisseria gonorrhoeae
- Bordetella pertussis
- Legionella pneumophila
- Chlamydophila pneumoniae
- Chlamydia trachomatis
- Mycoplasma genitalium
- Mycoplasma pneumoniae
- Ureaplasma urealyticum
Pregnancy and breastfeeding
Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects. Nevertheless, it is recommended that the drug be used with caution during breastfeeding.
Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes. And potentially useful in asthma and sinusitis via this mechanism. Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.
Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported. Clostridium difficile infection has been reported with use of azithromycin. Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.
In 2013 the FDA issued a warning that azithromycin “can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.” The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.
Mechanism of action
Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.
Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility. Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.
Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours. Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.
A team of researchers at the pharmaceutical company Pliva in Zagreb, SR Croatia, Yugoslavia, — Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić — discovered azithromycin in 1980. It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva’s license in other markets under the brand name Zithromax in 1991. Patent protection ended in 2005.
It is available as a generic medication. The wholesale cost is about US$0.18 to US$2.98 per dose. In the United States it is about US$4 for a course of treatment as of 2018. In India, it is about US$1.70 for a course of treatment.
In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US, whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.
- “Azithromycin Use During Pregnancy”. Drugs.com. 2 May 2019. Retrieved 24 December 2019.
- “Azithromycin International Brands”. Drugs.com. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
- “Azithromycin”. The American Society of Health-System Pharmacists. Archived from the original on 5 September 2015. Retrieved 1 August 2015.
- “Azithromycin use while Breastfeeding”. Archived from the original on 5 September 2015. Retrieved 4 September 2015.
- Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239. ISBN9780199534845. Archived from the original on 5 March 2016.
- Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN9783527607495.
- World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266. ISBN9789241515528. License: CC BY-NC-SA 3.0 IGO.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN9781284057560.
- “Azithromycin”. International Drug Price Indicator Guide. Retrieved 4 September 2015.
- “NADAC as of 2018-05-23”. Centers for Medicare and Medicaid Services. Retrieved 24 May 2018.
- “The Top 300 of 2019”. clincalc.com. Retrieved 22 December2018.
- Taylor SP, Sellers E, Taylor BT (2015). “Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly”. Am. J. Med. 128 (12): 1362.e1–6. doi:10.1016/j.amjmed.2015.07.032. PMID26291905.
- Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). “Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults”. Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID17278083.
- “Gonococcal Infections – 2015 STD Treatment Guidelines”. Archived from the original on 1 March 2016.
- Burton M, Habtamu E, Ho D, Gower EW (2015). “Interventions for trachoma trichiasis”. Cochrane Database Syst Rev. 11 (11): CD004008. doi:10.1002/14651858.CD004008.pub3. PMC4661324. PMID26568232.
- Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). “Clinical practice guideline (update): adult sinusitis”. Otolaryngol Head Neck Surg. 152 (2 Suppl): S1–S39. doi:10.1177/0194599815572097. PMID25832968.
- Hauk L (2014). “AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age”. Am Fam Physician. 89 (8): 676–81. PMID24784128.
- Neff MJ (2004). “AAP, AAFP release guideline on diagnosis and management of acute otitis media”. Am Fam Physician. 69 (11): 2713–5. PMID15202704.
- Randel A (2013). “IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis”. Am Fam Physician. 88 (5): 338–40. PMID24010402.
- The Guardian newspaper: ‘Super-gonorrhoea’ outbreak in Leeds, 18 September 2015Archived 18 September 2015 at the Wayback Machine
- Lippincott Illustrated Reviews : Pharmacology Sixth Edition. p. 506.
- “US azithromycin label”(PDF). FDA. February 2016. Archived(PDF) from the original on 23 November 2016.
- Simoens, Steven; Laekeman, Gert; Decramer, Marc (May 2013). “Preventing COPD exacerbations with macrolides: A review and budget impact analysis”. Respiratory Medicine. 107 (5): 637–648. doi:10.1016/j.rmed.2012.12.019. PMID23352223.
- Gotfried, Mark H. (February 2004). “Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD”. CHEST. 125 (2): 52S–61S. doi:10.1378/chest.125.2_suppl.52S. ISSN0012-3692. PMID14872001.
- Zarogoulidis, P.; Papanas, N.; Kioumis, I.; Chatzaki, E.; Maltezos, E.; Zarogoulidis, K. (May 2012). “Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases”. European Journal of Clinical Pharmacology. 68 (5): 479–503. doi:10.1007/s00228-011-1161-x. ISSN1432-1041. PMID22105373.
- Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles (2012). “Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics”. Mediators of Inflammation. 2012: 584262. doi:10.1155/2012/584262. PMC3388425. PMID22778497.
- Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). “Azithromycin anaphylaxis in children”. Int J Immunopathol Pharmacol. 27 (1): 121–6. doi:10.1177/039463201402700116. PMID24674687.
- Dart, Richard C. (2004). Medical Toxology. Lippincott Williams & Wilkins. p. 23.
- Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). “Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose”. Pharmacotherapy. 26 (1): 147–50. doi:10.1592/phco.2006.26.1.147. PMID16506357.
- Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133.
- Denise Grady (16 May 2012). “Popular Antibiotic May Raise Risk of Sudden Death”. The New York Times. Archived from the original on 17 May 2012. Retrieved 18 May 2012.
- Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). “Azithromycin and the Risk of Cardiovascular Death”. New England Journal of Medicine. 366(20): 1881–90. doi:10.1056/NEJMoa1003833. PMC3374857. PMID22591294.
- “FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms”. FDA. 12 March 2013. Archived from the original on 27 October 2016.
- “Archived copy”. Archived from the original on 14 October 2014. Retrieved 10 October 2014.
- Banić Tomišić, Z. (2011). “The Story of Azithromycin”. Kemija U Industriji. 60 (12): 603–617. ISSN0022-9830. Archived from the original on 8 September 2017.
- “Azithromycin: A world best-selling Antibiotic”. http://www.wipo.int. World Intellectual Property Organization. Retrieved 18 June 2019.
- Hicks, LA; Taylor TH, Jr; Hunkler, RJ (April 2013). “U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 368 (15): 1461–1462. doi:10.1056/NEJMc1212055. PMID23574140.
- Hicks, LA; Taylor TH, Jr; Hunkler, RJ (September 2013). “More on U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 369 (12): 1175–1176. doi:10.1056/NEJMc1306863. PMID24047077.
Keywords: Antibacterial (Antibiotics); Macrolides.
- “Azithromycin”. Drug Information Portal. U.S. National Library of Medicine.
|Trade names||Zithromax, Azithrocin, others|
|Other names||9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A|
|By mouth (capsule, tablet or suspension), intravenous, eye drop|
|Drug class||Macrolide antibiotic|
|Bioavailability||38% for 250 mg capsules|
|Elimination half-life||11–14 h (single dose) 68 h (multiple dosing)|
|Excretion||Biliary, kidney (4.5%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||748.984 g·mol−1 g·mol−1|
|3D model (JSmol)|
/////////AZITHROMYCIN, Antibacterial, Antibiotics, Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,
Substances Referenced in Synthesis Path
CAS-RN Formula Chemical Name CAS Index Name
76801-85-9 C37H70N2O12 2-deoxo-9a-aza-9a-homoerythromycin A 1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-eth- yl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-, [2R-(2
90503-04-1 C37H70N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
90503-05-2 C38H72N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
50-00-0 CH2O formaldehyde Formaldehyde
74-88-4 CH3I methyl iodide Methane, iodoTrade Names
Country Trade Name Vendor Annotation
D Ultreon Pfizer
Zithromax Pfizer Pharma/Gödecke/Parke-Davis
numerous generic preparations
F Azadose Pfizer
GB Zithromax Pfizer
I Azitrocin Bioindustria
Ribotrex Pierre Fabre
J Zithromac Pfizer
USA Azasite InSite Vision
Zithromax Pfizer as dihydrate
cps. 100 mg, 250 mg; Gran. 10%; susp. 200 mg (as dihydrate); tabl. 250 mg
Djokic, S. et al.: J. Antibiot. (JANTAJ) 40, 1006 (1987).
a DOS 3 140 449 (Pliva; appl. 12.10.1981; YU-prior. 6.3.1981).
US 4 517 359 (Pliva; 14.5.1985; appl. 22.9.1981; YU-prior. 6.3.1981).
b EP 101 186 (Pliva; appl. 14.7.1983; USA-prior. 19.7.1982, 15.11.1982).
US 4 474 768 (Pfizer; 2.10.1984; prior. 19.7.1982, 15.11.1982).
educt by ring expansion of erythromycin A oxime by Beckmann rearrangement:
Djokic, S. et al.: J. Chem. Soc., Perkin Trans. 1 (JCPRB4) 1986, 1881-1890.
Bright, G.M. et al.: J. Antibiot. (JANTAJ) 41, 1029 (1988). US 4 328 334 (Pliva; 4.5.1982; YU-prior. 2.4.1979).
stable, non-hygroscopic dihydrate: EP 298 650 (Pfizer; appl. 28.6.1988).
medical use for treatment of protozoal infections:
US 4 963 531 (Pfizer; 16.10.1990; prior. 16.8.1988, 10.9.1987).
|Molecular Weight:||329.31 g/mol|
Molnupiravir (development codes MK-4482 and EIDD-2801) is an experimental antiviral drug which is orally active (can be taken orally) and was developed for the treatment of influenza. It is a prodrug of the synthetic nucleoside derivative N4-hydroxycytidine, and exerts its antiviral action through introduction of copying errors during viral RNA replication. Activity has also been demonstrated against coronaviruses including SARS, MERS and SARS-CoV-2.
The drug was developed at Emory University by the university’s drug innovation company, Drug Innovation Ventures at Emory (DRIVE). It was then acquired by Miami-based company Ridgeback Biotherapeutics, who later partnered with Merck & Co. to develop the drug further.
In April 2020, a whistleblower complaint by former Head of US Biomedical Advanced Research and Development Authority (BARDA) Rick Bright revealed concerns over providing funding for the further development of molnupiravir due to similar drugs having mutagenic properties (producing birth defects). A previous company, Pharmasset, that had investigated the drug’s active ingredient had abandoned it. These claims were denied by George Painter, CEO of DRIVE, noting that toxicity studies on molnupiravir had been carried out and data provided to regulators in the US and UK, who permitted safety studies in humans to move forward in the spring of 2020. Also at this time, DRIVE and Ridgeback Biotherapeutics stated they planned future safety studies in animals.
After being found to be active against SARS-CoV-2 in March 2020, molnupiravir was tested in a preliminary human study for “Safety, Tolerability, and Pharmacokinetics” in healthy volunteers in the UK and US. In June 2020, Ridgeback Biotherapeutics announced it was moving to Phase II trials to test the efficacy of the drug as a treatment for COVID-19. Two trials of small numbers of hospitalized and non-hospitalized patients in the US and the UK were underway in July. In late July 2020, and without yet releasing any medical data, Merck, which had been partnering with Ridgeback Biotherapeutics on developing the drug, announced its intention to move molnupiravir to late stage trials beginning in September 2020. On October 19 2020, Merck began a one year Stage 2/3 trial focused on hospitalized patients.
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Example 10: Synthesis of EIDD-2801
A 1L round bottom flask was charged with uridine (25 g, 102.38 mmol) and acetone (700 mL). The reaction mixture was allowed to stir at rt. The slurry was then treated with sulfuric acid (0.27 mL, 5.12 mmol). Stirring was allowed to continue at rt for 18 hours. The reaction was quenched with 100 mL of trimethylamine and was used in the next step without further pruficication.
A 1L round bottom flask was charged with the reaction mixture from the previous reaction. Triethylamine (71.09 mL, 510.08 mmol) and 4-dimethylaminopyridine (0.62 g, 5.1 mmol) were then added. The flask was cooled using an ice bath and then 2-methylpropanoyl 2-methylpropanoate (17.75 g, 112.22 mmol) was slowly added. The reaction mixture was allowed to stir at rt until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 600 mL ethyl acetate and washed with saturated aqueous bicarbonate solution x 2, water x 2 and brine x 2. The organics were dried over sodium sulfate and concentrated under reduced pressure to yield a clear colorless oil. The crude product was used in the next step without further purification.
A 1L round bottom flask was charged with the crude product from above (36 g, 101.59 mmol) and MeCN (406.37 mL). The reaction mixture was allowed to stir until all the starting material was dissolved. Next, 1,2, 4-triazole (50.52 g, 731.46 mmol) was added followed by the addition of N,N-diethylethanamine (113.28 mL, 812.73 mmol). The reaction mixture was allowed to stir at rt until all solids dissolved. The reaction was then cooled to 0°C using an ice bath. Phosphorous oxychloride (24.44 mL, 152.39 mmol) was added slowly. The slurry that formed was allowed to stir under argon while slowly warming to rt. The reaction was then allowed to stir until complete by TLC (EtOAc). The reaction was then quenched by the addition of lOOmL of water. The slurry then became a dark colored solution, which was
then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water and brine. The organics were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (2 x 330 g columns). All fractions containing product were collected and concentrated under reduced pressure.
A 500 mL round bottom flask was charged with the product from the previous step (11.8 g, 29.11 mmol) and isopropyl alcohol (150 mL). The reaction mixture was allowed to stir at rt until all solids dissolved. Next, hydroxylamine (1.34 mL, 43.66 mmol) was added and stirring continued at ambient temperature. When the reaction was complete (HPLC) some solvent was removed under high vacuum at ambient temperature. The remaining solvent was removed under reduced pressure at 45°C. The resulting residue was dissolved in EtOAc and was washed with water and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield oil. Crystals formed upon standing at rt. The crystals were collected by filtration, washed with ether x 3, and dried in vacuo to provide the product as a white solid.
A 200 mL round bottom flask was charged with the product from the previous step (6.5 g, 17.6 mmol) and formic acid (100 mL, 2085.6 mmol). The reaction mixture was allowed to stir at rt overnight. The progress of the reaction was monitored by HPLC. The reaction mixture was concentrated under reduced pressure at 42°C to yield a clear, pale pink oil. Next, 30 mL of ethanol was added. Solvent was then removed under reduced pressure. MTBE (50 mL) was added to the solid and heated. Next, isopropyl alcohol was added and heating was continued until all solid material dissolved (5 mL). The solution was then allowed to cool and stand at rt.
A solid started to form after about lhr. The solids were collected by filtration, washed with MTBE, and dried in vacuo to yield the EIDD-2801 as a white solid. The filtrate was concentrated under reduced pressure to yield a sticky solid, which was dissolved in a small amount of isopropyl alcohol with heating. The solution was allowed to stand at rt overnight. A solid formed in the flask, which was collected by filtration, rinsed with isopropyl alcohol and MTBE, and dried in vacuo to an additional crop of desired product.
EIDD-2801 (25 g) was dissolved in 250 mL of isopropyl alcohol by heating to 70°C to give a clear solution. The warm solution was polish filtered and filtrate transferred to 2L three neck flask with overhead stirrer. It was warmed back to 70°C and MTBE (250 mL) was slowly added into the flask. The clear solution was seeded and allowed to cool slowly to rt with stirring for 18 hrs. The EIDD-2801 solid that formed was filtered and washed with MTBE and dried at 50°C under vacuum for l8hours. The filtrate was concentrated, redissolved in 50 mL isopropyl alcohol and 40 mL MTBE by warming to give clear solution and allowed to stand at rt to give a second crop of EIDD-2801.
Example 11: General synthesis for Deuteration
The lactone 389 (0.0325 mol) was added to a dry flask under an argon atmosphere and was then dissolved in dry THF (250 mL). The solution as then cooled to -78°C and a DIBAL-D solution in toluene (0.065 mol) was dropwise. The reaction was allowed to stir at -78°C for 3-4 hours. The reaction was then quenched with the slow addition of water (3 mL). The reaction was then allowed to stir while warming to rt. The mixture was then diluted with two volumes of diethyl ether and was then poured into an equal volume of saturated sodium potassium tartrate solution. The organic layer was separated, dried over MgSCri. filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with hexanes/ethyl acetate. The resulting lactol 390 was then converted to an acetate or benzolyate and subjected to cytosine coupling conditions and then further elaborated to N-hydroxycytidine.
ChemRxiv (2020), 1-3.
ChemRxiv (2020), 1-2
A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2
Synlett (2020), Ahead of Print.
A new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.
To a 20 mL vial was added N-hydroxycytidine acetonide ester 5 (0.25 g, 96% purity) followed by formic acid (4 mL). The resultant solution was stirred at room temperature for 4 h 20 min. Solvent was removed under reduced pressure and fresh EtOH (5 mL) was added. The resultant solution was again concentrated under vacuum to afford an oil. Methyl tert-butyl ether and IPA (5 mL each) were successively added as described earlier for preparation of compound 4 and concentrated to give 0.205 g of crude material (77% assay yield, 79% purity). This material was purified by silica gel column chromatography in 8 % MeOH/ Chloroform to afford 130 mg of EIDD-2801 as a solid (60% isolated yield corrected for purity, 98% purity) 1H NMR (600 MHz, CD3OD): δ 6.91 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 4.8 Hz, 1H), 5.61 (d, J = 8.2 Hz, 1H), 4.29 (d, J = 3.6 Hz, 2H), 4.14 (t, J = 4.9 Hz, 1H), 4.08 (p, J = 4.9 Hz, 2H), 2.62 (septet, J = 7.0 Hz, 1H), 1.19 (d, J = 7.0 Hz, 6H); 13C NMR (151 MHz, CD3OD): δ 178.6, 151.81, 146.44, 132.04, 99.84, 90.74, 82.88, 74.67, 71.80, 65.23, 35.45, 27.49, 19.65, 19.61.
One-Pot Transamination/Deprotection of 4 to EIDD-2801: To acetonide ester 4 (1.03 g, 77% Purity) in a 100 mL single neck round bottom flask was added hydroxylamine sulfate (1.09 g, 3.2 equiv.) followed by 40% IPA (20 mL prepared by mixing 12 mL of water and 8 mL of 99.5% IPA. The resultant solution was heated to 78˚C (internal temperature 72-73 ˚C) for 23 h upon which time HPLC showed the formation of EIDD-2801. Solvent was removed on a rotary evaporator and isopropanol (20 mL) was then added. The resulting slurry was sonicated for 5 minutes. The insoluble residue was then filtered and the filtrate concentrated under reduced pressure to afford crude material. (1.34 g, 38% purity, 69% assay yield). The resultant material was purified by silica gel chromatography (5-6% MeOH/DCM) to provide pure EIDD-2801 as two fractions (0.26 g, >99% purity, 36% corrected yield) as an yellow solid and 0.27 g (69.5% purity, 26% corrected yield) as a pinkish solid. The lower purity material was subjected to a second column purification again using 7% MeOH/ DCM to afford 0.137 g of material with 90% purity by NMR. The combined yield thus was estimated to be 53%. The 1H NMR spectrum of the product thus obtained matched the one obtained in the sequential approach as outlined above.
- A High‐Yielding Synthesis of EIDD‐2801 from Uridine,
Alexander Steiner, Desiree Znidar, Sándor B. Ötvös, David R. Snead, Doris Dallinger, C. Oliver Kappe,
Eur. J. Org. Chem. 2020.
EIDD-2801 was isolated in 69% yield (307 mg) and ≥99% purity as a white
1H-NMR (300 MHz, MeOH-d4) δ 6.91 (d, J= 8.3 Hz, 1H), 5.82 (d, J= 4.8 Hz, 1H), 5.61 (d, J= 8.2 Hz, 1H), 4.29
(d, J= 3.6 Hz, 2H), 4.15-4.07 (m, 3H), 2.62 (sept, J= 7.0 Hz, 1H), 1.18 (d, J= 7.0 Hz 6H);
13C-NMR (75 MHz,
MeOH-d4Ϳ δ 178.2, 151.5, 146.1, 131.7, 99.5, 90.4, 82.5, 74.3, 71.5, 64.9, 35.1, 19.3, 19.3. The NMR data
is in agreement with previously published values. HRMS (ESI, positive mode): m/z [M + H]+
: 330.1296, found: 330.1297.
C. Oliver Kappe, Doris Dallinger, University of Graz, Austria, and colleagues have developed an improved synthesis of EIDD-2801 from uridine (pictured below) by strategically reordering the synthetic steps. The reaction sequence starts with the activation of uridine with 1,2,4-triazole and continues with a telescoped acetonide protection/esterification and a telescoped hydroxyamination/acetonide deprotection. Telescoped reaction sequences consist of two or more than one one-pot procedures that are performed back-to-back without a work-up step in-between. A continuous flow process was used for the final acetonide deprotection, which improved selectivity and reproducibility.
To a solution of 5’-O-isobutyrylcytidine 4 (1.0 g, 90% purity, 2.87 mmol, 1.0 eq) in 2-propanol (15 ml), hydroxylamine sulphate (2.12 g, 12.93 mmol, 4.5 eq.) was added and reaction was stirred for 20 h at 78 C. Upon completion, the reaction was cooled to room temperature. The organic layer (upper layer) was separated from biphasic reaction mixture. The aqueous layer was washed with 2-propanol (2 X 5 mL). The combined organic layer was concentrated using rotary evaporation and the crude was purified by column chromatography with a gradient of 2-15% methanol in dichloromethane to yield EIDD-2801 (1) as a white solid (963 mg, 94% purity, 96% yield). 1H NMR (600 MHz, D2O) δ 6.98 (d, J = 8.3 Hz, 1H), 5.87 (d, J = 5.0 Hz, 1H), 5.78 (d, J = 8.2 Hz, 1H), 4.39 – 4.33 (m, 3H), 4.28 (dd, J = 6.6, 3.4 Hz, 2H), 2.69 (hept, J = 7.0 Hz, 1H), 1.17 (d, J = 3.7 Hz, 3H), 1.16 (d, J = 3.7 Hz, 3H). 13C NMR (126 MHz, D2O) δ 18.1, 18.2, 33.9, 48.8, 63.6, 69.6, 72.5, 81.0, 88.5, 98.8, 131.1, 151.1, 179.8 ppm; LRMS: 330.1 [M+H]+ ; HRMS (ESI): calcd. for C13H19N3O7 [M+H]+ 330.1296, found 330.1302; Purity: 94% (assessed by qNMR).
|Fig. 2 A new route to MK-4482 from cytidine.|
- Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, et al. (October 2019). “Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia”. Science Translational Medicine. 11 (515): eaax5866. doi:10.1126/scitranslmed.aax5866. PMC 6848974. PMID 31645453.
- Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK (April 2020). “Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model”. Translational Research. 218: 16–28. doi:10.1016/j.trsl.2019.12.002. PMID 31945316.
- Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, et al. (April 2020). “An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice”. Science Translational Medicine. 12 (541): eabb5883. doi:10.1126/scitranslmed.abb5883. PMC 7164393. PMID 32253226.
- Halford, Bethany. “An emerging antiviral takes aim at COVID-19”. Retrieved 1 August 2020.
- Cohen, Jon; Piller, Charles (13 May 2020). “Emails offer look into whistleblower charges of cronyism behind potential COVID-19 drug”. Science. Retrieved 1 August 2020.
- “COVID-19 First In Human Study to Evaluate Safety, Tolerability, and Pharmacokinetics of EIDD-2801 in Healthy Volunteers”. ClinicalTrials.gov. Retrieved 1 June 2020.
- “Ridgeback Biotherapeutics Announces Launch of Phase 2 Trials Testing EIDD-2801 as Potential Treatment for COVID-19”. Business Wire. Retrieved 4 July 2020.
- “A Safety, Tolerability and Efficacy of EIDD-2801 to Eliminate Infectious Virus Detection in Persons With COVID-19”. ClinicalTrials.gov. Retrieved 4 July 2020.
- “The Effect of EIDD-2801 on Viral Shedding of SARS-CoV-2 (COVID-19)”. ClinicalTrials.gov. Retrieved 4 July 2020.
- Court, Emma (31 July 2020). “Merck pushes ahead on COVID-19 treatment, vaccines”. Retrieved 31 July 2020.
- ClinicaL trials register : Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001)
Electron microscope image of SARS virus in a tissue culture isolate, courtesy of CDC Public Health Image Library.
The drug EIDD-1931 was effective against SARS and MERS viruses in the laboratory, and a modified version (EIDD-2801) could potentially be valuable against 2019-nCoV.
Emory, collaborators testing antiviral drug as potential treatment for coronaviruses
An antiviral compound discovered at Emory University could potentially be used to treat the new coronavirus associated with the outbreak in China and spreading around the globe. Drug Innovation Ventures at Emory (DRIVE), a non-profit LLC wholly owned by Emory, is developing the compound, designated EIDD-2801.
In testing with collaborators at the University of North Carolina at Chapel Hill and Vanderbilt University Medical Center, the active form of EIDD-2801, which is called EIDD-1931, has shown efficacy against the related coronaviruses SARS (Severe Acute Respiratory Syndrome)- and MERS-CoV (Middle East Respiratory Syndrome Coronavirus). Some of the data was recently published in Journal of Virology.
EIDD-2801 is an oral ribonucleoside analog that inhibits the replication of multiple RNA viruses, including respiratory syncytial virus, influenza, chikungunya, Ebola, Venezuelan equine encephalitis virus, and Eastern equine encephalitis viruses.
“We have been planning to enter human clinical tests of EIDD-2801 for the treatment of influenza, and recognized that it has potential activity against the current novel coronavirus,” says George Painter, PhD, director of the Emory Institute for Drug Development (EIDD) and CEO of DRIVE. “Based on the drug’s broad-spectrum activity against viruses including influenza, Ebola and SARS-CoV/MERS-CoV, we believe it will be an excellent candidate.”
“Our studies in the Journal of Virology show potent activity of the EIDD-2801 parent compound against multiple coronaviruses including SARS and MERS,” says Mark Denison, MD, the Stahlman Professor of Pediatrics and director of pediatric infectious diseases at Vanderbilt University School of Medicine. “It also has a strong genetic barrier to development of viral resistance, and its oral bioavailability makes it a candidate for use during an outbreak.”
“Generally speaking, seasonal flu is still a much more common threat than this coronavirus, however, novel emerging coronaviruses represent a considerable threat to global health as evidenced by the new 2019-nCoV,” said Ralph Baric, PhD, an epidemiology professor at the University of North Carolina’s Gillings School of Global Public Health. “But the reason the new coronavirus is so concerning is that it’s much more likely to be deadly than the flu – fatal for about one in 25 people versus one in 1,000 for the flu.”
The development of EIDD-2801 has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), under contract numbers HHSN272201500008C and 75N93019C00058, and from the Defense Threat Reduction Agency (DTRA), under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075, for the treatment of Influenza, coronavirus, chikungunya, and Venezuelan equine encephalitis virus.
About DRIVE: DRIVE is a non-profit LLC wholly owned by Emory started as an innovative approach to drug development. Operating like an early stage biotechnology company, DRIVE applies focus and industry development expertise to efficiently translate discoveries to address viruses of global concern. Learn more at: http://driveinnovations.org/
Emory-discovered antiviral is poised for COVID-19 clinical trials
The nucleoside inhibitor has advantages over Gilead’s remdesivir but has yet to be tested in humans
Asmall-molecule antiviral discovered by Emory University chemists could soon start human testing against COVID-19, the respiratory disease caused by the novel coronavirus. That’s the plan of Ridgeback Biotherapeutics, which licensed the compound, EIDD-2801, from an Emory nonprofit.
But remdesivir can only be given intravenously, meaning it would be difficult to deploy widely. In contrast, EIDD-2801 can be taken in pill form, says Mark Denison, a coronavirus expert and director of the infectious diseases division at Vanderbilt Medical School. Denison partnered with Emory and researchers at the University of North Carolina to test the compound against coronaviruses.
EIDD-2801 has other promising features. Many antivirals work by introducing errors into the viral genome, but, unlike other viruses, coronaviruses can fix some mistakes. In lab experiments, EIDD-2801 “was able to overcome the coronavirus proofreading function,” Denison says.
He also notes that while remdesivir and EIDD-2801 both block RNA polymerase, they appear to do it in different ways, meaning they could be complementary.
Unlike remdesivir, EIDD-2801 lacks human safety data. Ridgeback founder and CEO Wendy Holman says she expects the US Food and Drug Administration to give the green light for a Phase I study in COVID-19 infections within “weeks, not months.”
“weeks, not months.”
|Other names||MK-4482, EIDD-2801|
|Chemical and physical data|
|Molar mass||329.31 g·mol−1|
|3D model (JSmol)|
////////EIDD 2801, EMORY, CORONA VIRUS, COVID 19, mk 4482, molnupiravir, merck
NEW DRUG APPROVALS
|Application Id||Application Number||Application Date||Country||Title|
|US333828014||17170172||08.02.2021||US||N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO|
|US305251595||16755779||07.12.2018||US||N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO|
|WO2021159044||PCT/US2021/016984||07.02.2021||WO||N4-HYDROXYCYTIDINE AND DERIVATIVES AND ANTI-VIRAL USES RELATED THERETO|
|WO2021137913||PCT/US2020/054857||08.10.2020||WO||4′-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO|
Chloroquine is a medication used primarily to prevent and to treat malaria in areas where that parasitic disease is known to remain sensitive to its effects. A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection). Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.[verification needed] However, the agent is not without the possibility of serious side effects at standard doses, and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication. Chloroquine is also used as a medication for rheumatoid arthritis, lupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines). Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.
Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism. Antiviral activities, established and putative, are attributed to chloroquines inhibition of glycosylation pathways (of host receptor sialylation or virus protein post-translational modification), or to inhibition of virus endocytosis (e.g., via alkalisation of endosomes), or other possible mechanisms. Common side effects resulting from these therapeutic uses, at common doses, include muscle problems,[clarification needed] loss of appetite, diarrhea, and skin rash.[clarification needed] Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.
Chloroquine was discovered in 1934 by Hans Andersag. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world is about US$0.04. In the United States, it costs about US$5.30 per dose.
Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.
Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it. In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.
In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.
Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.
- Unwanted/uncontrolled movements (including tongue and face twitching) 
- Deafness or tinnitus.
- Nausea, vomiting, diarrhea, abdominal cramps
- Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)
- Signs of serious infection (such as high fever, severe chills, persistent sore throat)
- Skin itchiness, skin color changes, hair loss, and skin rashes.
- Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.
- Unpleasant metallic taste
- This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.
- Chloroquine retinopathy
- Electrocardiographic changes
- This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
- Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.
Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.
There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.
- Ampicillin– levels may be reduced by chloroquine;
- Antacids– may reduce absorption of chloroquine;
- Cimetidine– may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;
- Cyclosporine– levels may be increased by chloroquine; and
- Mefloquine– may increase risk of convulsions.
Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut. In 1961, a published compilation of case reports contained accounts of three children who took overdoses and died within 2.5 hours of taking the drug. While the amount of the overdose was not stated, the therapeutic index for chloroquine is known to be small. One of the children died after taking 0.75 or 1 gram, or twice a single therapeutic amount for children. Symptoms of overdose include headache, drowsiness, visual disturbances, nausea and vomiting, cardiovascular collapse, seizures, and sudden respiratory and cardiac arrest.
An analog of chloroquine – hydroxychloroquine – has a long half-life (32–56 days) in blood and a large volume of distribution (580–815 L/kg). The therapeutic, toxic and lethal ranges are usually considered to be 0.03 to 15 mg/l, 3.0 to 26 mg/l and 20 to 104 mg/l, respectively. However, nontoxic cases have been reported up to 39 mg/l, suggesting individual tolerance to this agent may be more variable than previously recognised.
Chloroquine’s absorption of the drug is rapid. It is widely distributed in body tissues. It’s protein binding is 55%.[ It’s metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. It’s excretion os ≥50% as unchanged drug in urine, where acidification of urine increases its elimination It has a very high volume of distribution, as it diffuses into the body’s adipose tissue.
Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.
Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning—in simplified terms, considering only this basic site—it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation) This decreases to about 0.2% at a lysosomal pH of 4.6.Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative “trapping” of the compound in lysosomes results.
Mechanism of action
The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.
Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.
Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.
Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion.  Parasites that do not form hemozoin are therefore resistant to chloroquine.
Resistance in malaria[edit source]
Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved. They effectively neutralize the drug via a mechanism that drains chloroquine away from the digestive vacuole. Chloroquine-resistant cells efflux chloroquine at 40 times the rate of chloroquine-sensitive cells; the related mutations trace back to transmembrane proteins of the digestive vacuole, including sets of critical mutations in the P. falciparum chloroquine resistance transporter (PfCRT) gene. The mutated protein, but not the wild-type transporter, transports chloroquine when expressed in Xenopus oocytes (frog’s eggs) and is thought to mediate chloroquine leak from its site of action in the digestive vacuole. Resistant parasites also frequently have mutated products of the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to Pfcrt. Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Recently, an altered chloroquine-transporter protein CG2 of the parasite has been related to chloroquine resistance, but other mechanisms of resistance also appear to be involved. Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.
Chloroquine has antiviral effects. It increases late endosomal or lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.
Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.
In Peru the indigenous people extracted the bark of the Cinchona plant trees and used the extract (Chinchona officinalis) to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.
Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it “Resochin”. It was ignored for a decade, because it was considered too toxic for human use. During World War II, United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.
Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.
Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.
In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted. Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.
Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19. These agencies noted contraindications for people with heart disease or diabetes. Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile. Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, “improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course.” Self-medication with chloroquine has caused one known fatality.
In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.
The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans. In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.
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|Trade names||Aralen, other|
|Other names||Chloroquine phosphate|
|Elimination half-life||1-2 months|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||319.872 g·mol−1|
|3D model (JSmol)|
//////////////CHLOROQUINE,, クロロキン, ANTIMALARIAL, COVID 19, CORONA VIRUS, Хлорохин , クロロキン , كلوروكين
CAS Registry Number: 50-65-7
Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations. This includes diphyllobothriasis, hymenolepiasis, and taeniasis. It is not effective against other worms such as pinworms or roundworms. It is taken by mouth.
Side effects include nausea, vomiting, abdominal pain, and itchiness. It may be used during pregnancy and appears to be safe for the baby. Niclosamide is in the anthelmintic family of medications. It works by blocking the uptake of sugar by the worm.
Niclosamide was discovered in 1958. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The wholesale cost in the developing world is about 0.24 USD for a course of treatment. It is not commercially available in the United States. It is effective in a number of other animals.
Side effects include nausea, vomiting, abdominal pain, constipation, and itchiness. Rarely, dizziness, skin rash, drowsiness, perianal itching, or an unpleasant taste occur. For some of these reasons, praziquantel is a preferable and equally effective treatment for tapeworm infestation.
Mechanism of action
Niclosamide’s metabolic effects are relevant to wide ranges of organisms, and accordingly it has been applied as a control measure to organisms other than tapeworms. For example, it is an active ingredient in some formulations such as Bayluscide for killing lamprey larvae, as a molluscide, and as a general purpose piscicide in aquaculture. Niclosamide has a short half-life in water in field conditions; this makes it valuable in ridding commercial fish ponds of unwanted fish; it loses its activity soon enough to permit re-stocking within a few days of eradicating the previous population. Researchers have found that niclosamide is effective in killing invasive zebra mussels in cool waters.
Niclosamide is being studied in a number of types of cancer. Niclosamide along with oxyclozanide, another anti-tapeworm drug, was found in a 2015 study to display “strong in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA)”.
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|Trade names||Niclocide, Fenasal, Phenasal, others|
|AHFS/Drugs.com||Micromedex Detailed Consumer Information|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||327.119 g/mol g·mol−1|
|3D model (JSmol)|
|Melting point||225 to 230 °C (437 to 446 °F)|
//////////Niclosamide ニクロサミド , никлосамид , نيكلوساميد , 氯硝柳胺 , covid 19, corona virus
Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum antiviral drug that is used in medicine for the treatment of various helminthic, protozoal, and viral infections. It is indicated for the treatment of infection by Cryptosporidium parvum and Giardia lamblia in immunocompetent individuals and has been repurposed for the treatment of influenza. Nitazoxanide has also been shown to have in vitro antiparasitic activity and clinical treatment efficacy for infections caused by other protozoa and helminths; emerging evidence suggests that it possesses efficacy in treating a number of viral infections as well.
Chemically, nitazoxanide is the prototype member of the thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives with antiparasitic and antiviral activity. Tizoxanide, an active metabolite of nitazoxanide in humans, is also an antiparasitic drug of the thiazolide class.
Nitazoxanide is an effective first-line treatment for infection by Blastocystis species and is indicated for the treatment of infection by Cryptosporidium parvum or Giardia lamblia in immunocompetent adults and children. It is also an effective treatment option for infections caused by other protozoa and helminths (e.g., Entamoeba histolytica, Hymenolepis nana, Ascaris lumbricoides, and Cyclospora cayetanensis).
As of September 2015, it is in phase 3 clinical trials for the treatment influenza due to its inhibitory effect on a broad range of influenza virus subtypes and efficacy against influenza viruses that are resistant to neuraminidase inhibitors like oseltamivir. Nitazoxanide is also being researched as a potential treatment for chronic hepatitis B, chronic hepatitis C, rotavirus and norovirus gastroenteritis.
Chronic hepatitis B
Nitazoxanide alone has shown preliminary evidence of efficacy in the treatment of chronic hepatitis B over a one-year course of therapy. Nitazoxanide 500 mg twice daily resulted in a decrease in serum HBV DNA in all of 4 HBeAg-positive patients, with undetectable HBV DNA in 2 of 4 patients, loss of HBeAg in 3 patients, and loss of HBsAg in one patient. Seven of 8 HBeAg-negative patients treated with nitazoxanide 500 mg twice daily had undetectable HBV DNA and 2 had loss of HBsAg. Additionally, nitazoxanide monotherapy in one case and nitazoxanide plus adefovir in another case resulted in undetectable HBV DNA, loss of HBeAg and loss of HBsAg. These preliminary studies showed a higher rate of HBsAg loss than any currently licensed therapy for chronic hepatitis B. The similar mechanism of action of interferon and nitazoxanide suggest that stand-alone nitazoxanide therapy or nitazoxanide in concert with nucleos(t)ide analogs have the potential to increase loss of HBsAg, which is the ultimate end-point of therapy. A formal phase Ⅱ study is being planned for 2009.
Chronic hepatitis C
Romark initially decided to focus on the possibility of treating chronic hepatitis C with nitazoxanide. The drug garnered interest from the hepatology community after three phase II clinical trials involving the treatment of hepatitis C with nitazoxanide produced positive results for treatment efficacy and similar tolerability to placebo without any signs of toxicity. A meta-analysis from 2014 concluded that the previous held trials were of low-quality and with held with a risk of bias. The authors concluded that more randomized trials with low risk of bias are needed to give any determine if Nitazoxanide can be used as an effective treatment for chronic hepatitis C patients.
Nitazoxanide has gone through Phase II clinical trials for the treatment of hepatitis C, in combination with peginterferon alfa-2a and ribavirin.Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events. Primarily GI-related adverse events were reported.
A randomised double-blind placebo-controlled study published in 2006, with a group of 38 young children (Lancet, vol 368, page 124-129) concluded that a 3-day course of nitazoxanide significantly reduced the duration of rotavirus disease in hospitalized pediatric patients. Dose given was “7.5 mg/kg twice daily” and the time of resolution was “31 hours for those given nitazoxanide compared with 75 hours for those in the placebo group.” Rotavirus is the most common infectious agent associated with diarrhea in the pediatric age group worldwide.
Teran et al.. conducted a study at the Pediatric Center Albina Patinö, a reference hospital in the city of Cochabamba, Bolivia, from August 2007 to February 2008. The study compared nitazoxanide and probiotics in the treatment of acute rotavirus diarrhea. They found Small differences in favor of nitazoxanide in comparison with probiotics and concluded that nitazoxanide is an important treatment option for rotavirus diarrhea.
Lateef et al.. conducted a study in India that evaluated the effectiveness of nitazoxanide in the treatment of beef tapeworm (Taenia saginata) infection. They concluded that nitazoxanide is a safe, effective, inexpensive, and well-tolerated drug for the treatment of niclosamide- and praziquantel-resistant beef tapeworm (Taenia saginata) infection.
A retrospective review of charts of patients treated with nitazoxanide for trichomoniasis by Michael Dan and Jack D. Sobel demonstrated negative result. They reported three case studies; two of which with metronidazole-resistant infections. In Case 3, they reported the patient to be cured with high divided dose tinidazole therapy. They used a high dosage of the drug (total dose, 14–56 g) than the recommended standard dosage (total dose, 3 g) and observed a significant adverse reaction (poorly tolerated nausea) only with the very high dose (total dose, 56 g). While confirming the safety of the drug, they showed nitazoxanide is ineffective for the treatment of trichomoniasis.
The side effects of nitazoxanide do not significantly differ from a placebo treatment for giardiasis; these symptoms include stomach pain, headache, upset stomach, vomiting, discolored urine, excessive urinating, skin rash, itching, fever, flu syndrome, and others. Nitazoxanide does not appear to cause any significant adverse effects when taken by healthy adults.
Information on nitazoxanide overdose is limited. Oral doses of 4 grams in healthy adults do not appear to cause any significant adverse effects. In various animals, the oral LD50 is higher than 10 g/kg.
Due to the exceptionally high plasma protein binding (>99.9%) of nitazoxanide’s metabolite, tizoxanide, the concurrent use of nitazoxanide with other highly plasma protein-bound drugs with narrow therapeutic indices (e.g., warfarin) increases the risk of drug toxicity. In vitro evidence suggests that nitazoxanide does not affect the CYP450 system.
The anti-protozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. PFOR inhibition may also contribute to its activity against anaerobic bacteria.
It has also been shown to have activity against influenza A virus in vitro. The mechanism appears to be by selectively blocking the maturation of the viral hemagglutinin at a stage preceding resistance to endoglycosidase H digestion. This impairs hemagglutinin intracellular trafficking and insertion of the protein into the host plasma membrane.
Nitazoxanide modulates a variety of other pathways in vitro, including glutathione-S-transferase and glutamate-gated chloride ion channels in nematodes, respiration and other pathways in bacteria and cancer cells, and viral and host transcriptional factors.
Following oral administration, nitazoxanide is rapidly hydrolyzed to the pharmacologically active metabolite, tizoxanide, which is 99% protein bound. Tizoxanide is then glucuronide conjugated into the active metabolite, tizoxanide glucuronide. Peak plasma concentrations of the metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours after oral administration of nitazoxanide, whereas nitazoxanide itself is not detected in blood plasma.
Roughly 2⁄3 of an oral dose of nitazoxanide is excreted as its metabolites in feces, while the remainder of the dose excreted in urine. Tizoxanide is excreted in the urine, bile and feces. Tizoxanide glucuronide is excreted in urine and bile.
Nitazoxanide is the prototype member of the thiazolides, which is a drug class of structurally-related broad-spectrum antiparasitic compounds. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water.
Nitazoxanide was originally discovered in the 1980s by Jean-François Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the USA were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in AIDS. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the FDA rejected an application based on uncontrolled studies.
Subsequently, Romark launched a series of controlled trials. A placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. Among malnourished children in Zambia with chronic cryptosporidiosis, a three-day course of therapy led to clinical and parasitologic improvement and improved survival. In Zambia and in a study conducted in Mexico, nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis. Recent studies have also found it to be effective against beef tapeworm(Taenia saginata).
Nitazoxanide is sold under the brand names Adonid, Alinia, Allpar, Annita, Celectan, Colufase, Daxon, Dexidex, Diatazox, Kidonax, Mitafar, Nanazoxid, Parazoxanide, Netazox, Niazid, Nitamax, Nitax, Nitaxide, Nitaz, Nizonide, NT-TOX, Pacovanton, Paramix, Toza, and Zox.
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Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. … Nitazoxanide (NTZ) is a main compound of a class of broad-spectrum anti-parasitic compounds named thiazolides. It is composed of a nitrothiazole-ring and a salicylic acid moiety which are linked together by an amide bond … NTZ is generally well tolerated, and no significant adverse events have been noted in human trials . … In vitro, NTZ and tizoxanide function against a wide range of organisms, including the protozoal species Blastocystis hominis, C. parvum, Entamoeba histolytica, G. lamblia and Trichomonas vaginalis 
- White CA (2004). “Nitazoxanide: a new broad spectrum antiparasitic agent”. Expert Rev Anti Infect Ther. 2 (1): 43–9. doi:10.1586/14787188.8.131.52. PMID 15482170.
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Nitazoxanide is effective in the treatment of protozoal and helminthic infections … Nitazoxanide is a first-line choice for the treatment of illness caused by C. parvum or G. lamblia infection in immunocompetent adults and children, and is an option to be considered in the treatment of illnesses caused by other protozoa and/or helminths.
- Sisson G1, Goodwin A, Raudonikiene A, Hughes NJ, Mukhopadhyay AK, Berg DE, Hoffman PS. (July 2002). “Enzymes associated with reductive activation and action of nitazoxanide, nitrofurans, and metronidazole in Helicobacter pylori”. Antimicrob. Agents Chemother. 46 (7): 2116–23. doi:10.1128/aac.46.7.2116-2123.2002. PMC 127316. PMID 12069963.
Nitazoxanide (NTZ) is a redox-active nitrothiazolyl-salicylamide
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Blastocystis is one of the most common intestinal protists of humans. … A recent study showed that 100% of people from low socio-economic villages in Senegal were infected with Blastocystis sp. suggesting that transmission was increased due to poor hygiene sanitation, close contact with domestic animals and livestock, and water supply directly from well and river . …
Table 2: Summary of treatments and efficacy for Blastocystis infection
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Nitazoxanide: intestinal amoebiasis: 500 mg po bid x 3 days
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new anthelmintic alternatives such as tribendimidine and Nitazoxanide have proved to be safe and effective against A. lumbricoides and other soil-transmitted helminthiases in human trials.
- Shoff WH (5 October 2015). Chandrasekar PH, Talavera F, King JW (eds.). “Cyclospora Medication”. Medscape. WebMD. Retrieved 11 January 2016.
Nitazoxanide, a 5-nitrothiazole derivative with broad-spectrum activity against helminths and protozoans, has been shown to be effective against C cayetanensis, with an efficacy 87% by the third dose (first, 71%; second 75%). Three percent of patients had minor side effects.
- Li TC, Chan MC, Lee N (September 2015). “Clinical Implications of Antiviral Resistance in Influenza”. Viruses. 7 (9): 4929–4944. doi:10.3390/v7092850. PMC 4584294. PMID 26389935.
Oral nitazoxanide is an available, approved antiparasitic agent (e.g., against cryptosporidium, giardia) with established safety profiles. Recently, it has been shown (together with its active metabolite tizoxanide) to possess anti-influenza activity by blocking haemagglutinin maturation/trafficking, and acting as an interferon-inducer . … A large, multicenter, Phase 3 randomized-controlled trial comparing nitazoxanide, oseltamivir, and their combination in uncomplicated influenza is currently underway (NCT01610245).
Figure 1: Molecular targets and potential antiviral treatments against influenza virus infection
- Teran, C. G.; Teran-Escalera, C. N.; Villarroel, P. (2009). “Nitazoxanide vs. Probiotics for the treatment of acute rotavirus diarrhea in children: A randomized, single-blind, controlled trial in Bolivian children”. International Journal of Infectious Diseases. 13(4): 518–523. doi:10.1016/j.ijid.2008.09.014. PMID 19070525.
- Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases. 12 (1): 80–82. doi:10.1016/j.ijid.2007.04.017. PMID 17962058.
- World Journal of Gastroenterology 2009 April 21, Emmet B Keeffe MD, Professor, Jean-François Rossignol The Romark Institute for Medical Research, Tampa
- Keeffe, E. B.; Rossignol, J. F. (2009). “Treatment of chronic viral hepatitis with nitazoxanide and second generation thiazolides”. World Journal of Gastroenterology. 15 (15): 1805–1808. doi:10.3748/wjg.15.1805. PMC 2670405. PMID 19370775.
- Nikolova, Kristiana; Gluud, Christian; Grevstad, Berit; Jakobsen, Janus C (2014). “Nitazoxanide for chronic hepatitis C”. Cochrane Database of Systematic Reviews (4): CD009182. doi:10.1002/14651858.CD009182.pub2. ISSN 1465-1858. PMID 24706397.
- “Romark Initiates Clinical Trial Of Alinia For Chronic Hepatitis C In The United States” (Press release). Medical News Today. August 16, 2007. Retrieved 2007-10-11.
- Franciscus, Alan (October 2, 2007). “Hepatitis C Treatments in Current Clinical Development”. HCV Advocate. Archived from the original on September 6, 2003. Retrieved 2007-10-11.
- Rossignol, Jean-François; Abu-Zekry, Mona; Hussein, Abeer; Santoro, M Gabriella (2006). “Effect of nitazoxanide for treatment of severe rotavirus diarrhoea: randomised double-blind placebo-controlled trial”. The Lancet. 368 (9530): 124–9. CiteSeerX 10.1.1.458.1597. doi:10.1016/S0140-6736(06)68852-1. PMID 16829296.
- Dan, M.; Sobel, J. D. (2007). “Failure of Nitazoxanide to Cure Trichomoniasis in Three Women”. Sexually Transmitted Diseases. 34 (10): 813–4. doi:10.1097/NMD.0b013e31802f5d9a. PMID 17551415.
- “Nitazoxanide”. MedlinePlus. Retrieved 9 April 2014.
- Shakya, A; Bhat, HR; Ghosh, SK (2018). “Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent”. Current Drug Discovery Technologies. 15 (3): 201–213. doi:10.2174/1570163814666170727130003. PMID 28748751.
- Rossignol, J. F.; La Frazia, S.; Chiappa, L.; Ciucci, A.; Santoro, M. G. (2009). “Thiazolides, a New Class of Anti-influenza Molecules Targeting Viral Hemagglutinin at the Post-translational Level”. Journal of Biological Chemistry. 284 (43): 29798–29808. doi:10.1074/jbc.M109.029470. PMC 2785610. PMID 19638339.
- White Jr, AC (2003). “Nitazoxanide: An important advance in anti-parasitic therapy”. Am. J. Trop. Med. Hyg. 68 (4): 382–383. doi:10.4269/ajtmh.2003.68.382. PMID 12875283.
- Lateef, M.; Zargar, S. A.; Khan, A. R.; Nazir, M.; Shoukat, A. (2008). “Successful treatment of niclosamide- and praziquantel-resistant beef tapeworm infection with nitazoxanide”. International Journal of Infectious Diseases. 12 (1): 80–2. doi:10.1016/j.ijid.2007.04.017. PMID 17962058.
- Cynthia Liu, Qiongqiong Zhou, Yingzhu Li, Linda V. Garner, Steve P. Watkins, Linda J. Carter, Jeffrey Smoot, Anne C. Gregg, Angela D. Daniels, Susan Jervey, Dana Albaiu. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Central Science 2020; doi:10.1021/acscentsci.0c00272
- “Nitazoxanide”. MedlinePlus Drug Information. U.S. National Library of Medicine. 28 July 2010. Retrieved 2010-08-19.
- “Parasitic infections”. Am J Transplant. 4 (Suppl 10): 142–55. 2004. doi:10.1111/j.1600-6135.2004.00677.x. PMID 15504227.
|Trade names||Alinia, Nizonide, and others|
|Protein binding||Nitazoxanide: ?
Tizoxanide: over 99%
|Metabolism||Rapidly hydrolyzed to tizoxanide|
|Elimination half-life||3.5 hours|
|Excretion||Renal, biliary, and fecal|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||307.283 g/mol g·mol−1|
|3D model (JSmol)|
//////////////nitazoxanide, corona virus, covid 19
- Molecular FormulaC11H15N5O3
- Average mass265.268 Da
222631-44-9, BCX-4430 (HCL salt form of galidesivir)
Galidesivir (BCX4430, Immucillin-A) is an antiviral drug, an adenosine analog (a type of nucleoside analog). It is developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease.
It also shows broad-spectrum antiviral effectiveness against a range of other RNA virus families, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses, flaviviruses and phleboviruses. BCX4430 has been demonstrated to protect against both Ebola and Marburg viruses in both rodents and monkeys, even when administered up to 48 hours after infection, and development for use in humans was then being fast-tracked due to concerns about the lack of treatment options for the 2013-2016 Ebola virus epidemic in West Africa.
When any new virus emerges, drug and vaccine developers spring into action, searching for products to stop it in its tracks. Drug discovery campaigns launch, vaccine development efforts ramp up, and everyone mobilizes to get it all into the clinic as quickly as possible.
The current pandemic, driven by a coronavirus known as SARS-CoV-2, is no different. Already, a Phase I study of an mRNA-based vaccine developed by Moderna has begun, and major pharma companies and small biotechs are working on other types of vaccines. But even if they work, the most optimistic timelines put a vaccine a year to 18 months away.
The more immediate approach to an outbreak is to scour the medicine cabinet for existing molecules that could be repurposed against a new virus. The most advanced potential treatment is Gilead Sciences’ remdesivir, an antiviral discovered during the 2014 Ebola epidemic. The compound is already being tested in four, Phase III trials—two in China and two in the US—against the respiratory disease COVID-19. Gilead expects the first dataset from those studies to come out in April.
A new paper from CAS explored remdesivir and other possible options the cabinet might contain (ACS Cent. Sci. 2020, DOI: 10.1021/acscentsci.0c00272). CAS, a division of the American Chemical Society, which publishes C&EN, looked at the landscape of patent and journal articles covering small molecules, antibodies, and other therapeutic classes to identify therapies with potential activity against COVID-19.
SARS-CoV-2, belongs to the same family as two coronaviruses responsible for earlier outbreaks, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Because all three feature structurally similar proteins that allow entry into and replication inside host cells, CAS searched for patent data related to those more well-studied coronaviruses.
C&EN has assembled the relevant small molecules identified by CAS, which can be explored by the stage in the viral life cycle they aim to disrupt.
|Patent ID||Title||Submitted Date||Granted Date|
|US7390890||Inhibitors of nucleoside metabolism||2007-08-23||2008-06-24|
|US7211653||Inhibitors of nucleoside metabolism||2005-02-03||2007-05-01|
|US6803455||Inhibitors of nucleoside metabolism||2003-05-22||2004-10-12|
|US6492347||Inhibitors of nucleoside metabolism||2002-05-23||2002-12-10|
|US6228847||Inhibitors of nucleoside metabolism||2001-05-08|
|Patent ID||Title||Submitted Date||Granted Date|
|EP1023308||INHIBITORS OF NUCLEOSIDE METABOLISM||2000-08-02||2005-09-07|
|US6066722||Inhibitors of nucleoside metabolism||2000-05-23|
- Warren TK, Wells J, Panchal RG, Stuthman KS, Garza NL, Van Tongeren SA, et al. (April 2014). “Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430” (PDF). Nature. 508 (7496): 402–5. Bibcode:2014Natur.508..402W. doi:10.1038/nature13027. PMID 24590073.
- Kamat SS, Burgos ES, Raushel FM (October 2013). “Potent inhibition of the C-P lyase nucleosidase PhnI by Immucillin-A triphosphate”. Biochemistry. 52 (42): 7366–8. doi:10.1021/bi4013287. PMC 3838859. PMID 24111876.
- Westover JB, et al. Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters. Antiviral Res. 2018 Aug;156:38-45. Westover, J. B.; Mathis, A.; Taylor, R.; Wandersee, L.; Bailey, K. W.; Sefing, E. J.; Hickerson, B. T.; Jung, K. H.; Sheridan, W. P.; Gowen, B. B. (2018). “Galidesivir limits Rift Valley fever virus infection and disease in Syrian golden hamsters”. Antiviral Research. 156: 38–45. doi:10.1016/j.antiviral.2018.05.013. PMC 6035881. PMID 29864447.
- Rodgers P (8 April 2014). “BioWar Lab Helping To Develop Treatment For Ebola”. Forbes Magazine.
- Julander JG, Siddharthan V, Evans J, Taylor R, Tolbert K, Apuli C, et al. (January 2017). “Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model”. Antiviral Research. 137: 14–22. doi:10.1016/j.antiviral.2016.11.003. PMC 5215849. PMID 27838352.
- Praveen Duddu. Coronavirus outbreak: Vaccines/drugs in the pipeline for Covid-19. clinicaltrialsarena.com 19 February 2020.
|Chemical and physical data|
|Molar mass||265.268 g·mol−1|
|3D model (JSmol)|
//////////////Galidesivir, Immucillin-A, OLF97F86A7, UNII:OLF97F86A7, галидесивир , غاليديسيفير , 加利司韦 , BCX4430, BCX 4430, CORONAVIRUS, COVID 19
Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used for the prevention and treatment of certain types of malaria. Specifically it is used for chloroquine-sensitive malaria. Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth. It is also being used as an experimental treatment for coronavirus disease 2019 (COVID-19).
Common side effects include vomiting, headache, changes in vision and muscle weakness. Severe side effects may include allergic reactions. Although all risk cannot be excluded it remains a treatment for rheumatic disease during pregnancy. Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.
Hydroxychloroquine was approved for medical use in the United States in 1955. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The wholesale cost in the developing world is about US$4.65 per month as of 2015, when used for rheumatoid arthritis or lupus. In the United States the wholesale cost of a month of treatment is about US$25 as of 2020. In the United Kingdom this dose costs the NHS about £ 5.15. In 2017, it was the 128th most prescribed medication in the United States with more than five million prescriptions.
Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.
The drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-Aminoquinoline compounds. There are a range of other contraindications  and caution is required if patients have certain heart conditions, diabetes, psoriasis etc.
The most common adverse effects are a mild nausea and occasional stomach cramps with mild diarrhea. The most serious adverse effects affect the eye, with dose-related retinopathy as a concern even after hydroxychloroquine use is discontinued. For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.
For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, convulsions, vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or liver failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo, weight loss, and occasionally urinary incontinence. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.
Children may be especially vulnerable to developing adverse effects from hydroxychloroquine.
One of the most serious side effects is retinopathy (generally with chronic use). People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to go up when a person takes the medication over 5 years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be computed from one’s height and weight using this calculator. Cumulative doses can also be calculated from this calculator. Macular toxicity is related to the total cumulative dose rather than the daily dose. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.
Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous cornea verticillata or vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine.
The macular changes are potentially serious. Advanced retinopathy is characterized by reduction of visual acuity and a “bull’s eye” macular lesion which is absent in early involvement.
Due to rapid absorption, symptoms of overdose can occur within a half an hour after ingestion. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.
Hydroxychloroquine overdoses are rarely reported, with 7 previous cases found in the English medical literature. In one such case, a 16-year-old girl who had ingested a handful of hydroxychloroquine 200mg presented with tachycardia (heart rate 110 beats/min), hypotension (systolic blood pressure 63 mm Hg), central nervous system depression, conduction defects (ORS = 0.14 msec), and hypokalemia (K = 2.1 meq/L). Treatment consisted of fluid boluses and dopamine, oxygen, and potassium supplementation. The presence of hydroxychloroquine was confirmed through toxicologic tests. The patient’s hypotension resolved within 4.5 hours, serum potassium stabilized in 24 hours, and tachycardia gradually decreased over 3 days.
Care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). HCQ can increase plasma concentrations of penicillamine which may contribute to the development of severe side effects. It enhances hypoglycemic effects of insulin and oral hypoglycemic agents. Dose altering is recommended to prevent profound hypoglycemia. Antacids may decrease the absorption of HCQ. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.
Specifically, the FDA drug label for hydroxychloroquine lists the following drug interactions :
- Digoxin (wherein it may result in increased serum digoxin levels)
- Insulin or antidiabetic drugs (wherein it may enhance the effects of a hypoglycemic treatment)
- Drugs that prolong QT interval and other arrhythmogenic drugs (as Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing ventricular arrhythmias if used concurrently)
- Mefloquine and other drugs known to lower the convulsive threshold (co-administration with other antimalarials known to lower the convulsion threshold may increase risk of convulsions)
- Antiepileptics (concurrent use may impair the antiepileptic activity)
- Methotrexate (combined use is unstudied and may increase the frequency of side effects)
- Cyclosporin (wherein an increased plasma cylcosporin level was reported when used together).
Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D6, 2C8, 3A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.
Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated, resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from 4 to 6. Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect. Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences. These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils. HCQ is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane.
Mechanism of action
Hydroxychloroquine increases lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs). Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process. Toll-like receptor 9 (TLR 9) recognizes DNA-containing immune complexes and leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells, therefore reducing anti-DNA auto-inflammatory process.
In 2003, a novel mechanism was described wherein hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system.
As with other quinoline antimalarial drugs, the mechanism of action of quinine has not been fully resolved. The most accepted model is based on hydrochloroquinine and involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths.
Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, Quinoric.
Hydroxychloroquine and chloroquine have been recommended by Chinese and South Korean health authorities for the experimental treatment of COVID-19. In vitro studies in cell cultures demonstrated that hydroxychloroquine was more potent than chloroquine against SARS-CoV-2.
On 17 March 2020, the AIFA Scientific Technical Commission of the Italian Medicines Agency expressed a favorable opinion on including the off-label use of chloroquine and hydroxychloroquine for the treatment of SARS-CoV-2 infection.
white solid (0.263 g, 78%). 1H NMR
(600 MHz, CDCl3
) δ 8.48 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.34 (dd, J = 8.8, 7.3 Hz, 1H), 6.39 (d, J = 5.4 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.70 (sx,J = 6.8 Hz, 1H), 3.55 (m, 2H), 2.57 (m, 5H), 2.49 (m, 2H),
1.74–1.62 (m, 1H), 1.65–1.53 (m, 3H), 1.31 (d, J = 6.9 Hz, 3H),
1.24 (d, J = 7.2 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 152.2,
149.5, 149.2, 135.0, 129.0, 125.4, 121.2, 117.4, 99.4, 58.6, 54.9,
53.18, 48.5, 47.9, 34.5, 24.1, 20.6, 11.9. Spectra were obtained
in accordance with those previously reported [38,39].
38. Cornish, C. A.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1985,
39. Münstedt, R.; Wannagat, U.; Wrobel, D. J. Organomet. Chem. 1984,
264, 135–148. doi:10.1016/0022-328X(84)85139-6
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Typical dose is 600mg per day. Costs 0.28157 per dose. Month has about 30 days.
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Hydroxychloroquine freebase molecule
|Trade names||Plaquenil, others|
|Other names||Hydroxychloroquine sulfate|
|By mouth (tablets)|
|Bioavailability||Variable (74% on average); Tmax = 2–4.5 hours|
|Elimination half-life||32–50 days|
|Excretion||Mostly Kidney (23–25% as unchanged drug), also biliary (<10%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||335.872 g/mol g·mol−1|
|3D model (JSmol)|
///////////Hydroxychloroquine, Hydroxy chloroquine, HCQ, ヒドロキシクロロキン , covid 19, coronavirus, antimalarial, гидроксихлорохин , هيدروكسيكلوروكين , 羟氯喹 , Oxychlorochin, Plaquenil , Plaquenil®,
- Molecular FormulaC22H25BrN2O3S
- Average mass477.414 Da
Umifenovir (trade names Arbidol Russian: Арбидол, Chinese: 阿比朵尔) is an antiviral treatment for influenza infection used in Russia and China. The drug is manufactured by Pharmstandard (Russian: Фармстандарт). Although some Russian studies have shown it to be effective, it is not approved for use in other countries. It is not approved by FDA for the treatment or prevention of influenza. Chemically, umifenovir features an indole core, functionalized at all but one positions with different substituents. The drug is claimed to inhibit viral entry into target cells and stimulate the immune response. Interest in the drug has been renewed as a result of the SARS-CoV-2 outbreak.
Testing of umifenovir’s efficacy has mainly occurred in China and Russia, and it is well known in these two countries. Some of the Russian tests showed the drug to be effective and a direct comparison with Tamiflu showed similar efficiency in vitro and in a clinical setting. In 2007, Arbidol (umifenovir) had the highest sales in Russia among all over-the-counter drugs.
Mode of action
Umifenovir inhibits membrane fusion. Umifenovir prevents contact between the virus and target host cells. Fusion between the viral envelope (surrounding the viral capsid) and the cell membrane of the target cell is inhibited. This prevents viral entry to the target cell, and therefore protects it from infection.
As well as specific antiviral action against both influenza A and influenza B viruses, umifenovir exhibits modulatory effects on the immune system. The drug stimulates a humoral immune response, induces interferon-production, and stimulates the phagocytic function of macrophages.
More recent studies indicate that umifenovir also has in vitro effectiveness at preventing entry of Ebolavirus Zaïre Kikwit, Tacaribe arenavirus and human herpes virus 8 in mammalian cell cultures, while confirming umifenovir’s suppressive effect in vitro on Hepatitis B and poliovirus infection of mammalian cells when introduced either in advance of viral infection or during infection.
In February 2020, Li Lanjuan, an expert of the National Health Commission of China, proposed using Arbidol (umifenovir) together with darunavir as a potential treatment during the 2019–20 coronavirus pandemic. Chinese experts claim that preliminary tests had shown that arbidol and darunavir could inhibit replication of the virus. So far without additional effect if added on top of recombinant human interferon α2b spray.
Side effects in children include sensitization to the drug. No known overdose cases have been reported and allergic reactions are limited to people with hypersensitivity. The LD50 is more than 4 g/kg.
In 2007, the Russian Academy of Medical Sciences stated that the effects of Arbidol (umifenovir) are not scientifically proven.
Russian media criticized lobbying attempts by Tatyana Golikova (then-Minister of Healthcare) to promote umifenovir, and the unproven claim that Arbidol can speed up recovery from flu or cold by 1.3-2.3 days. They also debunked claims that the efficacy of umifenovir is supported by peer-reviewed studies.
1,2-Dimethyl-5-hydroxyindole-3-acetic acid ethyl ester (I) is acetylated with acetic anhydride affording the O-acyl derivative (II) , which is brominated to the corresponding dibromide compound (III) . The reaction of (III) with thiophenol in KOH yields (IV) , which is then submitted to a conventional Mannich condensation with formaldehyde and dimethylamine in acetic acid, giving the free base of arbidol (V), which is treated with aqueous hydrochloric acid .
- “Full Prescribing Information: Arbidol® (umifenovir) film-coated tablets 50 and 100 mg: Corrections and Additions”. State Register of Medicines (in Russian). Open joint-stock company “Pharmstandard-Tomskchempharm”. Retrieved 3 June 2015.
- Recommended INN: List 65., WHO Drug Information, Vol. 25, No. 1, 2011, page 91
- Leneva IA, Russell RJ, Boriskin YS, Hay AJ (February 2009). “Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol”. Antiviral Research. 81 (2): 132–40. doi:10.1016/j.antiviral.2008.10.009. PMID 19028526.
- “FDA Approved Drugs for Influenza”. U.S. Food and Drug Administration.
- Leneva IA, Fediakina IT, Gus’kova TA, Glushkov RG (2005). “[Sensitivity of various influenza virus strains to arbidol. Influence of arbidol combination with different antiviral drugs on reproduction of influenza virus A]”. Terapevticheskii Arkhiv (Russian translation). ИЗДАТЕЛЬСТВО “МЕДИЦИНА”. 77 (8): 84–8. PMID 16206613.
- Wang MZ, Cai BQ, Li LY, Lin JT, Su N, Yu HX, Gao H, Zhao JZ, Liu L (June 2004). “[Efficacy and safety of arbidol in treatment of naturally acquired influenza]”. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae. 26 (3): 289–93. PMID 15266832.
- Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ (2008). “Arbidol: a broad-spectrum antiviral compound that blocks viral fusion”. Current Medicinal Chemistry. 15 (10): 997–1005. doi:10.2174/092986708784049658. PMID 18393857.
- Leneva IA, Burtseva EI, Yatsyshina SB, Fedyakina IT, Kirillova ES, Selkova EP, Osipova E, Maleev VV (February 2016). “Virus susceptibility and clinical effectiveness of anti-influenza drugs during the 2010-2011 influenza season in Russia”. International Journal of Infectious Diseases. 43: 77–84. doi:10.1016/j.ijid.2016.01.001. PMID 26775570.
- Boriskin YS, Pécheur EI, Polyak SJ (July 2006). “Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection”. Virology Journal. 3: 56. doi:10.1186/1743-422X-3-56. PMC 1559594. PMID 16854226.
- Shi L, Xiong H, He J, Deng H, Li Q, Zhong Q, Hou W, Cheng L, Xiao H, Yang Z (2007). “Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo”. Archives of Virology. 152 (8): 1447–55. doi:10.1007/s00705-007-0974-5. PMID 17497238.
- Glushkov RG, Gus’kova TA, Krylova LIu, Nikolaeva IS (1999). “[Mechanisms of arbidole’s immunomodulating action]”. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk (in Russian) (3): 36–40. PMID 10222830.
- Pécheur EI, Lavillette D, Alcaras F, Molle J, Boriskin YS, Roberts M, Cosset FL, Polyak SJ (May 2007). “Biochemical mechanism of hepatitis C virus inhibition by the broad-spectrum antiviral arbidol”. Biochemistry. 46 (20): 6050–9. doi:10.1021/bi700181j. PMC 2532706. PMID 17455911.
- Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ (January 2016). “The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses”. Journal of Virology. 90 (6): 3086–92. doi:10.1128/JVI.02077-15. PMC 4810626. PMID 26739045.
- Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM. Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: e02185-18. doi:10.1128/JVI.02185-18 PMID 30700611
- Ng E (4 February 2020). “Coronavirus: are cocktail therapies for flu and HIV the magic cure?”. South China Morning Post.
Bangkok and Hangzhou hospitals put combination remedies to the test.
- Zheng W, Lau M (4 February 2020). “China’s health officials say priority is to stop mild coronavirus cases from getting worse”. South China Morning Post.
- Lu H (January 2020). “Drug treatment options for the 2019-new coronavirus (2019-nCoV)”. Bioscience Trends. doi:10.5582/bst.2020.01020. PMID 31996494.
- “Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia”. 4 February 2020. Retrieved 24 February 2020.
- “АРБИДОЛ® (ARBIDOL)”. Vidal. Archived from the originalon 4 February 2009.
- “Resolution”. Meetings of the Presidium of the Formulary Committee. Russian Academy of Medical Sciences. 16 March 2007.
- “How do we plant federal ministers”. MKRU. 21 April 2011.
- Golunov I (23 December 2013). “13 most popular flu cures: do they work?”. Professional Journalism Platform.
- Reuters S. “Stick in the wheel”. Esquire.
- “Repetition – the mother of learning”. Esquire.
- “Мастерлек” Pharmaceuticals, Moscow, Russia. Patent number No. 2033157, Registry number No. 003610/01.
- (in Russian) Arbidol
- English published clinical studies and translations for Arbidol 1973–2016
|Oral (hard capsules, tablets)|
|Elimination half-life||17–21 hours|
|Excretion||40% excrete as unchanged umifenovir in feces (38.9%) and urine (0.12%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||477.41 g/mol g·mol−1|
|3D model (JSmol)|
Umifenovir is an indole-based, hydrophobic, dual-acting direct antiviral/host-targeting agent used for the treatment and prophylaxis of influenza and other respiratory infections.13 It has been in use in Russia for approximately 25 years and in China since 2006. Its invention is credited to a collaboration between Russian scientists from several research institutes 40-50 years ago, and reports of its chemical synthesis date back to 1993.13 Umifenovir’s ability to exert antiviral effects through multiple pathways has resulted in considerable investigation into its use for a variety of enveloped and non-enveloped RNA and DNA viruses, including Flavivirus,2 Zika virus,3 foot-and-mouth disease,4 Lassa virus,6 Ebola virus,6 herpes simplex,8, hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.13,9 This dual activity may also confer additional protection against viral resistance, as the development of resistance to umifenovir does not appear to be significant.13
Umifenovir is currently being investigated as a potential treatment and prophylactic agent for COVID-19 caused by SARS-CoV2 infections in combination with both currently available and investigational HIV therapies.1,16,17
Umifenovir is currently licensed in China and Russia for the prophylaxis and treatment of influenza and other respiratory viral infections.13 It has demonstrated activity against a number of viruses and has been investigated in the treatment of Flavivirus,2 Zika virus,3 foot-and-mouth disease,4 Lassa virus,6 Ebola virus,6 and herpes simplex.8 In addition, it has shown in vitro activity against hepatitis B and C viruses, chikungunya virus, reovirus, Hantaan virus, and coxsackie virus B5.13,9
Umifenovir exerts its antiviral effects via both direct-acting virucidal activity and by inhibiting one (or several) stage(s) of the viral life cycle.13 Its broad-spectrum of activity covers both enveloped and non-enveloped RNA and DNA viruses. It is relatively well-tolerated and possesses a large therapeutic window – weight-based doses up to 100-fold greater than those used in humans failed to produce any pathological changes in test animals.13
Umifenovir does not appear to result in significant viral resistance. Instances of umifenovir-resistant influenza virus demonstrated a single mutation in the HA2 subunit of influenza hemagglutinin, suggesting resistance is conferred by prevention of umifenovir’s activity related to membrane fusion. The mechanism through which other viruses may become resistant to umifenovir requires further study.13
Mechanism of action
Umifenovir is considered both a direct-acting antiviral (DAA) due to direct virucidal effects and a host-targeting agent (HTA) due to effects on one or multiple stages of viral life cycle (e.g. attachment, internalization), and its broad-spectrum antiviral activity is thought to be due to this dual activity.13 It is a hydrophobic molecule capable of forming aromatic stacking interactions with certain amino acid residues (e.g. tyrosine, tryptophan), which contributes to its ability to directly act against viruses. Antiviral activity may also be due to interactions with aromatic residues within the viral glycoproteins involved in fusion and cellular recognition,5,7 with the plasma membrane to interfere with clathrin-mediated exocytosis and intracellular trafficking,10 or directly with the viral lipid envelope itself (in enveloped viruses).13,12 Interactions at the plasma membrane may also serve to stabilize it and prevent viral entry (e.g. stabilizing influenza hemagglutinin inhibits the fusion step necessary for viral entry).13
Due to umifenovir’s ability to interact with both viral proteins and lipids, it may also interfere with later stages of the viral life cycle. Some virus families, such as Flaviviridae, replicate in a subcellular compartment called the membranous web – this web requires lipid-protein interactions that may be hindered by umifenovir. Similarly, viral assembly of hepatitis C viruses is contingent upon the assembly of lipoproteins, presenting another potential target.13
Umifenovir is rapidly absorbed following oral administration, with an estimated Tmax between 0.65-1.8 hours.14,15,13 The Cmax has been estimated as 415 – 467 ng/mL and appears to increase linearly with dose,14,15 and the AUC0-inf following oral administration has been estimated to be approximately 2200 ng/mL/h.14,15
Volume of distribution
Data regarding the volume of distribution of umifenovir are currently unavailable.
Data regarding protein-binding of umifenovir are currently unavailable.
Umifenovir is highly metabolized in the body, primarily in hepatic and intestinal microsomess, with approximately 33 metabolites having been observed in human plasma, urine, and feces.14 The principal phase I metabolic pathways include sulfoxidation, N-demethylation, and hydroxylation, followed by phase II sulfate and glucuronide conjugation. In the urine, the major metabolites were sulfate and glucuronide conjugates, while the major species in the feces was unchanged parent drug (~40%) and the M10 metabolite (~3.0%). In the plasma, the principal metabolites are M6-1, M5, and M8 – of these, M6-1 appears of most importance given its high plasma exposure and long elimination half-life (~25h), making it a potentially important player in the safety and efficacy of umifenovir.14
Enzymes involved in the metabolism of umifenovir include members of the cytochrome P450 family (primarily CYP3A4), flavin-containing monooxygenase (FMO) family, and UDP-glucuronosyltransferase (UGT) family (specifically UGT1A9 and UGT2B7).14,11
- Lu H: Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020 Jan 28. doi: 10.5582/bst.2020.01020. [PubMed:31996494]
- Haviernik J, Stefanik M, Fojtikova M, Kali S, Tordo N, Rudolf I, Hubalek Z, Eyer L, Ruzek D: Arbidol (Umifenovir): A Broad-Spectrum Antiviral Drug That Inhibits Medically Important Arthropod-Borne Flaviviruses. Viruses. 2018 Apr 10;10(4). pii: v10040184. doi: 10.3390/v10040184. [PubMed:29642580]
- Fink SL, Vojtech L, Wagoner J, Slivinski NSJ, Jackson KJ, Wang R, Khadka S, Luthra P, Basler CF, Polyak SJ: The Antiviral Drug Arbidol Inhibits Zika Virus. Sci Rep. 2018 Jun 12;8(1):8989. doi: 10.1038/s41598-018-27224-4. [PubMed:29895962]
- Herod MR, Adeyemi OO, Ward J, Bentley K, Harris M, Stonehouse NJ, Polyak SJ: The broad-spectrum antiviral drug arbidol inhibits foot-and-mouth disease virus genome replication. J Gen Virol. 2019 Sep;100(9):1293-1302. doi: 10.1099/jgv.0.001283. Epub 2019 Jun 4. [PubMed:31162013]
- Kadam RU, Wilson IA: Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):206-214. doi: 10.1073/pnas.1617020114. Epub 2016 Dec 21. [PubMed:28003465]
- Hulseberg CE, Feneant L, Szymanska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM: Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses. J Virol. 2019 Apr 3;93(8). pii: JVI.02185-18. doi: 10.1128/JVI.02185-18. Print 2019 Apr 15. [PubMed:30700611]
- Zeng LY, Yang J, Liu S: Investigational hemagglutinin-targeted influenza virus inhibitors. Expert Opin Investig Drugs. 2017 Jan;26(1):63-73. doi: 10.1080/13543784.2017.1269170. Epub 2016 Dec 14. [PubMed:27918208]
- Li MK, Liu YY, Wei F, Shen MX, Zhong Y, Li S, Chen LJ, Ma N, Liu BY, Mao YD, Li N, Hou W, Xiong HR, Yang ZQ: Antiviral activity of arbidol hydrochloride against herpes simplex virus I in vitro and in vivo. Int J Antimicrob Agents. 2018 Jan;51(1):98-106. doi: 10.1016/j.ijantimicag.2017.09.001. Epub 2017 Sep 7. [PubMed:28890393]
- Pecheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ: The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses. J Virol. 2016 Jan 6;90(6):3086-92. doi: 10.1128/JVI.02077-15. [PubMed:26739045]
- Blaising J, Levy PL, Polyak SJ, Stanifer M, Boulant S, Pecheur EI: Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking. Antiviral Res. 2013 Oct;100(1):215-9. doi: 10.1016/j.antiviral.2013.08.008. Epub 2013 Aug 25. [PubMed:23981392]
- Song JH, Fang ZZ, Zhu LL, Cao YF, Hu CM, Ge GB, Zhao DW: Glucuronidation of the broad-spectrum antiviral drug arbidol by UGT isoforms. J Pharm Pharmacol. 2013 Apr;65(4):521-7. doi: 10.1111/jphp.12014. Epub 2012 Dec 24. [PubMed:23488780]
- Teissier E, Zandomeneghi G, Loquet A, Lavillette D, Lavergne JP, Montserret R, Cosset FL, Bockmann A, Meier BH, Penin F, Pecheur EI: Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol. PLoS One. 2011 Jan 25;6(1):e15874. doi: 10.1371/journal.pone.0015874. [PubMed:21283579]
- Blaising J, Polyak SJ, Pecheur EI: Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014 Jul;107:84-94. doi: 10.1016/j.antiviral.2014.04.006. Epub 2014 Apr 24. [PubMed:24769245]
- Deng P, Zhong D, Yu K, Zhang Y, Wang T, Chen X: Pharmacokinetics, metabolism, and excretion of the antiviral drug arbidol in humans. Antimicrob Agents Chemother. 2013 Apr;57(4):1743-55. doi: 10.1128/AAC.02282-12. Epub 2013 Jan 28. [PubMed:23357765]
- Liu MY, Wang S, Yao WF, Wu HZ, Meng SN, Wei MJ: Pharmacokinetic properties and bioequivalence of two formulations of arbidol: an open-label, single-dose, randomized-sequence, two-period crossover study in healthy Chinese male volunteers. Clin Ther. 2009 Apr;31(4):784-92. doi: 10.1016/j.clinthera.2009.04.016. [PubMed:19446151]
- Wang Z, Chen X, Lu Y, Chen F, Zhang W: Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends. 2020 Feb 9. doi: 10.5582/bst.2020.01030. [PubMed:32037389]
- Nature Biotechnology: Coronavirus puts drug repurposing on the fast track [Link]
/////////////////Arbidol, umifenovir, covid 19, corona virus, Арбидол , 阿比朵尔 ,
|Synonyms:||T-705, T705, Favipiravir|
- Molecular FormulaC5H4FN3O2
- Average mass157.103 Da
C5H4FN3O2 : 157.1
The drug substance is a white to light yellow powder. It is sparingly soluble in acetonitrile and in methanol, and slightly soluble in water and in ethanol (99.5). It is slightly soluble at pH 2.0 to 5.5 and sparingly soluble at pH 5.5 to 6.1. The drug substance is not hygroscopic at 25°C/51% to 93%RH. The melting point is 187°C to 193°C, and the dissociation constant (pKa) is 5.1 due to the hydroxyl group of favipiravir. Measurement results on the partition ratio of favipiravir in water/octanol at 25°C indicate that favipiravir tends to be distributed in the 1-octanol phase at pH 2 to 4 and in the water phase at pH 5 to 13.
Any batch manufactured by the current manufacturing process is in Form A. The stability study does not show any change in crystal form over time; and a change from Form A to Form B is unlikely.
|melting point (°C)||187℃ to 193℃||https://www.pmda.go.jp/files/000210319.pdf|
|water solubility||slightly soluble in water||https://www.pmda.go.jp/files/000210319.pdf|
Favipiravir, also known as T-705, Avigan, or favilavir is an antiviral drug being developed by Toyama Chemical (Fujifilm group) of Japan with activity against many RNA viruses. Like certain other experimental antiviral drugs (T-1105 and T-1106), it is a pyrazinecarboxamide derivative. In experiments conducted in animals Favipiravir has shown activity against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyaviruses and alphaviruses.Activity against enteroviruses and Rift Valley fever virus has also been demonstrated. Favipiravir has showed limited efficacy against Zika virus in animal studies, but was less effective than other antivirals such as MK-608. The agent has also shown some efficacy against rabies, and has been used experimentally in some humans infected with the virus.
In February 2020 Favipiravir was being studied in China for experimental treatment of the emergent COVID-19 (novel coronavirus)disease. On March 17 Chinese officials suggested the drug had been effective in treating COVID in Wuhan and Shenzhen.
Discovered by Toyama Chemical Co., Ltd. in Japan, favipiravir is a modified pyrazine analog that was initially approved for therapeutic use in resistant cases of influenza.7,9 The antiviral targets RNA-dependent RNA polymerase (RdRp) enzymes, which are necessary for the transcription and replication of viral genomes.7,12,13
Not only does favipiravir inhibit replication of influenza A and B, but the drug shows promise in the treatment of influenza strains that are resistant to neuramidase inhibitors, as well as avian influenza.9,19 Favipiravir has been investigated for the treatment of life-threatening pathogens such as Ebola virus, Lassa virus, and now COVID-19.10,14,15
Mechanism of action
The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase. Other research suggests that favipiravir induces lethal RNA transversion mutations, producing a nonviable viral phenotype. Favipiravir is a prodrug that is metabolized to its active form, favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP), available in both oral and intravenous formulations. Human hypoxanthine guanine phosphoribosyltransferase (HGPRT) is believed to play a key role in this activation process. Favipiravir does not inhibit RNA or DNA synthesis in mammalian cells and is not toxic to them. In 2014, favipiravir was approved in Japan for stockpiling against influenza pandemics. However, favipiravir has not been shown to be effective in primary human airway cells, casting doubt on its efficacy in influenza treatment.
In 2014, Japan approved Favipiravir for treating viral strains unresponsive to current antivirals.
Ebola virus trials
Some research has been done suggesting that in mouse models Favipiravir may have efficacy against Ebola. Its efficacy against Ebola in humans is unproven. During the 2014 West Africa Ebola virus outbreak, it was reported that a French nurse who contracted Ebola while volunteering for MSF in Liberia recovered after receiving a course of favipiravir. A clinical trial investigating the use of favipiravir against Ebola virus disease was started in Guéckédou, Guinea, during December 2014. Preliminary results showed a decrease in mortality rate in patients with low-to-moderate levels of Ebola virus in the blood, but no effect on patients with high levels of the virus, a group at a higher risk of death. The trial design has been criticised by Scott Hammer and others for using only historical controls. The results of this clinical trial were presented in February 2016 at the annual Conference on Retroviruses and Opportunistic Infections (CROI) by Daouda Sissoko and published on March 1, 2016 in PLOS Medicine.
SARS-CoV-2 virus disease
In March 2020, Chinese officials suggested Favipiravir may be effective in treating COVID-19.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Drug Discoveries & Therapeutics. 2014; 8(3):117-120.
As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA viruses in vitro and in vivo. A four-step synthesis of the compound is described in this article, amidation, nitrification, reduction and fluorination with an overall yield of about 8%. In addition, we reported the crystal structure of the title compound. The molecule is almost planar and the intramolecular O−H•••O hydrogen bond makes a 6-member ring. In the crystal, molecules are packing governed by both hydrogen bonds and stacking interactions.
2.2.1. Preparation of 3-hydroxypyrazine-2-carboxamide To a suspension of 3-hydroxypyrazine-2-carboxylic acid (1.4 g, 10 mmol) in 150 mL MeOH, SOCl2 was added dropwise at 40°C with magnetic stirring for 6 h resulting in a bright yellow solution. The reaction was then concentrated to dryness. The residue was dissolved in 50 mL 25% aqueous ammonia and stirred overnight to get a suspension. The precipitate was collected and dried. The solid yellow-brown crude product was recrystallization with 50 mL water to get the product as pale yellow crystals (1.1 g, 78%). mp = 263-265°C. 1 H-NMR (300 MHz, DMSO): δ 13.34 (brs, 1H, OH), 8.69 (s, 1H, pyrazine H), 7.93-8.11 (m, 3H, pyrazine H, CONH2). HRMS (ESI): m/z [M + H]+ calcd for C5H6N3O2 + : 140.0460; found: 140.0457.
2.2.2. Preparation of 3-hydroxy-6-nitropyrazine-2- carboxamide In the solution of 3-hydroxypyrazine-2-carboxamide (1.0 g, 7 mmol) in 6 mL concentrate sulfuric acid under ice-cooling, potassium nitrate (1.4 g, 14 mmol) was added. After stirring at 40°C for 4 h, the reaction mixture was poured into 60 mL water. The product was collected by fi ltration as yellow solid (0.62 g, 48%). mp = 250-252°C. 1 H-NMR (600 MHz, DMSO): δ 12.00- 15.00 (br, 1H, OH), 8.97 (s, 1H, pyrazine H), 8.32 (s, 1H, CONH2), 8.06 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 163.12, 156.49, 142.47, 138.20, 133.81. HRMS (ESI): m/z [M + H]+ calcd for C5H5N4O4 + : 185.0311; found: 185.0304.
2.2.3. Preparation of 6-amino-3-hydroxypyrazine-2- carboxamide 3-Hydroxy-6-nitropyrazine-2-carboxamide (0.6 g, 3.3 mmol) and a catalytic amount of raney nickel were suspended in MeOH, then hydrazine hydrate was added dropwise. The resulting solution was refl uxed 2 h, cooled, filtered with diatomite, and then MeOH is evaporated in vacuo to get the crude product as dark brown solid without further purification (0.4 g, 77%). HRMS (ESI): m/z [M + H]+ calcd for C5H7N4O2 + : 155.0569; found:155.0509.
2.2.4. Preparation of 6-fluoro-3-hydroxypyrazine-2- carboxamide To a solution of 6-amino-3-hydroxypyrazine-2- carboxamide (0.4 g, 2.6 mmol) in 3 mL 70% HFpyridine aqueous at -20°C under nitrogen atmosphere, sodium nitrate (0.35 g, 5.2 mmol) was added. After stirring 20 min, the solution was warmed to room temperature for another one hour. Then 20 mL ethyl acetate/water (1:1) were added, after separation of the upper layer, the aqueous phase is extracted with four 20 mL portions of ethyl acetate. The combined extracts are dried with anhydrous magnesium sulfate and concentrated to dryness to get crude product as oil. The crude product was purified by chromatography column as white solid (0.12 g, 30%). mp = 178-180°C. 1 H-NMR (600 MHz, DMSO): δ 12.34 (brs, 1H, OH), 8.31 (d, 1H, pyrazine H, J = 8.0 Hz), 7.44 (s, 1H, CONH2), 5.92 (s, 1H, CONH2). 13C-NMR (75 MHz, DMSO): δ 168.66, 159.69, 153.98, 150.76, 135.68. HRMS (ESI): m/z [M + H]+ calcd for C5H5FN3O2 + : 158.0366; found: 158.0360.
Chemical Papers (2019), 73(5), 1043-1051.
Medicinal chemistry (Shariqah (United Arab Emirates)) (2018), 14(6), 595-603
Chemical Papers (2017), 71(11), 2153-2158.
Below is the link to the electronic supplementary material.
- Furuta, Y.; Takahashi, K.; Shiraki, K.; Sakamoto, K.; Smee, D. F.; Barnard, D. L.; Gowen, B. B.; Julander, J. G.; Morrey, J. D. (2009). “T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections”. Antiviral Research 82 (3): 95–102. doi:10.1016/j.antiviral.2009.02.198. PMID 19428599. edit
- WO 2000010569
- WO 2008099874
- WO 201009504
- WO 2010104170
- WO 2012063931
Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence.
For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used
Synthesis of Favipiravir
ZHANG Tao1, KONG Lingjin1, LI Zongtao1,YUAN Hongyu1, XU Wenfang2*
(1. Shandong Qidu PharmaceuticalCo., Ltd., Linzi 255400; 2. School of Pharmacy, Shandong University, Jinan250012)
ABSTRACT: Favipiravir was synthesized from3-amino-2-pyrazinecarboxylic acid by esterification, bromination with NBS,diazotization and amination to give 6-bromo-3-hydroxypyrazine-2-carboxamide,which was subjected to chlorination with POCl3, fluorination with KF, andhydrolysis with an overall yield of about 22％.
|compd 32 N||CH||C—CF3||N||H|
To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35° C., and the solution was stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the solution was stirred at 20 to 30° C. for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10° C., and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly yellowish white solid product.
1H-NMR (DMSO-d6) δ values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m), 1.67-1.81 (4H, m), 1.91-2.07 (4H, m), 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad)
4.11 ml of acetic acid was added at 5 to 15° C. to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5° C., and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product.
Examples 2 to 5
The compounds shown in Table 1 were obtained in the same way as in Example 1-1.
|Example No.||Organic amine||Example No.||Organic amine|
Dipropylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) 6 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz)
Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) 6 values: 0.36 (6H, t, J=7.3 Hz), 0.81 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m), 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz)
Dibenzylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) δ values: 4.17 (4H, s), 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz)
N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) δ values: 2.57 (3H, s), 4.14 (2H, s), 7.37-7.53 (5H, m), 8.02-8.08 (1H, m)
Preparation Example 1
300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.
1H-NMR (DMSO-d6) δ values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)
First patient enrolled in the North American Phase 3 clinical trials for investigational flu treatment drug
Eur J Med Chem. 2013 Apr;62:534-44. doi: 10.1016/j.ejmech.2013.01.015. Epub 2013 Jan 29.
|US3631036 *||Nov 4, 1969||Dec 28, 1971||American Home Prod||5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds|
|US3745161 *||Apr 20, 1970||Jul 10, 1973||Merck & Co Inc||Phenyl-hydroxy-pyrazine carboxylic acids and derivatives|
|US4404203 *||May 14, 1981||Sep 13, 1983||Warner-Lambert Company||Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents|
|US4545810 *||Mar 25, 1983||Oct 8, 1985||Sds Biotech Corporation||Herbicidal and plant growth regulant diphenylpyridazinones|
|US4565814 *||Jan 18, 1984||Jan 21, 1986||Sanofi||Pyridazine derivatives having a psychotropic action and compositions|
|US4661145 *||Sep 20, 1984||Apr 28, 1987||Rohm And Haas Company||Plant growth regulating 1-aryl-1,4-dihydro-4-oxo(thio)-pyridazines|
|US5420130||May 16, 1994||May 30, 1995||Synthelabo||2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics|
|US5459142 *||Aug 23, 1993||Oct 17, 1995||Otsuka Pharmaceutical Co., Ltd.||Pyrazinyl and piperazinyl substituted pyrazine compounds|
|US5597823||Jun 5, 1995||Jan 28, 1997||Abbott Laboratories||Tricyclic substituted hexahydrobenz [e]isoindole alpha-1 adrenergic antagonists|
|US6159980 *||Sep 15, 1997||Dec 12, 2000||Dupont Pharmaceuticals Company||Pyrazinones and triazinones and their derivatives thereof|
|EP0023358A1 *||Jul 28, 1980||Feb 4, 1981||Rohm And Haas Company||Process for the preparation of pyridazine derivatives|
|GB1198688A||Title not available|
|HU9401512A||Title not available|
|JPH09216883A *||Title not available|
|JPS5620576A||Title not available|
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T-705; Avigan; favilavir
3D model (JSmol)
CompTox Dashboard (EPA)
|Molar mass||157.104 g·mol−1|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
////////////FAVIPIRAVIR, ファビピラビル , 8916, Avigan, T-705, favilavir, COVID-19, coronavirus, antiinfluenza
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NEW DRUG APPROVALS
- Molecular FormulaC20H22N4O5
- Average mass398.413 Da
Trypsin-like protease inhibitor CAS 59721-29-8
MP 194, methanol, diethyl ether, Chemical and Pharmaceutical Bulletin, 2005, vol. 53, 8, pg. 893 – 898
Dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)phenylacetate monomethanesulfonate
C20H22N4O5▪CH4O3S : 494.52
Launched – 1985, in Japan by Ono for the oral treatment of postoperative reflux esophagitis and chronic pancreatitis.
Camostat mesilate is a synthetic serine protease inhibitor that has been launched in Japan by Ono for the oral treatment of postoperative reflux esophagitis and chronic pancreatitis. It has been demonstrated that the drug has the ability to inhibit proteases such as trypsin, kallikrein, thrombin, plasmin, and C1 esterase, and that it decreases inflammation by directly suppressing the activity of monocytes and pancreatic stellate cells (PSCs).
In 2011, orphan drug designation was received in the U.S. by Stason Pharmaceuticals for the treatment of chronic pancreatitis. In 2017, Kangen Pharmaceuticals acquired KC Specialty Therapeutics (formerly a wholly-owned subsidiary of Stason Pharmaceuticals).
Camostat (INN; development code FOY-305) is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. It is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis. It is approved in Japan for the treatment of pancreatitis.
DE 2548886; FR 2289181; GB 1472700; JP 76054530; US 4021472
The reaction of p-hydrophenylacetic acid (I) with N,N-dimethylbromoacetamide (II) by means of triethylamine in reftuxing acetonitrile gives N,N-dimethylcarbamoylmethyl-p-hydroxyphenylacetate (III), which is then condensed with p-guanidinobenzoyl chloride (IV) [obtained from the corresponding acid p-guanidinobenzoic acid (V) and thionyl chloride] in pyridine.
By reaction of N,N-dimethylcarbamoylmethyl-p-(p-aminobenzoyloxy)phenylacetate (VI) with cyanamide (VII).
Camostat mesilate, chemical name is 4-(4-guanidine radicals benzoyloxy group) toluylic acid-N, N-dimethyl carbamoyl methyl esters mesylate, be the non-peptide proteinoid enzyme inhibitors of Japanese little Ye medicine Co., Ltd. exploitation, first in January, 1985 go on the market with trade(brand)name Foipan in Japan.Pharmacological evaluation shows: camostat mesilate has very strong restraining effect to trypsinase, kallikrein, Tryptase, zymoplasm, C1 esterase, oral rear kassinin kinin generation system, fibrinolytic system, blood coagulation system and the complement system acting on rapidly body, suppress the exception of the enzymic activity of these systems hyperfunction, thus control the symptom of chronic pancreatitis, alleviating pain, reduce amylase value, the clinical alleviation for chronic pancreatitis acute symptom.In addition, this product is also used for the treatment of diffusivity blood vessel blood coagulation disease.Pharmacological evaluation also finds, camostat mesilate also has the effects such as anticancer, antiviral, and effectively can reduce proteinuria, and play the effect of preliminary conditioning, further research is still underway.Current this product not yet in Discussion on Chinese Listed, also without the report succeeded in developing.
A preparation method for camostat mesilate, comprises the steps:
(1), by 160g methylene dichloride DCM join stirring in reaction vessel, cooling, be cooled to start when 0–10 DEG C to drip 51g 50% dimethylamine agueous solution, drip 30g chloroacetyl chloride simultaneously; Drip process control temp 5–10 DEG C, system pH controls 4-7, at 5–10 DEG C, react 1h after dripping off, reaction process pH controls 5-7, and reaction terminates rear standing 20min, separatory, water layer is with 54g dichloromethane extraction, and organic layer is concentrating under reduced pressure below 80 DEG C, obtains 3-pyrrolidone hydrochloride, crude, 3-pyrrolidone hydrochloride, crude carries out underpressure distillation within 130 DEG C, obtains 3-pyrrolidone hydrochloride distillation product; Output is 31g;
(2), the 3-pyrrolidone hydrochloride of 30.6g, 9g triethylamine TEA, 0.4g sodium bisulfite and 40g p-hydroxyphenylaceticacid p-hydroxyphenylaceticacid drop in order in reaction vessel and carry out stirring at low speed, and then drip the triethylamine of 17.6g, dropping temperature 40-95 DEG C, drip off rear maintenance 80-95 DEG C reaction 3h, after reaction terminates, add aqueous solution of sodium bisulfite (0.05gNaHSO3+90gH2O), add and start more than temperature 70 C, add finishing temperature more than 48 DEG C, after adding, cool, crystal seed is added when 40 DEG C, keep cooling temperature 0-5 DEG C, crystallization 2h, filter after crystallization, filter cake 100g purified water is washed, camostat mesilate crude product is obtained after draining, camostat mesilate crude product, 50mL ethyl acetate are joined heating for dissolving in aqueous solution of sodium bisulfite (0.2g NaHSO3+20g H2O), after having dissolved, cooling crystallization, keep recrystallization temperature 0-5 DEG C, crystallization time 1h, suction filtration after crystallization, filter cake, with 10mL water washing, washs with 20mL ethyl acetate after draining again, again at 60 ± 3 DEG C of drying under reduced pressure 2h after draining, obtain camostat mesilate refined silk, output is about 47g,
(3), the camostat mesilate refined silk of 47g is joined heating for dissolving in 30mL acetonitrile, after dissolving terminates, cooling temperature is to 0-5 DEG C, crystallization 1h, after crystallization terminates, suction filtration, filter cake with 17mL acetonitrile wash, drain, drying under reduced pressure 2h at 60 ± 3 DEG C, obtain camostat mesilate product, output is about 45g.
German researchers identify potential drug for Covid-19
Scientists at the German Primate Center – Leibniz Institute for Primate Research have found that an existing drug may help treat Covid-19.
As well as Charité – Universitätsmedizin Berlin, the scientists worked with researchers at the University of Veterinary Medicine Hannover Foundation, the BG-Unfallklinik Murnau, the LMU Munich, the Robert Koch Institute and the German Center for Infection Research.
The research aimed to understand the entry of the novel coronavirus, SARS-CoV-2, into host cells, as well as determine approaches to block the process.
Research findings showed that SARS-CoV-2 requires cellular protein TMPRSS2 to enter hosts’ lung cells.
German Primate Center Infection Biology Unit head Stefan Pöhlmann said: “Our results show that SARS-CoV-2 requires the protease TMPRSS2, which is present in the human body, to enter cells. This protease is a potential target for therapeutic intervention.”
Summary: A clinically proven drug known to block an enzyme essential for the viral entry of Coronavirus into the lungs blocks the COVID 19 (SARS-CoV-2) infection. The drug, Camostat mesilate, is a drug approved in Japan to treat pancreatic inflammation. Results suggest this drug may also protect against COVID 19. Researchers call for further clinical trials.
Viruses must enter cells of the human body to cause disease. For this, they attach to suitable cells and inject their genetic information into these cells. Infection biologists from the German Primate Center – Leibniz Institute for Primate Research in Göttingen, together with colleagues at Charité – Universitätsmedizin Berlin, have investigated how the novel coronavirus SARS-CoV-2 penetrates cells. They have identified a cellular enzyme that is essential for viral entry into lung cells: the protease TMPRSS2. A clinically proven drug known to be active against TMPRSS2 was found to block SARS-CoV-2 infection and might constitute a novel treatment option.
The findings have been published in Cell.
Several coronaviruses circulate worldwide and constantly infect humans, which normally caused only mild respiratory disease. Currently, however, we are witnessing a worldwide spread of a new coronavirus with more than 101,000 confirmed cases and almost 3,500 deaths. The new virus has been named SARS coronavirus-2 and has been transmitted from animals to humans. It causes a respiratory disease called COVID-19 that may take a severe course. The SARS coronavirus-2 has been spreading since December 2019 and is closely related to the SARS coronavirus that caused the SARS pandemic in 2002/2003. No vaccines or drugs are currently available to combat these viruses.
Stopping virus spread
A team of scientists led by infection biologists from the German Primate Centre and including researchers from Charité, the University of Veterinary Medicine Hannover Foundation, the BG-Unfallklinik Murnau, the LMU Munich, the Robert Koch Institute and the German Center for Infection Research, wanted to find out how the new coronavirus SARS-CoV-2 enters host cells and how this process can be blocked. The researchers identified a cellular protein that is important for the entry of SARS-CoV-2 into lung cells. “Our results show that SARS-CoV-2 requires the protease TMPRSS2, which is present in the human body, to enter cells,” says Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center. “This protease is a potential target for therapeutic intervention.”
Since it is known that the drug camostat mesilate inhibits the protease TMPRSS2, the researchers have investigated whether it can also prevent infection with SARS-CoV-2. “We have tested SARS-CoV-2 isolated from a patient and found that camostat mesilate blocks entry of the virus into lung cells,” says Markus Hoffmann, the lead author of the study. Camostat mesilate is a drug approved in Japan for use in pancreatic inflammation. “Our results suggest that camostat mesilate might also protect against COVID-19,” says Markus Hoffmann. “This should be investigated in clinical trials.”
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|Molar mass||398.419 g·mol−1|
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/////////////Camostat, SARS-CoV-2, COVID-19, coronavirus, SARS-CoV-2, COVID-19, FOY305, FOY-S980, カモスタットメシル酸塩 日局収載 , Japan, Ono, oral treatment of postoperative reflux esophagitis, chronic pancreatitis.