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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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CHLOROQUINE, クロロキン;Хлорохин , クロロキン , كلوروكين


Chloroquine

Chloroquine.svg

CHLOROQUINE

N4-(7-Chloroquinolin-4-yl)-N1,N1-diethylpentane-1,4-diamine
Хлорохин [Russian] [INN]
クロロキン [Japanese]
كلوروكين [Arabic] [INN]
Formula
C18H26ClN3
CAS
54-05-7
Mol weight
319.8721
CAS Registry Number: 54-05-7
CAS Name: N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine
Additional Names: 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline
Manufacturers’ Codes: SN-7618; RP-3377
Molecular Formula: C18H26ClN3
Molecular Weight: 319.87
Percent Composition: C 67.59%, H 8.19%, Cl 11.08%, N 13.14%
Literature References: Prepd by the condensation of 4,7-dichloroquinoline with 1-diethylamino-4-aminopentane: DE 683692 (1939); H. Andersag et al., US 2233970 (1941 to Winthrop); Surrey, Hammer, J. Am. Chem. Soc. 68, 113 (1946). Review: Hahn in Antibiotics vol. 3, J. W. Corcoran, F. E. Hahn, Eds. (Springer-Verlag, New York, 1975) pp 58-78. Comprehensive description: D. D. Hong, Anal. Profiles Drug Subs. 5, 61-85 (1976). Comparative clinical trial with dapsone in rheumatoid arthritis: P. D. Fowler et al., Ann. Rheum. Dis. 43, 200 (1984); with penicillamine: T. Gibson et al., Br. J. Rheumatol. 26, 279 (1987).
Properties: mp 87°.
Melting point: mp 87°
Image result for CHLOROQUINE
Derivative Type: Diphosphate
CAS Registry Number: 50-63-5
Trademarks: Arechin (Polfa); Avloclor (AstraZeneca); Malaquin (Ahn Gook); Resochin (Bayer)
Molecular Formula: C18H26ClN3.2H3PO4
Molecular Weight: 515.86
Percent Composition: C 41.91%, H 6.25%, Cl 6.87%, N 8.15%, P 12.01%, O 24.81%
Properties: Bitter, colorless crystals. Dimorphic. One modification, mp 193-195°; the other, mp 215-218°. Freely sol in water; pH of 1% soln about 4.5; less sol at neutral and alkaline pH. Stable to heat in solns of pH 4.0 to 6.5. Practically insol in alcohol, benzene, chloroform, ether.
Melting point: mp 193-195°; mp 215-218°
Derivative Type: Sulfate
CAS Registry Number: 132-73-0
Trademarks: Aralen (Sanofi-Synthelabo); Nivaquine (Aventis)
Molecular Formula: C18H26ClN3.H2SO4
Molecular Weight: 417.95
Percent Composition: C 51.73%, H 6.75%, Cl 8.48%, N 10.05%, S 7.67%, O 15.31%
Therap-Cat: Antimalarial; antiamebic; antirheumatic. Lupus erythematosus suppressant.
Keywords: Antiamebic; Antiarthritic/Antirheumatic; Antimalarial; Lupus Erythematosus Suppressant.

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.[1] A benefit of its use in therapy, when situations allow, is that it can be taken by mouth (versus by injection).[1] Controlled studies of cases involving human pregnancy are lacking, but the drug may be safe for use for such patients.[verification needed][1][2] However, the agent is not without the possibility of serious side effects at standard doses,[1][3] and complicated cases, including infections of certain types or caused by resistant strains, typically require different or additional medication.[1] Chloroquine is also used as a medication for rheumatoid arthritislupus erythematosus, and other parasitic infections (e.g., amebiasis occurring outside of the intestines).[1] Beginning in 2020, studies have proceeded on its use as a coronavirus antiviral, in possible treatment of COVID-19.[4]

Chloroquine, otherwise known as chloroquine phosphate, is in the 4-aminoquinoline class of drugs.[1] 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.[1] In its use against rheumatoid arthritis and lupus erythematosus, its activity as a mild immunosuppressive underlies its mechanism.[1] 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.[5] 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][1] Serious side effects include problems with vision (retinopathy), muscle damage, seizures, and certain anemias.[1][6]

Chloroquine was discovered in 1934 by Hans Andersag.[7][8] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[9] It is available as a generic medication.[1] The wholesale cost in the developing world is about US$0.04.[10] In the United States, it costs about US$5.30 per dose.[1]

Medical uses

Malaria

Distribution of malaria in the world:[11]
♦ Elevated occurrence of chloroquine- or multi-resistant malaria
♦ Occurrence of chloroquine-resistant malaria
♦ No Plasmodium falciparum or chloroquine-resistance
♦ No malaria

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivaxP. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.[12][13]

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.[14] 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.[15]

Amebiasis

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.[16]

Rheumatic disease

As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus.[1]

Side effects

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.[17][18]

  • Unwanted/uncontrolled movements (including tongue and face twitching) [17]
  • Deafness or tinnitus.[17]
  • Nausea, vomiting, diarrhea, abdominal cramps[18]
  • Headache.[17]
  • Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)[17][18]
  • Signs of serious infection (such as high fever, severe chills, persistent sore throat)[17]
  • Skin itchiness, skin color changes, hair loss, and skin rashes.[18][19]
    • 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.[20]
  • Unpleasant metallic taste
    • This could be avoided by “taste-masked and controlled release” formulations such as multiple emulsions.[21]
  • Chloroquine retinopathy
  • Electrocardiographic changes[22]
    • 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.
  • Pancytopeniaaplastic anemia, reversible agranulocytosislow blood plateletsneutropenia.[23]

Pregnancy

Chloroquine has not been shown to have any harmful effects on the fetus when used for malarial prophylaxis.[24] 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.[23][25] Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.[24]

Elderly

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.[23]

Drug interactions

Chloroquine has a number of drug-drug interactions that might be of clinical concern:[citation needed]

Overdose

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.[26] 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.[23]

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).[27] 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.[27]

Pharmacology

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

Medical quinolines

Malaria

Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.

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,[28][29] autophagy, and apoptosis.[30]

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.[citation needed]

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.[citation needed]

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. [31] Parasites that do not form hemozoin are therefore resistant to chloroquine.[32]

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.[33] 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 PfcrtVerapamil, 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.[34] Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, as other mechanisms of resistance are likely.[citation needed]

Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniraminegefitinibimatinibtariquidar and zosuquidar.[35]

Antiviral

Chloroquine has antiviral effects.[36] 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.[37][38]

Chloroquine also seems to act as a zinc ionophore, that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.[39][40]

Other

Chloroquine inhibits thiamine uptake.[41] It acts specifically on the transporter SLC19A3.

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.

History

In Peru the indigenous people extracted the bark of the Cinchona plant[42] 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.[43] 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”.[44] 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.[45]

Society and culture

Resochin tablet package

Formulations

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.[46]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.[47]

Other animals

Chloroquine is used to control the aquarium fish parasite Amyloodinium ocellatum.[48]

Research

COVID-19

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.[49] Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.[50][51]

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19.[52][53] These agencies noted contraindications for people with heart disease or diabetes.[54] 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.[55] 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.”[56] Self-medication with chloroquine has caused one known fatality.[57]

On 24 March 2020, NBC News reported[58] a fatality due to misuse of a chloroquine product used to control fish parasites.[59]

Other viruses

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.[60]

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.[61]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.[62][63] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit lysosomal degradation of protein products.

 

 

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References

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  35. ^ Alcantara LM, Kim J, Moraes CB, Franco CH, Franzoi KD, Lee S, et al. (June 2013). “Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites”. Experimental Parasitology134 (2): 235–43. doi:10.1016/j.exppara.2013.03.022PMID 23541983.
  36. ^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases3(11): 722–7. doi:10.1016/s1473-3099(03)00806-5PMID 14592603.
  37. ^ Al-Bari MA (February 2017). “Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases”Pharmacology Research & Perspectives5 (1): e00293. doi:10.1002/prp2.293PMC 5461643PMID 28596841.
  38. ^ Fredericksen BL, Wei BL, Yao J, Luo T, Garcia JV (November 2002). “Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus”Journal of Virology76 (22): 11440–6. doi:10.1128/JVI.76.22.11440-11446.2002PMC 136743PMID 12388705.
  39. ^ Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ (1 October 2014). “Chloroquine is a zinc ionophore”PloS One9(10): e109180. doi:10.1371/journal.pone.0109180PMC 4182877PMID 25271834.
  40. ^ te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ (November 2010). “Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture”PLoS Pathogens6 (11): e1001176. doi:10.1371/journal.ppat.1001176PMC 2973827PMID 21079686.
  41. ^ Huang Z, Srinivasan S, Zhang J, Chen K, Li Y, Li W, et al. (2012). “Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy”PLOS Genetics8 (11): e1003083. doi:10.1371/journal.pgen.1003083PMC 3510038PMID 23209439.
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  44. ^ Krafts K, Hempelmann E, Skórska-Stania A (July 2012). “From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy”. Parasitology Research111 (1): 1–6. doi:10.1007/s00436-012-2886-xPMID 22411634.
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  46. ^ “Chloroquine”nih.gov. National Institutes of Health. Retrieved 24 March 2020.
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  49. ^ “Could an old malaria drug help fight the new coronavirus?”asbmb.orgArchived from the original on 6 February 2020. Retrieved 6 February 2020.
  50. ^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085PMID 15351731.
  51. ^ Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 Mar 11:105938. doi:10.1016/j.ijantimicag.2020.105938 PMID 32171740
  52. ^ “Physicians work out treatment guidelines for coronavirus”m.koreabiomed.com (in Korean). 13 February 2020. Archivedfrom the original on 17 March 2020. Retrieved 18 March 2020.
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  54. ^ “Plaquenil (hydroxychloroquine sulfate) dose, indications, adverse effects, interactions… from PDR.net”http://www.pdr.netArchivedfrom the original on 18 March 2020. Retrieved 19 March 2020.
  55. ^ Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. (March 2020). “In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)”. Clinical Infectious Diseasesdoi:10.1093/cid/ciaa237PMID 32150618.
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  57. ^ Edwards, Erika; Hillyard, Vaughn (23 March 2020). “Man dies after ingesting chloroquine in an attempt to prevent coronavirus”NBC News. Retrieved 24 March 2020.
  58. ^ “A man died after ingesting a substance he thought would protect him from coronavirus”NBC News. Retrieved 25 March 2020.
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  60. ^ Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M (October 2004). “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine”. Biochemical and Biophysical Research Communications323 (1): 264–8. doi:10.1016/j.bbrc.2004.08.085PMID 15351731.
  61. ^ Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R (November 2003). “Effects of chloroquine on viral infections: an old drug against today’s diseases?”. The Lancet. Infectious Diseases3(11): 722–7. doi:10.1016/S1473-3099(03)00806-5PMID 14592603.
  62. ^ Savarino A, Lucia MB, Giordano F, Cauda R (October 2006). “Risks and benefits of chloroquine use in anticancer strategies”. The Lancet. Oncology7 (10): 792–3. doi:10.1016/S1470-2045(06)70875-0PMID 17012039.
  63. ^ Sotelo J, Briceño E, López-González MA (March 2006). “Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial”. Annals of Internal Medicine144 (5): 337–43. doi:10.7326/0003-4819-144-5-200603070-00008PMID 16520474.
    “Summaries for patients. Adding chloroquine to conventional chemotherapy and radiotherapy for glioblastoma multiforme”. Annals of Internal Medicine144 (5): I31. March 2006. doi:10.7326/0003-4819-144-5-200603070-00004PMID 16520470.

External links

“Chloroquine”Drug Information Portal. U.S. National Library of Medicine.

Chloroquine
Chloroquine.svg
Chloroquine 3D structure.png
Clinical data
Pronunciation /ˈklɔːrəkwɪn/
Trade names Aralen, other
Other names Chloroquine phosphate
AHFS/Drugs.com Monograph
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 1-2 months
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.175 Edit this at Wikidata
Chemical and physical data
Formula C18H26ClN3
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

Hydroxychloroquine, ヒドロキシクロロキン, гидроксихлорохин , هيدروكسيكلوروكين , 羟氯喹 ,


ChemSpider 2D Image | hydroxychloroquine | C18H26ClN3O

 

Hydroxychloroquine
ヒドロキシクロロキン;
Formula
C18H26ClN3O
cas
118-42-3
sulphate 747-36-4
Mol weight
335.8715

 

гидроксихлорохин [Russian] [INN]
هيدروكسيكلوروكين [Arabic] [INN]
羟氯喹 [Chinese] [INN]
Oxychlorochin, Plaquenil Plaquenil®, 

Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used for the prevention and treatment of certain types of malaria.[2] Specifically it is used for chloroquine-sensitive malaria.[3] Other uses include treatment of rheumatoid arthritislupus, and porphyria cutanea tarda.[2] It is taken by mouth.[2] It is also being used as an experimental treatment for coronavirus disease 2019 (COVID-19).[4]

Common side effects include vomitingheadache, changes in vision and muscle weakness.[2] Severe side effects may include allergic reactions.[2] Although all risk cannot be excluded it remains a treatment for rheumatic disease during pregnancy.[5] Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.[2]

Hydroxychloroquine was approved for medical use in the United States in 1955.[2] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] The wholesale cost in the developing world is about US$4.65 per month as of 2015, when used for rheumatoid arthritis or lupus.[7] In the United States the wholesale cost of a month of treatment is about US$25 as of 2020.[8] In the United Kingdom this dose costs the NHS about £ 5.15.[9] In 2017, it was the 128th most prescribed medication in the United States with more than five million prescriptions.[10]

Medical use

Hydroxychloroquine treats malaria, systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritisporphyria cutanea tarda, and Q fever.[2]

In 2014, its efficacy to treat Sjögren syndrome was questioned in a double-blind study involving 120 patients over a 48-week period.[11]

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.[12]

Contraindications

The drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-Aminoquinoline compounds.[13] There are a range of other contraindications[14] [15] and caution is required if patients have certain heart conditions, diabetes, psoriasis etc.

Side effects[

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.[2] For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.[2]

For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acneanemia, 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 failureloss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigoweight loss, and occasionally urinary incontinence.[2] Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.[2]

Children may be especially vulnerable to developing adverse effects from hydroxychloroquine.[2]

Eyes

One of the most serious side effects is retinopathy (generally with chronic use).[2][16] 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.[17]

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.

Overdose

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.[18]

Interactions

The drug transfers into breast milk and should be used with care by pregnant or nursing mothers.[citation needed]

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 hypoglycemiaAntacids may decrease the absorption of HCQ. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.[19]

While there may be a link between hydroxychloroquine and hemolytic anemia in those with glucose-6-phosphate dehydrogenase deficiency, this risk may be low in those of African descent.[20]

Specifically, the FDA drug label for hydroxychloroquine lists the following drug interactions [13]:

  • 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).

Pharmacology[

Pharmacokinetics

Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D62C83A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.[21]

Pharmacodynamics

Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated,[22] 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.[23] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.[24] Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences.[25] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxisphagocytosis and superoxide production by neutrophils.[26] 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.[27]

Mechanism of action

Hydroxychloroquine increases[28] lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs).[citation needed] 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.[29]

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.[citation needed]

Brand names

It is frequently sold as a sulfate salt known as hydroxychloroquine sulfate.[2] 200 mg of the sulfate salt is equal to 155 mg of the base.[2]

Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, Quinoric.[30]

Research

COVID-19

Hydroxychloroquine and chloroquine have been recommended by Chinese and South Korean health authorities for the experimental treatment of COVID-19.[31][32] In vitro studies in cell cultures demonstrated that hydroxychloroquine was more potent than chloroquine against SARS-CoV-2.[33]

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.[34]

 

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Image result for hydroxychloroquine

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https://d-nb.info/1166863441/34

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,
2585–2598. doi:10.1039/P19850002585
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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  22. ^ Kaufmann, AM; Krise, JP (2007). “Lysosomal Sequestration of Amine-containing Drugs: Analysis and Therapeutic Implications”. Journal of Pharmaceutical Sciences96 (4): 729–46. doi:10.1002/jps.20792PMID 17117426.
  23. ^ Ohkuma, S; Poole, B (1978). “Fluorescence Probe Measurement of the Intralysosomal pH in Living Cells and the Perturbation of pH by Various Agents”Proceedings of the National Academy of Sciences of the United States of America75 (7): 3327–31. doi:10.1073/pnas.75.7.3327PMC 392768PMID 28524.
  24. ^ Ohkuma, S; Chudzik, J; Poole, B (1986). “The Effects of Basic Substances and Acidic Ionophores on the Digestion of Exogenous and Endogenous Proteins in Mouse Peritoneal Macrophages”The Journal of Cell Biology102 (3): 959–66. doi:10.1083/jcb.102.3.959PMC 2114118PMID 3949884.
  25. ^ Oda, K; Koriyama, Y; Yamada, E; Ikehara, Y (1986). “Effects of Weakly Basic Amines on Proteolytic Processing and Terminal Glycosylation of Secretory Proteins in Cultured Rat Hepatocytes”The Biochemical Journal240 (3): 739–45. doi:10.1042/bj2400739PMC 1147481PMID 3493770.
  26. ^ Hurst, NP; French, JK; Gorjatschko, L; Betts, WH (1988). “Chloroquine and Hydroxychloroquine Inhibit Multiple Sites in Metabolic Pathways Leading to Neutrophil Superoxide Release”. The Journal of Rheumatology15 (1): 23–27. PMID 2832600.
  27. ^ Fox, R (1996). “Anti-malarial Drugs: Possible Mechanisms of Action in Autoimmune Disease and Prospects for Drug Development”. Lupus5: S4–10. doi:10.1177/096120339600500103PMID 8803903.
  28. ^ Waller; et al. Medical Pharmacology and Therapeutics (2nd ed.). p. 370.
  29. ^ Takeda, K; Kaisho, T; Akira, S (2003). “Toll-Like Receptors”. Annual Review of Immunology21: 335–76. doi:10.1146/annurev.immunol.21.120601.141126PMID 12524386.
  30. ^ “Hydroxychloroquine trade names”Drugs-About.com. Retrieved 18 June 2019.
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External links

 

Hydroxychloroquine
Hydroxychloroquine.svg
Hydroxychloroquine.png

Hydroxychloroquine freebase molecule
Clinical data
Trade names Plaquenil, others
Other names Hydroxychloroquine sulfate
AHFS/Drugs.com Monograph
MedlinePlus a601240
License data
Pregnancy
category
  • AU: D [1]
  • US: N (Not classified yet) [1]
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Variable (74% on average); Tmax = 2–4.5 hours
Protein binding 45%
Metabolism Liver
Elimination half-life 32–50 days
Excretion Mostly Kidney (23–25% as unchanged drug), also biliary (<10%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.003.864 Edit this at Wikidata
Chemical and physical data
Formula C18H26ClN3O
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, гидроксихлорохинهيدروكسيكلوروكين羟氯喹Oxychlorochin, Plaquenil Plaquenil®, 

Arteflene


Arteflene
Arteflene
CAS : 123407-36-3 (Z-form)
 [1S-[1a,4b(Z),5a,8b]]-4-[2-[2,4-Bis(trifluoromethyl)phenyl]ethenyl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one
(1S,4R,5R,8S)-4-[(Z)-2,4-bis(trifluoromethyl)styryl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one
(1S,4R,5R,8S)-4-[(Z)-2,4-Bis(trifluoromethyl)styryl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one
Manufacturers’ Codes: Ro-42-1611
Properties: Crystalline stable material, mp 124°. Highly lipophilic, not sol in water. Stable in soln except in the presence of strong bases or strong reducing agents.
Melting point: mp 124°
Therap-Cat: Antimalarial
 
The oxidation of (5R)-(-)-carvone (I) with 3-chloroperbenzoic acid (3-CPB) in dichloromethane gives 5(R)-acetyl-2-methyl-2-cyclohexen-1-one (II), which is condensed with ethyltriphenylphosphonium bromide (III) by means of butyllithium in THF yielding 2-methyl-5(Z)-(1-methyl-1-propenyl)-2-cyclohexen-1-one (IV). The photochemical oxidation of (IV) in acetonitrile catalyzed by methylene blue affords (1R,4RS,5R,8S)-4,8-dimethyl-4-vinyl-2,3-dioxabicyclo[3.3.1]nonan-7-one (V), which is ozonolyzed with O3 in methanol to the corresponding aldehyde as a mixture of enantiomers, which is submitted to crystallization giving the (1S,4R,5R,8S)-isomer (VI). Finally, this compound is submitted to a Wittig condensation with 2,4-bis(trifluoromethyl)benzyltriphenylphosphonium bromide (VII) by means of sodium bis(trimethylsilyl)amide (NaBTSA) in dichloromethane.
……………………….
Literature References:
Synthetic sesquiterpene peroxide; structurally derived from the natural peroxides artemisinin, q.v. and yingzhaosu. Prepn: W. Hofheinz et al., EP 311955; eidem, US 4977184 (1989, 1990 both to Hoffmann-La Roche).
Series of articles on prepn, biological activities, pharmacokinetics and clinical evaluations: Trop. Med. Parasitol. 45, 261-291 (1994).

Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects


Graphical abstract: Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects

 

Graphical abstract: Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects

Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects

Dyanne L. Cruickshank, Yassir Younis, Nicholas M. Njuguna, Dennis S. B. Ongarora, Kelly Chibale and Mino R. Caira

CrystEngComm, 2014, 16, 5781 DOI:10.1039/C3CE41798K

http://pubs.rsc.org/en/Content/ArticleLanding/2014/CE/C3CE41798K?utm_medium=email&utm_campaign=pub-CE-vol-16-issue-26&utm_source=toc-alert#!divAbstract

3-(6-Methoxypyridin-3-yl)-5-(4-methylsulfonyl phenyl)-pyridin-2-amine (MMP) is a member of a novel class of orally active antimalarial drugs. This aminopyridine molecule has shown potent in vitro antiplasmodial activity and in vivo antimalarial activity in Plasmodium berghei-infected mice. The aqueous solubility of this molecule is, however, limited.

Thus investigations aimed at improving the physicochemical properties, including solubility, of MMP were accordingly conducted. Five salts of MMP were formed with co-former molecules saccharin, salicylic acid, fumaric acid, oxalic acid and suberic acid, but a cocrystal was obtained when the co-former adipic acid was employed.

All these new multi-component systems have been fully characterised using X-ray diffraction and thermal methods. Semi-quantitative, turbidimetric solubility tests in a phosphate-buffered saline solution at a pH of 7.4 were performed on the salts and the cocrystal of MMP. The saccharinate salt, fumarate salt and the cocrystal of MMP proved to have greater solubility than MMP itself. This work illustrates the importance of screening and modifying candidate drug compounds in their preliminary stages of development.
Alternative solid-state forms of a potent antimalarial aminopyridine: X-ray crystallographic, thermal and solubility aspects

 

Dyanne L. Cruickshank,a Yassir Younis,a Nicholas M. Njuguna,a Dennis S. B. Ongarora,a Kelly Chibalea and Mino R. Caira*a
*corresponding authors
aDepartment of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
E-mail: mino.caira@uct.ac.za;
Fax: +27 21 650 5195 ;
Tel: +27 21 650 3071

CrystEngComm, 2014,16, 5781-5792

DOI: 10.1039/C3CE41798K

 

Bulaquine a CDRI India Antimalarial


Figure imgf000005_0001

 

Bulaquine

CAS NO.: 79781-00-3

2(3H)-Furanone, dihydro-3-(1-((4-((6-methoxy-8-quinolinyl)amino)pentyl)amino)ethylidene)-,

 3-[l-[[4-[(6-methoxy-8-quinolinyl)amino]pentyl]amino]- ethyMene]-dihydro-2(3H)furanone

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

Aablaquine, Elubaquine, Bulaquine [INN], Compound 80/53, UNII-TSQ6U39Q3G, AC1MI1V2, CHEMBL2106578, CDRI 80/53
Molecular Formula: C21H27N3O3   Molecular Weight: 369.45738

 

BULAQUINE

https://www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=%22bulaquine%22%5BNM%5D

………………….

http://www.cdriindia.org/Bulaquin.htm

The Central Drug Research Institute has developed an antimalarial Drug – given in house number “Compound 80/53” and allotted International Nonproprietary Name (INN) as Bulaquin – which is a primaquine derivative.

Primaquine is the only drug available for use as anti-relapse, antimalarial for prophylactic in P.vivax malaria. However, this drug causes many side effects and the most commonly cited effect is methaemoglobinaemia in patients with G6PD deficiency. Higher doses of primaquine cause methaemoglobinaemia in most subjects and leukopenia in some. However, there is a small fraction of black population with G6PD deficiency who develop anaemia due to intravascular haemolysis at daily dose levels of 15 mg (base) and above.

It is being increasingly felt that the eroding efficacy of commonly used antimalarials has contributed substantially to the resurgence of malaria during last three decades. Although new antimalarials have appeared in the market during this time, none has yet supplemented chloroquine. There are no drugs in the market or in advanced stages of development that appear to be as well tolerated as chloroquine.

Combinations of existing antimalarials especially those now available in rural clinics and market hold great potential for effective, self-administered therapies for uncomplicated malaria, particularly where relapses are frequently encountered. Applying combined therapies to the problem should demand a high standard of proof of safety and efficacy in randomised double blind, placebo controlled trials.

Bulaquin is without any side effects that have been observed with primaquine. A comparative data analysis on initial (0 day pre-drug) and final (+7 day post-drug) values of haemoglobin, methaemoglobin, prothrombin time, partial thromboplastin time and fibrinogen in healthy human subjects treated with primaquine (15 mg OD x7 days) and Bulaquin (25 mg OD x7 days) have been carried out. The study has shown that one week primaquine treatment leads to rise in methaemoglobin levels from 3.97% to 16.32%, which is highly significant in comparison to the 2.29% and 3.02% levels of methaemoglobin before and after 7 days treatment with Bulaquin respectively. Thus, it is evident that primaquine treatment produces rise in methaemoglobin contrary to Bulaquine does not produce rise in methaemoglobin levels. This result manifests a clear superiority of Bulaquin over Primaquine.

Bulaquin has been licenced to Nicholas Piramal India Ltd., Mumbai for marketing. Nicholas Piramal has introduced Bulaquin alongwith chloroquine into the market as a combination pack under the trade name Aablaquine. The objective of the combined therapy is to control P.vivax malaria more effectively by providing initial cure and thereafter preventing relapses by use of this combination pack. It is hoped that the introduction of this combination pack of Bulaquin should contribute substantially to the ongoing National Malaria action programme advocated by Government of India.

http://www.google.com/patents/EP1292306A2?cl=en

Malaria, caused by a parasitic protozoan called Plasmodium, is one of the most serious and complex tropical parasitic diseases. Generally human malaria is caused by four species of malarial parasites which are Plasmodium falciparwn, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. Of these P. falciparum and P. vivαx are most widespread and cause most of the mortality and morbidity associated with these types of infections.

It is known that the malarial parasites undergo complex life cycle in humans, which is initiated through the bite of an infected female Anopheles mosquito. When the mosquito bites a host, some of the sporozoites are injected into the bloodstream of the host and through the circulation they reach the liver where they multiply and liberate merozoites into the bloodstream which then invade the erythrocytes. In case of infections caused by P. vivαx, most of the time the parasites remain dormant in the liver which stage is termed hypnozoites. Hypnozoites are reactivated and reinitiate blood stage parasitemias causing relapse. It has often been observed that people infected with P. vivax do not experience any symptoms for a very long period after their initial illness but become symptomatic after certain period (Korean J. Intern Med, 1999 Juk 14(2): 86-9).

A number of drugs ranging from those of natural origin to synthetic ones have been developed for the treatment of malaria. Quinine and artemisinin are the commonly known drugs of natural origin, which are mostly used for the treatment of malaria. A number of synthetic anti- malarial drugs such as chloroquine, mefloquine, primaquine, halofantrine, ainodiaquine, proguanil, maloprim are known in the literature. Of all the synthetic anti-malarial agents chloroquine has been the most widely prescribed drug for the treatment of malaria of all the types, for more than last 60 years.

Chloroquine has been the effective treatment so far for the P. vivax malarial infections, however, some strains of P. vivax have shown resistance to this well known drug {Ann. Trop. Med. ParasitoL, 1999 Apr; 93(3): 225-230). In recent years drug resistant malaria has become one of the most serious problems in malaria control. Drug resistance necessitates the use of drugs which are more expensive and may have dangerous side effects. To overcome the problems associated with drug resistance, treatments comprising combinations of anti-malarial agents are on the rise. A number of anti-malarial combinations are already known in the malarial chemotherapy. For example, a combination of amodiaquine and tetracycline, a combination of sulfadoxine and pyrimethamine known as fansidar, are known therapies for the treatment of P. falάparum. Also fansimef, a combination of mefloquine with sulfadoxine and pyrimetha min e is used against multidrug resistant strains of P. faldparum.

United States Patent No. 5 998 449 describes a method for the treatment of malaria wherein combination of atovaquone and proguanil is used for the treatment of malaria. In US Patent No. 5 834 505, combination of fenozan with another anti-malarial agent selected from artemisinin, sodium artesunate, chloroquine, mefloquine is described for the prophylactic and curative treatment of malaria.

All the aforementioned anti-malarial combinations reported heretofore are generally used for the treatment of P. faldparum. None of the standard anti-malarial combination treatment regimens have been found to be favourable for the treatment of P. vivax malaria which is the most relapsing type of malaria. For a very long time chloroquine was used for the treatment of infections caused by P. vivax, however, chloroquine eradicates only the asexual erythrocytic stages of P. vivax and does not eliminate the hypnozoites. Until recently primaquine has been the drug of choice for the treatment of malarial relapse. Generally the standard therapy for the P. vivax malarial infection comprises of a sequential chloroquine-primaquine combination treatment regimen wherein primaquine is administered for 14 days following the 3 days course of chloroquine. WHO (World Health Organisation) also recommends a 14 days primaquine treatment for P. vivax malarial infection. A shorter duration of cMoroquine-primaquine treatment regimen was also tried out wherein primaquine was administered only for 5 days following the chloroquine course. However, the outcome of the treatment was not encouraging, since the percentage relapse was more than the standard 14 days primaquine treatment regimen (Trans. R. Soc. Trop. Med. Hyg., 93(6), 641-643). Also primaquine is known to cause hemolytic anemia in persons deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) (Pharmacol Rev. 21: 73-103 (1969); Rev. Cubana Med trop, 1997; 49 (2): 136-8 ). Moreover, methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Needless to say that in the case of sequential combination therapy the patient may not complete the course once the symptoms of malaria are diminished, hence this may increase the chances of relapse. Thus, the chloroquine- primaquine treatment regimen is not safe with respect to toxicity of primaquine and has a further limitation from the standpoint of patient compliance due to longer duration of treatment.

Another anti-relapse agent namely tafenoquine is disclosed in United States Patent 4 617 394. Though more effective than primaquine, the drug was found to cause methemoglobin toxicity almost three times more than that of primaqu ie (Fundam. Appl. Toxicol. 1988, 10(2), 270-275), hence has drawbacks in terms of safety.

The compound, 3-[l-[[4-[(6-nιethoxy-8-quinolinyl)aιnino]pentyl)am.ino]- ethylidene]-dihydro-2(3H)furanone is a derivative of primaquine. It was described in Indian Patent Specification No. 158111 as 6-methoxy-8-(4-

N-(3′-aceto-4^5′-dihydro-2-furanylamino)- l-methylbutylamino)quinoline , the structure of which was revised to that represented by the following formula I. As per the revised structure, the compound is named 3-[l-[[4-

[(6-metJhoxy-8-quinolmyl)amino]pentyl]amino]ethylidene]-dihydro-2(3H)- furanone (hereinafter referred to as compound I). The revised structure is described in WHO Drug Information Vol. 13, No. 4, pg. 268 (1999).

Figure imgf000005_0001

The compound of formula (I) has been found to be safer and less toxic than the parent compound primaquine (Am. J. Trop. Med. Hyg, 1989 Dec; 41(6): 635-637). Its anti-relapse activity has been found to be comparable to primaquine.

Over the years primaquine was the only drug used for the radical cure of malaria caused by P. vivax. Primaquine is associated with a number of severe adverse effects, therefore there is a need to develop agents which are more effective and/ or less toxic than primaquine. The compound I has been found to exhibit anti-relapse activity comparable to Primaquine (Am. J. Trop. Med. Hyg., 41(6): 633-637 (1989)). However, this compound has been shown to cause less methemoglobin formation (Am. J. Trop Hyg., 41(6): 638-642 (1989) ) and also has less effect on anti-oxidant defence enzymes than primaquine (Biochem Pharmacol. 46(10): 1859- 1860 (1993) ). Thus, this primaquine derivative (I) is found to be less toxic as compared to the parent drug, primaquine.

Therefore, there is a longfelt need for a more practical, effective, patient compliant and safe remedy for the radical cure of P. vivax malarial infection.

The inventors have found that the longfelt need may be fulfilled by providing a treatment regimen consisting of regulated use of chloroquine and 3-[l-[[4-[(6-methoxy-8-quinolinyl)aιnino]pentyl]amino]ethylidene]- dihydro-2(3H)furanone of formula I over a period of between 5 to 8 days.

It has also been found that the treatment regimen may be executed most effectively and in a user friendly manner by providing a combination kit which comprises two anti-malarial agents, namely chloroquine and 3-[l- [[4-[(6-meth.oxy-8-qumolmyl)am^

…………………

The title enamine derivative is prepared by condensation of primaquine (I) with acetyl butyrolactone (II) by means of piperidine.

……………….

http://www.google.com/patents/EP1055427B1?cl=en

  • manufacture fo a medicament for the treatment of malaria of primaquine derivative N1-(3-ethylidinotetrahydrofuran-2-one)-N4-(6-methoxy-8-quinolinyl)-1,4-pentanediamine as a gametocytocidal agent. More particularly, this invention relates to the use of primaquine derivative N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine of formula 1 shown below useful for controlling the spread of malaria by virtue of its high therapeutic value as a gametocytocidal agent.
Figure 00010001
    • The primaquine derivative of the present invention does not damage either normal or G-6PD deficient erythrocytes to the extent it is observed with the use of primaquine.
      • scheme:

        Figure 00150001

The following example illustrates the details of the process of this invention:

N1– (3-ethylidinotetrahydrofuran-2-one)-N4– (6-methoxy-8-quinolinyl)-1,4-pentanediamine

  • A mixture of primaquine base (0.97g, 3.7 mmole) freshly distilled 3-acetyl-r-butyrolactone (1.0g, 7.8 mmole) and a base like piperidine (2-3 drops) were stirred under magnetic stirrer at room temperature. In an hour or so the reaction mixture solidified. The product was titrated in ether and filtered to get the product. It was crystallised from alcoholic solvent like propanol. Yield 0.89g, m.p. 118-120°C.

…………..


BELL A.: “Recent developments in the chemotherapy of malaria.” CURRENT OPINION IN ANTI-INFECTIVE INVESTIGATIONAL DRUGS, (2000) 2/1 (63-70). , XP001038054
2 * DUTTA, G. P. ET AL: “Radical curative activity of a new 8-aminoquinoline derivative ( CDRI 80/53) against Plasmodium cynomolgi B in monkeys” AM. J. TROP. MED. HYG. (1989), 41(6), 635-7 , 1989, XP001037488 cited in the application
3 * KAR, K. ET AL: “Pharmacology of compound CDRI 80/53;a potential new antirelapse antimalarial agent” INDIAN J. PARASITOL. (1988), 12, 259-62 , 1988, XP001034143
4 * NEWTON P. ET AL: “Malaria: New developments in treatment and prevention.” ANNUAL REVIEW OF MEDICINE, (1999) 50/- (179-192). , XP001036946
5 * PALIWAL, JYOTI KUMAR ET AL: “Simultaneous determination of a new antimalarial agent, CDRI compound 80/53, and its metabolite primaquine in serum by high-performance liquid chromatography” J. CHROMATOGR., BIOMED. APPL. (1993), 616(1), 155-60 , 1993, XP000955186
6 * PURI, S. K. ET AL: “Methemoglobin toxicity and hematological studies on malaria anti-relapse compound CDRI 80/53 in dogs” AM. J. TROP. MED. HYG. (1989), 41(6), 638-42 , 1989, XP001037486 cited in the application
7 * SETHI, N. ET AL: “Long term toxicity studies with a synthetic anti-relapse antimalarial compound 80/53 in rats and monkeys” INDIAN J. PARASITOL. (1993), 17(1), 15-26 , 1993, XP001034142
8 * VALECHA, NEENA ET AL: “Comparative antirelapse efficacy of CDRI compound 80/53 (Bulaquine) vs. primaquine in double blind clinical trial” CURR. SCI. (2001), 80(4), 561-563 , 2001, XP001037095
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