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From Pharmacy to the Pub — A Bark Conquers the World: Part 3
The long road from the structure determination to the total synthesis of quinine is an exciting detective story
OPRD PAPER-An Improved Manufacturing Process for the Antimalaria Drug artemether
OPRD PAPER-Streamlined Process for the Conversion of Artemisinin to Artemether
Correction to A Streamlined Process for the Conversion of Artemisinin to Artemether
The structure for β-artemether is shown above, with the correct stereochemistry shown at the anomeric (8a) position. … Assignments are correct for the α- and β-anomers of artemether and dihydroartemisinin as discussed in the text; only the structure drawings are in error. …The total synthesis of artemisinin from the Isopulegol ((-)-Isopulegol) began [JACS, 1983, 624].Contrast extracted from plants, is not an economical total synthesis method, but activity was found in the total synthesis of analogues are better practical significance of a thing. In this type of terpene total synthesis of natural products stereochemical conformation analysis is also very interesting. Hu menthol with MOMCl protected hydroxy, and get a double borohydride alcohol 1. Hydroboration Addition of anti-Markovnikov rule, which is replaced by hydrogen atoms added to the side of Quito, and the boron atoms added to the less substituted side. As the front side of the double bond MOM large steric hindrance, from the double rear borane adduct, resulting product1 . Compound 1 with a benzyl group protecting the primary alcohol, HCl removal of MOM protecting, PCC oxidation of the secondary alcohol to the ketone 3 . 3 with the hydrogen generating pull enolates LDA 4 , because of steric hindrance than hydrogen methyl, the nucleophilic reaction occurs in the torus , the form compound 5 . Ketone 5 and lithium reagent 6 an addition reaction, if one equivalent of lithium reagent, the resulting product was a 1:1 8 and 9 , if the 10-fold excess of lithium reagent, the resulting product was 8:1 8 and 9 . Lithium reagent 6 as a nucleophile large volume, its addition of cyclohexanone from the equatorial position to attack (such as an intermediate state 7 as shown), so that the generated key in an upright position hydroxyl group. Equivalent of lithium reagent no stereoselectivity of the reaction, but when a large excess of lithium, when chiral ketone 5 lithium reagent of the racemic 6 kinetic resolution becomes possible. Intermediate state 7 in, R configuration of the lithium reagent to Ketones speed is faster than its enantiomer S configuration lithium reagent. So generate eight faster than 9 , and finally get 8 and 9 of the ratio of 8:1. Lithium reagent 6, TMS air resistance maximum (A-value = 2.5 kcal / mol), OMe second air resistance (A-value = 0.75 kcal / mol), so that when the attack is downward TMS, OMe and H is determined by the relative position of cyclohexanone 2,6 substituent to the size and conformation of the decision, and should also be considered in the attack Burgi-Dunitz angle, so that the stereochemistry of the product unpredictable. Compound 8after removal of the benzyl protecting the primary alcohol with excess oxidized to carboxyl groups PCC automatically generate a macrolide 10 . 10 of the vinyl silane with m -CPBA and TFA into one11 , and then generate the enol methyl desilication TBAF ethers 12 , 12 and singlet oxygen reacts13 directly after treatment with acid artemisinin.
Ayurveda Cure of Malaria
Malaria is a worldwide problem. Ayurveda, the Indian system of medicine have answer to cure the Malaria and its complications.
http://www.slideshare.net/drdbbajpai/ayurveda-cure-of-malaria
The quinine-containing bark of the Cinchona tree is probably the most valuable drug the Americas gave the world
The quinine-containing bark of the Cinchona tree is probably the most valuable drug the Americas gave the world
Read more at chemistryviews
http://www.chemistryviews.org/details/ezine/4701281/From_Pharmacy_to_the_Pub_
_A_Bark_Conquers_the_World_Part_1.html
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to the tropical Andes forests of western South America. They are medicinal plants, known as sources for quinine and other compounds.
The name of the genus is due to Carolus “Carl” Linnaeus, who named the tree in 1742 after a Countess of Chinchón, the wife of a viceroy of Peru, who, in 1638, was introduced by native Quechua healers to the medicinal properties of cinchona bark. Stories of the medicinal properties of this bark, however, are perhaps noted in journals as far back as the 1560s–1570s.
It is the national tree of Ecuador and Peru.
Peru offers a branch of cinchona toScience (from a 17th-century engraving):Cinchona, the source of Peruvian bark, is an early remedy against malaria.
The medicinal properties of the cinchona tree were originally discovered by the Quechua peoples of Peru and Bolivia, and long cultivated by them as a muscle relaxant to halt shivering due to low temperatures. The Jesuit Brother Agostino Salumbrino (1561–1642), an apothecary by training and who lived in Lima, observed the Quechua using the quinine-containing bark of the cinchona tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was entirely unrelated to its effect in controlling shivering from cold, it was nevertheless the correct medicine for malaria. The use of the “fever tree” bark was introduced into European medicine by Jesuit missionaries (Jesuit’s bark). Jesuit Barnabé de Cobo (1582–1657), who explored Mexico and Peru, is credited with taking cinchona bark to Europe. He brought the bark from Lima to Spain, and afterwards to Rome and other parts of Italy, in 1632. AfterSpanish colonization of the Americas, the Jesuit missionaries were the first to bring the Jesuit’s bark cinchona compound to Europe in 1632. To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings beginning in the early 19th century.
Meanwhile, also in the 19th century, the plant’s seeds and cuttings were smuggled out for new cultivation at cinchona plantations in colonial regions of tropical Asia, notably by the British to the British Raj and Ceylon (present day India and Sri Lanka), and by theDutch to Java in the Dutch East Indies (present day Indonesia).
As a medicinal herb, cinchona bark is also known as Jesuit’s bark or Peruvian bark. The bark is stripped from the tree, dried, and powdered for medicinal uses. The bark is medicinally active, containing a variety of alkaloids including the antimalarial compoundquinine and the antiarrhythmic quinidine. Currently, their use is largely superseded by more effective modern medicines.
quinine
cinchonine
Launch of semi-synthetic artemisinin a milestone for malaria, synthetic biology
| Apr 11th, 2013 | |
Launch of semi-synthetic artemisinin a milestone for malaria, synthetic biology |
|
| (Nanowerk News) Twelve years after a breakthrough discovery in his University of California, Berkeley, laboratory, professor of chemical engineering Jay Keasling is seeing his dream come true. | |
| On April 11, the pharmaceutical company Sanofi will launch the large-scale production of a partially synthetic version of artemisinin, a chemical critical to making today’s front-line antimalaria drug, based on Keasling’s discovery.read more at nanowerk
http://www.nanowerk.com/news2/biotech/newsid=29955.php The “semi-synthetic” artemisinin is chemically modified to an active drug, such as artesunate, and combined in ACT with another antimalarial drug to lessen the chance that the malaria parasite will develop resistance to artemisinin. Sanofi plans to produce 35 tons of artemisinin in 2013 and, on average, 50 to 60 tons a year by 2014, which will translate to between 80 and 150 million ACT treatments. Sweet wormwood was used in ancient Chinese therapy to treat various illnesses, including fevers typical of malaria. In the 1970s, Chinese scientists rediscovered it and identified its active ingredient, artemisinin, and artemisinin is now extracted from sweet wormwood grown commercially in China, Southeast Asia and Africa. The quality, supply and cost have been unpredictable and inconsistent, however. Keasling’s goal was to create a synthetic version with a stable and ideally lower price that could be produced in sufficient quantity to treat the 300-500 million cases of malaria that arise each year. Sanofi and OneWorld Health, the not-for-profit drug development affiliate of the Program for Appropriate Technology in Health (PATH), have launched a commercial-scale production line for semisynthetic artemisinin, a move they say is “a pivotal milestone in the fight against malaria”. Global demand for artemisinin is the most effective malaria treatment available but the existing botanical supply – which is derived from the sweet wormwood plant – is inconsistent. Therefore, Sanofi says that having “multiple sources of high-quality artemisinin will strengthen the artemisinin supply chain, contribute to a more stable price and ultimately ensure greater availability of treatment”. The company notes that the production line at its facility in Garessio, Italy, will be able to produce enough artemisinin, using technology developed by US firm Amyris, for around 80-150 million artemisinin-based combination therapies by 2014. |
ELQ-300, Promising new antimalarial to enter clinical testing phase
ELQ-300
6-chloro-7-methoxy-2-methyl-3-{4-[4-(trifluoromethoxy)phenoxy]phenyl}quinolin-4(1H)-one
21 MAR 2013
A promising new antimalarial drug with the potential to cure and block transmission of the mosquito-borne disease has been discovered by researchers.
The drug, known as ELQ-300, has demonstrated preventative transmission-blocking and a low likelihood of developing rapid resistance to major strains of malaria parasites.
Researchers say it is also likely that the drug could be produced more cheaply than existing antimalarials.
ELQ-300 is now moving into clinical testing.
This new treatment was developed by the Medicines for Malaria Venture (MMV) drug discovery initiative, which is made up of researchers from Oregon Health & Science University in Portland, Drexel University in Philadelphia, University of South Florida and Monash University in Australia.
The full details of their research was published yesterday in the Science Translational Medicine journal.
During the process of creating the drug, researchers discovered and developed a series of potent compounds to combat malaria quinolones.
From this series, they narrowed down the most effective drug candidates to one lead drug, ELQ-300.
“This is one of the first drugs ever to kill the malaria parasite in all three stages of its life cycle,” said Dr Kyle, a member of the Global Infectious Diseases Research team at the USF College of Public Health.
“So, it may become part of a new-generation therapy that not only treats sick people and prevents them from getting ill, but also blocks the transmission of malaria from mosquitoes to humans … If the drug can break the parasite life cycle, we may ultimately eradicate the disease.”
Malaria is a tropical disease that kills nearly one million people a year, mostly in developing countries.
ELQ-300 was derived from the first antimalarial quinolone, endochin, discovered more than 60 years ago but never pursued as a treatment because it appeared not to work in humans.
Researchers used new technology to develop this latest class of drug.
“This was a very challenging project requiring years of hard work, collaboration across disciplines, and a good portion of luck,” said Dr. Manetsch, from the University of South Florida.
ELQ-300 is an experimental antimalarial medication. It is an endochin-like quinolone and the first in a new class of antimalarials known as quinolone-3-diarylethers.[1]
ELQ-300 acts as an inhibitor of the mitochondrial cytochrome bc1 complex (complex III in the electron transport chain).[1] In preclinical studies with mice, it was found to be highly active against Plasmodium falciparum and Plasmodium vivax at all life cycle stages that play a role in the transmission of malaria, and to have good oral bioavailability.[1]
- Nilsen A et al (2013). “Quinolone-3-diarylethers: a new class of antimalarial drug”.Science Translational Medicine 5 (177): 177ra37. doi:10.1126/scitranslmed.3005029.ISSN 1946-6234.
- “NIH-Supported Researchers Identify New Class of Malaria Compounds” (Press release). U.S. National Institutes of Health. March 20, 2013.
- A Nilsen et al, Sci. Transl. Med., 2013, DOI:10.1126/scitranslmed.3005029
- ‘ELQ-300 targets the parasite mitochondrion,’ Riscoe says. In most organisms, the primary function of the mitochondria is to produce energy by making adenosine triphosphate (ATP). ‘But in the parasite, the primary function is to produce the pyrimidine building blocks for DNA [thymine and cytosine].’ The molecule prevents the synthesis of those bases, which prevents the parasite from reproducing, so it dies.
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