Orally Active, Hydrolytically Stable, Semisynthetic, Antimalarial Trioxanes in the Artemisinin Family

• Published in: Journal of medicinal chemistry Vol. 42; no. 2; pp. 300 - 304
• Main Authors: Posner, Gary H, Parker, Michael H, Northrop, John, Elias, Jeffrey S, Ploypradith, Poonsakdi, Xie, Suji, Shapiro, Theresa A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.01.1999; Amer Chemical Soc
• Subjects: Administration, Oral; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - administration & dosage; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Artemisinins; Biological and medical sciences; Chemistry, Medicinal; Drug Stability; Heterocyclic Compounds - administration & dosage; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Hydrolysis; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Sesquiterpenes - chemistry; Spectrophotometry, Infrared; MECHANISM(S); ACID; CONVERSION; QINGHAOSU ARTEMISININ; MALARIA; DERIVATIVES; NEUROTOXICITY; ENDOPEROXIDES; CHEMOTHERAPY; GLYCOSYL FLUORIDES; Endoperoxide; Antimalarial; Furan derivatives; Oxygen heterocycle; Pyrrole derivatives; Antiprotozoal agent; Peracetal; Plasmodium falciparum; Structure activity relation; Parasiticid; Chemical synthesis; Protozoa; Apicomplexa; Rodentia; Oral administration; Tetracyclic compound; Parasitosis; In vitro; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Organic peroxide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980529v

In only three chemical operations, natural trioxane lactone artemisinin (1) was converted into a series of C-10 carbon-substituted 10-deoxoartemisinin compounds 4 − 9. The three steps involved lactone reduction, replacement of the anomeric lactol OH by F using diethylaminosulfur trifluoride, and finally boron trifluoride-promoted substitution of F by aryl, heteroaryl, and acetylide nucleophiles. All of these C-10 nonacetal, chemically robust, enantiomerically pure compounds 4 − 9 have high antimalarial potencies in vitro against Plasmodium falciparum malaria parasites, and furans 5a and 5b and pyrrole 7a are antimalarially potent also in vivo even when administered to rodents orally.