Structure−Activity Relationships of the Antimalarial Agent Artemisinin. 8. Design, Synthesis, and CoMFA Studies toward the Development of Artemisinin-Based Drugs against Leishmaniasis and Malaria

• Published in: Journal of medicinal chemistry 2003-09, Vol.46 (20), p.4244-4258
• Main Authors: Avery, Mitchell A, Muraleedharan, Kannoth M, Desai, Prashant V, Bandyopadhyaya, Achintya K, Furtado, Marise M, Tekwani, Babu L
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Artemisinins - chemical synthesis; Artemisinins - chemistry; Artemisinins - pharmacology; Biological and medical sciences; Clone Cells; Drug Design; Inhibitory Concentration 50; L-Lactate Dehydrogenase - analysis; L-Lactate Dehydrogenase - metabolism; Leishmania donovani - drug effects; Malaria, Falciparum - drug therapy; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Sesquiterpenes - chemical synthesis; Sesquiterpenes - chemistry; Sesquiterpenes - pharmacology; Static Electricity; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030181q

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure−activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9β position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9α substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9β analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.