Synthesis and Structure–Activity Relationships of 4-Pyridones as Potential Antimalarials

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• 作者：Clive L. Yeates ; John F. Batchelor ; Edward C. Capon ; Neil J. Cheesman ; Mitch Fry ; Alan T. Hudson ; Mary Pudney ; Helen Trimming ; James Woolven ; José ; M. Bueno ; Jes&#xfa ; s Chicharro ; Esther Ferná
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 8, 2008
• 年：2008
• 卷：51
• 期：9
• 页码：2845 - 2852
• 全文大小：157K
• 年卷期：v.51,no.9(May 8, 2008)
• ISSN：1520-4804

文摘

A series of diaryl ether substituted 4-pyridones have been identified as having potent antimalarial activity superior to that of chloroquine against Plasmodium falciparum in vitro and murine Plasmodium yoelii in vivo. These were derived from the anticoccidial drug clopidol through a systematic study of the effects of varying the side chain on activity. Relative to clopidol the most active compounds show >500-fold improvement in IC₅₀ for inhibition of P. falciparum in vitro and about 100-fold improvement with respect to ED₅₀ against P. yoelii in mice. These compounds have been shown elsewhere to act selectively by inhibition of mitochondrial electron transport at the cytochrome bc₁ complex.