Analogues of Fenarimol Are Potent Inhibitors of Trypanosoma cruzi and Are Efficacious in a Murine Model of Chagas Disease

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• 作者：Martine Keenan ; Michael J. Abbott ; Paul W. Alexander ; Tanya Armstrong ; Wayne M. Best ; Bradley Berven ; Adriana Botero ; Jason H. Chaplin ; Susan A. Charman ; Eric Chatelain ; Thomas W. von Geldern ; Maria Kerfoot ; Andrea Khong ; Tien Nguyen ; Joshua D. McManus ; Julia Morizzi ; Eileen Ryan ; Ivan Scandale ; R. Andrew Thompson ; Sen Z. Wang ; Karen L. White
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4189-4204
• 全文大小：415K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, and the results of structure鈥揳ctivity investigations leading to potent analogues with low nM IC₅₀s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.