Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

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• 作者：Martine Keenan ; Jason H. Chaplin ; Paul W. Alexander ; Michael J. Abbott ; Wayne M. Best ; Andrea Khong ; Adriana Botero ; Catherine Perez ; Scott Cornwall ; R. Andrew Thompson ; Karen L. White ; David M. Shackleford ; Maria Koltun ; Francis C. K. Chiu ; Julia Morizzi ; Eileen Ryan ; Michael Campbell ; Thomas W. von Geldern ; Ivan Scandale ; Eric Chatelain ; Susan A. Charman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：56
• 期：24
• 页码：10158-10170
• 全文大小：551K
• ISSN：1520-4804

文摘

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.