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

作者：Keenan Martine^*; Abbott Michael J; Alexander Paul W; Armstrong Tanya; Best Wayne M; Berven Bradley; Botero Adriana; Chaplin Jason H; Charman Susan A; Chatelain Eric; von Geldern Thomas W; Kerfoot Maria; Khong Andrea; Tien Nguyen; McManus Joshua D; Morizzi Julia; Ryan Eileen; Scandale Ivan; Thompson R Andrew; Wang Sen Z; White Karen L

来源：Journal of Medicinal Chemistry, 2012, 55(9): 4189-4204.

DOI：10.1021/jm2015809

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-activity investigations leading to potent analogues with low nM IC(50)s 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.

• 出版日期2012-5-10