Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of chagas disease

Martine Keenan, Michael J Abbott, Paul W Alexander, Tanya Armstrong, Wayne Morris Best, Bradley Berven, Adriana Botero, Jason Hugh Chaplin, Susan Ann Charman, Eric Chatelain, Thomas W von Geldern, Maria Kerfoot, Andrea Khong, Tien Thuy Nguyen, Joshua D McManus, Julia Morizzi, Eileen Ryan, Ivan Scandale, Richard Christopher Andrew Thompson, Sen Z WangKaren Louise White

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Abstract

We report the discovery of nontoxic fungicide fenarimol 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 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.
Original languageEnglish
Pages (from-to)4189 - 4204
Number of pages16
JournalJournal of Medicinal Chemistry
Volume55
Issue number9
DOIs
Publication statusPublished - 2012

Cite this

Keenan, M., Abbott, M. J., Alexander, P. W., Armstrong, T., Best, W. M., Berven, B., ... White, K. L. (2012). Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of chagas disease. Journal of Medicinal Chemistry, 55(9), 4189 - 4204. https://doi.org/10.1021/jm2015809