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

Abstract

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 9 Pg. 4189-204 (May 10 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22536986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrimidines
• Trypanocidal Agents

Topics

• Animals
• Cell Line
• Chagas Disease (drug therapy, metabolism, parasitology)
• Disease Models, Animal
• Gas Chromatography-Mass Spectrometry
• Inhibitory Concentration 50
• Male
• Mice
• Nuclear Magnetic Resonance, Biomolecular
• Pyrimidines (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Trypanocidal Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Trypanosoma cruzi (drug effects)