Discovery of Novel Benzimidazole containing small molecules for the potential treatment of Chagas Disease

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCATS	CHEM-9

Authors

• D. K. Luci
• W. Lea
• M. Shen
• A. Rodriguez
• A. Jadhav
• A. Simeonov
• D. J. Maloney

Abstract

Chagas disease is one of the most prevalent parasitic diseases in world, affecting millions of people, primarily in Central and South America. The disease is caused by infection from the protozoan parasite Trypanosoma-cruzi (T. cruzi). Symptoms are typically mild in the acute phase (e.g. fever, headache), yet become more severe (e.g. gastrointestinal lesions and cardiopathy) in the chronic stage of the disease. Benznidazole and nifurtimox are the only available treatments; these compounds are effective in the early stages of the disease but are less so in chronically infected patients. Moreover, both compounds often result in undesirable side effects and resistance to these agents has been reported. As such, an urgent need exists for novel small molecule therapeutics with improved efficacy and less toxicity. An HTS screen at the NCGC was conducted aimed at discovering inhibitors of the cruzain enzyme, a cysteine protease which is essential for survival of the T. cruzi parasite. From that screen, several potent inhibitors, including a reversible covalent purine nitrile, ML092 and a non-covalent reversible benzimidazole-based chemotype, ML217 were developed. Interestingly, further biological characterization of ML217 and related analogs revealed the anti-parasitic activity to be independent of cruzain inhibition. The details of those studies are discussed.

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