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ACS medicinal chemistry letters DOI:10.1021/ml400403u

Diversity-oriented synthesis yields a new drug lead for treatment of chagas disease.

Publication TypeJournal Article
Year of Publication2014
AuthorsDandapani, S, Germain, AR, Jewett, I, le Quement, S, Marie, JC, Muncipinto, G, Duvall, JR, Carmody, LC, Perez, JR, Engel, JC, Gut, J, Kellar, D, Siqueira-Neto, JL, McKerrow, JH, Kaiser, M, Rodriguez, A, Palmer, MA, Foley, M, Schreiber, SL, Munoz, B
JournalACS medicinal chemistry letters
Date Published2014/02/13

A phenotypic high-throughput screen using ∼100,000 compounds prepared using Diversity-Oriented Synthesis yielded stereoisomeric compounds with nanomolar growth-inhibition activity against the parasite Trypanosoma cruzi, the etiological agent of Chagas disease. After evaluating stereochemical dependence on solubility, plasma protein binding and microsomal stability, the SSS analogue (5) was chosen for structure-activity relationship studies. The p-phenoxy benzyl group appended to the secondary amine could be replaced with halobenzyl groups without loss in potency. The exocyclic primary alcohol is not needed for activity but the isonicotinamide substructure is required for activity. Most importantly, these compounds are trypanocidal and hence are attractive as drug leads for both acute and chronic stages of Chagas disease. Analogue (5) was nominated as the molecular libraries probe ML341 and is available through the Molecular Libraries Probe Production Centers Network.