Open AccessDiversity-Oriented Synthesis Yields a New Drug Lead for Treatment of Chagas Disease
Author(s) -
Sivaraman Dandapani,
Andrew Germain,
Ivan Jewett,
Sebastian Le Quement,
JeanCharles Marié,
Giovanni Muncipinto,
Jeremy R. Duvall,
Leigh C. Carmody,
José R. Perez,
Juan C. Engel,
Jiří Gut,
Danielle Kellar,
Jair L. Siqueira-Neto,
James H. McKerrow,
Marcel Kaiser,
Ana Rodrı́guez,
Michelle Palmer,
Michael A. Foley,
Stuart L. Schreiber,
Benito Muñoz
Publication year - 2014
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml400403u
Subject(s) - chagas disease , diversity (politics) , lead (geology) , disease , drug , computer science , computational biology , data science , medicine , intensive care medicine , pharmacology , virology , biology , political science , paleontology , law
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.