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ACS Med Chem Lett. 2013 Dec 29;5(2):149-53. doi: 10.1021/ml400403u. eCollection 2014 Feb 13.

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

Author information

1
Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
2
Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
3
Swiss Tropical and Public Health Institute , Socinstr. 57, Basel, Switzerland ; University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
4
Department of Microbiology, New York University School of Medicine , 550 First Avenue, New York, New York 10016, United States.
5
Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States ; Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.

Abstract

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.

KEYWORDS:

Chagas disease; Molecular Libraries Probe Production Centers Network; Trypanosoma cruzi; diversity-oriented synthesis; high-throughput screening; infectious disease; neglected disease; phenotypic assay

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