title: Diversity-oriented synthesis yields a new drug lead for treatment of chagas disease.
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.
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Dandapani
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Germain
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Jewett
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Sebastian
authors.initials: S
authors.lastname: le Quement
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Marie
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muncipinto
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Carmody
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Engel
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Danielle
authors.initials: D
authors.lastname: Kellar
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: Jair Lage
authors.initials: JL
authors.lastname: Siqueira-Neto
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco , 1700 Fourth Street, San Francisco, California 94158, United States.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstr. 57, Basel, Switzerland ; University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Department of Microbiology, New York University School of Medicine , 550 First Avenue, New York, New York 10016, United States.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Foley
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Center for the Science of Therapeutics, Therapeutics Platform, Broad Institute of MIT and Harvard , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
keywords: Chagas disease; Molecular Libraries Probe Production Centers Network; Trypanosoma cruzi; diversity-oriented synthesis; high-throughput screening; infectious disease; neglected disease; phenotypic assay