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

Authors
  • Dandapani, Sivaraman
  • Germain, Andrew R
  • Jewett, Ivan
  • le Quement, Sebastian
  • Marie, Jean-Charles
  • Muncipinto, Giovanni
  • Duvall, Jeremy R
  • Carmody, Leigh C
  • Perez, Jose R
  • Engel, Juan C
  • Gut, Jiri
  • Kellar, Danielle
  • Siqueira-Neto, Jair Lage
  • McKerrow, James H
  • Kaiser, Marcel
  • Rodriguez, Ana
  • Palmer, Michelle A
  • Foley, Michael
  • Schreiber, Stuart L
  • Munoz, Benito
Type
Published Article
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society
Publication Date
Feb 13, 2014
Volume
5
Issue
2
Pages
149–153
Identifiers
DOI: 10.1021/ml400403u
PMID: 24900788
Source
Medline
Keywords
License
Unknown

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.

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