Optimization of chloronitrobenzamides (CNBs) as therapeutic leads for human African trypanosomiasis (HAT)

Jong Yeon Hwang, David Smithson, Fangyi Zhu, Gloria Holbrook, Michele C. Connelly, Marcel Kaiser, Reto Brun, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei. Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC 50 = 27 nM for T. b. brucei, 7 nM for T. b. rhodesiense, and 2 nM for T. b. gambiense) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies.

Original languageEnglish
Pages (from-to)2850-2860
Number of pages11
JournalJournal of Medicinal Chemistry
Volume56
Issue number7
DOIs
StatePublished - Apr 11 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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