Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50 = 120 nM for Trypanosoma b. brucei, 18 nM for Trypanosoma b. rhodesiense, and 38 nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50 > 25 μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2 > 4 h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.

Original languageEnglish
Pages (from-to)4127-4131
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2013

Bibliographical note

Funding Information:
This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital .

Keywords

  • Drug discovery
  • Parasitology
  • Trypanosomes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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