Antitrypanosomal Chloronitrobenzamides

Angela K Carrillo, Tara Man Kadayat, Jong Yeon Hwang, Yizhe Chen, Fangyi Zhu, Gloria Holbrook, Kirsten Gillingwater, Michele C Connelly, Lei Yang, Marcel Kaiser, R Kiplin Guy

Research output: Contribution to journalArticlepeer-review

Abstract

Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense ( Tbg) or Trypanosoma brucei rhodesiense ( Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC 50 for over 24 h and achieving peak brain concentrations exceeding 7 μM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.

Original languageEnglish
Pages (from-to)3437-3447
Number of pages11
JournalJournal of Medicinal Chemistry
Volume67
Issue number5
DOIs
StatePublished - Mar 14 2024

Keywords

  • Humans
  • Animals
  • Mice
  • Trypanosomiasis, African/drug therapy
  • Trypanosoma brucei rhodesiense
  • Trypanosoma brucei gambiense
  • Trypanosoma brucei brucei
  • Trypanocidal Agents/toxicity

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