Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

Andrew M. Thompson, Patrick D. O'Connor, Andrew J. Marshall, Amanda F. Francisco, John M. Kelly, Jennifer Riley, Kevin D. Read, Catherine J. Perez, Scott Cornwall, R. C.Andrew Thompson, Martine Keenan, Karen L. White, Susan A. Charman, Bilal Zulfiqar, Melissa L. Sykes, Vicky M. Avery, Eric Chatelain, William A. Denny

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

Original languageEnglish
Article number112849
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume207
DOIs
Publication statusPublished - 1 Dec 2020

Keywords

  • Bioluminescence imaging
  • Chagas disease
  • In vivo efficacy
  • Library screening
  • Pharmacokinetics
  • Pretomanid

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