Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis

Tomayo Berida, Samuel R. McKee, Shamba Chatterjee, Destinee L. Manning, Wei Li, Pankaj Pandey, Siddharth Kaushal Tripathi, Yassin Mreyoud, Asya Smirnov, Robert J. Doerksen, Mary Jackson, Christian Ducho, Christina L. Stallings, Sudeshna Roy

Research output: Contribution to journalArticlepeer-review

Abstract

The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against Mtb. The potent analogs demonstrated no cytotoxicity in mammalian cells at over 100 times the effective concentration required in Mtb and were bactericidal against Mtb during infection of macrophages. In the exploratory ADME investigations, we observed suboptimal ADME characteristics, which prompted us to identify potential metabolic liabilities for further optimization. Our preliminary investigations into the mechanism of action suggest that this series is not engaging the promiscuous targets that arise from many phenotypic screens. We selected for resistant mutants with the nanomolar potent nitro-containing compound 20 and identified resistant isolates with mutations in genes required for coenzyme F420 biosynthesis and the nitroreductase Ddn. This suggests that the aromatic nitro-1,2,4-triazolyl pyridines are activated by F420-dependent Ddn activity, similar to the nitro-containing TB drug pretomanid. We were able to circumvent the requirement for F420-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.

Original languageEnglish
Pages (from-to)2282-2298
Number of pages17
JournalACS Infectious Diseases
Volume9
Issue number11
DOIs
StatePublished - Nov 10 2023

Keywords

  • 1,2,4-triazole-3-thiones
  • Mycobacterium tuberculosis
  • antitubercular agents
  • drug-resistant TB
  • narrow-spectrum antibacterials

Fingerprint

Dive into the research topics of 'Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this