Structure-directed identification of pyridine-2-methylamine derivatives as MmpL3 inhibitors for use as antitubercular agents

Yu Wen, Shichun Lun, Yuxue Jiao, Wei Zhang, Ting Liu, Fan Yang, Jie Tang, William R. Bishai, Li Fang Yu

Research output: Contribution to journalArticlepeer-review

Abstract

Mycobacterial membrane protein Large 3 (MmpL3), an inner membrane protein, plays a crucial role in the transport of mycolic acids that are essential for the viability of M. tuberculosis and has been a promising therapeutic target for new anti-TB agents. Herein, we report the discovery of pyridine-2-methylamine antitubercular compounds using a structure-based drug design strategy. Compound 62 stands out as the most potent compound with high activity against M. tb strain H37Rv (MIC = 0.016 μg/mL) as well as the clinically isolated strains of MDR/XDR-TB (MIC = 0.0039–0.0625 μg/mL), low Vero cell toxicity (IC50 ≥ 16 μg/mL), and moderate liver microsomal stability (CLint = 28 μL/min/mg). Furthermore, the resistant mutant of S288T due to single nucleotide polymorphism in mmpL3 was resistant to pyridine-2-methylamine 62, demonstrating compound 62 is likely target to MmpL3.

Original languageEnglish (US)
Article number115351
JournalEuropean Journal of Medicinal Chemistry
Volume255
DOIs
StatePublished - Jul 5 2023

Keywords

  • MDR and XDR tuberculosis
  • MmpL3
  • Pyridine-2-methylamine
  • Structure-based drug design

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Organic Chemistry

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