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

  • Eur J Med Chem. 2023 Jul 5;255:115351. doi: 10.1016/j.ejmech.2023.115351.
Yu Wen  1 ,  Shichun Lun  2 ,  Yuxue Jiao  1 ,  Wei Zhang  1 ,  Ting Liu  1 ,  Fan Yang  3 ,  Jie Tang  4 ,  William R Bishai  5 ,  Li-Fang Yu  6
Affiliations
  • 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 2. Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States.
  • 3. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address: [email protected].
  • 4. Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 5. Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States. Electronic address: [email protected].
  • 6. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address: [email protected].
PMID: 37116266 DOI: 10.1016/j.ejmech.2023.115351
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.

Keywords
MDR and XDR tuberculosis; MmpL3; Pyridine-2-methylamine; Structure-based drug design.
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