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

doi:10.1016/j.ejmech.2023.115351

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. Epub 2023 Apr 21.

Authors

Yu Wen¹, Shichun Lun², Yuxue Jiao¹, Wei Zhang¹, Ting Liu¹, Fan Yang³, Jie Tang⁴, William R Bishai⁵, Li-Fang Yu⁶

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: fyang@chem.ecnu.edu.cn.
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: wbishai1@jhmi.edu.
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: lfyu@sat.ecnu.edu.cn.

PMID: 37116266
PMCID: PMC10239758 (available on 2024-07-05)
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 (CL_int = 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.

MeSH terms

Antitubercular Agents* / metabolism
Bacterial Proteins
Membrane Proteins / metabolism
Membrane Transport Proteins / metabolism
Microbial Sensitivity Tests
Mycobacterium tuberculosis* / metabolism
Pyridines / metabolism
Pyridines / pharmacology

Substances

Antitubercular Agents
Bacterial Proteins
Membrane Proteins
Membrane Transport Proteins
Pyridines
MmpL3 protein, Mycobacterium tuberculosis

Grants and funding

R01 AI155602/AI/NIAID NIH HHS/United States