Structure-directed identification of pyridine-2-methylamine derivatives as MmpL3 inhibitors for use as antitubercular agents.
Structure-directed identification of pyridine-2-methylamine derivatives as MmpL3 inhibitors for use as antitubercular agents.
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DOI：
10.1016/j.ejmech.2023.115351
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发表时间：
2023-04
影响因子：
6.7
通讯作者：
Yu Wen;S. Lun;Yuxue Jiao;Wei Zhang;Ting Liu;Fan Yang;Jie Tang;W. Bishai;Lifang Yu
中科院分区：
文献类型：
--
作者：
Yu Wen;S. Lun;Yuxue Jiao;Wei Zhang;Ting Liu;Fan Yang;Jie Tang;W. Bishai;Lifang Yu
分枝杆菌膜蛋白Large 3(MmpL3)是一种内膜蛋白，在霉菌酸的运输中起着至关重要的作用，而霉菌酸是FM生存所必需的。结核和已经成为新的抗结核药物的一个有前途的治疗靶点。在这里，我们报告了使用基于结构的药物设计策略发现的吡啶-2-甲胺抗结核化合物。化合物62是最有效的化合物，对M有很高的活性。结核分枝杆菌H37Rv株(最低抑菌浓度为0.016μg/m L)，以及临床分离的耐多药/广泛耐药结核分枝杆菌(MIC=0.0039-0.0625 m in/m in g/m L)，较低的Vero细胞毒性(IC_(50)=16 m in/m l)，以及中等的肝微球稳定性(CLINT=2.28μL/m in/m g)。此外，MmpL3单核苷酸多态性导致的S288T抗性突变株对吡啶-2-甲胺62具有抗性，表明化合物62可能是针对MmpL3的靶标。
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 ofM. tuberculosisand 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. Compound62stands out as the most potent compound with high activity againstM. 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 inmmpL3was resistant to pyridine-2-methylamine62, demonstrating compound62is likely target to MmpL3.