Zhang Xuan, Lun Shichun, Li Yu-Xin, Zhang Wei, Zhou Ruo-Yi, Liu Ting, Yang Fan, Tang Jie, Bishai William R, Yu Li-Fang
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.
Center for Tuberculosis Research, Department of Medicine, Division of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, MD, 21231-1044, United States.
Eur J Med Chem. 2025 Feb 5;283:117148. doi: 10.1016/j.ejmech.2024.117148. Epub 2024 Dec 15.
Targeting the biosynthetic pathway of mycolic acid is highly attractive to researchers in the field of novel anti-tubercular drug development. Pks13-TE is an essential catalytic component in the last assembling step of mycolic acid, and the co-crystal structures of the Pks13-TE-inhibitor complex provide insight into ligand recognition. Based on a structure-guided strategy, N-aryl indole derivatives were designed, synthesized, and evaluated for their antitubercular activities. Compound 44 was identified as the most promising compound with high potency against M. tb H37Rv (MIC = 0.07 μM) and a favorable metabolic profile in human liver microsomes. Moreover, compound 44 exhibited oral bioavailability in a serum inhibition titration (SIT) assay, which warrants further development.
靶向分枝菌酸的生物合成途径对新型抗结核药物研发领域的研究人员极具吸引力。Pks13-TE是分枝菌酸最后组装步骤中的关键催化成分，Pks13-TE-抑制剂复合物的共晶体结构为配体识别提供了深入见解。基于结构导向策略，设计、合成并评估了N-芳基吲哚衍生物的抗结核活性。化合物44被确定为最具潜力的化合物，对结核分枝杆菌H37Rv具有高效力（MIC = 0.07 μM），且在人肝微粒体中具有良好的代谢特征。此外，化合物44在血清抑制滴定（SIT）试验中表现出口服生物利用度，值得进一步开发。
