Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.
Hongyi ZhaoYongxin GaoWei LiLi ShengKeli CuiBin WangLei FuMeng GaoZiyun LinXiaowen ZouMary JacksonHaihong HuangYu LuDongfeng ZhangPublished in: Journal of medicinal chemistry (2022)
In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 μg/mL) and low cytotoxicity (IC 50 > 64 μg/mL). Compound 32 displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K + channel, and good in vivo efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against M. smegmatis expressing wild-type and mutated variants of the mmpL3 gene from M. tuberculosis ( mmpL3tb ) and determining their effect on mycolic acid biosynthesis using a [ 14 C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents.
Keyphrases
- drug resistant
- mycobacterium tuberculosis
- multidrug resistant
- wild type
- acinetobacter baumannii
- pulmonary tuberculosis
- hiv aids
- emergency department
- single cell
- high throughput
- gene expression
- molecular docking
- genome wide
- anti inflammatory
- cell wall
- adverse drug
- molecular dynamics simulations
- genome wide identification