Synthesis and Biological Evaluation of Platensimycin Analogues with Improved Antimycobacterial Activity.

KasA and KasB are promising drug targets against Mycobacterium tuberculosis and infectious nontuberculous mycobacteria, while most lead compounds are in the preclinical development stage. Herein, a platensimycin (PTM) analogue library consisting of 340 members was first screened to identify 46 PTM thioethers with superior activity compared to that of PTM against Mycobacterium smegmatis. Next, 19 PTM thioethers were chosen and semisynthesized from PTM oxirane (7), together with seven PTM ether derivatives and 6-ido, 6-bromo-, and 6-thiocyanato PTM. Most of them showed stronger antimycobacterial activity than PTM. In particular, one thioether Ec42 exhibited superior antimycobacterial activity to INH in M. smegmatis-infected mouse model. Molecular docking analysis revealed that Ec42 may bind to the active sites of KasA and KasB. Our study revealed that these PTM derivatives significantly expand dual inhibitors for KasA and KasB, and suggest that late-stage functionalization of natural antibiotics targeting mycolic acid biosynthesis remains fruitful for antimycobacterial drug discovery.