A series of N?aryl pyrrothine derivatives was designed, synthesized and evaluated for their antibacterial activity.?Among them, compound 6e exhibited antibacterial activity against clinical isolates of rifampin?resistant S. aureus with MIC value of 1?2 ?g/mL. Compound 6e also displayed good inhibitory activity against E. coli RNA polymerase with IC50 value of 12.0 ? 0.9 ?M. Molecular docking studies suggested?that compound 6e might interact with the switch region of bacterial polymeraseBacterial RNA polymerase (RNAP) is a validated drug target for broad?spectrum antibiotics, and its ?switch region? is considered as the promising binding site for novel antibiotics. Based on the core scaffold of dithiolopyrrolone, a series of N?aryl pyrrothine derivatives was designed, synthesized and evaluated for their antibacterial activity. Compounds generally displayed more active against Gram?positive bacteria, but less against Gram?negative bacteria. Among them, compound 6e exhibited moderate antibacterial activity against clinical isolates of rifampin?resistant Staphylococcus aureus with MIC value of 1?2 ?g/mL, and inhibited Escherichia coli RNAP with IC50 value of 12.0 ? 0.9 ?M. In addition, compound 6e showed certain degree of cytotoxicity against HepG2 and LO2 cells. Furthermore, molecular docking studies suggested that compound 6e might interact with the switch region of bacterial RNAP in a similar conformation to myxopyronin A. Together, the N?aryl pyrrothine scaffold is a promising lead for discovery of antibacterial drugs acting against bacterial RNAP.

» Author: Mo?Han Huang, Bo Kong, Jie?Yun Meng, Yu?Bin Lv, Yan?Fen Peng, Yi?Ping Chen, Xiang?Duan Tan

» Reference: doi:10.1111/cbdd.13736

» Publication Date: 03/06/2020

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