Synthesis and biological evaluation of novel N-2,4-dimethoxyphenyl dithiolopyrrolone derivatives as bacterial RNA polymerase inhibitors

Eighteen novel N-2,4-dimethoxyphenyl dithiolopyrrolone derivatives inhibiting bacterial RNA polymerase (RNAP) were synthesized based on dithiolopyrrolone scaffold. Some compounds displayed potent antimicrobial activity against Gram-positive bacteria of Staphylococcus aureus and Streptococcus pneumoniae, but not the Gram-negative bacteria of Escherichia coli and Pseudomonas aeruginosa. Moreover, the most promising compound 7b showed potent antibacterial activity against clinical isolates of MRSA, VRSA, RRSA, and MPRSP with MIC values in the range of 0.125–2 μg/mL, and potent inhibitory activity against Escherichia coli RNAP with IC₅₀ value of 19.4 ± 1.3 μM. In addition, compound 7b showed cytotoxicity against LO2 cells with IC₅₀ value of 18.5 ± 1.89 μM. Molecular docking studies revealed that compound 7b interacted with the switch region of the bacterial RNAP. Taken together, compound 7b might serve as a lead structure for developing potent bacterial RNAP inhibitors.