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

AbstractEighteen novelN-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 ofStaphylococcus aureus andStreptococcus pneumoniae, but not the Gram-negative bacteria ofEscherichia coli andPseudomonas aeruginosa. Moreover, the most promising compound7b 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 againstEscherichia coli RNAP with IC50 value of 19.4  ± 1.3 μM. In addition, compound7b showed cytotoxicity against LO2 cells with IC50 value of 18.5  ± 1.89 μM. Molecular docking studies revealed that compound7b interacted with the switch region of the bacterial RNAP. Taken together, compound7b might serve as a lead structure for developing potent bacterial RNAP inhibitors.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research