Synthesis and biological evaluation of nusbiarylin derivatives as bacterial rRNA synthesis inhibitor with potent antimicrobial activity against MRSA and VRSA

[Display omitted] •Nusbiarylin derivatives displayed excellent antibacterial activity against various clinical methicillin-resistance Staphylococcus aureus (MRSA) and vancomycin-resistance S. aureus (VRSA) strains.•The minimum inhibitory concentration (MIC) was lowered to 0.5 μg/mL, comparable to marketed antibiotics.•Mechanistic studies validated the inhibitory mechanism to bacterial rRNA synthesis.•In silico study of pharmacokinetic properties demonstrated drug-likeness. Bacterial transcription is a valid but underutilized target for antimicrobial agent discovery because of its function of bacterial RNA synthesis. Bacterial transcription factors NusB and NusE form a transcription complex with RNA polymerase for bacterial ribosomal RNA synthesis. We previously identified a series of diarylimine and -amine inhibitors capable of inhibiting the interaction between NusB and NusE and exhibiting good antimicrobial activity. To further explore the structural viability of these inhibitors, coined “nusbiarylins”, 36 new derivatives containing diverse substituents at the left benzene ring of inhibitors were synthesized based upon isosteric replacement and the structure–activity relationship concluded from earlier studies. Some of the derivatives displayed good to excellent antibacterial efficacy towards a panel of clinically significant pathogens including methicillin-resistance Staphylococcus aureus (MRSA) and vancomycin-resistance S. aureus (VRSA). In particular, compound 22r exhibited the best antimicrobial activity with a minimum inhibitory concentration (MIC) of 0.5 μg/mL. Diverse mechanistic studies validated the capability of 22r inhibiting the function of NusB protein and bacterial rRNA synthesis. In silico study of drug-like properties also provided promising results. Overall, this series of derivatives showed potential antimicrobial activity and drug-likeness and provided guidance for further optimization.