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Bacterial 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 minimum inhibition concentration value of 1–2 μg/ml and inhibited Escherichia coli RNAP with IC50 value of 12.0 ± 0.9 μM. 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.