New sulfonamide-tethered coumarin derivatives as potential DNA gyrase inhibitors: Design, synthesis, antimicrobial evaluation, and in silico study

Abstract

A new series of coumarin-6-sulfonamide derivatives 3–16 have been synthesized via simple and convenient coupling reaction of coumarin-6-sulfonyl chloride with different sulfa drugs and various amino-heterocycles. The antimicrobial activity of the new compounds was evaluated against S. aureus ATCC 6538, E. coli ATCC 25933, C. albicans ATCC 10231, and A. niger NRRL A-326. Compound 12 showed potent antimicrobial activities against all pathogenic strains, with MIC values of 4.88 μg/mL against S. aureus and 9.76 μg/mL against C. albicans, exceptionally 4-fold more potent than neomycin control drug (MIC= 19.53 and 39.06 μg/mL respectively), and an MIC value of 39.06 μg/mL against E. coli, equipotent with neomycin. Meanwhile, compound 10 was equipotent with neomycin against both S. aureus and C. albicans. Additionally, compound 14 was equipotent with neomycin against S. aureus, and 2-fold more potent that neomycin against C. albicans. Further investigations showed that compounds 10 and 12 strongly inhibited DNA gyrase (IC50= 2.463 and 1.793μg/mL respectively), with compound 12 being closely equipotent with the reference novobiocin drug (IC50= 1.425μg/mL). Docking studies of compounds 10 and 12 on the active site of DNA gyrase confirmed their ability to form stable complexes with the target enzyme. According to ADME data, the bioavailability profile of compound 12 was high, and its physicochemical and pharmacological characteristics were consistent with Lipinski's RO5 anticipated constraints. Collectively, these data strongly highlight the efficiency of our multidisciplinary approach in the field of novel potent antimicrobial DNA gyrase inhibitors.