The emergence of antibiotic resistance to S. aureus and M. tuberculosis, particularly MRSA, VRSA, and drug-resistant tuberculosis, poses a serious threat to human health. Towards discovering new antibacterial agents, we designed and synthesized a series of new naphthalimide-thiourea derivatives and evaluated them against a panel of bacterial strains consisting of E. coli, S. aureus, K. pneumoniae, P. aeruginosa, A. baumannii and various mycobacterial pathogens. Compounds 4a, 4l, 4m, 4n, 4q, 9f, 9l, 13a, 13d, 13e, 17a, 17b, 17c, 17d, and 17e demonstrated potent antibacterial activity against S. aureus with MIC 0.03-8 μg mL-1. In addition, these compounds have also exhibited potent inhibition against MDR strains of S. aureus, including VRSA with MICs 0.06-4 μg mL-1. Compounds 4h, 4j, 4l, 4m, 4q, 4r, 9a, 9b, 9c, 9d, 9e, 9g, 9h, 9j, 13f and 17e also exhibited good antimycobacterial activity against M. tuberculosis with MIC 2-64 μg mL-1. The cytotoxicity assay using Vero cells revealed that all the compounds were non-toxic and exhibited a favorable selectivity index (SI >40). Time kill kinetics data indicated that compounds exhibited concentration-dependent killing. Furthermore, in silico studies were performed to decipher the possible mechanism of action. Comprehensively, these results highlight the potential of naphthalimide-thiourea derivatives as promising antibacterial agents.
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