Maltose-Conjugated Thiosemicarbazones from Substituted Benzaldehydes: Synthesis and Inhibitory Activity against Gram-(+) and Gram-(−) Bacteria

The increasing prevalence of multidrug-resistant bacteria necessitates the development of new antibacterial scaffolds with improved efficacy and safety. Thiosemicarbazones are known for their diverse antibacterial activities, and carbohydrate conjugation can enhance solubility and biocompatibility. In this study, a series of β-maltosyl thiosemicarbazones of substituted benzaldehydes ( 6a – u ) were synthesized and evaluated for their antibacterial activity against representative Gram-(+) and Gram-(−) bacterial strains. These compounds displayed a wide range activity range with MIC of 0.78–400 μg mL –1 . Compounds 6b, 6c, 6f, 6i, 6n, 6q, and 6r were the most active, exhibiting MIC values as low as 0.78 μg mL –1 against several pathogens and, in some cases, comparable to ciprofloxacin and vancomycin. Structure–activity relationship analysis revealed a strong dependence on aromatic substitution patterns. Analogues bearing electron-withdrawing substituents (Cl, Br, and NO 2 ) on the benzene ring showed markedly enhanced antibacterial activity, whereas electron-donating substituents (−OH, −OCH 3 ) generally reduced antibacterial activity. Enzyme inhibition assays identified compound 6f as a potent inhibitor of Staphylococcus aureus DNA gyrase and compound 6b as a strong topoisomerase IV inhibitor. Importantly, the most active compounds showed a low cytotoxicity toward WI-38 human fibroblast cells.