Synthesis, antimicrobial evaluation and molecular modeling studies of novel thiosemicarbazides/semicarbazides derived from p-aminobenzoic acid

The development of novel antimicrobial agents is critical to combat life-threatening drug-resistant bacterial and fungal pathogens. In the present study, a new series of p-aminobenzoic acid (PABA) derivatives carrying thiosemicarbazide/semicarbazide moiety were designed, synthesized, and studied for their antimicrobial activity. The target molecules (3a–f, 4a–f) were achieved by the reaction of 4-aminobenzohydrazide, obtained from PABA, and various phenyl isothiocyanates/isocyanates. Following structural characterization by spectroscopic methods (¹H NMR, ¹³C NMR, FT-IR, and LC-MS analyses), the synthesized compounds were tested for their antimicrobial activity against Staphylococcus aureus, Escherichia coli, Candida albicans, and their clinical isolates. Thiosemicarbazides with lipophilic substituents on the phenyl ring were identified as the most active compounds in this series. Among the studied molecules, compound 3e, thiosemicarbazide derivative with trifluoromethyl groups on the phenyl moiety, showed the best antimicrobial activity. Physicochemical parameters of the compounds were computed to predict the drug-likeness of the title compounds. Finally, molecular docking studies were performed in the allosteric binding pocket of ᴅ-alanine:ᴅ-alanine ligase (Ddl) to explain the potential antibacterial activity mechanism of 3e against S. aureus strains.