Synthesis and Exploration of Antibacterial Activity, Molecular Docking, and DFT Studies of Some Benzothiazole–Urea(Thiourea) Hybrid Compounds

Abstract

A series of benzothiazole derivatives (3a–o) were synthesized, structurally characterized by IR, ¹H‐NMR, ¹³C‐NMR, and elemental analysis, and assessed for their in vitro antibacterial efficacy against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. The outcomes revealed differing levels of activity, with compounds 3c, 3j, and 3n identified as the most effective, exhibiting significant inhibition zones and low minimum inhibitory concentrations (MICs) that are comparable to, though typically lower than, those of the reference antibiotic ciprofloxacin. To explore the structure‐activity relationships, density functional theory (DFT) calculations were executed, delivering insights into the electronic characteristics and reactivity of the most active compounds (3c, 3n, 3j). These calculations indicated a link between smaller HOMO–LUMO energy gaps and increased reactivity. Following this, molecular docking studies were performed to investigate the possible action mechanism against S. aureus tyrosyl‐tRNA synthetase (TyrRS), an essential bacterial enzyme. The docking findings displayed favorable binding energies for the active compounds, with 3j (−9.3 Kcal/mol) and 3n (−8.6 Kcal/mol) showing robust interactions, which aligned well with their observed antibacterial effectiveness. An extensive analysis of interaction profiles pinpointed key amino acid residues engaged in binding, suggesting that TyrRS inhibition is a likely mechanism. This study highlights the potential of benzothiazole derivatives, combined with urea and thiourea derivatives, as promising candidates for the development of new antibacterial agents.