A new isatin-triazole-based thiosemicarbazone Schiff base, DITHB, was synthesized through a multistep route involving propargylation, azide formation, Cu(I)-catalyzed azide-alkyne cycloaddition and Schiff base condensation reaction. The compound was characterized by NMR, FT-IR, UV-Vis spectroscopy, and density functional theory calculations. DFT optimization at the B3LYP/6-311++G(d,p) level confirmed a conjugated molecular framework containing multiple electron-rich heteroatomic sites. Frontier molecular orbital analysis showed HOMO and LUMO energies of -5.774 and -3.056 eV, respectively, with an energy gap of 2.718 eV, indicating moderate chemical stability together with suitable electronic reactivity. MEP, ELF, LOL and RDG analyses further revealed the presence of reactive oxygen, nitrogen, and sulfur centers, π-electron delocalization, hydrogen-bonding regions, and weak noncovalent interactions that may contribute to molecular stability and biological recognition. UV-Vis and TD-DFT analyses showed major absorption bands at 626.24 and 424.51 nm, assigned mainly to n→π* and π→π* transitions, while electron-hole analysis indicated intramolecular charge-transfer character in the excited states. The compound displayed promising antibacterial activity against Micrococcus luteus and Salmonella typhimurium, with inhibition zones reaching 21.6 and 24.44 mm at 100 μg/mL, respectively. Molecular docking suggested favorable binding with bacterial proteins 4J32 and 6KQB, with binding energies of -6.75 and -5.29 kcal/mol, supported by hydrogen bonding, π-interactions, and hydrophobic contacts. Molecular dynamics simulations further supported the relative stability of the protein-ligand complexes. Overall, the combined experimental and computational results indicate that DITHB is a promising antibacterial scaffold with favorable electronic, structural, and binding characteristics for further medicinal chemistry development.
Balasubramanian et al. (Fri,) studied this question.