Electronic structure, reactivity, and predicted biological activity of halogenated isatin-pyridine Schiff bases: a DFT study

Isatin derivatives have been at the forefront of pharmaceutical research, displaying a wide range of biological activities, including antioxidant, antimicrobial, and anticancer properties. In this study, twelve isatin-pyridine Schiff bases were evaluated using density functional theory (DFT) methods to examine the influence of pyridyl ring orientation (2-, 3-, and 4-aminopyridine) and C6-halogen substitution (F, Cl, Br) on electronic structure and reactivity. Frontier molecular orbitals and global reactivity descriptors were calculated to evaluate donor–acceptor properties, charge-transfer ability, and electronic stability. The 2-aminopyridine derivatives display the highest occupied molecular orbital (HOMO) energies, lowest unoccupied molecular orbital (LUMO) energies, and smallest energy gaps. Chlorine- and bromine-substituted derivatives show enhanced electrophilicity, electronegativity, and ∆N max , while fluorine has minimal influence. DFT analysis reveals that 6-chloro-3-(2-pyridylimine)-indole-2-one and 6-bromo-3-(2-pyridylimine)-indole-2-one are the most promising candidates, as their electronic features are consistent with enhanced biological activity. These findings provide a basis for the rational design of next-generation isatin-Schiff bases with optimized reactivity and improved biological potential.