Influence of halogen substitution on the electronic structure and reactivity of bexarotene-derived hydrazones: insights from DFT descriptors

Bexarotene is a clinically approved anticancer agent belonging to the retinoid class. Integrating the retinoid scaffold with a hydrazone moiety represents a promising strategy for modulating electronic properties relevant to receptor binding and desired biological activity. However, the electronic effects of halogen substitution within the retinoid–hydrazone framework have not been systematically studied. To address this gap, this study investigates the effects of substituent position, halogen type, and halogen load on the electronic structure and reactivity of a series of bexarotene-derived hydrazones. Density functional theory (DFT) calculations were carried out for six bexarotene–hydrazone derivatives (V1–V6), enabling the evaluation of frontier molecular orbital energies and global reactivity descriptors. In the series, V2 emerged as the strongest electron acceptor, demonstrating the highest electronegativity, the largest electrophilicity index, and the lowest unoccupied molecular orbital (LUMO) energy. The para -bromo analogue V4 displayed a similarly narrow highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gap, although it demonstrated more donor-like behavior. The dichloro derivative V3, on the other hand, had the widest energy gap and the highest hardness and was recognized as the most electronically stable derivative. The ortho -chloro derivative V6 showed strong similarity to V3 in several descriptors, showing that substituent position can rival the number of halogens in determining reactivity. Overall, these electronic patterns provide a basis for future drug design, demonstrating how targeted substituent modification within the bexarotene–hydrazone scaffold can guide the development of new molecules with more favorable physicochemical properties.