Design and biological evaluation of sulfonamide–chalcone hybrids with in vitro tumor-selective cytotoxicity against oral squamous cell carcinoma: SAR, QSAR, and in silico ADME studies

Multidrug resistance and off-target toxicity remain major challenges in the treatment of oral squamous cell carcinoma (OSCC). In this study, sulfonamide-chalcone hybrids were designed by combining the chalcone scaffold with a benzenesulfonamide moiety to explore tumor-selective cytotoxicity and structure-activity relationships. Thirty-two N-(4-(3-(aryl)prop-2-enoyl)phenyl)benzenesulfonamide derivatives, including 17 previously unreported compounds, were synthesized via base-catalyzed Claisen-Schmidt condensation and characterized by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Cytotoxicity was evaluated against the human OSCC cell lines Ca9-22 and HSC-2 and non-malignant human gingival fibroblasts and human pulp cells. Compounds 5, 13, 21, 30, and 32 showed the most favorable activity/selectivity profiles, with 50% cytotoxic concentration values of 1.6–2.2 µM against Ca9-22 cells and tumor-selectivity index values of 14.6–21.1. Structure-activity relationship analysis indicated that meta- and para-substitution patterns generally favored tumor-selective cytotoxicity, whereas bulky ortho-substituents reduced activity. Descriptor-based quantitative structure-activity relationship analysis suggested associations between cytotoxicity and molecular shape, polarizability, electronic properties, polarity, and surface descriptors. In silico studies indicated variable gastrointestinal absorption among the selected lead compounds, while none were predicted to permeate the blood–brain barrier. The selected leads also complied with Lipinski’s Rule of Five. Overall, these findings suggest that sulfonamide–chalcone hybrids represent potentially useful tumor-selective cytotoxic scaffolds for further OSCC-focused optimization. (Figure presented.) © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2026.