Design, synthesis and QSAR-based antitumor signaling pathway analysis of pyrazoline- benzenesulfonamides mediated by cytostatic G1 arrest

Pyrazole and pyrazoline derivatives are heterocyclic compounds with notable anticancer activity, and some are already in clinical use. Although many such compounds have been reported to induce apoptosis through G2/M arrest, studies on pyrazole/pyrazoline-benzenesulfonamides in both malignant and non-malignant cells from the same tissue are limited. In this work, we designed and synthesized 95 pyrazoline-benzenesulfonamides having 4[5-Aryl-3-(phenyl/p-tolyl/4-methoxyphenyl/4-fluorophenyl/thiophene-3-yl)-4,5-dihydro-1H-pyrazole-1-yl] benzenesulfonamides (1-95) chemical structure and evaluated their cytotoxicity in oral cancer cells (Ca9-22, HSC-2) and normal oral cells (HGF, HPLF). Among them, three compounds (56, 63, and 94) exhibited strong tumor selectivity. These compounds induced G1 arrest without subG1 accumulation or apoptosis, suggesting a non-apoptotic mechanism. QSAR analysis showed that tumor-specificity correlated with descriptors reflecting molecular topology, charge distribution, and size. Tox21 database screening indicated possible involvement of multiple signaling pathways, including ERRPGC, AhR, TSHR, VDR, and PPAR delta. Notably, estrogen-related receptor activation with PGC agonist may contribute to tumor selectivity, treatment resistance, and malignancy. Overall, our findings highlight the tumor-specific potential of pyrazoline-benzenesulfonamides and the importance of predicting optimal chemical structures through molecular descriptors to guide the design compounds in future studies.