Sulfonamide-arylidene hybrids featuring flexible hydrazide and rigid triazole linkers: design, synthesis, and evaluation as carbonic anhydrase inhibitors with anti-breast cancer potential

This work examines the correlation between structural alterations of sulfanilamide derivatives and their potency as inhibitors hCAs, specifically the tumor-associated isoforms IX and XII. The introduction of diverse arylidene scaffolds via a hybrid linker method, which integrates a flexible hydrazide with a rigid triazole moiety, resulted in improved biological activity. The majority of synthesized compounds exhibited potent and specific inhibition of hCA IX and XII. Compounds 10a and 10b were identified as the most efficacious, with 10a showing marked anticancer potency towards MCF-7, MCF-7-ADR, MDA-MB-231, and 4T1 breast cancer cell lines, surpassing the potency of doxorubicin. Mechanistic investigations utilizing MCF-7 cells treated with 10a demonstrated elevated pro-apoptotic Bax levels, reduced anti-apoptotic Bcl-2 levels, and a twofold increase in the Bax/Bcl-2 ratio, signifying a robust induction of apoptosis. Moreover, a 56 % downregulation of CDK4/6 indicated successful inhibition of cell cycle progression. Docking simulations carried out to confirm the advantageous interactions with the active sites of hCA IX and XII.