N-acylated aminoguanidine-benzenesulfonamides: rational design, synthesis, and dual apoptotic mechanisms of anticancer activity involving VEGFR-2 inhibition and VEGFR-2-independent pathways.

The discovery of potent and selective anticancer agents remains a major focus in medicinal chemistry. Here, we report the rational design, synthesis, and biological evaluation of N-acylated aminoguanidine derivatives incorporating the benzenesulfonamide scaffold, a privileged motif present in several clinically relevant anticancer drugs. The compounds were evaluated for in vitro cytotoxic activity against MCF-7 (breast), HCT-116 (colorectal), and HeLa (cervical) cancer cell lines. Several derivatives exhibited potent cytotoxicity, with IC50 values below 10 μM, highlighting their promising anticancer potential. Mechanistic studies confirmed the induction of apoptosis in treated cancer cells. Structure-activity relationship (SAR) analysis demonstrated that a 4-(trifluoromethyl)phenyl group at R1 consistently enhanced cytotoxicity, while naphthyl, styryl, and coumarin moieties further modulated potency. Methyl or hydroxyl substituents reduced activity, emphasizing the importance of electronic and steric effects. Compounds 8 and 17, the most active derivatives, were further evaluated for VEGFR-2 inhibition. Compound 17 selectively inhibited VEGFR-2 (IC50 = 2.3 μM) and moderately induced apoptosis in MCF-7 cells via non-mitochondrial, VEGFR-2-dependent pathways. In contrast, compound 7, inactive against VEGFR-2, triggered G2/M arrest and pronounced apoptosis in HeLa cells, indicating a VEGFR-2-independent mechanism. These findings support further development of N-acylated aminoguanidine-benzenesulfonamides as promising agents with dual mechanisms of action.