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.

Aminoguanidines; Anticancer agents; Apoptosis; Benzenesulfonamide; Rational design; Synthesis.