Computational insights into novel benzenesulfonamide-1,3,4-thiadiazole hybrids as a possible VEGFR-2 inhibitor: design, synthesis and anticancer evaluation with molecular dynamics studies

Abstract

Vascular endothelial growth factor VEGFR-2 has been acknowledged as one of the possible targets for anticancer agents. Considering the pharmacophore features of sorafenib, ten benzenesulfonamide-1,3,4-thiadiazole hybrids 5a–d and 8a–e were synthesized via the cyclization reaction of hydrazine-1-carbodithioate 2 with a bundle of different hydrazonoyl chlorides 3a–d and 6a–e. The preliminary screening of their cytotoxic effect revealed potent inhibition of HepG-2 where 8c and 8e showed the best IC₅₀ of 11.80 and 4.08 μM, respectively, compared to 13.60 μM of staurosporine. Their VEGFR-2 molecular docking simulations illustrated the crucial binding pattern with Glu917, Cys919, Glu885, Asp1046, and Lys868 for kinase inhibition with binding energy −7.90 and 8.40 kcal mol⁻¹, respectively. Moreover, the molecular dynamics simulation of 8c and 8e revealed possible VEGFR-2 binding demonstrating MM-PBSA ΔG_binding, −9.1 and −9.8 kcal mol⁻¹, respectively. Additionally, 8c established 1 to 3 hydrophilic stable H-bonds, while 8e formed 1 to 2 H-bonds throughout the simulation.