Novel sulfonamide-tethered Schiff bases as anti-proliferative agents with VEGFR-2 inhibitory activity: Synthesis, biological assessment, and molecular dynamic simulations

Abstract

Schiff bases tethered with sulfonamide functionality (6a-l) are reported as potential anticancer agents and apoptotic inducers. The anti-proliferative activities of the tested Schiff bases were evaluated against breast (MCF7) and hepatocellular (HepG2) cancer cells. Additionally, their potential activity against cancer-related carbonic anhydrase (CA) isoforms IX and XII was assessed, and VEGFR-2, as enzyme targets. All the tested molecules displayed good anticancer activities against both cancer cells, with IC50 values ranging from 90 nM to 6.11 µM. The most effective compounds were unable to inhibit CA isoforms, which may be attributed to the bulkiness of the methoxy group, but they had a strong inhibitory effect on VEGFR-2. Moreover, Schiff bases 6i and 6j effectively boosted HepG2 cells apoptosis by around 23 and 19 times, respectively. In the pre-G1 phase, both compounds exhibited similar cell-cycle arrest behavior. Finally, the effects of 6i and 6j on the apoptotic markers caspase-3, Bcl-2, and Bax, were explored. In silico studies assessed drug-likeness and pharmacokinetics properties and the binding mode and stability.