Novel thioureido-benzenesulfonamide derivatives with enaminone linker as potent anticancer, radiosensitizers and VEGFR2 inhibitors

In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2/KDR/Flk-1 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10-13b as most active Anticancer agents with IC₅₀ equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 µM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2/KDR/Flk-1 kinase Enzyme. The results demonstrated highly potent dose-related VEGFR2/KDR/Flk-1 inhibition with IC₅₀ values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC₅₀ by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2/KDR/Flk-1 active site and they showed binding affinity in a similar way to sorafenib.

Benzenesulfonamides; HEPG2; VEGFR2.