Design, Synthesis and Molecular Docking Studies of some Tetrahydropyrimidine Derivatives as Possible Fascin Inhibitors

Abstract

Eight derivatives of tetrahydropyrimidine scaffold were designed and prepared as hybrid compounds possessing the structural features of both Monastrol as an anticancer drug and Nifedipine as a Fascin blocking agents. All of the compounds were evaluated for their cytotoxic potency and the ability to inhibit 4T1 breast cancer cells migration. Then they were investigated in silico for their ability to inhibit the Fascin protein using molecular docking simulation. The most potent and the weakest compounds according to the in vitro cytotoxicity assay were 4d and 4a with IC50 values of 193.70 and 248.75 micromol, respectively. The least cytotoxic compound (4a) was one of the strongest ones in binding to the Fascin binding site according to molecular docking results. 4a and 4e inhibited the 4T1 cells migration better than other compounds. They were more potent than Nifedipine in inhibiting the migration process. In silico studies proved 4h as the most potent Fascin inhibitor in terms of DeltaGbind although it was not inhibiting migration. The controversy between the in vitro and in silico results may cancel the postulation of the involvement of the Fascin inhibition in the migration inhibition. However, the considerable anti-migratory effects of some of the synthesized compounds proved it reasonable to perform further in vivo experiments to introduce novel tumor metastasis inhibitors.