Biological Evaluation and Molecular Modeling of 3,4-dihydropyrimidine- 2(1H)-one Derivatives as Cytotoxic Agents on Breast Cancer In Vitro

Background: Kinesins and tubulin inhibitors have attracted researchers’ attention as hopeful targets for achieving effective anticancer agents. Dihydropyrimidine-2-ones (DHPMs) inhibit motor proteins Eg5 in the polymerization process of tubulin, also scaffold bearing benzothiazole heterocycle can block tubulin polymerization/depolymerization. Objective: In this study, the cytotoxic effects and molecular modeling of newly synthesized derivatives of DHPM that were designed by the Scaffold-hopping approach were investigated as potential dual-inhibitors of Eg5 and tubulin. Methods: We investigated the cytotoxic effects of DHPMs derivatives by MTT assay and measureing the Caspase 3 activity. Also, molecular modeling studies were performed by AutoDock4 and GROMACS 4.5.6. Results: According to the results, the d2 derivative (IC50 = 68.58 ± 7, SI = 2.57) eliminates MDA-MB- 231 cells in a dose-dependent manner through caspase-dependent and caspase-independent cell death pathways. Molecular docking studies revealed that the d2 compound could interact with both Eg5 and tubulin key residues. MD simulation also demonstrated the stability of the studied ligand-receptor complexes during the 30 ns of the production run. The effectiveness of substitutions at C4 of the DHPM ring was obtained 4-acetoxy-phenyl, 4-methoxyphenyl, and 4-nitrophenyl, respectively. Conclusion: The findings of the present study provide evidence that DHPM C5 amide derivatives bearing benzothiazole ring might be considered as promising lead compounds for the discovery of novel and multi-target antitumor agents.