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
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.