Monastrol derivatives: in silico and in vitro cytotoxicity assessments

Background and purpose: Cancer is the leading cause of death in today s world, therefore the efforts to achieve anticancer drugs with higher potency and fewer side effects have always been conducted by researchers in the field of pharmaceutical chemistry. Monastrol, a cytotoxic small molecule, from dihydropyrimidinone scaffold, is an inhibitor of the kinesin-5 protein. So, efforts to identify more derivatives of this molecule have been of interest. Experimental approach: Some of monastrol s analogs as Eg5 inhibitors with different substitution patterns were analyzed, synthesized, and their cytotoxic effects were evaluated on MCF-7 and HeLa cancerous cells in vitro using the MTT assay. The structure-activity relationship (SAR) was studied in silico by molecular docking. Findings / Results: Among all proposed structures, in ducking study, those with hydrophobic moieties on the C2-N3 region, those with a hydroxyl group on the phenyl on C4 position, and those with a carboxylic group on C5 were the best candidates. In vitro studies, on the other side, emphasized that monastrol still was the most potent derivative. Another finding was the more moderate activity of synthesized compounds on the HeLa cell compared to the MCF-7 cell line. During different challenges for substitution at 5-position, some earlier reports around the dihydropyrimidinone reactions were questioned. It seems that the change at the position 5 is not merely accessible, as earlier reports claimed. Also, we could not achieve any better cell cytotoxicity by the larger group in the thiourea region or position 5; nonetheless, it seems that the introduction of a methylene group at this position could be beneficial. Conclusion and implications: The initial results of this study were valuable in terms of design and synthesis and will be useful for future investigations.