Unexpected Synthesis, Single-Crystal X-ray Structure, Anticancer Activity, and Molecular Docking Studies of Certain 2-((Imidazole/Benzimidazol-2-yl)thio)-1-arylethanones

In connection with our research program concerning development of novel effective benzimidazole-based anticancer candidates, herein we describe a new unexpected synthetic route to obtain a series of 2-((imidazole/benzimidazol2-yl)thio)1-arylethanones endowed with promising anti-breast cancer and Cyclin-dependent kinase 2 (CDK2) inhibitory activities. Contrary to expectations, products for the reaction of 2-mercaptoimidazole/benzimidazole 2a,b with beta-keto esters 6a-c were unambiguously assigned as 2-((imidazol/benzimidazol2-yl)thio)1-arylethanones 10a-f based on NMR spectroscopy and single-crystal X-ray crystallographic analyses. In vitro anticancer activities for herein reported imidazole/benzimidazoles 10a-f were assessed through a cell-based assay against human breast cancer T4-7D and MCF-7 cell lines. Benzimidazoles 10d-f exerted better anti-proliferative action towards T4-7D and MCF-7 cell lines than their corresponding imidazole counterparts 10a-c. Furthermore, a molecular docking study suggested CDK2 kinase as a potential enzymatic target for benzimidazoles 10d-f, and investigated their possible binding pattern and interactions within CDK2 active site. Thereafter, benzimidazoles 10d-f were in vitro examined for their CDK2 inhibitory action, where they exerted good activity. Finally, several key ADME and druglikeness properties were predicted by the SwissADME online tool. Interestingly, benzimidazoles 10d-f were found to have no violations in all druglikeness rules (Veber, Lipinski, Ghose, Muegge, and Egan). In addition, they had neither PAINS nor structural alerts (Brenks). In conclusion, benzimidazoles 10d-f demonstrated not only a promising anticancer activities but also an acceptable ADME and physicochemical properties especially benzimidazole 10e.