No abstract

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 β–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.

Recently considerable attention has been devoted to the synthesis of new derivatives of quinoline on the account of their reported biological activities 1-8. From the literature survey, several methods have been described for the elaboration of substituted quinolines 9-11 , which as a class have been reported to have anticancer and antileukemic activity. Different mechanisms account for the cytotoxic effect of this class of compounds, the most prominent mechanism was the inhibition of carbonic anhydrase isozymes. Cancer is a top killer of human beings, thus great urgency to develop highly efficacious and minimally toxic treatments for cancer. Although tremendous progress has been achieved in the development of novel cancer treatments, most of the current cancer drugs usually exhibit high toxicity and are severely resisted by tumor cells in the clinic. This dilemma is particularly true for DNA-damaging agents, the mainstay of cancer treatment 12. Quinolines were found to possess several pharmacological properties, including anticancer activity 13-17. It was also found that the acetamide derivatives constitute an important class of drug, with several types of pharmacological agents possessing anticancer activity 18-21 among others. A large number of structurally novel quinolines have ultimately been reported to show substantial anticancer activity in vitro and in vivo 22. Several mechanisms have been reported for anticancer activity of the quinoline sulfonamide compounds and the most prominent of these