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

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.

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…CDK2 is involved in cell cycle regulation and is considered to be a member of the CDK1 subfamily [79]. Al-Warhi et al synthesized six imidazole/benzimidazole thioarylethanone derivatives as potential cytotoxic agents against T47D and MCF-7 breast cancer cell lines; these compounds were also tested for CDK2 inhibitory activity [82]. Among these molecules, imidazoles 70 and 71 (see Figure 7 CDK4 and CDK6 promote progression through the G 1 cell cycle phase, while CDK1 is critical in mitosis and is the only CDK that is essential for cell cycle progression in mammalian cells [81].…”

Benzimidazole‐based protein kinase inhibitors: Current perspectives in targeted cancer therapy

“…NMR spectra along with X‐ray crystallographic analysis revealed an unexpected synthetic route for a series of 2‐[(imidazole/benzimidazole‐2‐yl)thio]‐1‐arylethanones, which were investigated for their antiproliferative activity against human breast cancer T4‐7D and MCF‐7 cell lines (Al‐Warhi et al, 2020). Benzimidazole analogues 9a , 9b , and 9c (Figure 3) exerted the greatest activity compared to their imidazole analogues with IC 50 values of 8.04, 11.17, and 34.94 μM against T4‐7D, while they gave an IC 50 of 12.9, 4.53, and 23.07 μM against MCF‐7, respectively, compared to the reference compound Staurosporine (T4‐7D IC 50 = 7.19 μM and MCF‐7 IC 50 = 6.67 μM).…”

Design and Synthesis of Novel Imidazole Derivatives Possessing Triazole Pharmacophore with Potent Anticancer Activity, and In Silico ADMET with GSK-3β Molecular Docking Investigations

“…Being a group of highly diversified structures, nitrogen rich heterocycles and their fused systems are widely incorporated into the structure of various pharmacologically active agents and synthetic drugs [6]. Among these bioactive heterocycles, imidazole derivatives [7], particularly substituted thioimidazoles are known in medicinal chemistry as antiobesity [8], antitubercular [9], antidiabetic [10], anticancer [11][12][13], antimicrobial [14,15], and antioxidant agents [16]. 1,2,3-triazoles have also marked their position as a significant pharmacophore from nitrogen rich heterocyclic compounds with spectacular therapeutic potential [17,18].…”