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.
Highlights
On account of their existence in several natural bioactive compounds and some naturally occurring nucleotides in addition to their significant roles as therapeutics in diverse clinical applications, imidazole and benzimidazole are occupying a featured position in the synthetic medicinal chemistry [1,2,3,4].Imidazoles and benzimidazoles are quite unique and universally privileged scaffolds, which are core units in numerous drugs and drug candidates [5] such as angiotensin II receptor antagonists, H+ /K+ -ATPases inhibitors, H1 -antihistamines, anthelmintics, and anticancer agents
These salt intermediates were subjected to ester hydrolysis, affording the corresponding acid arylethanones (1) as well as 3–arylthiazolo[3,2-a]benzimidazole derivatives (3) series [20,21,22], in the intermediates 8a–f, respectively, that subsequently decarboxylated to produce the salt products 9a–f
This study describes the reaction of 2–mercaptoimidazole (2a) and 2-mercaptobenzimidazole (2b) with β–keto esters 6a–c in an attempt to obtain a new series of ethyl 2–((imidazol/benzimidazol2
Summary
On account of their existence in several natural bioactive compounds and some naturally occurring nucleotides in addition to their significant roles as therapeutics in diverse clinical applications, imidazole and benzimidazole are occupying a featured position in the synthetic medicinal chemistry [1,2,3,4]. The explored benzimidazole derivatives 1 (Figure 1) displayed promising anticancer action toward triple-negative MDAMB4–68 breast cancer cell line, in addition to induction of apoptosis in the same cells. In both previous studies, the target benzimidazole derivatives 1 were prepared through reaction of 2-mercaptobenzimidazole 2b, R = –(CH)4 − , with different acetophenones in boiling glacial acetic acid and two equivalents of concentrated sulfuric acid, with sequent neutralization for the produced sulfate salts yielding 2–((benzimidazol2–yl)thio)1–arylethanones 3 in a good yield [20,21]
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