Benzimidazole: A Promising Scaffold as Multitargeted Anticancer Agents - A Review of Chemistry and Mechanisms and Therapeutic Prospects
Cancer is still one of the biggest challenges facing global public health, and accounts for the second largest number of deaths globally. The design, discovery, and development of active anticancer agents including antitumor, antiproliferative, and antineoplastic agents therefore has been an important goal of current drug research. A longstanding hurdle in traditional cytotoxic treatment regimens is the poor selectivity for cancer cells, leading to harmful side effects in normal tissues. Given purine's significance in biology, there has been a tremendous amount of research on the substitution of the purine nucleoside scaffold with various bioisosteres, such as benzimidazole, which is considered a bioisostere of the purine nucleoside scaffold, is a privileged pharmacophore in medicinal chemistry due to its wide range of biological activities such as antiulcer, antioxidant, anti-HIV reverse transcriptase (HIV-RT) inhibitor, anticancer, anthelmintic, antimicrobial, and antihistaminic. The benzimidazole scaffold has been widely explored as a template in the development of drugs for cancer and antineoplastic therapeutics. Various transformations at different positions of the benzimidazole core have been obtained leading to the development of a wide range of active compounds exhibiting potent antiproliferative activities. This review provides an inclusive overview of the medicinal chemistry of substituted benzimidazole derivatives with special emphasis on their SAR explanations that influence their cytotoxic activity against diverse human tumor cell lines. Major mechanistic targets investigated include cyclin dependent kinase (CDK) inhibition, DNA topoisomerase inhibition, poly (ADP-ribose) polymerase (PARP) inhibition, dihydrofolate reductase (DHFR) inhibition, protein tyrosine kinase (PTK) inhibition, and microtubule disruption. The discussion also focuses on benzimidazole-based anticancer agents that have been clinically approved as well as potential investigational leads, demonstrating the sustained importance of this scaffold in oncology drug discovery