Benzimidazole: A Promising Scaffold as Multitargeted Anticancer  Agents - A Review of Chemistry and Mechanisms and Therapeutic  Prospects

Safaa P. Bahnam; Ahmed A. J. Mahmood

doi:10.64943/ljacs.2026.010202

Authors

Safaa P. Bahnam Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq https://orcid.org/0000-0002-4710-7417
Ahmed A. J. Mahmood Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq https://orcid.org/0000-0002-5761-4025

DOI:

https://doi.org/10.64943/ljacs.2026.010202

Keywords:

benzimidazole, anticancer agents, CDK inhibitors, topoisomerase inhibitors, PARP inhibitors, DHFR inhibitors, tyrosine kinase inhibitors

Abstract

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

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