TL;DR
A systematic overview of advances reported over 2023–2026 in the anticancer activity of benzimidazole derivatives is provided and can serve as a basis for a further search for novel benzimidazole skeleton-containing anticancer agents.
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
In this review, we explore recent advances in the chemical and pharmacological development of pyrazole derivatives, with a focus on their anticancer activity and multi-target therapeutic potential. Pyrazoles, as five-membered heterocycles, exhibit favorable chemical properties that support structural modification for diverse biological applications. Their ability to modulate key molecular targets, particularly kinases, renders them promising candidates for drug discovery. Special emphasis is placed on their role as inhibitors of the Epidermal Growth Factor Receptor (EGFR), a critical target in non small cell lung cancer (NSCLC) therapy. The review outlines synthetic strategies for N-((5-phenyl-1H-pyrazol-3-yl) carbamothioyl) benzamide derivatives, evaluates their biological activity, and discusses structure–activity relationships (SAR). Molecular docking studies and mechanistic insights are also highlighted, offering a comprehensive foundation for future design and development of pyrazole-based anticancer agents.
These findings highlight benzimidazole derivatives, particularly 16a and 17b and their nanoparticle formulations, as promising anticancer candidates, driven primarily by strong cellular potency and favorable safety, substantiating their potential as lead candidates for further optimization and therapeutic development.
Benzimidazole is one of the most prestigious heterocyclic motifs, with a variety of biological applications. Over the years, diverse benzimidazole hybrids have proved single or multi‐protein kinase inhibitory activity. Some examples were approved by the Food and Drug Administration (FDA) for use in the treatment regimens of certain types of cancers, other benzimidazole‐based protein kinase inhibitors are still in clinical trials. Additionally, different research groups have employed different approaches for the design of novel benzimidazole hybrids targeting protein kinases in oncology. In the current review article, a comprehensive overview is provided on the incorporation of the benzimidazole scaffold in FDA‐approved drugs, as well as in clinical trial candidates being developed as protein kinase inhibitors for cancer treatment. Additionally, recent advances in rational design strategies, molecular modeling, protein kinase inhibition, antiproliferative activity, and structure–activity relationships (SAR) of novel benzimidazole‐based hybrids targeting single or multiple kinases are summarized.
Pyridopyrimidine is an important heterocyclic scaffold widely explored in anticancer drug discovery. Its structural similarity to purine enables effective interaction with various biological targets, mainly kinases involved in cancer progression. This manuscript presents recent developments reported between 2021 and 2026, focusing on the biological evaluation, and structure–activity relationships of pyridopyrimidine derivatives. Many of these synthesized compounds act as inhibitors of key targets such as EGFR, CDK4/6, and the PI3K/mTOR pathway, which are closely associated with tumor growth, survival, and resistance mechanisms. Other targets such as ATR and PIM are also explored. Recent studies show that structural modifications, including substitution on the core ring and hybridization with pharmacologically active moieties like triazoles and thiazolidinediones, significantly improve anticancer activity. Several derivatives have demonstrated strong antiproliferative effects against different cancer cell lines and are capable of inducing apoptosis and cell cycle arrest. In addition, molecular docking and other computational studies support their binding efficiency and help explain their mechanisms of action. There is also increasing interest in the development of dual-target or multi-target inhibitors to overcome drug resistance and enhance therapeutic effectiveness. Overall, pyridopyrimidine- and pyridopyrimidinones-based compounds continue to show great promise as potential anticancer agents. Further research combining synthetic chemistry, biological studies, and computational approaches may lead to the development of more effective and safer drugs in the future.
Hydrazones have gained significant attention in the field of medicinal chemistry because of their ease of preparation, crystalline nature, structural flexibility and broad-spectrum biological activity. Additionally, N-containing heterocycles have always contributed to anticancer drug discovery, with 73% of FDA-approved anticancer drugs based on them. Recently, the idea of hybrid drug design that synergistically combines two or more pharmacologically active molecules has become an effective strategy in discovering new anticancer drugs. Hence, combining two bioactive fragment hydrazones and N-containing heterocycles can be considered an effective strategy for discovering potent anticancer drugs. Among these, heterocycle–hydrazone hybrids derived from quinoline, indole, triazole, benzimidazole and isatin have displayed promising anticancer activities, with some of the studies even approaching in vivo evaluation. Overall, this review focuses on the anticancer activities of these hydrazone hybrids, their in vitro cytotoxic results, the proposed mechanism of action of the most active compound, cell death pathway results, docking studies, and cell cycle-arrest results. In addition, various synthetic strategies of hydrazones, including conventional methods, microwave and ultrasonication irradiation techniques, diazonium salt-derived methods and solvent-free reaction conditions, have been reported. Furthermore, the kinetics of hydrazone synthesis is described in brief.
