Benzimidazole derivatives as kinase inhibitors: Synthetic strategies, and therapeutic prospects in cancer

The benzimidazole framework is an important heterocyclic pharmacophore in medicinal chemistry, particularly recognised for its structural bioisosterism with purine nucleotides. This resemblance enables it to successfully target multiple kinase signalling pathways, including VEGFR, EGFR, and RAF which promote defining tumor characteristics like unchecked proliferation and angiogenesis. Given that kinase dysregulation is a major factor in cancer progression, creating new benzimidazole – based inhibitors is crucial for progressing cancer treatment. This review assesses the development of benzimidazole derivatives as kinase inhibitors from 2015 to now. The main emphasis is on outlining the structure - activity relationship (SAR) and therapeutic potential of these hybrids in the treatment of cancer. The research additionally examines a variety of synthetic methods and microwave – assisted cyclization, solvent - free processes and the use of environment friendly catalysts including boric acid, sodium hypophosphite, and lead peroxide. It additionally examines biological validation methods, including NCI-60 cell line screening, enzymatic inhibition assays, and molecular docking studies that clarify the binding mechanism in kinase catalytic domains. Contemporary eco- friendly synthetic methods effectively enhance benzimidazole synthesis, attaining significant yields and purity while significantly minimizing reaction durations and hazardous waste. Biologically, derivatives show strong anticancer properties, with multiple compounds achieving nanomolar IC 50 values. Mechanistic evaluation validates their capacity to promote apoptosis and initiate cell cycle halt at G2 /M or G0/G1 phases. Benzimidazole derived hybrids constitute a highly promising category of multi-target kinase inhibitors. Through the combination of sustainable chemical methods and focused molecular design, these scaffolds present a feasible approach to enhancing the efficiency and ecological responsibility of pharmaceutical development for future kinase inhibitors. • Benzimidazole scaffold remains a privileged core in kinase inhibitor design. • Review compiles benzimidazole-based kinase inhibitors reported from 2015 to 2025. • Diverse synthetic strategies including green chemistry has been discussed. • Computational insights including docking in kinase inhibition summarized. • Future perspectives on benzimidazole hybrids for selective cancer therapy outlined.