The emerging role of Oxadiazole derivatives as VEGFR and EGFR inhibitors in Cancer therapy.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) play a key role in cell proliferation, angiogenesis, and cell migration. Both pathways are recognised as key mediators of tumor angiogenesis and metastasis. Drugs that target multiple cellular pathways are generally more effective than those that inhibit a single pathway. The cumulative research over the past several decades has led to the development of many drugs effective against EGFR and VEGFR, but the complexity of the tumors resulted in the emergence of resistance to monotherapy with either EGFR or VEGFR inhibitors. Available evidence suggests that inhibition of both EGFR and VEGFR can overcome the tumor resistance and will significantly improve the clinical outcomes. Notably, oxadiazole derivatives have been shown to demonstrate greater tumor growth inhibition by targeting both EGFR and VEGFR pathways compared with standard treatments. Oxadiazoles are bio-isosteres of amides and esters that contribute to hydrogen bond formation within the receptors and enhance the anticancer activity. For example, drug zibotentan, an oxadiazole ring-containing drug present in phase III clinical trials, has shown anticancer effects by slowing down cancer progression and improving survival rates in some patients. This review article highlights the importance of dual EGFR and VEGFR pathway inhibition, summarizes common methods for synthesizing oxadiazole ring derivatives, and discusses the VEGFR and EGFR inhibitory potential of oxadiazole derivatives reported between 2019 and 2025. The structure-activity relationship (SAR) studies and docking insights presented in this article could help medicinal chemists in designing and developing next-generation VEGFR and EGFR inhibitors.