ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Heterocyclic anticancer agents targeting VEGFR-2: synthetic approaches to key scaffolds

Shraddha D. Bhor, Kalyani R. Thombre, Krishna R. Gupta, and Milind J. Umekar

Department of Pharmaceutical Chemistry, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, India

E-mail: shraddhadilipbhor01@gmail.com

Abstract:

Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is a major anticancer target because angiogenesis drives tumour growth and metastasis. Small-molecule inhibitors built on heterocyclic scaffolds offer strong potential due to their favourable drug-like properties and structural flexibility. Notably, imidazole, pyrrole, pyrazole, pyrimidine, nicotinamide, quinoxaline, and benzoxazole derivatives have shown promising VEGFR-2 inhibition. Important synthetic approaches for heterocyclic scaffolds that target VEGFR-2 are compiled in this review. With an emphasis on synthesis, structure–activity correlations (SAR), and biological assessments of these scaffolds, a thorough literature search of the last ten to fifteen years was carried out using PubMed, Scopus, and Web of Science. Within the VEGFR-2 active site, each scaffold class interacts in a unique way. By simulating ATP binding, imidazole and pyrimidine derivatives exhibit significant kinase selectivity, whereas nicotinamide, quinoxaline, and benzoxazole improve hydrophobic interactions. Hydrogen bonds and π–π stacking are strengthened by pyrazole and pyrrole rings. Potency, selectivity, and pharmacokinetics are further enhanced by structural changes such fused rings and electron-donating or withdrawing groups. Numerous substances showed sub-micromolar to nanomolar IC₂₀ values and favorable cytotoxicity. These heterocyclic scaffolds provide flexibility for adjusting pharmacological characteristics, and improvements in synthesis and SAR have enhanced their potency, selectivity, and drug-like characteristics. But issues like low bioavailability and metabolic instability still arise. Heterocyclic scaffolds offer a strong basis for the development of anticancer medications that target VEGFR-2. Synthesis and molecular design developments keep opening up new avenues for the development of potent and specific VEGFR-2 inhibitors.

Graphical abstract

Scaffolds for VEGFR-2 Inhibitors with improved anticancer treatment

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-026-04729-1

Chemical Papers 80 (6) 5849–5903 (2026)