Design, Synthesis, and Evaluation of Hydrazide-Based VEGFR-2 Inhibitors With Antiangiogenic Potential

Angiogenesis is crucial for solid tumor growth and metastasis. Inhibiting this process, particularly via the vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor-2 (VEGFR-2) signaling axis, is an effective anticancer strategy. We report the design and synthesis of 53 hydrazide-based derivatives incorporating essential pharmacophoric features for VEGFR-2 inhibition. Two synthetic routes were employed: one involving condensation of chloroacetylated amides with p-hydroxybenzaldehyde or 6-hydroxy-2-naphthaldehyde, followed by reaction with benzohydrazides; the other using substituted phenyl or naphthalene cores to probe hydrophobic interactions. Structures were confirmed by FTIR, NMR, LC-MS, and HPLC. The compounds were evaluated for cytotoxicity and VEGFR-2 inhibitory/antiangiogenic activity via in vitro tube formation assays. SA7 emerged as a lead, showing potent cytotoxicity against various human cancer cell lines with low-micromolar IC50 values. VEGFR-2 kinase inhibition confirmed its efficacy (IC50 = 2.206 mu M), comparable to sorafenib (IC50 = 2.218 mu M). SA7, SA9, and SA50 significantly inhibited capillary-like network formation. Molecular docking revealed key interactions with VEGFR-2 ATP-binding residues. In vivo, SA7 suppressed HCT116 xenograft growth more effectively than irinotecan. These results position SA7 and its analogs as promising VEGFR-2 inhibitors with strong antiproliferative and antiangiogenic potential.