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

ABSTRACT 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 IC 50 values. VEGFR‐2 kinase inhibition confirmed its efficacy (IC 50 = 2.206 µM), comparable to sorafenib (IC 50 = 2.218 µM). 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.