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<p>A series of novel 2-aminopyridine derivatives were designed, synthesized, and evaluated as VEGFR-2 inhibitors. Structure-activity relationship (SAR) studies revealed that incorporation of a hydrazone linker significantly enhanced inhibitory activity, while replacement of the terminal pyridine ring with bulkier heterocycles (1,3,4-oxadiazole or imidazo[<i>1</i>,<i>2-a</i>]pyridine) led to reduced potency. Among the hydrazone derivatives, compound 27 exhibited the most potent VEGFR-2 inhibitory activity (IC<sub>50</sub> = 4.2 nM), substantially outperforming the reference drug AAL993 (IC<sub>50</sub> = 35.0 nM), and also showed strong anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) (IC<sub>50</sub> = 0.032 µM) and concentration-dependent suppression of HUVEC tube formation. Molecular docking revealed that its high affinity is attributed to key hydrogen bonds with Cys919 (hinge region), Asp1046 (DFG motif), and Glu885 (C-helix), along with favorable hydrophobic interactions in the back pocket. In silico ADMET predictions suggested favorable drug-like properties for the most active compounds. Collectively, these findings establish the 2-aminonicotinohydrazide scaffold as a promising template for further development of VEGFR-2 inhibitors.</p> Graphical Abstract <p></p>

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Design, synthesis, and biological evaluation of novel 2-aminopyridine derivatives as potent VEGFR-2 inhibitors

  • 期刊论文

  • 发表日期：

    2026年6月29日

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  • Hui-min Liao,
  • Xi-meng Wan,
  • Yang Jin,
  • Ping Gong

摘要

A series of novel 2-aminopyridine derivatives were designed, synthesized, and evaluated as VEGFR-2 inhibitors. Structure-activity relationship (SAR) studies revealed that incorporation of a hydrazone linker significantly enhanced inhibitory activity, while replacement of the terminal pyridine ring with bulkier heterocycles (1,3,4-oxadiazole or imidazo[1,2-a]pyridine) led to reduced potency. Among the hydrazone derivatives, compound 27 exhibited the most potent VEGFR-2 inhibitory activity (IC50 = 4.2 nM), substantially outperforming the reference drug AAL993 (IC50 = 35.0 nM), and also showed strong anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) (IC50 = 0.032 µM) and concentration-dependent suppression of HUVEC tube formation. Molecular docking revealed that its high affinity is attributed to key hydrogen bonds with Cys919 (hinge region), Asp1046 (DFG motif), and Glu885 (C-helix), along with favorable hydrophobic interactions in the back pocket. In silico ADMET predictions suggested favorable drug-like properties for the most active compounds. Collectively, these findings establish the 2-aminonicotinohydrazide scaffold as a promising template for further development of VEGFR-2 inhibitors.

Graphical Abstract