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Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound <b>14o</b> with R₁ = CH₃, showed the best capacity for inhibiting APN with an IC₅₀ value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound <b>14o</b> possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound <b>14o</b> exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of <b>14o</b> with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His²⁹⁷, Glu²⁹⁸ and His³⁰¹. Meanwhile, the terminal phenyl group and another phenyl group of <b>14o</b> interacted with S₂′ and S₁ pockets via hydrophobic effects, respectively.