Design, Docking, <scp>ADMET</scp> , Pass, Synthesis and Bio‐Evaluation of Novel 7‐ <scp>O</scp> ‐Substituted Chrysin‐Based <scp>VEGFR</scp> ‐2 Inhibitors

VEGFR-2 is a critical target in cancer therapy, facilitating tumor angiogenesis, yet existing inhibitors face toxicity and resistance issues. Chrysin, a flavonoid with anticancer properties, has VEGFR-2 characteristics but suffers from poor pharmacokinetics. A series of 7-O-substituted chrysin derivatives was designed to improve binding and drug-like properties by integrating key hydrogen-bonding groups and hydrophobic elements, informed by VEGFR-2 structural analysis. To design and assess novel chrysin derivatives through computational predictions and molecular docking; synthesize and characterize selected derivatives; and evaluate their antioxidant and anticancer activities in vitro, to identify effective candidates that exhibit favourable pharmacokinetics and safety. Chrysin derivatives featuring alkylamino and ester substituents were designed using molecular docking against VEGFR-2. ADMET profiling was conducted to anticipate pharmacokinetics and toxicity. In silico cytotoxicity of chrysin and its hybrids was assessed using CLC-Pred 2.0 on the basis of PASS analysis and further analyzed on nine breast cancer cell lines via BC CLC-Pred. Selected derivatives were synthesized via alkylation and esterification and characterized using UV, IR, NMR, and mass spectrometry. Antioxidant activity was evaluated with the DPPH assay, whereas anticancer efficacy against MCF-7 and normal cell lines was measured through cell viability assays, comparing IC₅₀ values to ascorbic acid and sorafenib. Docking studies indicated strong binding affinities, particularly for ester derivatives. ADMET predictions suggested favorable drug-like characteristics. Compound C7 demonstrated remarkable antioxidant activity (IC₅₀ = 0.6 μM), exceeding both chrysin and ascorbic acid. In anticancer tests, C7 and C8 displayed significant cytotoxicity (IC₅₀ = 1.0 and 1.5 μM, respectively), outperforming chrysin and nearing sorafenib efficacy. All other hybrids were found to have moderate inhibitory properties as compared to sorafenib, but better than chrysin. The improved bioactivity and predicted safety of C7 and C8 highlight the efficacy of rational structural modifications in optimizing natural products. Their dual antioxidant and anticancer properties underscore their potential as lead compounds for VEGFR-2-targeted breast cancer treatments. Ester-substituted chrysin derivatives, specifically C7 and C8, demonstrate promising VEGFR-2 inhibition and therapeutic potential, warranting further exploration as multifunctional anticancer agents.