Value Addition to Citrus maxima Peels: Extraction and Modification of Naringenin into Hydrazones Derivatives for Anti‐Breast Cancer and Osteogenic Activity via In Vitro and In Silico Studies

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ABSTRACT This study investigates the value addition of Citrus maxima fruit peels by extracting Naringenin and chemically modifying it into hydrazone derivatives to enhance its anti‐cancer and anti‐osteoporotic potential. The compounds ( 2a – f ) were synthesised using simple and efficient chemistry. Their pharmacokinetic properties, molecular docking and simulations were evaluated against key hormonal targets, EGFR, ERα, ERβ, HER2 and PR. The cytotoxicity of the compounds was assessed against MCF‐7 and SiHa cell lines using MTT assay, while their osteogenic potential was evaluated using osteoblast differentiation and bone mineralization assays. Amongst other compounds, 2d and 2f exhibited significant anti‐breast cancer activity, with IC 50 values of 36 and 20 µM, respectively. Fluorinated derivative 2d demonstrated a strong osteogenic effect by enhancing osteoblast differentiation at 10 and 100 nM concentrations and significant bone mineralization, along with anti‐breast cancer properties, potentially due to its distinct physicochemical characteristics, including a small atomic radius and high electronegativity. Importantly, the synthesized compounds showed no inherent toxicity toward non‐cancerous HEK 293 cells and healthy osteoblasts. Molecular docking studies revealed improved ERα binding, further validated by 100 ns molecular dynamics simulations. SwissADME analysis confirmed favourable physicochemical properties, supporting the drug‐like potential of these derivatives.

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