Novel 4-((3-fluorobenzyl)oxy)benzohydrazide derivatives as promising anti-prostate cancer agents: Synthesis, characterization and in vitro & in silico biological activity studies

In this study, ten novel halogenated arylidenehydrazide derivatives were synthesized and characterized through ¹H, ¹³C APT, ¹⁹F NMR, HSQC, HMBC, HRMS, and FT-IR techniques. Cytotoxic evaluations against PC3 prostate cancer and HUVEC cell lines identified compounds 8 and 14 as lead candidates, achieving IC₅₀ values of 4.49 µM and 4.78 µM, respectively, with notable selectivity indexes of 12.15 and 11.78, underscoring their specificity against PC3 cells. Molecular docking studies targeting AR, VEGFR1, EGFR, and VEGFR2 suggested potential inhibitory mechanisms, with compounds 8 and 14 displaying substantial binding affinities for AR and VEGFR1. Compound 8 achieved IFD scores of -12.900 kcal/mol for AR and -10.895 kcal/mol for VEGFR1, while compound 14 recorded scores of -10.323 kcal/mol and -10.379 kcal/mol, respectively. Complementary MM-GBSA analyses revealed favorable binding energies, with compound 8 yielding ΔG values of -76.60 kcal/mol (AR) and -78.08 kcal/mol (VEGFR1) and compound 14 showing -80.67 kcal/mol (AR) and -78.61 kcal/mol (VEGFR1). MD simulations confirmed complex stability over 50 ns, indicating that compound 14 exhibited enhanced binding stability with key residues in AR and VEGFR1. ADME predictions highlighted drug-like properties, particularly for compounds 8 and 14, with high lipophilicity and favorable absorption characteristics, despite low aqueous solubility. SAR analysis emphasized the beneficial impact of halogen substitutions on potency and selectivity, establishing compounds 8 and 14 as promising candidates for further therapeutic development.