Exploring highly selective polymethoxy fenamate isosteres as novel anti-prostate cancer agents: Synthesis, biological activity, molecular docking, molecular dynamics, and ADME studies

Abstract

In this study, we synthesized and characterized sixteen new polymethoxy-substituted hydrazone derivatives. These compounds were evaluated for their in vitro cytotoxic activity against human prostate cancer (PC3) and human umbilical vein endothelial (HUVEC) cell lines. Compounds 5, 6, 7, and 11 exhibited significant cytotoxic effects with high selectivity index. Molecular docking studies and MM-GBSA binding free energy calculations were performed against tubulin protein. Compound 7 emerged as a particularly promising candidate, displaying an IC50 value of 1.49 µM against PC3 cells and a selectivity index of 264. Compound 7 achieved impressive docking score -13.655 kcal/mol against tubulin and formed stable hydrogen bonds and π-π stacking interactions with key residues in this protein. MD simulations confirmed the stability of the 7-tubulin complex. ADME analysis indicated that compound 7 has favorable absorption, solubility, and permeability properties, with minimal rule violations. The SAR analysis highlighted the significance of specific functional groups in enhancing the compound\"s cytotoxic and binding properties. Overall, compound 7 is identified as a leading candidate due to its exceptional cytotoxicity, high selectivity index, strong binding affinities, and favorable pharmacokinetic profile, making it a top candidate for further investigation and development as a novel anticancer agent.