Oxadiazole derivatives as potent androgen receptor inhibitors: Design, synthesis, and anticancer evaluation

Prostate Cancer remains one of the most prevalent malignancies worldwide, necessitating the continuous development of novel therapeutic agents. In this study, a series of novel oxadiazole-based compounds (MS01-MS15) were synthesized and evaluated for their Anticancer potential against PC-3 prostate Cancer cell lines. The MTT assay revealed significant cytotoxic effects, with percentage inhibition reaching up to 97.32 % and IC₅₀ values ranging from 370.37 nM to 838.14 nM. In comparison, the standard drug bicalutamide exhibited an IC₅₀ value of 158.03 nM. Molecular docking studies using Autodock Vina demonstrated strong interactions between the synthesized compounds and the Androgen Receptor (PDB ID: 1Z95), with binding affinities ranging from -6.5 to -9.0 kcal/mol. Notably, MS14, featuring a fluorine substituent at the para position, emerged as the most potent compound, exhibiting the highest binding affinity (-9.0 kcal/mol) and the lowest IC₅₀ value (370.37 nM). Moreover, ROS production assay and Androgen Receptor inhibition assay has shown promising results for MS-14 as compared to standard drug. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents, particularly fluorine and chlorine, enhanced the Anticancer efficacy, whereas bulkier and electron-donating groups diminished activity. Importantly, validation in androgen-sensitive LNCaP cells confirmed that MS14 retained significant antiproliferative activity, achieving up to 78.2 % inhibition at 1000 nM, thereby supporting its dual AR-dependent and AR-independent modes of action. These findings underscore the potential of oxadiazole derivatives as promising Androgen Receptor inhibitors for prostate Cancer therapy.

Androgen receptor inhibitors; Cytotoxicity; Molecular docking; Oxadiazole derivatives; Prostate cancer; Structure-activity relationship (SAR).