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 IC values ranging from 370.37 nM to 838.14 nM. In comparison, the standard drug bicalutamide exhibited an IC 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 IC 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.