Synthesis, bioactivity, and molecular docking studies: novel arylpiperazine derivatives as potential new-resistant AR antagonists

The majority of patients with androgen-dependent prostate cancer (PCa) develop resistance to hormone therapy after approximately 18-24 months of androgen deprivation therapy treatment. During this process, PCa cells progressively lose their sensitivity to androgens and evolve into castration-resistant prostate cancer leading to uncontrolled tumor growth and ultimately the failure of endocrine therapy. To develop potential anti-prostate cancer agents, in this study, we identified a novel ether-type arylpiperazine derivative as a potent androgen receptor (AR) antagonist, uncovering a series of effective antiproliferative compounds. The derivatives (<b>7, 11, 17, 19, 20, 21, 22, 23</b>, and <b>24</b>) demonstrated strong cytotoxicity against cancer cells, with <b>17, 19, 20</b>, and <b>23</b> showing significant androgen receptor antagonistic activity (Inhibition% >60) and robust AR binding affinities. The structure-activity relationship (SAR) of these developed derivatives was discussed based on data. Docking study suggested that the compound <b>19</b> mainly bind to AR ligand binding pocket site through Van der Waals' force interactions. This research presents a promising lead compound for developing anticancer agents targeting prostate cancer therapy.