Benzothiazole‐Piperazine Hybrids Effectively Target C4‐2 Castration‐Resistant Prostate Cancer Cells in vitro Implicated through Computational Studies

A series of new analogs based on benzothiazole‐piperazine conjugates were synthesized and assessed to investigate their anticancer properties using in vitro and in silico techniques. The compounds 3 a–3 h were tested against prostate (C4‐2) cancer cells, and the results revealed that all the compounds showed significant inhibitory activity against C4‐2 cells (> 50 % inhibition at 20 μM) . Among all, 2‐(4‐(pyrimidin‐2‐yl) piperazin‐1‐yl) benzo[d]thiazole demonstrated the most prominent activity in the cell viability assay conducted displaying an IC ₅₀ value of 19.98 μM . In vitro studies have demonstrated that the compound can selectively target the androgen receptor (AR) and reduce the expression of several androgen‐responsive genes, including EAF2, ELL2, PSA and CALR genes, in castration‐resistant prostate cancer cells. Molecular docking results also revealed that all the compounds exhibited good energy binding scores against the androgen receptor target (PB ID: 2PNU) particularly compound 3 g which showed a maximum binding energy of −9.87  kcal/mol followed by other compounds as well as the established prostate cancer drug, enzalutamide, with a binding energy of −5.66 kcal/mol. Docking results were further supported by MD simulation studies, which confirmed that the ligand+protein complex was in stable conformation throughout the simulation time of 100 nanoseconds. Collectively, the present results, stemming from a combination of in vitro and in silico examinations, demonstrate that compound 3 g displays notable anti‐cancer characteristics, implying its viability as a prospective anti‐cancer pharmaceutical subject to clinical validation and subsequent development.