Introduction: The androgen receptor inhibitor, Enzalutamide, has demonstrated effectiveness against castration-resistant prostate cancer, leading to clinical benefits and increased survival rates in men. However, the emergence of AR mutation (F876L) converts Enzalutamide from an antagonist to an agonist, indicating the rapid evolution of resistance. To overcome this resistance mechanism, our goal is to design and develop novel Enzalutamide analogues. Methods: We designed a dataset of Enzalutamide derivatives using the shape and electrostatic features of Enzalutamide to match the pharmacophoric features necessary for tight binding with the androgen receptor. Based on this design strategy, ten novel derivatives, including 5,5-dimethyl-3-(6-substituted benzo[d]thia/oxazol-2-yl)-2-thioxo-1-(4-(trifluoromethyl) pyridin-2-yl) imidazolidin-4-one (6a-j), were selected for synthesis. In-vitro evaluations of all compounds were performed on prostate cancer cell lines DU-145, LNCaP, and PC3. Results: Two compounds, 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one (6c) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one (6h), showed promising in-vitro antiproliferative activity against prostate cancer cell lines, with IC50 values ranging from 18.26 to 20.31µM. The binding mechanism of these potential androgen receptor inhibitors was further studied through molecular docking, molecular dynamics simulations, and MM-GBSA binding free energy calculations. The results of these analyses were found to be in agreement with the in-vitro studies, providing strong theoretical support for our hypothesis. Conclusion: Our study aimed to overcome resistance caused by the AR mutation in Enzalutamide treatment by designing novel analogues. Two compounds (6c and 6h) showed promising in-vitro antiproliferative activity against prostate cancer. Molecular docking and simulations supported our hypothesis, providing insights into the binding mechanism. Further research is needed to explore the therapeutic potential of these analogues in overcoming castration resistance. [ABSTRACT FROM AUTHOR]