Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents

The androgen receptor inhibitor, Enzalutamide, proved effective against castration resistance prostate cancer, has demonstrated clinical benefits and increased survival rate in men. However, AR mutation (F876L) converts Enzalutamide from antagonist to agonist indicating a rapid evolution of resistance. Hence, our goal is overcome this mechanism by designing developing novel analogues. We designed dataset derivatives using Enzalutamide's shape electrostatic features match with pharmacophoric essential for tight binding the receptor. Based on design strategy ten were selected 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) synthesis. All compounds evaluated in-vitro cancer cell lines DU-145, LNCaP PC3. Interestingly, two 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl) imidazolidin-4-one (6c, IC50 – 18.26 20.31μM) 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one (6h, successful promising antiproliferative activity lines. potential inhibitors was further studied molecular docking, dynamics simulations MM-GBSA free energy calculations found agreement vitro studies. It provided strong theoretical support hypothesis.