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

Bhole, Ritesh P., Chikhale, Rupesh V. ORCID:, Wavhale, Ravindra D., Asmary, Fatmah Ali, Almutairi, Tahani Mazyad, Alhajri, Hassna Mohammed and Bonde, Chandrakant G. (2021) Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents. Heliyon, 7 (3). ISSN 2405-8440

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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 to overcome this resistance mechanism by designing and developing novel Enzalutamide analogues. We designed a dataset of Enzalutamide derivatives using Enzalutamide's shape and electrostatic features to match with pharmacophoric features essential for tight binding with the androgen receptor. Based on this design strategy ten novel derivatives 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) for synthesis. All the compounds were evaluated in-vitro on prostate cancer cell lines DU-145, LNCaP and PC3. Interestingly, two compounds 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 to 20.31μM) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one (6h, IC50 – 18.26 to 20.31μM) were successful with promising in-vitro antiproliferative activity against prostate cancer cell lines. The binding mechanism of potential androgen receptor inhibitors was further studied by molecular docking, molecular dynamics simulations and MM-GBSA binding free energy calculations and found in agreement with the in vitro studies. It provided strong theoretical support to our hypothesis.

Item Type: Article
Uncontrolled Keywords: binding energy calculations,hybrid molecules,imidazolidinone derivatives,molecular docking,molecular dynamics simulations,prostate cancer,general,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Science > School of Pharmacy
Faculty of Science > School of Chemistry
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Depositing User: LivePure Connector
Date Deposited: 13 Mar 2021 00:47
Last Modified: 23 Oct 2022 02:17
DOI: 10.1016/j.heliyon.2021.e06227

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