A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound 9a was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial in silico study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure-activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens.

Department of Biophysics and Physical Chemistry Faculty of Pharmacy in Hradec Králové Charles University Ak Heyrovského 1203 8 50003 Hradec Králové Czech Republic

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Králové Charles University Ak Heyrovského 1203 8 50003 Hradec Králové Czech Republic

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Králové Charles University Ak Heyrovského 1203 8 50003 Hradec Králové Czech Republic

Department of Pharmacology and Toxicology Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 76 32300 Plzeň Czech Republic

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