Prostate cancer is the second leading cause of cancer death in men. Androgen receptor (AR) inhibitor is one of class of drug used in this disease. AR inhibitors include bicalutamide, flutamide, nilutamide, apalutamide, darolutamide and enzalutamide. Among them Flutamide is being selected because it causes liver damage on long term use that can be serious or life-threatening. In the current study, Bioisosteric approach has been used for amide group in the Flutamide molecule in order to develop the newer analogues having lesser side effects like liver damage, which is major cause of the drug withdrawal. Therefore amide bioisosteres of it are designed using bioisosteric approach in order to develop relatively safe compounds. A wide variety of amide bioisosteres of Flutamide were generated i.e., Ester, Amide, Reverse amide, Urea, Carbamate, Reverse Ester, Thioamide, 1,2,4-oxadiazole, Sulphonamide, Ketone etc., using MolOpt. Pharmacokinetic and toxicity (ADMET) properties of newly designed analogues are computed by using ADMElab2.0 and pkCSM. Druglikeness and Drugscore was calculated by PEO. All the ligands obey the Lipinski rule and had good human intestinal absorption. Flutamide is used as the reference drug. The results indicate that compound 002 and 022 showed NR-AR binding (desirable in Prostate cancer) and QED value (measure of drug likeness; > 0.67) comparable with the standard drug. These compounds showed low toxicity [human hepatotoxicity (H-HT) and drug induced liver injury (DILI)] as compared to Flutamide. This study could lead to the further development of potent AR antagonist for the treatment of prostate cancer.