Background:Androgen Receptor (AR) is one of the highly explored targets for the treatment of prostate cancer. Emergence of point mutation in the Ligand Binding Domain (LBD) of AR has resulted in the development of resistance against AR antagonist. The point mutation T877A, W741L and F876L confers resistance to flutamide, bicalutamide and enzalutamide respectively. There are no AR antagonist in the present clinical set up without resistance. Hence, our aim in this study is to design a novel molecule to overcome the resistance caused by point mutation.Methods:Here, we developed novel AR antagonist bearing (5-methyl-1H-pyrazol-3-yl)-1, 3,4-oxadiazole core by rational drug design. The test molecules 8a-h were synthesized from the corresponding dihydrazide compounds 7a-h on treatment with phosphorous oxychloride on reflux conditions. The structure of the molecules was confirmed from the spectral data such as IR, 1H-NMR, HRMS and 13C-NMR. The synthesized compounds were screened for cytotoxicity in prostate cancer cell lines LNCaP-FGC and PC3. The confirmation of AR mediated activity of the test compounds were confirmed by gene expression study. The interaction of the best active ligands with mutant AR was predicted and drug design was rationalized through docking studies.Results:The test compounds 8a-h were synthesized and the structures were conformed using suitable techniques like IR, 1H-NMR, HRMS and 13C-NMR. Among the tested compounds, 8b and 8d showed potent anti-proliferative activity against mutant AR cell lines. Further, these compounds significantly decreased the gene expression of prostate cancer biomarker.Conclusion:In this study, we have identified a potential hit molecule for AR antagonism that could be further developed to obtain a potent clinical candidate.