<p>Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder which is caused by abrupt degeneration of dopaminergic neuronal cells in the substantia nigra pars compacta (SNPc) area of the midbrain. Adenosine A_2A receptors have become promising therapeutic targets for PD; however, many A_2A receptor antagonists face challenges, such as limited accessibility or failure in clinical trials due to poor selectivity and bioavailability. To identify novel A_2A receptor antagonists, a 3D-QSAR-pharmacophore modeling approach was employed, involving virtual screening of ZINC, NCI, and MayBridge databases. The virtual hits were filtered via ADMET criteria to select compounds with favorable bioavailability and solubility profiles. From the MayBridge database, a potent monocyclic A_2A receptor antagonist, AW00032 (N-(furan-2-ylmethyl)-5-methylthiazole-4-yl) thiophene-2-sulfonamide, was identified. AW00032 possessed key pharmacophoric features: two lipophilic hydrogen bond acceptors, one hydrophobic aliphatic/aromatic group, and one aromatic ring. Docking analysis revealed AW00032 had a strong binding affinity for A_2A receptors (1.23&#xa0;nM, ∆G −&#xa0;10.49&#xa0;kcal/mol), and its ADMET profile indicated good bioavailability. In 6-OHDA induced SH-SY5Y cells, AW00032 increased dopamine levels and tyrosine hydroxylase (TH) expression, demonstrating its potential as an A_2A receptor antagonist. AW00032, discovered through 3D-QSAR pharmacophore modeling, also reduced reactive oxygen species (ROS) levels and showed depletion in mitochondrial dysfunction in 6-OHDA-induced SH-SY5Y cells. It exhibited A_2A receptor antagonist activity comparable to the standard antagonist ZM241385, partially restoring dopamine and TH levels. Furthermore, AW00032 improved behavioral symptoms in haloperidol-induced C-57 bl/6 mice.</p> Graphical Abstract <p>3D-QSAR modeling identifies AW00032 as A_2AR antagonist, restoring DA and TH levels in vitro, and improving behavioral symptoms in Haloperidol mice.</p> <p></p>