Inhibiting c-Abl kinase pharmacologically is necessary because of its role in oxidative stress and neurodegeneration. When activated, it causes the accumulation of α-synuclein and dopaminergic neuron damage, leading to Parkinson's disease (PD). Reports of the effectiveness of c-Abl inhibitors repurposed for PD were accompanied by both hope and numerous concerns. Therefore, there is an urgent need for alternative c-Abl inhibitors. We employed a machine-learning-based QSAR model to identify potential actives against c-Abl kinase, screening selected FDA-approved and phase 1 drugs; optimizing the compounds' structures through bioisostere replacement; conducting molecular docking algorithms (HTVS, SP, XP, and Prime's Molecular Mechanics with Generalized Born and Surface Area (Prime-MMPBSA)); in silico pharmacokinetic profiling; and structural stability and dynamics studies for 200 ns. From 3605 drugs and 1456 bioisosteres, two bioisosteres of indobufen (indobufen 25 and 22) showed promising potential against c-Abl kinase. As the two bioisosteres returned the closest docking scores (14.880 and - 14.265 kcal mol-1, respectively) to the control drug (nilotinib, - 15.312 kcal mol-1), the Prime-MMGBSA calculations returned - 81.92 and - 84.07 kcal mol-1, respectively; MMPBSA calculations after a 200-ns MD simulation run returned - 48.20 ± 3.69 kcal mol-1 and - 49.94 ± 3.05 kcal mol-1, respectively. This indicates their stability compared to other test compounds, as supported by the RMSD, RMSF, PCA, and DCCM results. Finally, both bioisosteres interacted with MET 318, ASP 381, TYR 253, ALA 269, and PHE 317 in the c-Abl active site. We present these bioisosteres as potential candidates for the treatment or management of PD targeting c-Abl kinase. However, in vitro and in vivo experiments to validate the findings are urgently required.