Negi_2025_J.Comput.Aided.Mol.Des_39_10

Neurodegenerative diseases (NDDs) like Alzheimer's and Parkinson's, characterized by gradual loss of neuronal structure and function, results in cognitive and motor impairments. These complex disorders involve multiple pathogenic mechanisms, including neurotransmitter imbalances, oxidative stress, and protein misfolding, necessitating multifunctional therapeutic approaches. Piperidine and isatin are valuable scaffolds in drug design due to their favorable pharmacokinetic profiles, ability to cross blood-brain barrier, and ease of modification. This study focuses on design, synthesis, and evaluation of benzylpiperidine-isatin hybrids as dual inhibitors targeting key enzymes implicated in NDDs: monoamine oxidases (MAO-A/B) and acetylcholinesterase (AChE). Strategic hybridization of piperidine and isatin produced novel benzylpiperidine-isatin hybrids, combining pharmacological benefits of both scaffolds. Synthesized hybrids were tested for MAO-A/B and AChE inhibitory effects. 15 emerged as a lead inhibitor for both MAO-A (IC(50) = 0.108 +/- 0.004 microM, competitive and reversible) and AChE (IC(50) = 0.034 +/- 0.002 microM, mixed and reversible), outperforming donepezil in AChE inhibition. 4 showed significant MAO-B inhibition (IC(50) = 0.057 +/- 0.001 microM, competitive and reversible). SAR studies identified crucial structural elements for potency and selectivity, while molecular docking revealed key interactions stabilizing the enzyme-inhibitor complexes. MD simulations of lead molecules demonstrate the ligand's suitability for strong and consistent binding to the respective proteins. Lead compounds were non-neurotoxic, exhibited good antioxidant properties, and had favorable in silico ADMET predictions. These findings suggest that benzylpiperidine-isatin hybrids hold promise as multifunctional agents against NDDs, warranting further refinement to enhance their efficacy and safety.