Design, synthesis, and evaluation of benzylpiperidine-derived hydrazones as dual inhibitors of monoamine oxidases and acetylcholinesterase

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by cognitive decline and memory loss, with currently available treatments offering limited effectiveness, underscoring the need for multifunctional therapies. This study investigates benzylpiperidine derivatives as dual inhibitors of monoamine oxidases (MAOs) and acetylcholinesterase (AChE), enzymes implicated in AD pathology. Benzylpiperidine-derived hydrazones (4-13) were designed, synthesized and evaluated for inhibition against AChE and MAO-A/B isoforms. Among all, compounds 8 and 5 demonstrated a balanced multifunctional profile, effectively inhibiting MAO-A, MAO-B, and AChE. Compound 8 exhibited high potency against AChE (IC50 = 0.064 +/- 0.001 mu M), comparable to donepezil (IC50 = 0.084 +/- 0.002 mu M), with moderate inhibition of MAO-A (IC50 = 2.55 +/- 0.02 mu M) and MAO-B (IC50 = 1.47 +/- 0.06 mu M). Conversely, compound 5 displayed strongest inhibition against MAO-A (IC50 = 0.26 +/- 0.01 mu M) and MAO-B (IC50 = 0.116 +/- 0.005 mu M) within the series, along with moderate AChE inhibition (IC50 = 3.70 +/- 0.14 mu M). Both compounds showed antioxidant activity, though mild neurotoxicity. Molecular docking studies highlighted crucial intermolecular interactions, including pi-pi stacking and H-bonding, essential for ligand-protein stabilization. Computational ADMET predictions suggested favorable drug-like properties, while conformational alignment studies further elucidated their binding efficiency compared to reference drugs. These findings showcase benzylpiperidine derivatives as potential multifunctional agents for further development in AD treatment, with compounds 8 and 5 emerging as primary leads for additional refinement.