Identification of a nanomolar, selective MAO-B inhibitor from piperidine-based chalcones with anti-Parkinson potential.
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A library of twenty-seven piperidine-based chalcones (PBCs) was designed, synthesised via microwave-assisted methodology, and subsequently evaluated for their inhibitory activity against monoamine oxidases (MAO-A/B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The PBCs exhibited potent and selective inhibition of MAO-B, with IC50 values ranging from 0.014 to >40 μM, while activity towards MAO-A was negligible (>40 μM). Among them, PBC21 was the most active (IC50 = 0.014 ± 0.0026 μM), whereas PBC1, PBC2, and PBC5 showed comparable potencies around 0.5-0.6 μM. Kinetic and reversibility studies identified PBC21 as a mixed, reversible MAO-B inhibitor (Kᵢ = 6.0 ± 2.8 nM). In contrast, cholinesterase inhibition was modest, with AChE activity ranging from 9.36 to >40 μM (best: PBC7, IC50 = 9.36 ± 0.15 μM) and BChE activity from 16.63 to >40 μM (best: PBC3, IC50 = 16.63 ± 1.94 μM). Selected sub-micromolar MAO-B inhibitors were further evaluated for in vitro metabolic stability and blood-brain barrier permeability. Among them, PBC21 exhibited a favourable microsomal stability profile in both rat and human liver microsomes, indicating improved metabolic robustness compared with the reference compound. Although experimental permeability assays were limited by compound adsorption to assay membranes, in silico prediction suggested that PBC21 possesses adequate oral bioavailability and the capacity to penetrate the blood-brain barrier. The most potent and selective MAO-B inhibitor, PBC21, was further evaluated in an MPTP-induced rat model of Parkinson's disease. Behavioural assessments including open field, pole, bar, rotarod, and forced swim tests demonstrated significant improvement in locomotor activity and motor coordination compared with the MPTP-treated group. Notably, PBC21 exhibited efficacy comparable to the reference drug selegiline in several parameters, highlighting its potential as a promising antiparkinsonian lead candidate. Molecular docking and molecular dynamics simulations were performed to elucidate the binding mode of PBC21 towards hMAO isoforms. The results indicated stable accommodation of PBC21 within the hMAO-B catalytic cavity through hydrophobic interactions and transient engagement with aromatic cage residues, while weaker interactions were observed with hMAO-A, consistent with the experimentally observed selectivity. Based on the results obtained, it is proposed that PBC21 is a potent and selective MAO-B inhibitor. These findings position PBC21 as a promising lead compound in the treatment of neurodegenerative diseases such as Parkinson's disease.