Inhibition of monoamine oxidase by fluorobenzyloxy chalcone derivatives

Abstract

Inhibition of monoamine oxidase-B (MAO-B) decelerates the breakdown of dopamine in the brain, consequently augmenting dopaminergic neurotransmission, which is a critical pathway for ameliorating motor symptomatology of Parkinson's disease (PD). Chalcones are widely recognized as the lead inhibitors of MAO-B and hold significant therapeutic value for PD. Inspired by safinamide's pharmacophoric features, the study focuses on designing, synthesizing, and evaluating a novel series of fluorinated benzyloxy chalcone derivatives as selective MAO-B inhibitors. Thirteen fluorobenzyloxy chalcone derivatives were synthesized and evaluated for their inhibition of monoamine oxidase (MAO). All compounds showed better inhibition of MAO-B than of MAO-A. Compound (E)1-(4-bromophenyl)-3-(2-((3-fluorobenzyl)oxy)phenyl)prop-2-en-1-one (FBZ13) most potently inhibited MAO-B with an IC₅₀ value of 0.0053 μM, followed by (E)3-(2-((3-fluorobenzyl)oxy)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one (FBZ6) (IC₅₀ = 0.023 μM). The IC₅₀ value of FBZ13 was 4.0 times lower than that of reference drug safinamide. All compounds showed weak MAO-A inhibition, FBZ13 and FBZ6 displayed exceptionally high selectivity for MAO-B. Kinetic studies confirmed that these two compounds function as competitive and reversible MAO-B inhibitors. Additionally, PAMPA results indicated excellent membrane permeability and CNS bioavailability for FBZ13 and FBZ6, highlighting their promise as central nervous system-active agents. In vitro antioxidant assays evaluated the activities of enzymes (SOD, CAT, GSH, and GPx) in human neuroblastoma cells exposed to lipopolysaccharide (LPS). Treatment with compounds FBZ6 and FBZ13 (10 μM each) significantly enhanced enzyme activities, mitigating LPS-induced oxidative stress. Lead compounds were stabilized in protein–ligand complexes by the π–π stacking, which enabled them to bind to the active site of hMAO-B effectively. These results suggest that FBZ6 and FBZ13 are potent reversible selective MAO-B inhibitors, and they can be used as potential agents for the treatment of neurological disorders such as Alzheimer's diseases and PD.