Title : Designing novel chromone derivatives as neuroprotective agents
Abstract:
Neurodegenerative diseases such as Parkinson’s and Alzheimer’s are progressive and currently incurable disorders caused by the degeneration of nerve cells. This deterioration results in a gradual decline in both mental and physical health. A key factor in neurodegeneration is the oxidative deamination of biologically significant monoamines, a process catalyzed by monoamine oxidases (MAOs). In mammals, MAOs exist in two isoforms—MAO-A and MAO-B—which differ in substrate selectivity. MAO-A primarily metabolizes tyramine, norepinephrine, and serotonin, whereas MAO-B predominantly targets dopamine and beta-phenylethylamine, showing a preference for sterically hindered amines.
Elevated MAO-B levels in the brain contribute to the α-carbon oxidation of dopamine, playing a significant role in the progression of Parkinson’s and Alzheimer’s diseases. Additionally, MAO-B promotes the production of reactive oxygen species (ROS), leading to cellular damage and cognitive decline, particularly as its levels increase with age. As a result, MAO-B inhibition has emerged as a key therapeutic strategy for managing these neurodegenerative disorders by enhancing dopaminergic neurotransmission.
However, selective inhibition of MAO-B is crucial, as non-selective inhibition of both MAO-A and MAO-B can lead to severe metabolic complications. One such complication is the “tyramine reaction,” where interactions between dietary amines and monoamine oxidase inhibitors (MAOIs) cause adverse physiological effects.
Both natural and synthetic oxygen heterocycles have been investigated as potential selective MAO-B inhibitors. Among them, chromones—a class of oxygen heterocycles—have garnered significant interest due to their diverse pharmacological properties, including MAO-B inhibition, as well as anti-cancer, antimicrobial, antioxidant, and anti-HIV activities. Functionalized chromones, particularly those with benzyloxy substitutions at the C-7 position and carboxamide functions at C-3, have shown promise as selective MAO-B inhibitors.
In this study, a series of bifunctional chromone derivatives—7-benzyloxy-2,3-dimethyl-4-oxo-4H-chromene-8-carboxamides (5a–5l)—were synthesized from 7-hydroxy-2,3-dimethyl chromone via a key intermediate, 7-benzyloxy-2,3-dimethyl-8-carboxylic acid. The synthesis involved Jones oxidation followed by amide coupling using HBTU/HOBt as a selective coupling agent. The resulting compounds were evaluated for in vitro inhibitory activity against human MAO-A and MAO-B.
Among the tested compounds, 5c and 5e exhibited potent MAO-B inhibition, with IC50 values in the nanomolar range, surpassing the standard inhibitor Selegiline. Additionally, five compounds (5b, 5c, 5e, 5g, and 5k) demonstrated high selectivity for MAO-B, with selectivity index (SI) values exceeding 50. Notably, compound 5e exhibited reversible MAO-B inhibition, with a relative recovery of 69.9% in dialysis studies.
Molecular docking studies using the Genetic Optimization of Ligand Docking (GOLD) method further confirmed the selectivity of these chromone carboxamides. Strong positive interactions were observed between the synthesized compounds and hMAO-B, while repulsive interactions with hMAO-A reinforced their selectivity. These findings highlight the potential of chromone derivatives as promising candidates for selective MAO-B inhibitors in the treatment of neurodegenerative diseases.
