Title : Designing novel chromone derivatives as selective human monoamine oxidase b inhibitors
Abstract:
Neurodegenerative diseases such as Parkinson’s and Alzheimer’s are progressive, incurable disorders characterized by the degeneration of nerve cells. This deterioration leads to a gradual decline in mental and physical health. One key factor in neurodegeneration is the oxidative deamination of biologically significant monoamines, catalyzed by monoamine oxidases (MAOs). In mammals, MAOs exist in two isoforms, MAO-A and MAO-B, which differ in their substrate selectivity. MAO-A metabolizes tyramine, norepinephrine, and serotonin, while MAO-B predominantly metabolizes dopamine and beta-phenylethylamine with a preference for sterically hindered amines. Elevated levels of MAO-B in the brain are associated with the α-carbon oxidation of dopamine, contributing significantly to Parkinson’s and Alzheimer’s diseases. Additionally, MAO-B promotes the production of reactive oxygen species (ROS), causing cellular damage and contributing to cognitive decline as its levels increase with aging. Inhibiting MAO-B has thus become a primary therapeutic approach for managing Parkinson’s and Alzheimer’s diseases, as it enhances dopaminergic neurotransmission.
However, the development of selective MAO-B inhibitors is crucial since non-selective inhibition of both MAO-A and MAO-B can lead to severe metabolic complications, such as the “tyramine reaction,” where interactions between dietary amines and MAOIs cause adverse physiological effects. Natural and synthetic oxygen heterocycles have been explored as potential selective MAO-B inhibitors. Among these, chromones, a class of oxygen heterocycles, have garnered significant interest for their pharmacological properties, including MAO-B inhibition, anti-cancer, antimicrobial, antioxidant, and anti-HIV activities. Functionalized chromones, particularly those with benzyloxy substitutions at C-7 and carboxamide functions at C-3, have demonstrated notable 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, using Jones oxidation and HBTU/HOBt as a selective amide coupling agent. The synthesized compounds were evaluated for in vitro human MAO-A and MAO-B inhibitory activity.
Compounds 5c and 5e exhibited potent MAO-B inhibition, with IC50 values in the nanomolar range, surpassing the standard inhibitor Selegiline. Five compounds (5b, 5c, 5e, 5g, and 5k) demonstrated high selectivity for MAO-B, with selectivity index (SI) values exceeding 50. Notably, compound 5e showed reversible MAO-B inhibition with a relative recovery of 69.9% in dialysis studies. Docking studies using the Genetic Optimization of Ligand Docking (GOLD) method revealed strong positive interactions between these chromone carboxamides and hMAO-B, with repulsive interactions for hMAO-A, further affirming their selectivity. These findings highlight the potential of chromone derivatives as promising candidates for MAO-B selective inhibitors in treating neurodegenerative diseases.
