Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Abstract

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC50 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.

6-Methoxyflavone and Donepezil Behavioral Plus Neurochemical Correlates in Reversing Chronic Ethanol and Withdrawal Induced Cognitive Impairment

“… 47 Dopamine D1-like receptors, when activated in the hippocampus, enhance memory formation and monoamine oxidase-B (MAO-B) inhibitors have been reported to raise extracellular dopamine levels in this brain region. 78 Intriguingly, O-methylated flavonoids inhibit MAO-B, 79 which may contribute to increased dopamine levels in the hippocampus and the positive impact of 6-MOF on spatial memory in the Y-maze. Correspondingly, augmented brain noradrenaline levels improve cognition, 80 and in our study, chronic ethanol plus 6-MOF produced a specific frontal cortical noradrenaline upsurge likely to improve Y-maze performance.…”

Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

“…The absence of substituents on ring B showed a slight preference for MAO-A in a manner similar to the flavone chrysin [39]. Monosubstitution on ring B of the flavonol scaffold decreased the SI of MAO-A versus MAO-B, improving the activity towards MAO-A in a manner comparable to the flavonols rhamnocitrin [40], 4 -O-methyl kaempferol, and 3, 4 -O-methyl kaempferol [41], while disubstitution of ring B resulted in the loss of MAO-A activity as seen with the flavonols quercetin [39] and isorhamnetin [42]. Dioxygenation at positions C-3 and C-4 on ring B resulted in the loss of selectivity towards MAO-B in a manner similar to the flavone luteolin [43], while methoxylation of the same positions gained MAO-B selectivity in a manner similar to vetulin [11] and diosmetin [42], respectively.…”

Role of Natural Compounds and Target Enzymes in the Treatment of Alzheimer’s Disease

“…Chelerythrine was a reversible competitive MAO-A inhibitor (Ki = 0.22 µM) with a substantially higher potency than the marketed medication toloxatone, with an IC50 value of 1.10 µM [79]. The natural O-methylated flavonoid, with strong potency (IC50 33 nM; Ki 37.9 nM) and >292-fold selectivity against human MAO-A (vs. MAO-B), is a novel therapeutic lead for the treatment of NDs [80]. The other natural compounds, such as morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM), and fisetin (IC50 = 7.33 µM), were notable MAO inhibitors with MAO-A selectivity [80].…”

“…The natural O-methylated flavonoid, with strong potency (IC50 33 nM; Ki 37.9 nM) and >292-fold selectivity against human MAO-A (vs. MAO-B), is a novel therapeutic lead for the treatment of NDs [80]. The other natural compounds, such as morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM), and fisetin (IC50 = 7.33 µM), were notable MAO inhibitors with MAO-A selectivity [80]. As compared to known drugs, natural products have fewer side effects and are efficient for the inhibition of these enzymes.…”