New Frontiers in Selective Human MAO-B Inhibitors

Abstract

Accumulating evidence shows a relationship between the human MAO-B (hMAO-B) enzyme and neuropsychiatric/degenerative disorder, personality traits, type II alcoholism, borderline personality disorders, aggressiveness and violence in crime, obsessive-compulsive disorder, depression, suicide, schizophrenia, anorexia nervosa, migraine, dementia, and PD. Thus, MAO-B represents an attractive target for the treatment of a number of human diseases. The discovery, development, and therapeutic use of drugs that inhibit MAO-B are major challenges for future therapy. Various compounds and drugs that selectively target this isoform have been discovered recently. These agents are synthetic compounds or natural products and their analogues, including chalcones, pyrazoles, chromones, coumarins, xanthines, isatin derivatives, thiazolidindiones, (thiazol-2-yl)hydrazones, and analogues of marketed drugs. Despite considerable efforts in understanding the binding interaction with specific substrates or inhibitors, structural information available for the rational design of new hMAO-B inhibitors remains unsatisfactory. Therefore, the quest for novel, potent, and selective hMAO-B inhibitors remains of high interest.

Molecular aspects of monoamine oxidase B

“…Many medicinal chemistry groups are nonetheless pursuing the search for a high affinity reversible inhibitor for MAO B. The chemical families and lead structures had been reviewed recently (Carradori and Silvestri, 2015).…”

Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs: Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities

“…Because of their potential neuroprotective effects, MAO-B inhibitors may be useful for the treatment of Alzheimer's disease. [6][7][8] Several natural and synthetic cinnamic acid amides and their esters were found to possess various biological properties such as antioxidant, 9,10) anti-inflammatory, 11) anti-tumor, 12) cytoprotective, 13,14) protection of β-amyloid protein aggregation, 15) tyrosinase inhibitory, 16,17) α-glucosidase inhibitory, 18,19) cholinesterase inhibitory, 20) and MAO inhibitory [21][22][23] activities. However, no systematically evaluated data are available on the antioxidant and MAO and ChE inhibitory activities of cinnamic acid derivatives.…”

“…1), and the structureactivity relationships (SARs) of the cinnamic acid derivatives with respect to antioxidant capacity and MAO and ChE inhibitory activities were investigated. feic acid, ferulic acid and p-coumaric acid were reacted with biogenic amines (i.e., serotonin, dopamine, tyramine, vanillylamine) to get amide compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), and with alcohols (i.e., 3,4-dihydroxyphenethylalcohol, 4-hydroxyphenethylalcohol, phenethylalcohol) to get ester compounds (13, 14, 16-22) (Chart 1). Their yields were satisfactory.…”

“…MAO-B inhibitor has been shown to be an important drug lead for several diseases. 8) Thus compound 20 may serve as such a drug lead.…”

Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1–42)-induced toxicity

“…All these studies suggest a strong link between MAO hyperactivity and Aβ fibrillogenesis in AD as well as the rational for studying, in experimental models of AD, the neuroprotective efficacy of MAO inhibitors (MAOIs), an interesting class of antidepressants currently used for the management of treatment-resistant depression (Shulman et al, 2013). MAOIs are presently studied for their neuroprotective properties as new promising drugs for cognitive impairment in AD and other dementias (Baker et al, 2007;Binda et al, 2011;Basile et al, 2014;Cai, 2014;Carradori and Silvestri, 2015). It has been hypothesized that neuroprotective activity of MAOIs can be independent of their MAO inhibition (Al-Nuaimi et al, 2012) and dual inhibitors combining anti-acetyl cholinesterase and MAO activities in one molecular entity are currently studied (Yáñez and Viña, 2013), although no study has yet examined yet whether MAOIs can prevent Aβ aggregation and reduce fibril formation.…”