title: Monoamine oxidase inhibitory activities of heterocyclic chalcones.
abstract: Studies have shown that natural and synthetic chalcones (1,3-diphenyl-2-propen-1-ones) possess monoamine oxidase (MAO) inhibition activities. Of particular importance to the present study is a report that a series of furanochalcones acts as MAO-B selective inhibitors. Since the effect of heterocyclic substitution, other than furan (and more recently thiophene, piperidine and quinoline) on the MAO inhibitory properties of the chalcone scaffold remains unexplored, the aim of this study was to synthesise and evaluate further heterocyclic chalcone analogues as inhibitors of the human MAOs. For this purpose, heterocyclic chalcone analogues that incorporate pyrrole, 5-methylthiophene, 5-chlorothiophene and 6-methoxypyridine substitution were examined. Seven of the nine synthesised compounds exhibited IC50 values <1 μM for the inhibition of MAO-B, with all compounds exhibiting higher affinities for MAO-B compared to the MAO-A isoform. The most potent MAO-B inhibitor (4h) displays an IC50 value of 0.067 μM while the most potent MAO-A inhibitor (4e) exhibits an IC50 value of 3.81 μM. It was further established that selected heterocyclic chalcones are reversible and competitive MAO inhibitors. 4h, however, may exhibit tight-binding to MAO-B, a property linked to its thiophene moiety. We conclude that high potency chalcones such as 4h represent suitable leads for the development of MAO-B inhibitors for the treatment of Parkinson's disease and possibly other neurodegenerative disorders.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Corné
authors.initials: C
authors.lastname: Minders
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: arina.lourens@nwu.ac.za.
authors.forename: Anna C U
authors.initials: AC
authors.lastname: Lourens
mesh_terms: D000978:Antiparkinson Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D007700:Kinetics; D007735:Kynuramine / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000608571:1-(1H-pyrrol-2-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one; C000608572:3-(3-bromo-4-fluorophenyl)-1-(5-methylthiophen-2-yl)prop-2-en-1-one; D000978:Antiparkinson Agents; D047188:Chalcones; D006845:Hydrocarbons, Fluorinated; D008996:Monoamine Oxidase Inhibitors; D011758:Pyrroles; D013876:Thiophenes; D007735:Kynuramine; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human
keywords: Chalcone; Competitive; Inhibition; Monoamine oxidase (MAO); Reversible