title: Inhibition of monoamine oxidase by 3,4-dihydro-2(1H)-quinolinone derivatives.
abstract: In the present study, a series of 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The 3,4-dihydro-2(1H)-quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives which have been reported to act as MAO-B inhibitors. The results document that the quinolinones are highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. An analysis of the structure-activity relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro-2(1H)-quinolinone scaffold leads to significantly more potent inhibition compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and phenylpropoxy substitution on this position. It may be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising leads for the therapy of Parkinson's disease.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Letitia
authors.initials: L
authors.lastname: Meiring
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
mesh_terms: D006801:Humans; D007700:Kinetics; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D015363:Quinolones; D011994:Recombinant Proteins; D008995:Monoamine Oxidase
keywords: 3,4-Dihydro-2(1H)-quinolinone; Monoamine oxidase; Reversible inhibition; Selectivity; Structure–activity relationship