title: Inhibition of monoamine oxidase by C5-substituted phthalimide analogues.
abstract: Literature reports that isatin as well as C5- and C6-substituted isatin analogues are reversible inhibitors of human monoamine oxidase (MAO) A and B. In general, C5- and C6-substitution of isatin leads to enhanced binding affinity to both MAO isozymes compared to isatin and in most instances result in selective binding to the MAO-B isoform. Crystallographic and modeling studies suggest that the isatin ring binds to the substrate cavities of MAO-A and -B and is stabilized by hydrogen bond interactions between the NH and the C2 carbonyl oxygen of the dioxoindolyl moiety and water molecules present in the substrate cavities of MAO-A and -B. Based on these observations and the close structural resemblances between isatin and its phthalimide isomer, a series of phthalimide analogues were synthesized and evaluated as MAO inhibitors. While phthalimide and N-aryl-substituted phthalimides were found to be weak MAO inhibitors, phthalimide homologues containing C5 substituents were potent reversible inhibitors of recombinant human MAO-B with IC(50) values ranging from 0.007 to 2.5 μM and moderately potent reversible inhibitors of recombinant human MAO-A with IC(50) values ranging from 0.22 to 9.0 μM. By employing molecular docking the importance of hydrogen bonding between the active sites of MAO-A and -B and the phthalimide inhibitors are highlighted.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Clarina I
authors.initials: CI
authors.lastname: Manley-King
authors.forename: Jacobus J
authors.initials: JJ
authors.lastname: Bergh
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007313:Insecta; D007510:Isatin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010797:Phthalimides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D008996:Monoamine Oxidase Inhibitors; D010797:Phthalimides; D007510:Isatin; D008995:Monoamine Oxidase