title: Monoamine oxidase inhibition by selected anilide derivatives.
abstract: A series of anilide derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The most potent inhibitors among the derivatives that were initially evaluated were (2E)-N-(3-chlorophenyl)-3-phenylprop-2-enamide (2c) and (2E)-N-(3-bromophenyl)-3-phenylprop-2-enamide (2d) with IC(50) values of 0.53 μM and 0.45 μM, respectively. These derivatives exhibited reversible and selective inhibition of MAO-B with binding affinities 37 fold higher for MAO-B than for MAO-A. Analysis of the possible binding interactions of these inhibitors with active site models of human MAO-A and -B led to the design of phenolic and benzonitrile derivatives of 2c and 2d. Among these were (2E)-N-(3-chlorophenyl)-3-(4-hydroxyphenyl)prop-2-enamide (7c) and (2E)-N-(3-bromophenyl)-3-(4-hydroxyphenyl)prop-2-enamide (7d) which inhibited MAO-B selectively and reversibly with IC(50) values of 0.032 μM and 0.026 μM, respectively. These inhibitors were at least 14 fold more potent than 2c and 2d. This study concludes that N,3-diphenylprop-2-enamide is a suitable scaffold for the design of selective MAO-B inhibitors and structural modifications to enhance the binding affinities of the inhibitors for the MAO-B active site include substitution with halogens on the N-phenyl ring and substitution with hydroxyl and nitrile functional groups on the para and meta positions, respectively, of the C3 phenyl ring. Possible binding modes of these structures within the MAO-B active site are proposed with the emphasis on the interactions of the inhibitor halogens and the hydroxyl and nitrile functional groups with active site residues and water molecules.
authors: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors: Lesetja
authors: L
authors: Legoabe
authors: Johann
authors: J
authors: Kruger
authors: Anél
authors: A
authors: Petzer
authors: Jacobus J
authors: JJ
authors: Bergh
authors: Jacobus P
authors: JP
authors: Petzer
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
chemical_list: D000813:Anilides; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; D008995:Monoamine Oxidase