Monoamine oxidase inhibition by selected anilide derivatives

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dc.contributor.author Bergh, Jacobus Johannes
dc.contributor.author Kruger, Johann
dc.contributor.author Legoabe, Lesetja Jan
dc.contributor.author Petzer, Jacobus Petrus
dc.contributor.author Petzer, Anél
dc.date.accessioned 2012-10-04T06:43:06Z
dc.date.available 2012-10-04T06:43:06Z
dc.date.issued 2011
dc.identifier.citation Legoabe, L.J. et al. 2011. Monoamine oxidase inhibition by selected anilide derivatives. European journal of medicinal chemistry, 46(10):5162-5174. [http://www.journals.elsevier.com/european-journal-of-medicinal-chemistry/] en_US
dc.identifier.issn 1223-5234
dc.identifier.issn 1768-3254 (Online)
dc.identifier.uri http://hdl.handle.net/10394/7435
dc.description Published under the auspices of the French Société de Chimie Thérapeutique (SCT) en_US
dc.description.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 IC50 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 IC50 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. en_US
dc.language.iso en en_US
dc.publisher Elsevier en_US
dc.subject Monoamine oxidase B en_US
dc.subject reversible inhibitor en_US
dc.subject selectivity en_US
dc.subject anilide en_US
dc.subject benzimidazole en_US
dc.subject molecular docking en_US
dc.title Monoamine oxidase inhibition by selected anilide derivatives en_US
dc.type Article en_US

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