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dc.contributor.authorBergh, Jacobus Johannes
dc.contributor.authorKruger, Johann
dc.contributor.authorLegoabe, Lesetja Jan
dc.contributor.authorPetzer, Jacobus Petrus
dc.contributor.authorPetzer, Anél
dc.date.accessioned2012-10-04T06:43:06Z
dc.date.available2012-10-04T06:43:06Z
dc.date.issued2011
dc.identifier.citationLegoabe, 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.issn1223-5234
dc.identifier.issn1768-3254 (Online)
dc.identifier.urihttp://hdl.handle.net/10394/7435
dc.descriptionPublished under the auspices of the French Société de Chimie Thérapeutique (SCT)en_US
dc.description.abstractA 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.isoenen_US
dc.publisherElsevieren_US
dc.subjectMonoamine oxidase Ben_US
dc.subjectreversible inhibitoren_US
dc.subjectselectivityen_US
dc.subjectanilideen_US
dc.subjectbenzimidazoleen_US
dc.subjectmolecular dockingen_US
dc.titleMonoamine oxidase inhibition by selected anilide derivativesen_US
dc.typeArticleen_US


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