title: Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors.
abstract: Previous studies have shown that harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with harmine has been recently solved. This crystal structure shows that close to the methoxy group of the harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their K(i) values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a K(i) against MAO-A of 3.6nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a K(i) value of 221.6nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K(i) value of 4.3nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.
authors.affiliation: Drug Design and Discovery Center, Laboratoire de Chimie Biologique Structurale, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Reniers
authors.forename: S
authors.initials: S
authors.lastname: Robert
authors.forename: R
authors.initials: R
authors.lastname: Frederick
authors.forename: B
authors.initials: B
authors.lastname: Masereel
authors.forename: S
authors.initials: S
authors.lastname: Vincent
authors.forename: J
authors.initials: J
authors.lastname: Wouters
mesh_terms: D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002243:Carbolines; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase