Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors

J. Reniers, S. Robert, R. Frederick, B. Masereel, S. Vincent, J. Wouters

Research output: Contribution to journalArticle

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 3.6 nM. 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 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K i value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.

Original languageEnglish
Pages (from-to)134-144
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number1
DOIs
Publication statusPublished - 1 Jan 2011

Fingerprint

Carbolines
Monoamine Oxidase Inhibitors
Monoamine Oxidase
Harmine
Derivatives
Bearings (structural)
Crystal structure
Binding Sites

Keywords

  • β-Carboline
  • Docking
  • MAO inhibition
  • X-ray

Cite this

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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 3.6 nM. 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 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K i value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.",
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Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors. / Reniers, J.; Robert, S.; Frederick, R.; Masereel, B.; Vincent, S.; Wouters, J.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 1, 01.01.2011, p. 134-144.

Research output: Contribution to journalArticle

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AU - Robert, S.

AU - Frederick, R.

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AU - Vincent, S.

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