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Bioorganic & medicinal chemistry

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


PMID 21183355

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.

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286044
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