Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors
(2011) European Journal of Medicinal Chemistry — Vol. 19, n° 1, p. 134-144 (2011)
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- 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 Ki 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 Ki 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 Ki value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a Ki 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. © 2010 Elsevier Ltd. All rights reserved.
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Reniers, J., Robert, S., Frédérick, R., Masereel, B., Vincent, S., & Wouters, J. (2011). Synthesis and evaluation of β-carboline derivatives as potential monoamine oxidase inhibitors. European Journal of Medicinal Chemistry, 19(1), 134-144. https://doi.org/10.1016/j.bmc.2010.11.041 (Original work published 2011)