8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase

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dc.contributor.author Bergh, Jacobus Johannes
dc.contributor.author Petzer, Jacobus Petrus
dc.contributor.author Strydom, Belinda
dc.date.accessioned 2012-10-04T06:50:47Z
dc.date.available 2012-10-04T06:50:47Z
dc.date.issued 2011
dc.identifier.citation Strydom, B. et al. 2011. 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase. European journal of medicinal chemistry, 46(8):3474-3485. [http://www.journals.elsevier.com/european-journal-of-medicinal-chemistry/] en_US
dc.identifier.issn 0223-5234
dc.identifier.issn 1768-3254 (Online)
dc.identifier.uri http://hdl.handle.net/10394/7436
dc.description Published under the auspices of the French Société de Chimie Thérapeutique (SCT) en_US
dc.description.abstract Recently it was reported that a series of 8-benzyloxycaffeine analogues are potent reversible inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to discover additional C8 oxy substituents of caffeine that lead to potent MAO inhibition, a series of related 8-aryl- and alkyloxycaffeine analogues were synthesized and their MAO-A and -B inhibition potencies were compared to those of the 8-benzyloxycaffeines. The results document that while the 8-substituted-oxycaffeine analogues inhibited both human MAO isoforms, they displayed a high degree of selectivity for MAO-B. 8-(3-Phenylpropoxy)caffeine, 8-(2-phenoxyethoxy)caffeine and 8-[(5-methylhexyl)oxy]caffeine were found to be the especially potent MAO-B inhibitors with IC50 values ranging from 0.38 to 0.62 μM. These inhibitors are therefore 2.5–4.6 fold more potent MAO-B inhibitors than is 8-benzyloxycaffeine (IC50 = 1.77 μM). It is also demonstrated that, analogous to 8-benzyloxycaffeine, halogen substitution on the phenyl ring of the C8 substituent significantly enhances MAO binding affinity. For example, the most potent MAO-B inhibitor of the present series is 8-[2-(4-bromophenoxy)ethoxy]caffeine with an IC50 value of 0.166 μM. This study also reports possible binding orientations of selected oxy caffeines within the active site cavities of MAO-A and MAO-B. en_US
dc.language.iso en en_US
dc.publisher Elsevier en_US
dc.subject Monoamine oxidase en_US
dc.subject reversible inhibition en_US
dc.subject 8-Aryloxycaffeine en_US
dc.subject 8-Alkyloxycaffeine en_US
dc.subject caffeine en_US
dc.subject molecular docking en_US
dc.title 8-Aryl- and alkyloxycaffeine analogues as inhibitors of monoamine oxidase en_US
dc.type Article en_US

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