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

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.

The synthesis of 8-aryl- and alkyloxycaffeine analogues (5) with enhanced MAO-B inhibition potencies compared the lead compound, 8-benzyloxycaffeine (2).Figure optionsDownload as PowerPoint slideHighlights
► 8-(2-Phenoxyethoxy)caffeine is identified as a new promising lead for reversible inhibition of MAO-B.
► Halogen substitution on the phenyl ring further enhances binding affinity to MAO-B.
► Alkyloxycaffeine analogue, 8-[(5-methylhexyl)oxy]caffeine, surprisingly also acts as a potent MAO-B inhibitor.
► For aryloxy substituted caffeiens, a linker consisting of 4 atoms is optimal for MAO-B inhibition.