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Previous studies have documented that substituted 8-oxycaffeines act as inhibitors of human monoamine oxidase (MAO) B. A particularly potent inhibitor among the reported compounds was 8-(2-phenoxyethoxy)caffeine with an IC50 value of 0.383 µM towards MAO-B. In an attempt to improve on the inhibition potency of this compound and to discover highly potent reversible MAO-B inhibitors, in the present study, a series of 8-(2-phenoxyethoxy)caffeine analogues containing various substituents on C4 of the phenoxy ring, were synthesized and evaluated as inhibitors of human MAO-A and -B. The results show that the 8-(2-phenoxyethoxy)caffeine analogues are selective and reversible MAO-B inhibitors with the most potent homologue, 8-{2-[4-(trifluoromethyl)phenoxy]ethoxy}caffeine, exhibiting an IC50 value of 0.061 μM. These highly potent inhibitors are useful leads in the design of therapies for neurodegenerative disorders such as Parkinson's disease.

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