A novel series of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones as selective monoamine oxidase (MAO) A inhibitors

• C3- and C6-substituted coumarins were evaluated for MAO A and MAO B activity.
• A spaced basic amino function in C3-position is accepted for MAO A.
• 6-Amino and 6-hydroxy substituents were the most potent inhibitors of MAO A.
• Molecular modeling for 6-OH compound yielded interactions with Gln-215 and Phe-208.
• The in vitro findings were confirmed with in vivo data (DOPAC, 5-HIAA, 3-MT).

A series of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones (coumarins) have been synthesized and their inhibitory activity to human monoamine oxidase A (MAO A) and B (MAO B) determined. Incorporation of a basic amino function in the C3 position together with substitution at the C6 position produced novel coumarin compounds with selectivity for the MAO A subtype. Substitution in the C6 position with small hydrophilic groups such as hydroxy (19, IC50 = 1.46 μM) or amino (18, IC50 = 3.77 μM) gave the most potent and selective compounds for MAO A. These compounds also showed excellent aqueous solubility properties. Compound 18 [6-amino-3-(pyrrolidin-1-ylmethyl)chromen-2-one] administrated in vivo induced in rat brain a neurotransmitter metabolite profile typical of MAO A inhibition: decreased 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) but increased 3-methoxytyramine (3-MT) levels.

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