Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease

• The multi-target compound, ASS234, inhibits cholinesterases and monoamine oxidases.
• The rate of inactivation of monoamine oxidase A by ASS234 is similar to clorgyline.
• MAO B-ASS234 adduct crystal structure shows modification of the flavin cofactor.
• ASS234 selectivity of 105 for MAO A comes from the low Ki and low partition ratio.

Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/KI = 3 × 106 min− 1 M− 1) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor.

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