In the present study, a series of 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The 3,4-dihydro-2(1H)-quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives which have been reported to act as MAO-B inhibitors. The results document that the quinolinones are highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. An analysis of the structure-activity relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro-2(1H)-quinolinone scaffold leads to significantly more potent inhibition compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and phenylpropoxy substitution on this position. It may be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising leads for the therapy of Parkinson's disease.
Keywords: 3,4-Dihydro-2(1H)-quinolinone; Monoamine oxidase; Reversible inhibition; Selectivity; Structure–activity relationship.
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