Fine molecular tuning at position 4 of 2H-chromen-2-one derivatives in the search of potent and selective monoamine oxidase B inhibitors

The effects on the inhibition potencies of monoamine oxidase isoforms A (MAO-A) and B (MAO-B) depending upon changes in the physicochemical properties (size, shape, H-bonding, lipophilicity, etc.) of substituents at the C4 position of 2H-chromen-2-one derivatives were extensively investigated, and the results significantly added to our knowledge on this class of MAO inhibitors. All the 67 examined compounds showed high MAO-B selectivity, some of them achieving potency in the low nanomolar range. In particular, the 7-metachlorobenzyloxy-4-oxyacetamido-2H-chromen-2-one (entry 62) showed single digit nanomolar MAO-B potency (IC50 \ubc 3.1 nM) and high selectivity over the MAO-A isoform (selectivity ratio \ubc 7244). The great variety of the investigated substituents at C4 of the 2H-chromen-2- one nucleus, combined with binding models generated from docking studies carried out on selected compounds, allowed us to shed light on the main molecular requirements for potent and selective MAOB inhibition, highlighting the dominant role of the steric effects. Interestingly, many of the designed substituents could be metabolically related to each other (e.g., CH3/CH2OH/CHO/COOH; NH2/NHCH3, NHAc), and therefore the results obtained may help in predicting the in vivo activity of some putative metabolites of lead MAO-B inhibitors