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Comparison of these data with previously reported
docking experiments with MAO-B inhibitors17 confirms
the role of residues TYR 345 and TYR 398 as lateral
cleft delimitation in the common binding pattern of
coumarin and 4,5-dihydro-(1H)-pyrazole derivatives.
The main difference between the two binding modes is
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In conclusion, in this work the synthesized coumarin-3-
acyl derivatives were tested against MAO-A and MAO-
B to assay their potency as inhibitors. Among the tested
derivatives we selected coumarin-3-carboxylic acids 2a–e
as potent anti-MAO agents, derivatives 2a and 2b being
highly selective against the MAO-B isoform. Coumarin-
3-acyl chlorides 3a–e showed strong anti-MAO activity
against both isoforms, especially compound 3d, which
shows the highest activity against MAO-B. Unfor-
tunately this compound showed a very low selectivity
index.
The bidimensional molecular descriptors generated in
our study cannot fully account for the inhibition of
activity and selectivity of our compounds against the
MAO-A and B enzymes. 3D descriptors based on the
solvent accessible surface qualitatively indicate the role
of the steric effect of ester derivatives (which are less
active) with respect to acid and chloride compounds
(which are more active). MAO-B docking experiments,
examined as the probability of occupancy of the enzyme
cleft, are crucial to improve the correlation with pIC50
and provide binding modes partially corresponding to
the interactions found with another series of inhibi-
tors.17 Availability of the MAO-A crystallographic
structure will be necessary to complete the correlation
study with selectivity inhibition data.
€
13. Bergstrom, M.; Westerberg, G.; Nemeth, G.; Traut, M.;
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The information from this study is important for the
rational drug design of more potent/selective MAO
inhibitors based on the coumarin scaffold.
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Acknowledgements
This work was supported by grants from MURST.
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References and notes
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and were used without purification. Bovine brain mito-
chondria (MAO) were isolated according to Basford.26 In
all experiments the AO activities of the beef brain
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according to Matsumoto et al.27 using kinuramine as a
substrate at four different final concentrations ranging
from 5 lM to 0.1 mM. Briefly, the incubation mixtures
contained: 0.1 mL of 0.25 M potassium phosphate buffer
(pH 7.4), mitochondria (6 mg/mL) and drug solutions with
a final concentration ranging from 0 to 10ꢁ3 lM.
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