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testing the even more sterically crowded 7-{[(E)-3-(5-
phenyl-5-methyl-4-oxo-4,5-dihydro-2-furanyl)-2-prope-
nyl]oxy}-2H-chromen-2-one (10) and the 7-{[(2E, 4E)-6-
oxo-2,4-heptadienyl]oxy}-2H-chromen-2-one (13).
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The latter can be considered an open analogue of 6,
lacking the bulky gem-dimethylfuranone substructure.
Compound 10, as expected, was one of the less active
compounds prepared by us, whereas the even lower
activity of the open analogue 13 was quite surprising.
Evidently, the likely positive effect arising from the
removal of the steric crowding of the furanone moiety is
cancelled by other structural features, such as a higher
conformational flexibility and/or the lack of an sp3
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well documented,15,16,19 we calculated the partition
coefficients of our compounds using the CLOG P pro-
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nity. It is worth nothing that this result may be indica-
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shown by compounds of either high or low lipophilicity.
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In summary, we discovered that geiparvarin and some
of its analogues are potent and selective MAO-B inhib-
itors. These findings may be kept well in mind in the
design of new geiparvarin derivatives targeting other
important physiopathological conditions.28
20. Kennedy, R. O; Thornes, R. D., Eds.; Coumarins: Biol-
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Structural modifications on either the coumarin or the
furanone moiety of geiparvarin 1 are deleterious for MAO
activity. In contrast, removal of the methyl group on the
alkenoxy bridge afforded derivative 6 which displayed the
highest MAO-B inhibitory potency (pIC50=7.55) with an
outstanding 850-fold selectivity for the MAO-B isoform.
28. Bocca, C.; Gabriel, L.; Maglietta, A. Chem. Biol. Interact.
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Acknowledgements
30. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron
2002, 58, 4851.
The Italian authors wish to thank MIUR (Rome, Italy)
for financial support.
31. Conformational analysis of inhibitor 3 was performed by
means of the CONF module implemented within the QXP
software package (Rel.2001, available upon request from C.
McMartin at cmcma@ix,netcom.com). 1000 Monte Carlo
runs were performed followed by conjugate gradient mini-
mization. The molecular superposition was made as follows:
the centroids of the two aromatic rings of the coumarin system
References and Notes
1. Bach, A. W. L.; Lan, N. C.; Johnson, D. L.; Abell, C. W.;