1482
K. Watanabe et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1478–1483
Table 3. Memory-improving activity
Compound
R1
R2
Lipid peroxidation inhibitory
activity IC50 (lM)
Memory-improving activity
MED (mg/kg, po)
17
19
32
35
36
37
38
39
40
41
43
44
45
47
51
52
53
61
62
64
69
71
77
78
79
CH3
CH3
n-C4H9
n-C4H9O
i-C4H9
10.7
5.1
7.8
4.5
6.6
9.0
7.3
10.0
8.4
5.7
4.0
7.9
6.9
9.7
6.3
8.1
6.7
91
0.1
0.3
CH3
CH3
30
a
n-C5H11O
(CH3)2CH(CH2)2O
n-C6H13
a
CH3
CH3
0.3
a
CH3
CH3
n-C6H13
c-C6H11
n-C7H15
n-C7H15
n-C8H17
O
0.1
30
CH3
CH3
a
O
O
CH3
CH3
30
n-C10H21
n-C10H21
n-C12H25
Ph
0.3
0.1
0.1
CH3
CH3
O
O
CH3
CH3
0.3
a
PhO
PhCH2O
a
a
a
a
CH3
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
n-C5H11
(CH3)2CH(CH2)2O
O
7.2
8.5
8.5
10.5
10.9
7.9
8.3
n-C6H13
n-C8H17
O
O
30
n-C10H21
O
0.1
0.1
0.1
0.1
Ph
PhO
PhCH2O
MED, minimal effective dose.
a Not active at 0.1 mg/kg, po.
12. Chauhan, V.; Chauhan, A. Pathophysiology 2006, 13, 195.
13. Dexter, D. T.; Carter, C. J.; Wells, F. R.; Javoy-Agid, F.;
Agid, Y.; Lees, A.; Jenner, P.; Marsden, C. D.
J. Neurochem. 1989, 52, 381.
14. Alam, Z. I.; Jenner, A.; Daniel, S. E.; Lees, A. J.; Cairns,
N.; Marsden, C. D.; Jenner, P.; Halliwell, B. J. Neuro-
chem. 1997, 69, 1196.
Acknowledgments
The authors thank Dr. Dino Nisato and Dr. Hiroshi
Tanaka for critical reading of the manuscript.
References and notes
15. Selley, M. L. Free Radical Biol. Med. 1998, 25, 169.
16. Zhang, Y.; Dawson, V. L.; Dawson, T. M. Neurobiol. Dis.
2000, 7, 240.
17. Foley, P.; Riederer, P. J. Neurol. 2000, 247(Suppl. 2), II82.
18. Halliwell, B. J. Neurochem. 1992, 59, 1609.
1. Sies, H. Antioxidants in Disease Mechanism and Therapy;
Academic Press: San Diego, CA, 1997.
2. Barnham, K. J.; Masters, C. L.; Bush, A. I. Nat. Rev. Drug
Discov. 2004, 3, 205.
`
19. Carrı, M. T.; Ferri, A.; Cozzolino, M.; Calabrese, L.;
3. Sayre, L. M.; Smith, M. A.; Perry, G. Curr. Med. Chem.
2001, 8, 721.
4. Mariani, E.; Polidori, M. C.; Cherubini, A.; Mecocci, P. J.
Chromatogr. B 2005, 827, 65.
5. Markesbery, W. R. Free Radic. Biol. Med. 1997, 23, 134.
6. Markesbery, W. R.; Carney, J. M. Brain Pathol. 1999, 9,
133.
Rotilio, G. Brain Res. Bull. 2003, 61, 365.
20. Barber, S. C.; Mead, R. J.; Shaw, P. J. Biochim. Biophys.
Acta 2006, 1762, 1051.
21. Schmidley, J. W. Stroke 1990, 21, 1086.
22. Peters, O.; Back, T.; Lindauer, U.; Busch, C.; Megow, D.;
Dreier, J.; Dirnagl, U. J. Cereb. Blood Flow Metab. 1998,
18, 196.
7. Smith, M. A.; Rottkamp, C. A.; Nunomura, A.; Raina, A.
K.; Perry, G. Biochem. Biophys. Acta 2000, 1502, 139.
8. Arlt, S.; Beisiegel, U.; Kontush, A. Curr. Opin. Lipidol.
2002, 13, 289.
23. Love, S. Brain Pathol. 1999, 9, 119.
24. Abe, K.; Yuki, S.; Kogure, K. Stroke 1988, 19, 480.
25. Nishi, H.; Watanabe, T.; Sakurai, H.; Yuki, S.; Ishibashi,
A. Stroke 1989, 20, 1236.
9. Giasson, B. I.; Ischiropoulos, H.; Lee, V. M.-Y.; Troja-
nowski, J. Q. Free Radical Biol. Med. 2002, 32, 1264.
10. Butterfield, D. A.; Lauderback, C. M. Free Radical Biol.
Med. 2002, 32, 1050.
11. Zaprilla, P.; Mulero, J.; Xandri, J. M.; Santo, E.;
Caravaca, G.; Morillas, J. M. Curr. Med. Chem. 2006,
13, 1075.
26. Kawai, H.; Nakai, H.; Suga, M.; Yuki, S.; Watan-
abe, T.; Saito, K. J. Pharmacol. Exp. Ther. 1997,
281, 921.
27. The edaravone acute brain infarction study group. Car-
diovasc. Dis. 2003, 15, 222.
28. Watanabe, K.; Morinaka, Y.; Iseki, K.; Watanabe, T.;
Yuki, S.; Nishi, H. Redox Rep. 2003, 8, 151.