4642
D. Shao et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4639–4642
Lieu, Y. P.; Wong, H. S.; Pang, Y. P. Bioorg. Med. Chem.
1999, 7, 351; (c) Carlier, P. R.; Chow, E. S. H.; Han, Y. F.;
Liu, J.; El, Y. J.; Pang, Y. P. J. Med. Chem. 1999, 42, 4225.
5. (a) Camps, P.; Achab, R. E.; Morral, J.; Torrero, D. M.;
Badia, A.; Banos, J. E.; Vivas, N. M.; Barril, X.; Orozco,
M.; Luque, F. J. J. Med. Chem. 2000, 43, 4657; (b) Camps,
P.; Achab, R. E.; Gorbig, D. M.; Morral, J.; Torrero, D.
M.; Badia, A.; Banos, J. E.; Vivas, N. M.; Barril, X.;
Orozco, M.; Luque, F. J. J. Med. Chem. 1999, 42, 3227; (c)
Carlier, P. R.; Du, D. M.; Han, Y.; Liu, J.; Pang, Y. P.
Bioorg. Med. Chem. Lett. 1999, 9, 2335.
6. McKenna, M.; Proctor, G. R.; Young, L. C.; Harvey,
A. L. J. Med. Chem. 1997, 40, 3516.
7. Savini, L.; Campiani, G.; Gaeta, A.; Pellerano, C.;
Fattorusso, C.; Chiasserini, L.; Fedorko, J. M.; Saxena,
A. Bioorg. Med. Chem. Lett. 2001, 11, 1779.
8. Marco, J. L.; Rios, C.; Carreiras, M. C.; Banos, J. E.;
Badia, A.; Vivas, N. M. Bioorg. Med. Chem. 2001, 9, 727.
9. Tabarrini, O.; Cecchetti, V.; Temperini, A.; Filipponi, E.;
Lamperti, M. G.; Fravoloni, A. Bioorg. Med. Chem. 2001,
9, 2921.
10. Rios, C.; Marco, J. L.; Carreiras, M. D. C.; Chinchon, P.
M.; Garcia, A. G.; Villarroya, M. Bioorg. Med. Chem.
2002, 10, 2077.
through its four major functional groups: the benzyl
moiety, the piperidine nitrogen, the nitrogen–hydrogen
of the amide, and the acridine moiety. Near the bottom
of the gorge, one face of the benzyl ring displays classic
parallel p–p stacking with the six-membered ring of the
˚
Trp84 indole, the ring-to-ring distance is 3.62A between
Trp84 and the benzyl ring. In the constricted region,
halfway up the gorge, the charged nitrogen of the piperi-
dine ring makes a cation–p interaction with the phenyl
˚
ring of Phe330, with the distances of 4.61A between
the nitrogen and the aromatic ring. The nitrogen–hydro-
gen of the amide makes an hydrogen bond with the oxy-
˚
gen of Tyr121, the distance is 3.4A. At the top of the
gorge the acridine ring stacks against the indole of
Trp279, in the peripheral binding site, by a classical p–
˚
p interaction with the distances of 3.75A.
˚
In the homolog the molecular chain length of 3 is 16.8A,
it approaches in the distance of the two tacrine-binding
sites,4a which is 16A, 3 derives its potency and selectivity
˚
from simultaneous binding to the peripheral and cata-
lytic sites of AChE.
11. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.;
Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 1053.
5. Conclusion
12. Marco, J. L.; Rios, C.; Garcia, A. G.; Villarroya, M.;
Carreiras, M. C.; Martins, C.; Eleuterio, A.; Morreale, A.;
Orozco, M.; Luque, F. J. Bioorg. Med. Chem. 2004, 12,
2199.
13. Kawakami, Y.; Inoue, A.; Kawai, T.; Wakita, M.;
Sugimoto, H.; Hopfinger, A. Bioorg. Med. Chem. 1996,
4, 1429.
In summary, the hybrids of tacrine–E2020 and some re-
lated compounds were synthesized and their bioactivi-
ties on AD were assayed. The optimum inhibitor 3 is
much more potent and selective than tacrine. The mode-
ling studies clearly indicate that ligand 3 is nicely accom-
modated by AChE, engaging in appropriate hydrogen
bond interactions. It is useful for the modification of
the hybrids and design of new AChE inhibitors. Further
studies on hybrids are in progress and will be reported in
due course.
14. 3 (fumaric salt) mp 186–188°C (d) 1H NMR (400MHz,
DMSO-d6, ppm): d 8.24 (t, 1H, J=5.6Hz), 8.18 (d, 1H,
J=8.4Hz), 7.88 (d, 1H, J=8.5Hz), 7.73 (t, 1H, J=7.2Hz),
7.45 (t, 1H, J=7.2Hz), 7.37–7.26 (m, 5H), 7.14 (br s, 1H),
6.58 (s, 2H), 4.35 (s, 2H), 3.68 (s, H), 3.14 (q, 2H,
J=6.5Hz), 2.97 (br s, 2H), 2.90 (br d, 2H, J=12.1Hz),
2.69(br s, 2H), 2.15 (t, 2H, J=10.0Hz), 1.83–1.81 (m, 4H),
1.64 (d, 2H, J=11.7Hz), 1.35–1.21 (m, 5H) 13C NMR
(100MHz DMSO-d6, ppm): 168.3, 166.8, 154, 152.8,
140.4, 134.8, 134.5, 131.3, 129.9, 128.3, 127.9, 124.5,
124.2, 121.8, 116.7, 112.3, 60.7, 52.1, 49.4, 36.2, 35.3, 31.6,
30.1, 29.4, 23.6, 21.7, 20.9; IR (KBr): 3291, 2942, 1714,
1677, 1276, 1188, 983, 630cmÀ1: EI-MS MS (m/z): 456
(M+). Anal. Calcd for C29H36N4OÆC4H4O4: C 69.21, H
7.04, N 9.78. Found: C 68.92, H 7.01, N 9.74.
References and notes
1. Bartus, R. T.; Dean, R. L.; Beer, B.; Lippa, A. S. Science
1982, 217, 489.
2. Davis, K. L.; Powchik, P. Lancet 1995, 345, 625.
3. Gracon, S. I.; Berghoff, W. G. In Pharmacological
Treatment of Alzheimer’ Disease. Molecular and Neurobi-
ological Foundations; Brioni, J. D., Decker, M. W., Eds.;
Wiley-Liss Inc: New York, 1997; pp 389–408.
4. (a) Pang, Y. P.; Quiram, P.; Jelacic, T.; Hong, F.;
Brimijoin, S. J. Biol. Chem. 1996, 271, 23646; (b) Carlier,
P. R.; Han, Y. F.; Chow, E. S. H.; Li, C. P. L.; Wang, H.;
15. Ellman, G. L.; Courtney, K. D.; Andres, V. J.; Feather-
stone, R. M. Biochem. Pharm. 1961, 7, 88.
16. Kryer, G.; Silman, I.; Sussman, J. L. Structure 1999, 7,
297.