1534
Z.-J. Zhan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1532–1534
Table 1
vetted as a strong inhibitor of AChE with significantly high selectiv-
ity over BChE. BChE is a serine hydrolase, produced in the liver and
enriched in the circulation. In addition, it is also present in adipose
tissue, intestine, smooth muscle cells, white matter of the brain,
and many other tissues.13 Unlike AChE, which plays a vital role
in the central and peripheral nervous systems, the physiological
function of BChE remains unclear.14,15 Despite having no identified
endogenous substrate, BChE plays a key role in detoxification, by
degrading esters such as succinylcholine and cocaine.16,17 Herein,
Compound 17 can be used as a lead compound for further optimi-
zation for the potential use of treatment of AD.
50% Inhibitory concentration of compounds against AChE and BChE
No.
IC50 (nM)
Selectivity
AChE
BChE
7.6
103.7
61.3
14.9
5.8
105.4
1021.6
88.7
1a
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1.0
11.9
914.3
168.1
29.9
38.7
441.8
264.3
66.5
66.2
6.4
Sevenfold AChE
10-fold AChE
15-fold BChE
Sevenfold BChE
Fivefold BChE
Threefold AChE
Twofold AChE
Threefold BChE
—
Eightfold AChE
18-fold AChE
—
Eightfold AChE
—
39.6
516.8
113.5
8.5
935.3
829.9
14.1
Acknowledgment
7.3
The financial support of the Natural Science Foundation of PR
China (20702049) is gratefully acknowledged.
113.0
735.0
4.2
Threefold AChE
174-fold AChE
8.5
1397.5
Supplementary data
a
Physostigmine and phenserine were used as positive controls.
Supplementary data associated with this article can be found, in
As shown in Table 1, most of physostigmine derivatives showed
potent inhibition against AChE, especially 12 and 13 exhibiting the
same level of activities as physostigmine. The reason could be that
all these derivatives retained the carbamoyl group, the pharmaco-
phore of physostigmine.6 Apparently these derivatives only con-
taining electron-withdrawn substituent (Cl, Br, CN) reduced their
AChE potencies (4, 5, 8, and 9) comparing to phenserine (3) and
its analogues,6g In contrast, methyl/methoxyl groups, electron-do-
nor substituent maintained or improved their AChE potencies. In
particular, compound 12 displayed nearly twofold improvement
in AChE potency and only a marginal decline in BChE activity to af-
ford an AChE selectivity of 18-fold. On the other hand, compound
15, an analogue with larger size electron-donor substitution (iso-
propyl) in 20 and 60 position of phenyl, almost lost its inhibition
against AChE. Furthermore, those analogues with substitution in
para-position of phenyl reduced their AChE potencies (4, 5, and
6) comparing to phenserine, even if the substitution was elec-
tron-donor. These results clearly showed that small electron-donor
substituents in meta- or ortho-position of phenyl are better choices
for the retention of AChE inhibition potency.
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