Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates

Article abstract of DOI:10.1021/jm701491k

In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1-14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1-13 showed good cholinesterases inhibitory activities in vit

Full text of DOI:10.1021/jm701491k

J. Med. Chem. 2008, 51, 713–716
713
Letters
major drugs approved for the clinical treatment of AD.3,4 The
rationale for its use was related to the elevation of ACh levels
that can compensate for the cholinergic deficiency associated
with the brain lesions in patients with AD. Nevertheless, the
deficiency of tacrine in clinic has been related mainly to elevated
liver transaminase levels and dose-related, low-selective pe-
ripheral cholinergic effects. And it can halt the progression of
AD for only about a year.5,6 Thus, the search for tacrine
analogues or related new candidates is still of interest to
medicinal chemists involved in AD research.
Synthesis and Biological Evaluation of
NO-Donor-Tacrine Hybrids as
Hepatoprotective Anti-Alzheimer Drug
Candidates
Lei Fang,†,‡ Dorothea Appenroth,§ Michael Decker,†,
Michael Kiehntopf,# Carolin Roegler,† Thomas Deufel,#
Christian Fleck,§ Sixun Peng,‡ Yihua Zhang,*,‡ and
Jochen Lehmann*,†
Developing novel agents with multiple effects is one of
common strategies in today’s search for new treatments of
AD.7,8 Many such compounds have been reported, such as
homodimeric tacrine congeners,9 lipoic acid-tacrine hybrids,10
tacrine-dihydropyridine hybrids,11 galantamine-nitrate deriva-
tives,12 and so on. The activity of many of these compounds
has been improved by the introduction of the second pharma-
cophores. Here we have designed and synthesized a series of
tacrine hybrids with NO-donating nitrato- and diazeniumdiolate
(NONOate) moieties connected via an alkylenediamine-type
spacer. NO-releasing derivatives have currently come into focus
in the treatment of cancer, inflammation, and vascular diseases.
Some of them have performed fairly well because NO is a key
signaling molecule involved in the regulation of many physi-
ological processes.13 NO is also reported to play an important
role in the nervous system and some NO donors or NO mimetic
molecules have had a positive effect on the treatment of AD.14
Though the mechanism is not yet clear, two effects of NO might
be very important: it increases blood supply and it relieves
inflammatory reactions in the brain, both of which are thera-
peutically beneficial for patients with AD. In the design of the
target molecules, an alkylenediamine side chain is introduced
at the 9-position of the tacrine-like heterocycle. The side chain
is considered to be not only as a spacer between tacrine and
the NO donor, but also beneficial for inhibiting the periphery
anion site (PAS) of AChE,10 which is thought to relate to the
neurotoxic cascade of AD through AChE-induced amyloid-ꢀ
aggregation.15 In addition, a protonatable nitrogen containing
side chain of the tacrine-like heterocycle has been suggested to
significantly improve the inhibitory potency of cholinesterase
(ChE) because of the interaction with the midgorge recognition
site.16 Therefore, the rationale of the target compounds is a
synergic action of the NO donor, the tacrine-like heterocycle
and the alkylenediamine spacer might yield potent but less toxic
drug candidates for the better and safer treatment of AD.
Institute of Pharmacy, Institute of Pharmacology and Toxicology,
and Institute of Clinical Chemistry, Friedrich-Schiller-UniVersity
Jena, D-07743 Jena, Germany, Center of Drug DiscoVery, China
Pharmaceutical UniVersity, 210009 Nanjing, People’s Republic of
China, and Medicinal Chemistry Program, McLean Hospital,
HarVard Medical School, Belmont, Massachusetts 02478
ReceiVed NoVember 30, 2007
Abstract: In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine
hybrids (1-14) were synthesized and evaluated for their ability to inhibit
cholinesterases and for vasorelaxation effects. Compounds 1-13
showed good cholinesterases inhibitory activities in vitro, while 14,
particularly, was highly selective, preferring butyrylcholinesterase rather
than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14)
moderately relaxed the porcine pulmonary arteries in organ bath. In
the hepatotoxicity study, significant hepatotoxicity was caused by tacrine
but not by 9.
Alzheimer’s disease (ADa) is recognized as one of the most
severe conditions affecting the aged and is life-threatening for
this group of people. The disease is characterized by neuronal
loss, synaptic damage, and vascular plaques. Many pathologic
factors, such as the deficiency of synaptic acetylcholine (ACh)
and other related neurotransmitters, the formation of neuritic
and vascular plaque, poor blood supply in the brain, and the
inflammation of neurons, are known to cause this disease.1 Over
time, the knowledge about pathogenesis and the development
of the neurodegeneration associated with AD has been organized
into two main theories, namely, the cholinergic and the amyloid
hypotheses, which focus on the loss of cholinergic neurotrans-
mission and the emergence of the toxic amyloid plaque,
respectively.2 To date, most of the therapeutic strategies for
patients with AD are based on these two theories. Tacrine, a
reversible acetylcholinesterase inhibitor (AChEI), is one of the
The synthesis of amine- and amide-linked nitrate- and
NONOate-tacrine hybrids is outlined in Schemes 1 and 2.
Because an alkylenediamine side chain was introduced to the
hybrids, the synthesis did not utilize tacrine itself as a starting
material, but 9-chloro-1,2,3,4-tetrahydroacridine17 was reacted
with alkylenediamines to produce the important intermediates
9-aminoalkylamino-1,2,3,4-tetrahydroacridines 15a,b. To syn-
thesize the amine-linked tacrine hybrids 5–10, the bromoalkanols
were nitrated by 100% HNO3 and, subsequently, the bro-
moalkylnitrates were condensed with 15 to yield the target
compounds. Intermediates 15a,b were acylated by the corre-
sponding bromoacyl chloride to give the halogenated intermedi-
ates 16a-d and then conveniently converted to the amide-linked
* To whom correspondence should be addressed. Tel: +49-3641-94-
9803 (J.L.); +86-25-86635503 (Y.Z.). Fax: +49-3641-94-9802 (J.L.);
+86-25-86635503 (Y.Z.). E-mail: j.lehmann@uni-jena.de (J.L.); zyhtgd@
sohu.com (Y.Z.).
†
Institute of Pharmacy, Friedrich-Schiller-University Jena.
China Pharmaceutical University.
Institute of Pharmacology and Toxicology, Friedrich-Schiller-University
‡
§
Jena.
Harvard Medical School.
Institute of Clinical Chemistry, Friedrich-Schiller-University Jena
Abbreviations: AD, Alzheimer’s disease; ACh, acetylcholine; AChEI,
#
a
acetylcholinesterase inhibitor; PAS, peripheral anionic site; ChE, cholines-
terase; HMPA, hexamethylphosphotriamide; CDI, N,N′-carbonyldiimidazole;
BuChE, butyrylcholinesterase; ISDN, isosorbide dinitrate; ASAT, aspartate
aminotransferase; LDH, lactate dehydogenase.
10.1021/jm701491k CCC: $40.75
2008 American Chemical Society
Published on Web 01/31/2008

714 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Scheme 1. General Method for the Synthesis of 1-12a
Letters
a Reagents and conditions: (a) POCl3, reflux, 3 h; (b) H2N(CH2)mNH2, pentanol, reflux, 18 h; (c) 100% HNO3, CH2Cl2, -5 °C; (d) K2CO3, CH2Cl2, 24 h,
rt; (e) Br(CH2)mCOCl, CH2Cl2, -5 °C, 0.5 h; (f) CH3CN, AgNO3, reflux, 8 h; (g) CH3OH, Na; (h) K2CO3, HMPA, 72 h, rt.
Scheme 2. General Method for the Synthesis of 13 and 14a
Table 1. Inhibition of AChE and BuChE (IC50 Values) and Selectivity
Expressed as the Ratio of the Resulting IC50 Values
IC50 (nM) ( SEMa
cmpd
AChE
BuChE
selectivity ratiob
1
2
3
4
5
6
7
8
28.2 ( 4.0
93.0 ( 37
22.6 ( 7.4
45.7 ( 14
10.0 ( 2.3
6.4 ( 0.5
13.5 ( 3.1
28.0 ( 14
12.1 ( 3.1
15.1 ( 3.2
5.2 ( 1.4
5.5 ( 1.8
21.7 ( 9.7
13.8 ( 0.9
9.9 ( 1.1
10.8 ( 1.5
15.3 ( 4.7
41.0 ( 5.6
5.5 ( 1.3
7.3 ( 2.0
36.5 ( 3.7
5.1 ( 1.0
2.1
3.3
1.9
3.0
1.9
1.2
0.3
0.8
0.6
1.7
2.3
1.2
12.6
31.0
0.6
8.8
6.3 ( 0.6
11.1 ( 2.4
5.6 ( 0.7
9
10
11
12
13
14
21
tacrine
18.1 ( 3.6
35.5 ( 3.8
50.7 ( 7.5
69.5 ( 9.2
226.0 ( 91
21.6 ( 2.7
45.1 ( 6.9
a Data is the mean of at least three determinations. b Selectivity ratio )
(IC50 of AChE)/(IC50 of BuChE).
The ChE inhibitory activity of 1-14 was measured in vitro
using Ellman’s assay20,21 (Table 1). With the exception of 14
(226.0 nM), all target compounds showed good inhibitory
activity against AChE with IC50 values varying from 5.2 to 93
nM. Compared to tacrine (45 nM), the potency of 6, 7, and 9
(6.4, 6.3, and 5.6 nM) is 7 ∼ 8-fold improved. The effect levels
of all compounds against butyrylcholinesterase (BuChE) were
also similar to tacrine (5.1 nM) with IC50 values varying from
5.2 to 41.0 nM. These results seem consistent with the previous
reports of lipoic acid-tacrine hybrids10 and huperzine A-tacrine
hybrids.16 Among all of the compounds, compound 6 and 9
showed potent inhibitory effects on both AChE and BuChE,
while 14 seems special, showing a significant selectivity toward
BuChE with a 31-fold selective ratio. BuChE inhibition has
a Reagents and conditions: (a) 100% HNO3, CH2Cl2, 1.5 h, rt; (b) NaOH,
ethanol, 3 h, rt; (c) CDI, CH2Cl2, 1.5 h, rt; (d) 15, 3 h, rt.
nitrates 1–4 by treatment with AgNO3 in dry CH3CN. For the
NONOate derivatives 11 and 12, compound 18 was first
prepared according to a previously reported protocol18 and then
reacted with 16 in HMPA in the presence of K2CO3 to offer
the target compounds. Pivalic acid was also used as a further
spacer, resulting in 13, 14, and analogue 21. Compound 2019
or pivalic acid was activated by CDI and then reacted with 15
to give the corresponding product.

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 715
recently been regarded as therapeutically beneficial for AD,
because BuChE seems able to act as an alternative to compen-
sate AChE for processing of AD.22 The selectivity of 14 is likely
due to the large steric hindrance of the spacer. At the midgorge
level AChE and BuChE differ in their amino acid composition,
because AChE presents several aromatic residues that are
replaced by smaller aliphatic ones in BuChE. These structural
differences are supposed to be responsible for the larger
electrostatic gradient and for the narrower void along the AChE
gorge with respect to BuChE.23 Given the considerable steric
demand of 14, it seems understandable that 14 binds to BuChE
much more easily than to AChE. To determine the influence of
the nitrate group on the selectivity of BuChE, compound 21
was also synthesized and screened for its ability to inhibit ChEs.
The results showed the ability of 21 to inhibit AChE (21.6 nM)
is significantly improved compared to 14 (226.0 nM), while
the ability to inhibit BuChE is reduced. Thus, the selectivity
toward BuChE disappears, which indicates the nitrate group of
14 may be necessary for developing such selectivity, though
whether the influence of the nitrate group originates from the
electrostatic effect or the steric hindrance remains unclear.
The poor blood supply to the brain has recently been
considered an important pathologic factor initiating the progres-
sion of AD. NO donors can significantly increase blood supply
by relaxing vessels.24 To determine their vasorelaxation effects,
compounds 1, 9, 11, and 14, which effectively inhibited ChEs
in vitro and stand for the amide-linked nitrate derivatives, amine-
linked nitrate derivatives, NONOate derivatives, and pivalic
acid-linked derivatives, respectively, were selected for use in
an in vitro vascular relaxation assay (organ bath) using PGF2R-
precontracted porcine pulmonary arteries. Isosorbide dinitrate
(ISDN) and tacrine were chosen as positive and negative
controls, respectively. The results are shown in Figure 1.
Expectedly, ISDN showed the strongest activity with an EC50
value of 0.42 µM. Compared to tacrine, compounds 1, 9, and
14 showed moderate vasorelaxation effects with EC50 values
varying from 3.68 to 10.47 µM, while the activity of 11 is
relatively low, with an EC50 value of 22.54 µM. In this tacrine-
NONOate hybrid, the NONOate moiety is protected prodrug-
like and, thus, can not spontaneously release NO under the in
vitro conditions of the organ bath.
Figure 1. Concentration–response curves for the vasorelaxant effects
of tacrine, ISDN, and compounds 1, 9, 11, and 14 on PGF2R (3 mM)-
precontracted porcine pulmonary arteries in vitro. Data are means (
SEM from 4 to 6 independent experiments.
of the parent compound, compound 9 was chosen to be tested
its hepatotoxicity. After equimolar doses of tacrine and 9 were
administered, levels of aspartate aminotransferase (ASAT),
lactate dehydogenase (LDH) and albumin in serum as well as
the concentration of protein in liver tissue were investigated
(Table 2). Compared to the control, significant hepatotoxicity
was caused by tacrine, as indicated by the increased activity of
the ASAT and LDH as well as by the reduced concentration of
albumin and protein in liver tissue. In contrast, the values in
compound 9 group appeared to remain unchanged. Clearly,
compound 9 did not show any hepatotoxicity, but tacrine did.
In summary, we have designed and synthesized 14 novel tacrine
hybrid compounds with NO-donating nitrate and NONOate
moieties connected to the tacrine template via an alkylenediamine-
type spacer. All compounds effectively inhibited ChEs in vitro.
Three target compounds (6, 7, and 9), in particular, showed 7 ∼
8-fold higher AChE inhibitory activity compared to tacrine, while
compound 14 was found to be selective toward BuChE rather than
AChE. Compounds 1, 9, 11, and 14 moderately relaxed the porcine
pulmonary arteries in in vitro vasorelaxation experiments (organ
bath), aided by the NO donor part of the molecule. In the in vivo
hepatotoxicity studies, tacrine, but not compound 9, was found to
cause serious hepatotoxicity. The results suggest that these NO-
donor-tacrine hybrids, especially compound 9, may be considered
to be novel more potent and safer anti-Alzheimer’s drug candidates.
The hepatotoxicity is a main limitation for the clinical use
of tacrine. It is reported to elevate levels of liver transaminase
and decrease albumin concentration.25 NO production in the
liver is usually increased in response to acute insult with
hepatotoxicants and may become a mediator of the tissue
damage.26 Some NO donors, like V-PYRRO/NO27 and nitrate,28
are reportedly able to prevent the liver from injury. To determine
whether the introduction of a NO donor could improve the safety
Acknowledgment. The financial support of “DAAD Sand-
wich Program” Scholarship (08. 2006 ∼ 09. 2008) is very
gratefully acknowledged. Appreciation is expressed to Mrs. Petra
Wiecha for the technical assistance.
Supporting Information Available: Experimental procedures
for the synthesis of 1-14 and detailed procedures of pharmacologi-
Table 2. Influence of Equimolar Doses (5.93 µmol/100 g b.wt.) of Tacrine and 9 on the Activity of ASAT and LDH, as well as the Albumin
Concentration in Serum, and Protein Concentration in Liver Tissuea
serum
liver tissue
ASAT [µmol/s]
albumin [g/l]
LDH [µmol/s]
protein [mg/g]
time
tacrine
cmpd 9
tacrine
cmpd 9
tacrine
cmpd 9
tacrine
cmpd 9
before
12 h
20 h
36 h
2.5 ( 0.3
4.5 ( 0.8b
3.4 ( 0.3
3.1 ( 0.4
2.1 ( 0.2
2.3 ( 0.2
2.8 ( 0.4
2.1 ( 0.2
16.3 ( 0.5
16.0 ( 0.4
15.0 ( 0.2b
13.1 ( 0.3b
16.7 ( 0.5
16.6 ( 0.5
17.1 ( 0.6
15.1 ( 0.7
4.2 ( 0.8
5.5 ( 0.9
10.0 ( 3.2b
6.5 ( 1.5
4.6 ( 0.6
4.4 ( 0.6
5.6 ( 0.3
4.1 ( 0.4
138 ( 1
n.d.
n.d.
143 ( 1
123 ( 9
118 ( 4
92 ( 2b
a Results are compared to control values before the administration. b Statistical significant difference to control values before administration (Student’s
t-test, p e 0.05, n ) 3–6).

716 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
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JM701491K