Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors

Article abstract of DOI:10.1055/s-0032-1329963

The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl

Full text of DOI:10.1055/s-0032-1329963

Original Article 655
Synthesis, Biological Activity and Molecular Modeling
of 4-Fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-
9-ylamino)-alkyl]-benzamide Derivatives as
Cholinesterase Inhibitors
Authors
P. Szymański1, M. Markowicz1, M. Bajda2, B. Malawska2, E. Mikiciuk-Olasik1
Affiliations
1 Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
2 Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow,
Poland
Key words
Abstract
compounds 4a and 4d. These compounds, in
comparison with tacrine, were characterized by
the similar values of IC50. Among all obtained
compounds, 4d presented the highest selectivity
towards inhibition of acetylcholinesterase.
Molecular modeling studies revealed that all
derivatives presented similar extended confor-
mation in the gorge of acetylcholinesterase, how-
ever, there were 2 main conformations in the
active center of butyrylcholinesterase: bent and
extended conformation.
▶
Alzheimer’s disease
tacrine
fluorobenzoic acid
docking
●
▼
▶
●
The aim of this study was to synthesize and
determine the biological activity of new deri-
vatives of 4-fluorobenzoic acid and tetrahy-
droacridine towards inhibition of cholinesterases.
Compounds were synthesized in condensation
reaction between 9-aminoalkyl-tetrahydroacri-
dines and the activated 4-fluorobenzoic acid.
Properties towards inhibition of acetyl- and
butyrylcholinesterase were estimated according
to Ellman’s spectrophotometric method. Among
synthesized compounds the most active were
▶
●
▶
●
▶
●
Ellman’s method
Supporting information available online at http:/
www.thieme-connect.de/ejournals/toc/amf
Introduction
At the early stage of AD it is very difficult to dif-
ferentiate the disease symptoms and memory
decline connected with advanced age. [3] AD is
frequently diagnosed on the basis of the patient
history, accompanied by relatives’ history, and
clinical observations of cardinal neurological
symptoms of the disease. For routine diagnosis of
AD conventional structural neuroimaging (com-
puter tomography (CT) and magnetic resonance
(MR)) is widely utilized. Nevertheless, these neu-
roimaging methods are not sufficient for detec-
tion of early structural changes in the brain.
Therefore, more advanced neuroimaging tech-
niques including positron emission tomography
(PET), single photon emission CT (SPECT), and
functional magnetic resonance imaging (MRI)
give opportunity for identification of the earliest
abnormalities during the disease course [4].
Pathogenesis of AD is complex, and is associated
with alterations of certain neurotransmitter sys-
tems in the central nervous system. The most
significant changes concern a deficit of choliner-
gic transmission which contributes to learning
and memory dysfunction. The level of acetyl-
choline (ACh) depends on activities of 2 ACh-
hydrolysing enzymes – acetylcholinesterase (AChE)
and butyrylcholinesterase (BChE). It was thought
▼
Progressive mental and cognitive deterioration in
old age has been identified and described
throughout history. At the beginning this patho-
logical state was called ‘dementia’. This term is
derived from the Latin (‘de-‘ means ‘out from’
and ‘mens’ is ‘the mind’). Alzheimer’s disease
(AD), the most common form of dementia, was
first identified in 1906 by German neurologist
Alois Alzheimer. Some years later Emil Kraepelin
named recognized disorder as Alzheimer’s dis-
ease [1]. Since its discovery more than 100 years
ago, there have been many scientific discoveries
in AD research. One of them is relation between
memory decline and the number of plaques and
tangles in the patient’s brain.
received 27.07.2012
accepted 21.10.2012
Bibliography
DOI http://dx.doi.org/
10.1055/s-0032-1329963
Published online:
November 15, 2012
Arzneimittelforschung 2012;
62: 655–660
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0004-4172
The diagnostic procedure and therapeutic man-
agement of AD have been areas of interest for
many scientists. During the last 10 years there has
been made enormous progress in understanding
of potential risk factors, molecular basis of patho-
logical lesions and brain regions which are
affected. However, AD still remains one of incura-
ble diseases. It is believed that there is an urgent
need to develop effective disease-modifying treat-
ments to slow or stop progression of AD [2].
Correspondence
P. Szymański, PhD
Department of Pharmaceutical
Chemistry and Drug Analyses
Medical University
Muszyńskiego 1
90-151 Lodz
Poland
Tel.: +48/42/677 92 90
Fax: +48/42/677 92 50
pawel.szymanski@umed.lodz.pl
Szymański P et al. New derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Arzneimittelforschung 2012; 62: 655–660

656 Original Article
Fig. 1 Structures of fluorinated ligands: (4-[18 F]
FDP) – a, (2-[18 F]fluoro-CP-118,954) – b, 3-[1-(4-
[
18 F]fluorobenzyl)piperidin-4-yl]-1-(1-methyl-1H-
indol-3-yl)propan-1-one – c [6,9,10].
that the main enzyme responsible for ACh hydrolysis is AChE,
ion channel modulators, histamine antagonists, calcium channel
blockers, nootropics, and other [13]. Furthermore, there have
been studies conducted on novel compounds that present
cholinesterase inhibition activity. Among them there are for
example: phenserine, metrifonate and ambemonium [12].
Incorporation of fluorine atoms into drug candidate structure is
becoming a commonplace, and enables to obtain various
improved properties, such as enhanced binding interactions,
metabolic stability, changes in physical properties, and selective
reactivity [14]. Therefore, it is of vital importance to search for
highly selective and potent compounds with fluorine atoms in
their structure with AChE inhibitory properties. Bis-(6-fluoro)-
tacrines, synthesized by Hu et al. were found to be more potent
in inhibiting rat AChE than tacrine and the unsubstituted bis-
tacrine [15].
Development of new therapies for AD is extremely important,
thus in continuation of our previous study [16], we present syn-
thesis of a new series of amino derivatives of tetrahydroacridine
coupled with fluorobenzoic acid as potential multifunctional
drugs. Fluorobenzoic acid, for the first time coupled with tet-
rahydroacridine derivatives, possesses dual course of action.
Firstly, it could improve anticholinesterase activity and, after
radiolabeling, it could be regard as a potential marker for diag-
nostic imaging. Within this study all synthesized compounds
were evaluated towards inhibition of both cholinesterases, and
studies of molecular modeling were performed to estimate the
binding mode with both enzymes.
however, significant evidence pointing to the role of BChE in
physiological cholinergic function has appeared [5]. Apart from
ACh hydrolysis these both enzymes exhibit noncholinergic func-
tions which include participation in many cellular processes,
neuron development and differentiation, regional cerebral blood
flow, and in the amyloid cascade [2,3].
It has been reported that the ratio BChE/AChE gradually elevates
in AD brain, partially because of the progressive loss of the
cholinergic synapses where AChE activity is located. Thus, the
use of BChE inhibitors in treating moderate to severe forms of
AD might be favorable, and, on the other hand, AChE has become
an attractive target for the diagnosis of AD due to the significant
reduction in its activity. Two radioligand approaches: radiola-
beled substrates and inhibitors of AChE might be used in in vivo
studies of AChE. [6] Radiolabeled AChE inhibitors have been
developed as a means of visualizing the AChE density, however,
some radioligands (for example [11C]physostigmine, N-[11C]
methyltacrine) allow only nonspecific binding in the brain
regions because of their low selectivity of AChE over BChE and
mild binding properties to AChE [6–8]. There are also available
18F-labeled radioligands, such as 1-(4-[18F]fluorobenzyl)-4-
[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine
FDP), [9]
3-[1-(4-[18F]fluorobenzyl)piperidin-4-yl]-1-(1-
(4-[18F]
methyl-1H-indol-3-yl)propan-1-one, its 3-[18F]fluoromethyl-
benzyl derivative [10]. A novel radioligand 5,7-dihydro-3-
[ 2 - [ 1 - ( 2 -f l u o ro b e n z yl ) - 4 - p i p e r i d i nyl ] et hyl ] - 6 H -
pyrrolo[3,2,f]-1,2-benzisoxazol-6-one (2-[18F]fluoro-CP-118,954)
in in vivo distribution studies demonstrated a high level of radio-
ligand accumulation both in the striatum and the olfactory
Materials and Methods
▶
tubercle, which are AChE-rich regions [6] ( Fig. 1) .
●
▼
E ffective treatment is as much important as early diagnosis of
AD. Nowadays the only class of drugs used in the treatment of
the cognitive and functional symptoms of AD is acetylcho-
linesterase inhibitors (AChEIs), which contribute to the retarda-
tion of AD progression. There are 4 AChEIs that are widely
approved for mild to moderate AD. These are: tacrine (now
tacrine is withdrawn), donepezil, rivastigmine and galantamine
[11,12].
Due to the fact that there has been made deep insight into the
pathological background of Alzheimer’s and understanding of
the disease, researchers have contributed to the development of
several new treatment strategies that might have the potential
to change the course of AD. There are currently in development
neuroprotective, and neuron-restorative drugs, such as agonists
of the nicotinic acetylcholine receptors (nAChRs), serotonin
antagonists, γ-aminobutyric acidB (GABAB) antagonists,
N-methyl-D-aspartate (NMDA) receptor antagonists and NMDA
Chemistry
Accomplished synthesis of all compounds comprised 3 stages.
The first part involved preparation of the heterocycle and, after-
wards, connection of it with aliphatic chain varying in number
of carbon atoms. Then, we combined obtained moiety with
4-fluorobenzoic acid which was activated by 2-chloro-4,6-dime-
thoxy-1,3,5-triazine (CDMT). As previously reported [15] we
prepared 9-chloro-1,2,3,4-tetrahydroacridine by the cyclization
of anthranilic acid with cyclohexanone in POCl3. The next step of
synthesis involved reaction between 9-chloro-1,2,3,4-tetrahy-
droacridine and the appropriate ω-diamine (2 equivalents) in
presence of phenol and sodium iodide [17,18].
Intermediates (2a–2e) were obtained according to previously
published protocols [16,19–24]. The last step of the synthesis
was to couple activated 4-fluorobenzoic acid with compounds
(2a–2e) in 2 independent steps in a one-pot synthesis. In the
first phase, the carboxylic group of fluorobenzoic acid was acti-
Szymański P et al. New derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Arzneimittelforschung 2012; 62: 655–660

Original Article 657
Fig. 2 Synthesis of compounds 3a–3e and
4a–4e. Reagents: a 4-fluorobenzoic acid, CDMT,
methylmorpholine, THF; b HCl/ether. Compounds
2a–2e were obtained according to previous papers
[ 1 6 , 1 9 – 2 4 ] .
vated by CDMT in tetrahydrofuran (THF) and N-methylmorpho-
line at −5° C, the intermediate product could hardly be isolated.
[25,26] After 4h to the reaction mixture compounds (2a–2e) in
small volume of THF were added dropwise and mixed for 24h
The resulting compounds (3a–3e) were then converted into
GoldSuite 4.1 (CCDC) the protein was prepared. All histidine
residues were protonated at Nε, the hydrogen atoms were added,
ligand and water molecules were removed and the binding site
was defined as all amino acid residues within 10 Å from bis-(7)-
tacrine for AChE and 20 Å from the glycerol molecule, present in
the active center of BChE. A standard set of genetic algorithm
with population size 100, number of operations 100000 and
clustering with a tolerance of 1Å were applied. As a result 10
ligand poses, sorted by GoldScore (AChE) and ChemScore (BChE)
function value were obtained. The results were visualized by
PyMOL 0.99rc6 (DeLano Scientific LLC).
hydrochlorides (4a–4e) by crystallization from HCl in ether
▶
(
Fig. 2) .
●
Accurate description of the synthesis of all compounds, and the
descriptions of spectra confirming their structures are available
in Supplementary material section.
Biochemical studies
Materials: Acetylthiocholine iodide (ATChI) and 5,5′-dithiobis-
(2-nitrobenzoic acid) (DTNB) were purchased from Sigma
Chemical Co. (St. Louise, MO). Sodium hydrogen phosphate
anhydride and sodium dihydrogen phosphate were from J.T.
Baker (Europe). All other chemicals used were of analytical
grade and the highest chromatographic purity available.
Results
▼
The biological testing was conducted according to spectrophoto-
metric Ellman’s method [27–29]. We estimated acetylcho-
linesterase and butyrylcholinesterase activity of all synthesized
compounds. Among the group of synthesized compounds the
most active towards AChE inhibition were molecules 4a, and 4d
which possess 5 and 8 carbon atoms in the aliphatic chain
between fluorobenzoic acid and tetrahydroacridine, respec-
tively. However, these compounds exhibited IC50 value similar to
tacrine. In our previous study [16], we described synthesis and
biological evaluation of 3 derivatives of fluorobenzoic acid and
1,2,3,4-tetrahydroacridin-9-ylamine with 2, 3 and 4 carbon
atoms in the aliphatic chain. These 3 compounds were charac-
terized, in comparison with tacrine, by 4-fold higher inhibitory
activity towards AChE, suggesting that introduction of aliphatic
chain was a good alteration. However, according to the results of
our current study incorporation of longer than 4 carbon atoms
aliphatic chain between fluorobenzoic acid and tetrahydroacrid-
ine did not contribute to the higher activity towards AChE inhi-
bition. Unfortunately, on the basis of the result of the study, we
cannot observe a straightforward relationship between the
length of aliphatic chain and the activity of the synthesized
compounds.
Enzymes: Acetylcholinesterase from Electrophorus electricus
(electric eel) – Type III and butyrylcholinesterase from equine
serum were obtained from Sigma Chemical Co. (St. Louise, MO).
Enzyme assays: The activity of synthesized compounds
towards inhibition AChE and BChE was measured according to
the method of Ellman et al., [27] using acetylthiocholine as sub-
strate. The compounds 4a–4d activities of the cholinoesterases
were assayed as described earlier [28,29].
Acetylthiocholine iodide at 7 concentrations in phosphatate-
buffered solution (0.1M, pH 8.0) and solution of 5,5’-dithiobis-
(2-nitrobenzoic acid) (DTNB, 0.05ml, 0.5M) were mixed in the
absence and presence of compounds 4a–4d. Then AChE from
Electrophorus electricus at a concentration 5 units/ml was added
to the samples to a final volume 3 ml and placed at 37 °C in the
cuvette holder of a PerkinElmer fluorescence spectrophotome-
ter. The emission spectra were recorded with wavelength set at
412nm after 1min. Butyrylcholinesterase (BChE) inhibitory
activity studies were carried out similarly using 5 units/ml of
BChE instead of AChE in a final volume 3 ml.
In our latest study [30] we presented synthesis and biological
evaluation of derivatives of 4-fluorobenzoic acid and 2,3-dihy-
dro-1H-cyclopenta[b]quinoline. We reported that incorporation
of a 5 membered ring significantly influenced the activity of
synthesized compounds towards inhibition of AChE. However,
similarly to the current study, we could not come to conclusion
that together with the length of aliphatic chain between fluor-
obenzoic acid and 2,3-dihydro-1H-cyclopenta[b]quinolone the
activity of synthesized compounds was increased. In that study
the most active were compounds with those with 2 and 4 car-
bon atoms in aliphatic chain. These compounds were 5- and
11-fold more active than tacrine, respectively. However, unlikely
to our previous study [16], the compound with 3 carbon atoms
in aliphatic chain between fluorobenzoic acid and 2,3-dihydro-
Statistical analysis: The drug concentration producing the
50% AChE and BChE activity inhibition (IC50) was calculated by
non-linear and linear regression.
Molecular modeling
The 3-dimentional structure of ligands was created by Corina
on-line (Molecular Networks) and then prepared with Sybyl 8.0
(Tripos). Atom types were checked, hydrogen atoms were added
and then Gasteiger-Marsili charges were assigned. Ligands were
docked to acetylcholinesterase from 2CKM and butyrylcho-
linesterase from 1P0I crystal complex. Before docking with
Szymański P et al. New derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Arzneimittelforschung 2012; 62: 655–660

658 Original Article
1H-cyclopenta[b]quinolone moiety is 2-fold less active than
were 2 main conformations in the active center of butyrylcho-
linesterase: bent conformation and extended one. The new
series of compounds acted as dual binding site acetylcholineste-
rase inhibitors i.e. all inhibitors interacted with catalytic and
peripheral active center. The most potent compound 4a created
the most advantageous interactions in the active gorge due to
tacrine, and, as a consequence, we cannot observe the increased
activity for all compounds with the shortest aliphatic chain. On
the other hand, unlikely to the current study, among the com-
pounds based on, 3-dihydro-1H-cyclopenta[b]quinolone with
longer aliphatic chain the one with 7 carbon atoms in the chain
was 2-fold more active than tacrine.
the 5 carbon linker which provided the best fit of the outermost
▶
In case of inhibition of BChE all synthesized constituents, apart
from 4a (similar IC50 value), were characterized by lower BChE
fragments of molecule to both active sites ( Fig. 3) .
●
The tacrine fragment formed a characteristic sandwich with
Trp84 and Phe330 by π-π stacking. The protonated form of
tacrine gave hydrogen bond with carbonyl group of His440. The
linker was located in the middle of gorge where it created hydro-
phobic interactions, mainly with Tyr334. The phenyl ring of ben-
zamide formed the second characteristic sandwich by π-π
stacking with Trp279 and Tyr70. It also created CH-π interac-
tions with Tyr121. In case of longer linkers (8 or 9 methylene
groups) the phenyl ring was slightly shifted and it resulted in a
slightly lower activity (compounds 4d, 4e). The carbonyl group
of benzamide moiety created H-bond with hydroxyl substituent
from Tyr121. In case of compounds 4b and 4c the carbonyl group
could be oriented at opposite direction and in that position it
wasn’t able to form hydrogen bond which could result in slightly
decreased activity. The fluorine substituent created hydropho-
bic interactions mainly with side chain of Ile175 and also with
Trp279 and Tyr70. Obtained compounds showed 2 different
binding modes with butyrylcholinesterase. For the most active
inhibitory activity in comparison with tacrine.
▶
●
Table 1 contains also values of relative inhibitory effects
towards acetylcholinesterase (ratio IC50 BChE/AChE) and
butyrylcholinesterase (ratio IC50 AChE/BChE).
All synthesized compounds are characterized simultaneously by
higher selectivity for AChE and lower selectivity for BChE in
comparison with tacrine. Also in case of compounds presented
in our previous paper [16] we observed higher selectivity for
AChE and lower selectivity for BChE when compared with
tacrine. The most selective towards BChE among synthesized
constituents was compound 4a, however, it was still 4-fold less
selective in comparison to tacrine. It could be a promising result,
as Greig et al. reported that selective BChE inhibition may amel-
iorate a cholinergic deficit, which likely worsens in AD due to
increased activity of BChE [5].
Molecular modeling studies revealed the binding mode of
obtained compounds. All derivatives presented similar extended
conformation in the gorge of acetylcholinesterase whereas there
Table 1 I C 50 values of activities
towards acetylcholinesterase and
butyrylcholinesterase.
Compounds
AChE
BChE
Selectivity for
AChEb
Selectivity for
BChE c
Inhibition IC50
(nM) ±SEMa
,
Inhibition IC50
(nM) ±SEMa
,
4a
5.30±0.15
24.30±0.8
22.80±1.4
5.60±0.4
0.05±0.006
3.96±0.17
4.87±0.6
0.01
0.16
0.21
8.96
0.23
5.49
106
4b
4c
6.14
4.68
0.11
4.29
273
4d
4e
50.2±4.4
13.40±4.0
5.46±1.00
3.12±0.23
0.02±0.006
THA
a Means±SEM of 3 experiments
b Selectivity for AChE is defined as IC50(BChE)/IC50(AChE)
c Selectivity for BChE is defined as IC50(AChE)/IC50(BChE)
Fig. 3 Binding mode of compound 4a with
acetylcholinesterase.
Szymański P et al. New derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Arzneimittelforschung 2012; 62: 655–660

Original Article 659
Fig. 4 Binding mode of compound 4a with
butyrylcholinesterase.
compound 4a the docking runs were more converged and it
However, there is still a great need to search for new compounds
with anticholinesterase activity and, simultaneously, high selec-
tivity and specificity. Therefore, we decided to synthesize a novel
series of tetrahydroacridine derivatives. We synthesized 5 novel
tetrahydroacridine derivatives coupled for the first time with
fluorobenzoic acid as a series of acetylcholinesterase inhibitors
with high activity. We estimated inhibitory properties towards
inhibition of AChE and BChE. Compounds 4a, and 4d had similar
activity towards AChE in comparison with tacrine.
In case of BChE all compounds were less active towards its inhi-
bition in comparison with tacrine. Only compound 4a had
slightly lower activity towards BChE than tacrine. Compound 4a,
which has high selectivity towards BChE, appear to be promising
and encourage us for further optimization, because of detrimen-
tal role of BChE in AD.
Acquired data is of extreme importance because we obtained 2
compounds (4a and 4d) with good activities and special selec-
tivity towards enzymes which suggest that these compounds
might be utilized in further studies in direction to AD therapy.
On the other hand simultaneous radiolabelling with fluorine
isotope (18F) and the following estimation of the level of both
cholinesterases certainly could be regarded as novelty. It would
enable to indicate the progress of neurodegeneration advance-
ment of nerve cells.
▶
occurred in bent conformation ( Fig. 4) .
●
The tacrine moiety interacted by π-π stacking with Trp82 and
formed hydrophobic interactions with Ile442. Protonated form
of tacrine created hydrogen bond with carbonyl group of His438.
Chain was directed to Tyr332. Fluorobenzamide was located in
hydrophobic region which was set by Phe329, Phe398, Trp231,
Leu286 and Ala199. In case of compounds 4b and 4c the
extended conformation appeared but still the bent one was
dominated. The compounds with longer linker (4d, 4e) pre-
sented mainly extended conformation with fluorobenzamide
moiety near Phe278 and Tyr282. The diversification of binding
modes for 4b and 4c or interactions with lower amount of
hydrophobic residues for 4d and 4e could result in a bit decreased
potency. Concluding, the compound 4a presented the most
advantageous binding mode with acetyl- and butyrylcholineste-
rase which made it the most active inhibitor in the whole series.
On the basis of the current stage of knowledge the next step of
our study will be labeling of compounds presented in this work
with 18F atoms and then evaluation them as radioligands for the
in vivo mapping of AChE. Replacement of fluorine atom with the
radioactive fluorine isotope will enable to use the synthesized
compounds for scintigrapic diagnosis by means of positron
emission tomography (PET).
In summary, this study describes synthesis and biochemical
evaluation towards inhibition of acetylcholinesterase and
butyrylcholinesterase. Two novel compounds (4a and 4d)
showed similar to tacrine anticholinesterase activity and are
characterized by promising selectivity towards enzymes.
Conclusion
▼
Enhancement of cholinergic function in the central nervous sys-
tem in the course of AD is very important. This goal might be
achieved by use of acetylcholinesterase inhibitors such as
tacrine, the first AChEI drug approved by FDA for clinical use,
rivastigmine, galantamine and donepezil.
Szymański P et al. New derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Arzneimittelforschung 2012; 62: 655–660

660 Original Article
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Acknowledgements
▼
Financial support by grant (N N405 669940) from National Sci-
ence Centre in Poland and the Medical University of Lodz (No
502-03/3-015-01/502-34-006) is gratefully acknowledged.
Conflict of Interest
▼
The authors declare that they have no conflict of interest.
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