Current Topics in Research

Synthesis of 9-Aminoacridine Derivatives

as Anti-Alzheimer Agents

American Journal of Alzheimers

Disease & Other Dementias
1-7
The Author(s) 2015
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1533317515603115
aja.sagepub.com

Rabya Munawar, MPhil1, Nousheen Mushtaq, PhD1,

Sadia Arif, M.Phil1, Ahsaan Ahmed, PharmD1,
Shamim Akhtar, PhD1, Sumaira Ansari, MPharm1,
Sadia Meer, M.Phil1, Zafar S. Saify, PhD2,
and Muhammad Arif, PhD1

Abstract
In the present study, some 9-aminoacridine derivatives have been synthesized by condensation of 9-aminoacridine with
substituted phenacyl, benzoyl, and benzyl halides (RM1-RM6). Compounds were investigated for acetylcholinesterase and
butyrylcholinesterase inhibition potential, considering these enzymes playing a key role in Alzheimers disease. All derivatives
showed better inhibition of enzymes than the standard galantamine, whereas except RM4, all exhibit better results than tacrine,
a well-known acridine derivative used for the treatment of Alzheimers disease.
Keywords
9-aminoacridine (9AA), Alzheimer, cholinesterases (ChE), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), tacrine

Introduction
1,2

Acridine-based pharmacophore has been found to be associated with a wide spectrum of biological activities, especially
for the treatment of Alzheimers disease (AD) by inhibiting
cholinesterases (ChE).3 In symptomatic improvement of AD,
acetylcholinesterase (AChE) has proven to be the most viable
therapeutic goal because cholinergic deficit is a constant and
early finding in this AD. There are 2 types of ChEs, AChE and
butyrylcholinesterase (BuChE). Several available drugs target
both AChE and BuChE in AD, but some are more selective.4
9-Aminoacridine (9AA) and its derivatives have long been
known to be reversible inhibitors of acetyl cholinesterase, the
most familiar of which is 9-amino-1,2,3,4-tetrahydroacridine,
tacrine (Cognex, Pfizer Pharmaceuticals).5 This was the first
nonclassical inhibitor of AChE approved by the Food and Drug
Administration (FDA) in 19936 that binds to both AChE and
BuChE.7 However, widespread use of tacrine was limited as
it caused a number of side effects including nausea, vomiting,
dizziness, diarrhea, seizures, and liver toxicity. Short half-life
of tacrine was another major problem.8 Eventually, tacrine was
discontinued due to hepatotoxicity.9
Physostigmine, first-tested AChE inhibitor (AChEI),
originally extracted from calabar beans. Physostigmine could
improve memory in people with or without dementia, but this
property has been limited by the very short half-life.10 A
number of physostigmine derivatives were synthesized, and
some are failing in clinical trials due to severe side effects.4

Rivastigmine (Exelon, Novartis Pharmaceuticals), a physostigmine derivative, is a centrally selective ChEI that was approved
in 2000. Rivastigmine exhibits a low level of hepatotoxicity11,12 but frequently associated with side effects such as nausea, vomiting, anorexia, diarrhea, headache, fatigue, malaise,
sweating, somnolence, dyspepsia, and sinusitis.13,14
Donepezil (Aricept, Pfizer Pharmaceuticals) is another nonclassic, centrally acting, reversible, noncompetitive AChEI that
was approved in 1997 for mild to moderate AD and dementia
and has little potential for hepatotoxicity,11,15 but on high dose,
transient nausea, diarrhea, and insomnia were reported.16
Galantamine (Razadyne, Global Pharmaceuticals),
approved in 2000, an alkaloid found in plants of the family
Amaryllidaceae, is a reversible inhibitor of AChE but does not
inhibit BuChE and used for mild to moderate AD and dementia, and no hepatotoxicity is reported11,12 but associated with
adverse events such as nausea, vomiting, diarrhea, anorexia,

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of
Karachi, Karachi, Pakistan
2
HEJ Research Institute of Chemical Sciences (ICCBS), University of Karachi,
Karachi, Pakistan

Corresponding Author:
Rabya Munawar, Department of Pharmaceutical Chemistry, Faculty of
Pharmacy, University of Karachi, Karachi 7400, Pakistan.
Email: pharmacistrabya@gmail.com

Downloaded from aja.sagepub.com by guest on October 7, 2015

American Journal of Alzheimers Disease & Other Dementias

b
a
NH2

b
N

Stirring (5-12hrs) rt

reflux (50C, 15-78hrs)

H
X

NH

N
b
a

NH2

c
R

Stirring (5-12hrs) rt
b

reflux (50C, 15-78hrs)

NH2

Compounds Codes

RM1

Br

Br

O
C

RM2

NO2

NO2

NO2

Br

Br
X

RM6

Br

CH3

Figure 1. The synthetic scheme of compounds RM1, RM2, RM3, RM4, RM5, and RM6.
Downloaded from aja.sagepub.com by guest on October 7, 2015

Cl

O
C

RM5

O
C

RM4

Cl

O
C

RM3

Br

H2
C

H2
C

Cl

Munawar et al

Chemicals and Instruments

Table 1. Acetylcholinesterase (AChE) and Butyrylcholinesterase

(BuChE) Inhibiting Activity.

Compounds
Codes
RM1
RM2
RM3
RM4
RM5
RM6
9AA (lead)
Galantamine
(standard)
Tacrine
(standard)

AChE Inhibition,
Inhibitory Concentration
50% (IC50) + SEM
(nmol/L)
0.022
0.0033
0.010
0.0715
0.015
0.0127
0.046
1.6

+ 0.00046
+ 0.0011
+ 0.00
+ 0.00195
+ 0.001
+ 0.00
+ 0.00
+ 0.000167

All reagents were reagent grade purchased from Merck (Germany) and Sigma-Aldrich Company (Germany) and distilled
twice. The monitoring of the reaction and purity of the final
product were determined by thin-layer chromatography on
silica gel 60 GF254 (Merck). Thin-layer chromatography spot
was visualized in UV light at 254 and 365 nm on HPUVIS
Desaga (Heidelberg, Germany). Melting points were recorded
on STUART (Bibby Sterlin Ltd, UK), SMP3 melting point
apparatus, and were uncorrected. Spectroscopic data were
recorded on ultraviolet spectrophotometer (CECIL 7200,
USA), IR spectrophotometer (FTIR-8900; Shimadzu, Japan)
using KBr disc, mass spectrometer (JEOL JMS-HX110,
Japan), and 1H-NMR (Bruker Advance 300, France) in
Dimethyl sulfoxide deprotonated (DMSO) at 300 MHz using
tetramethylsilane as an internal standard.

BuChE Inhibition,
Inhibitory Concentration
50% (IC50) + SEM
(nmol/L)
0.0011 +
0.0011 +
0.00046 +
0.0062 +
0.0004 +
0.0004 +
0.0014 +
6.6 +

0.021 + 0.002

0.00
0.00
0.00
0.000208
0.00
0.00
0.00
0.00038

0.051 + 0.005

Abbreviation: SEM, standard error of the mean.

Synthesis of Compounds
To a solution of 0.0025 mol/L 9AA in Acetone (15-20 mL), the
substituted phenacyl, benzoyl, and benzyl halides (0.0025 mol/
L) were added. Reaction mixture was stirred for 5 to 12 hours at
room temperature and then refluxed for 15 to 78 hours at 50 C.
After cooling, the solid precipitates were separated through
vacuum filtration and washed with acetone. Purification was
done through recrystallization using double solvent system
(ethanol and ether). Pure compounds were dried in vacuum
desiccators over silica beads. Melting point was recorded, and
spectral studies were done for the confirmation of the resultant
product (Figure 1).

muscle cramps, headaches, dizziness, fatigue, and insomnia

as a result of cholinergic stimulation.17,18
Naturally derived drugs such as huperzine A and huperzine
B are potent ChEIs. The huperzine A had the least amount of
activity against BuChE.19 Huperzine A is considered to be the
drug of choice in China for the treatment of memory disorders.
Side effects would be expected to be similar in nature to other
ChEIs.4
Although available cholinesterase inhibitors (AChEIs) provide benefit in AD, all these drugs exhibit varied side effects
and complications such as low bioavailability, shorter halflife, and hepatotoxicity.20-22
The present study is an attempt to find better ChEI, a crucial target for the treatment of AD. All synthesized acridine
derivatives showed promising AChE and BuChE inhibition.
Pharmacophoric regions are also determined, highlighting the
important structural features of ligands, which may be a great
help and guidance for the designing of effective anti-Alzheimer
drug.23

N-(30 -Bromophenyl-200 -oxoethyl)acridine-9-ammonium

bromide (RM1)
Light yellow powder, yield: 71.25%. melting point decomposed
(m.p. d) 215 C, UV(MeOH) e: 1817200. IR (KBr) nmax (cm1):
3107.1, 2993.3, 1595.0, 1479.3, EIMS (HBr) [M]: m/z 390.
1
H-NMR (DMSO, 300 MHz): d 3.498 (s, 2H, H-11), 7.5487.596 (t, J 6.3 Hz, 3H, H-2, H-7, H-13), 7.949-8.301

Table 2. Pharmacophoric Features of Parent, Synthesized Derivatives, and Standards.

Compounds
9AA
RM1
RM2
RM3
RM4
RM5
RM6
Galantamine
Physostigmine
Rivastigmine
Tacrine

Aromatic
Region(s)

Hydrophobic
Region(s)

Hydrogen Bond
Acceptor(s)

Hydrogen Bond
Donor(s)

Ionic Interaction Positive/

Negative

3
4
4
4
4
5
4
1
1
1
2

2
4
3
2
5
4
4
2
2
4
1

1
2
6
4
2
1
1
3
2
2
1

1
1
1
1
1
1
1
1
1
0
1

0
1/0
0
1/0
0
1/0
1/0
1/0
1/0
1/0
1/0

Downloaded from aja.sagepub.com by guest on October 7, 2015

American Journal of Alzheimers Disease & Other Dementias

Table 3. Shared Pharmacophoric Features of Parent, Synthesized Derivatives, and Standards.

Compounds
9AA, RM1, RM2, RM3, RM4,
RM5, RM6
Galantamine, RM1, RM3
Galantamine, RM2, RM4
Galantamine, RM5, RM6
Physostigmine, RM1, RM3
Physostigmine, RM2, RM4
Physostigmine, RM5, RM6
Rivastigmine, RM1, RM3
Rivastigmine, RM2, RM4
Rivastigmine, RM5, RM6
Tacrine RM1, RM3
Tacrine RM2, RM4
Tacrine RM5, RM6

Aromatic
Region(s)

Hydrophobic
Region(s)

Hydrogen Bond
Acceptor(s)

Hydrogen Bond
Donor(s)

1
0
1
1
0
1
1
0
1
2
2
2

2
1
2
0
2
1
2
2
2
1
1
1

1
1
1
0
1
0
1
0
1
1
1
1

0
0
0
1
0
1
0
0
0
1
1
1

1/0
0
1/0
1/0
0
1/0
0
0
0
1/0
0
1/0

Figure 2. Two- and 3-dimensional picture of galantamine. Blue

indicates aromatic region; yellow, hydrophobic region; red, hydrogen
bond acceptor; green, hydrogen bond donor; blue star, positive ionic
interaction.

Ionic Interaction Positive/

Negative

Figure 3. Two- and 3-dimensional picture of physostigmine. Blue

indicates aromatic region; yellow, hydrophobic region; red, hydrogen
bond acceptor; green, hydrogen bond donor; blue star, positive ionic
interaction.

(m, 6H, H-1, H-3, H-6, H-8, H-12, H-14), 8.723-8.752 (d, J
8.7 Hz, 3H, H-4, H-5, H-15).

N-(Acridine-9-yl)-30 , 50 dinitrobenzamide (RM2)

Dark yellow powder, yield: 99.6%. m.p. d 277 C. UV (MeOH)
e: 1115120. IR (KBr) nmax (cm1): 3342.4, 3139.9, 1658.7,
1502.4, EIMS (HCl) [M]: m/z 388. 1H-NMR (DMSO,
300 MHz): d 7.503-7.552 (t, J 7.2 Hz. 2H, H-2, H-7),
7.854-7.963 (m, 6H, H-1, H-3, H-4, H-5, H-6, H-8), 8.618.630 (d, J 8.7 Hz, 3H, H-11, H-12, H-13).

N-(40 -Nitrophenyl-200 -oxoethyl)acridine-9-ammonium

bromide (RM3)
Mustard yellow powder, yield: 99%. m.p. d 243 C. UV
(MeOH) e: 1046820. IR (KBr) nmax (cm1): 3190.0, 3109.0,
1649.0, 1595.0, 1479.3, EIMS (HBr) [M]: m/z 357.
1
H-NMR (DMSO, 300 MHz): d 3.352 (s, 2 H, H-11), 7.5117.560 (d, J 7.2 Hz, 4H, H-2, H-3, H-6, H-7), 7.847-7.966

Figure 4. Two- and 3-dimensional picture of rivastigmine. Blue

indicates aromatic region; yellow, hydrophobic region; red, hydrogen
bond acceptor; blue star, positive ionic interaction.

(m, 6H, H-1, H-4, H-5, H-8, H-12, H-15), 8.587-8.615(d, J

8.4 Hz, 2H, H-13, H-14).

N-(Acridine-9-yl)-40 -bromobenzamide (RM4)

Florescent yellow powder, yield: 92.2%. m.p. d 275 C. UV
(MeOH) e: 792960. IR (KBr) nmax (cm1): 3340, 3138,

Downloaded from aja.sagepub.com by guest on October 7, 2015

Munawar et al

N-(40 -Methylbenzyl)Acridine-9-Ammonium Chloride

(RM6)
Yellow crystals, yield: 25.68%. m.p. 221 C, UV (MeOH) e:
858380. IR (KBr) nmax (cm1): 3182.3, 3049.2, 1485.1,
1392, EIMS (HCl) [M]: m/z 334. 1H-NMR (DMSO, 300
MHz): d 3.323-3.299 (d, J 4.2 Hz, 5H, H-11 H-16),
7.272-7.322 (t, J 7.5 Hz, 2H, H-12, H-15), 7.600-7.649
(t, J 6.9 Hz, 4H, H-2, H-7, H-13, H-14), 7.73-7.821
(m, 4H, H-1, H-3, H-6, H-8), 8.354-8.382 (d, J 8.4 Hz,
2H, H-4, H-5).
Figure 5. Two- and 3-dimensional picture of tacrine. Blue indicates
aromatic region; yellow, hydrophobic region; red, hydrogen bond
acceptor; green, hydrogen bond donor; blue star, positive ionic
interaction.

Pharmacology
All the compounds were screened for AChE and BChE inhibition activity. Electric eel AChE (EC 3.1.1.7), equine serum
BuChE (EC 3.1.1.8), acetylthiocholine iodide, butyrylthiocholine chloride, and 5,50 -dithiobis(2-nitrobenzoic) acid (DTNB)
were purchased from Sigma (St Louis, Missouri). Buffers and
other chemicals were of analytical grades.

Enzyme Inhibition Assay

Figure 6. Three-dimensional picture showing shared features of 9aminoacridine (9AA), RM1, RM2, RM3, RM4, RM5, and RM6. Yellow, hydrophobic region; red, hydrogen bond acceptor; green,
hydrogen bond donor.

All the assays were performed under 100 mmol/L sodium

phosphate buffer, pH 8.0, using a 96-well microplate on SpectraMax340 (Molecular Device [U.S.A]). One hundred and
fifty microliters of 100 mmol/L sodium phosphate buffer
(pH 8), 10 mL DTNB, 10 mL of test compound (9AA derivatives) solution, and 20 mL AChE or BuChE solution were
mixed and incubated for 15 minutes at 25 C. The reaction was
then initiated with the addition of 10 mL acetylthiocholine
iodide or butyrylthiocholine chloride in that order. The activity was determined by measuring the increase in absorbance at
412 nm. The AChE and BuChE inhibiting activities were
measured by slightly modifying the spectrophotometric
method developed by Ellman.12

Result and Discussion

1

1589.2, 1479.3, EIMS (HCl) [M]: m/z 377. H-NMR

(DMSO, 300 MHz): d 7.505-7.555 (d, J 7.5 Hz, 2H, H2, H-7), 7.852-7.964 (m, 6H, H-1, H-3, H-6, H-8, H-12,
H-13), 8.597-8.06 (d, J 8.7 Hz, 4H, H-4, H-5, H-11, H14).

N-(40 -Bromobenyl)acridine-9-ammonium bromide

(RM5)
Fluorescent yellow powder, yield: 39.9%. m.p. d 280 C. UV
(MeOH) e: 310800. IR (KBr) nmax (cm1): 3307.7, 3109.0,
1595, 1477.4, EIMS (HBr) [M]: m/z 363. 1H-NMR
(DMSO, 300 MHz): d 3.326 (s, 2H, H-11), 8.698-8.726
(d, J 8.4 Hz, 2H, H-4, H-5), 7.183 (s, 2H, H-12, H-15),
7.559-7.688 (m, 4H, H-2, H-7, H-13, H-14), 7.835-8.039
(m, 4H, H-1, H-3, H-6, H-8).

All the newly synthesized molecules (RM1-RM6) were tested

for their inhibition activities toward AChE and BuChE according to the modified Ellman method with parent molecule
(9AA) and standards, galantamine and tacrine (Table 1). The
ChE inhibition results were summarized in Table 1. The result
showed that the target compounds possessed significantly even
better ChE inhibition than galantamine and tacrine. In case of
galantamine taken as standard, all derivatives showed better
activity against AChE and BuChE. As compared to tacrine,
compounds showed inhibitory potential against AChE in the
order of RM2 > RM3 > RM6 > RM5 > RM1 > RM4. Only
RM4 showed weak AChE inhibition than tacrine, whereas
against BuChE, all derivatives showed better results than
tacrine. All synthesized compounds presented more potent
inhibitory activity against BuChE (IC50 value 0.003-0.0715
nmol/L) as compared to AChE (IC50 value 0.0004-0.006
nmol/L).

Downloaded from aja.sagepub.com by guest on October 7, 2015

American Journal of Alzheimers Disease & Other Dementias

region, and 1 ionic interaction. There is a possibility that all of

these regions or some of them may be involved to interact with
the active binding sites of enzymes.
Overall, this 3-dimensional structural investigation of
synthesized compounds with different standards generates
pharmacophoric regions showing good sharing of different
important regions in structures. Several binding studies of
the various cholinesterase inhibitory ligands with the target
enzymes indicate the significance of hydrogen bonding (HB)
and HPB interactions.28,29 In the present pharmacophoric
investigation, all the synthesized compounds present greater
number of hydrogen bondings (HBs 1-6) and HPB interactions
(2-5) as compared to all standards (HB 1-3 and HPB 1-4).
Presence of more HBs and HPB regions in the synthesized
compounds provides possible justification of better enzymes
inhibition as compared to standards.
Figure 7. Three-dimensional picture showing shared features of
tacrine, RM1, RM2, RM3, RM4, RM5, and RM. Blue indicates aromatic
region; yellow, hydrophobic region; red, hydrogen bond acceptor;
green, hydrogen bond donor; blue star, positive ionic interaction.

Ligand-Based Pharmacophoric Study of Synthesized

Compounds
Pharmacophoric study was carried out using the software
LigandScout 3.02 [i1_10] with ChemDraw Ultra 8.0 for structure drawing. Important features were identified after analyzing
the structures of the synthesized compounds along with the
standards generated by LigandScout. The obtained main features of all the synthesized compounds were then superimposed
into different standard ligands to get the shared features indicating the similar important binding regions, which may be
involved in binding with the target.

Acetylcholinesterase and BuChE Inhibition

Pharmacophoric regions of the synthesized molecules determined with the help of the software LigandScout revealing
the important structural features (Table 2). Donepezil, rivastigmine, galantamine, and tacrine approved by the United States
Food and Drug Administration (FDA) and marketed for the
treatment of AD.24-27
Tacrine, physostigmine, rivastigmine, and galantamine
taken as standard in this study are extensively investigated for
the ChE inhibition as a major targets in AD.6 In pharmacophoric generation, these standards displayed 5 to 9 pharmacophoric
features (Figures 25). 9-Aminoacridine has 7 pharmacophoric
regions, whereas synthesized molecules (RM 1-6) comprised
around 10 to 14 pharmacophoric regions (Figure 6) including
hydrogen bond donor(s), hydrogen bond acceptor(s), ionic
interaction, hydrophobic (HPB), and aromatic region(s).
All synthesized molecules showed maximum shared features with tacrine as compared to other standards (Table 3).
Tacrine shared 6 pharmacophoric regions with phenacyl, benzoyl, and benzyl derivatives (Figure 7) including 1 hydrogen
bond acceptor, 1 hydrogen bond donor, 2 aromatic and 1 HPB

Conclusion
In the given study, synthesized 9AA derivatives displayed highly
significant potential for AChE and BuChE inhibition. As these
enzymes have been studied and considered as a major target for
the treatment of Alzheimer, better result than standards indicating the pronounced potential of these compounds to be used as
anti-Alzheimer agents. These compounds have been selected
to be investigated further for their toxicity profile as well as studied at molecular level for their binding mode with the target.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article: Work has
been done by the support of research grant of University of Karachi,
Karachi, Pakistan.

References
1. Vilma P, Eduardas T. New ethacridine derivatives as the potential
antifungal and antibacterial preparations. Medicina (Kaunas).
2007;43(8):657-663.
2. Baguey BC, Zhuang L, Marshall EM. Experimental solid tumour
activity of N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide.
Cancer Chemother Pharmcol. 1995;36(3):244-248.
3. Mehul MP, Mimansha DM, Saurabh KP. Bernthsen synthesis,
antimicrobial activities and cytotoxicity of acridine derivatives.
Bioorg Med Chem Lett. 2010;20(21):6324-6326.
4. Mehta M, Adem A, Sabbagh M. New acetylcholinesterase inhibitors for Alzheimers disease. Int J Alzheimers Dis. 2012;2012:
728983.
5. Walker TM, Starr B, Dewhurst BB, Atterwill C. Potential neurotoxicity of a novel aminoacridine analogue. Hum Exp Toxicol.
1995;14(6):469-474.
6. Korabecnya J, Musilekb K, Holasa O, et al. Synthesis and in vitro
evaluation of N-alkyl-7-methoxytacrine hydrochlorides as

Downloaded from aja.sagepub.com by guest on October 7, 2015

Munawar et al

7.

8.
9.

10.
11.
12.

13.

14.

15.

16.

17.

18.

potential cholinesterase inhibitors in Alzheimer disease. Bioorg

Med Chem Lett. 2010;20(20):6093-6095.
Giacobini E. Cholinesterase inhibitors for Alzheimers therapy: from tacrine to future applications. Neurochem Int. 1998;
32(5-6):413-419.
Tacrine. Drugs in Clinical Trials. Alzheimer Research Forum,
http://www.alzforum.org/drg/drc/detail.asp?id90.
Tumiatti V, Minarini A, Bolognesi ML, Milelli A, Rosini M,
Melchiorr C. Tacrine derivatives and Alzheimers disease. Curr
Med Chem. 2010;17(17):1825-1838.
Coelho F, Birks J. Physostigmine for Alzheimers disease.
Cochrane Database Syst Rev. 2001;(2):CD001499.
Brisks J. Cholinesterase inhibitors for Alzheimers disease.
Cochrane Database Syst Rev. 2006;(1):CD005593.
Ballard CG, Perry EK. In: Giacobini E, Martin Dunitz, eds.
Butyrylcholinesterase its Function and Inhibitors. London,
UK: CRC Press; 2003:123.
Corey-Bloom J, Anand R, Veach J. A randomized trial evaluating
the efficacy and safety of ENA 713 (rivastigmine tartrate), a new
acetylcholinesterase inhibitor, in patients with mild to moderately
severe Alzheimers disease. Int J Geriatr Psychopharmacol.
1998;1(2):55-65.
Onor ML, Trevisiol M, Aguglia E. Rivastigmine in the treatment
of Alzheimers disease: an update. Clin Intervent Aging. 2007;
2(1):17-32.
Lemke T, Williams DA, Roche V, Zito SW. Foyes Principles of
Medicinal Chemsitry, 6th edn. Baltimore, USA: Lippincott, Williams and Wilkins; 2008:361-392.
Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil
improves cognition and global function in Alzheimer disease: a
15-week, double-blind, placebo-controlled Study. Arch Intern
Med. 1998;158(9):1021-1031.
Coyle J and Kershaw P. Galantamine, a cholinesterase inhibitor
that allosterically modulates nicotinic receptors: effects on the
course of Alzheimers disease. Biol Psychiatry. 2001;49(3):
289-299.
Olin J, Schneider L. Galantamine for Alzheimers disease.
Cochrane Database Syst Rev. 2000;(3):CD001747.

19. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine
A in the treatment of Alzheimers disease: an updated meta-analysis. J Neural Transm. 2009;116(4):457-465.
20. Kim FE. Drug affecting cholinergic neurotransmission. In: Thomas LL, David AW, Victoria FR, William ZS, eds. Foyes Principles of Medicinal Chemistry. New Dehli, India: Wolters Kluwer
Pvt Ltd: 361, 363, 374-375, 377-378.
21. Inestrosa NC, Alvarez A, Perez CA, et al. Acetylcholinesterase
accelerates assembly of amyloid-beta-peptides into Alzheimers
fibrils: possible role of the peripheral site of the enzyme. Neuron.
1996;16(4):881-891.
22. Kadiyala M, Ponnusankar S, Elango K. Screening of siddha medicinal plants for its in-vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity. Pharmacogn Mag. 2014;10(suppl
2):S294-S298.
23. Chen Y, Jang YJ, Zhov JW, Yu QS, You QD. Identification of
ligand features essential for HDACs inhibitors by pharmacophore
modeling. J Mol Graph Model. 2008;26(7):1160-1168.
24. Munoz-Torrero D. Acetylcholinesterase inhibitors as diseasemodifying therapies for Alzheimers disease. Curr Med Chem.
2008;15(24):2433-2455.
25. Relkin NR. Beyond symptomatic therapy: a re-examination of
acetylcholinesterase inhibitors in Alzheimers disease. Expert Rev
Neurother. 2007;7(6):735-748.
26. Wishart DS, Knox C, Guo AC, et al. DrugBank: a comprehensive
resource for in silico drug discovery and exploration. Nucleic
Acids Res. 2006;34(database issue):668-672.
27. Nordberg A. Mechanisms behind the neuroprotective actions of
cholinesterase inhibitors in Alzheimers disease. Alzheimer Dis
Assoc Disord. 2006;20(1):S12-S18.
28. Khan I, Nisar M, Khan N, et al. Structural insights to investigate
Conypododiol as a dual cholinesterase inhibitor from Asparagus
adscendens. Fitoterapia. 2010;81(8):1020-1025.
29. Gupta S and Mohan CG. Dual binding site and selective acetylcholinesterase inhibitors derived from integrated pharmacophore
models and sequential virtual screening. Biomed Res Int. 2014;
2014:291214.

Downloaded from aja.sagepub.com by guest on October 7, 2015