Synthesis, antimicrobial and cholinesterase enzymes inhibitory activities of indeno imidazoles and X-ray crystal structure of 3a,8a-dihydroxy-1,3- diphenyl-1,3,3a,8a-tetrahydro-indeno [1,2-d]imidazole-2,8-dione

Article abstract of DOI:10.1007/s10870-012-0288-7

Two indeno imidazoles have been synthesized by the reaction of ninhydrin with diphenylurea and diphenylthiourea. The structures have been determined by spectral analysis. The supramolecular behavior of 3a,8a-Dihydroxy- 1,3-diphenyl-1,3,3a,8a-tetrahydro-indeno[1,2-d]imidazole- 2,8-dione (1) was thoroughly analyzed and reported using X-ray single crystal technique and concepts. The presence of oxygen and nitrogen atoms led to very interesting supramolecularmotifs interactions such as nitrogen-oxygen, nitrogen- nitrogen, oxygen-oxygen, nitrogen-hydrogen, and oxygen- hydrogen. 3a,8a-dihydroxy-1,3- diphenyl-2-thioxo-2,3,3a,8atetrahydro- 1H-indeno[1,2-d]imidazol-8-one 2 showed good antibacterial activity against B. subtilis and P. aeruginosa, while 3a,8a-dihydroxy-1,3-diphenyl-1,3,3a,8a-tetrahydroindeno[ 1,2-d]imidazole-2,8- dione 1 only showed antibacterial activity against P. aeruginosa. Both of 1 and 2 were inactive against C. albicans. Derivative 2 demonstrated good cholinesterase enzyme activity unlike derivative 1 which has weak inhibitory activity against these enzymes. Furthermore, 2 was found to be a selective butyrylcholinesterase enzyme inhibitor that has potential use for prevention of further neurodegeneration as well for symptomatic treatment of Alzheimer patients. Springer Science+Business Media, LLC 2012.

Full text of DOI:10.1007/s10870-012-0288-7

J Chem Crystallogr (2012) 42:783–789
DOI 10.1007/s10870-012-0288-7
ORIGINAL PAPER
Synthesis, Antimicrobial and Cholinesterase Enzymes Inhibitory
Activities of Indeno Imidazoles and X-Ray Crystal Structure
of 3a,8a-Dihydroxy-1,3-diphenyl-1,3,3a,8a-tetrahydro-indeno
[1,2-d]imidazole-2,8-dione
•
Raza Murad Ghalib Rokiah Hashim Solhe F. Alshahateet
•
•
•
Sayed Hasan Mehdi Othman Sulaiman Kit-Lam Chan
•
•
•
Vikneswaran Murugaiyah Ali Jawad
Received: 28 December 2011 / Accepted: 7 February 2012 / Published online: 19 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Two indeno imidazoles have been synthesized by
the reaction of ninhydrin with diphenylurea and diphenyl-
thiourea. The structures have been determined by spectral
analysis. The supramolecular behavior of 3a,8a-Dihydroxy-
1,3-diphenyl-1,3,3a,8a-tetrahydro-indeno[1,2-d]imidazole-
2,8-dione (1) was thoroughly analyzed and reported using
X-ray single crystal technique and concepts. The presence of
oxygen and nitrogen atoms led to very interesting supramo-
lecularmotifsinteractionssuchasnitrogen–oxygen, nitrogen–
nitrogen, oxygen–oxygen, nitrogen–hydrogen, and oxygen–
hydrogen. 3a,8a-dihydroxy-1,3-diphenyl-2-thioxo-2,3,3a,8a-
tetrahydro-1H-indeno[1,2-d]imidazol-8-one 2 showed good
antibacterial activity against B. subtilis and P. aeruginosa,
while 3a,8a-dihydroxy-1,3-diphenyl-1,3,3a,8a-tetrahydro-
indeno[1,2-d]imidazole-2,8-dione 1 only showed antibacte-
rial activity against P. aeruginosa. Both of 1 and 2 were
inactive against C. albicans. Derivative 2 demonstrated good
cholinesterase enzyme activity unlike derivative 1 which has
weak inhibitory activity against these enzymes. Furthermore,
2 was found to be a selective butyrylcholinesterase enzyme
inhibitor that has potential use for prevention of further neu-
rodegeneration as well for symptomatic treatment of Alzhei-
mer patients.
Keywords Synthesis ꢀ Crystal structure ꢀ
3a,8a-Dihydroxy-1,3-diphenyl-1,3,3a,8a-tetrahydro-
indeno[1,2-d]imidazole-2,8-dione ꢀ
3a,8a-Dihydroxy-1,3-diphenyl-2-thioxo-2,3,3a,8a-
tetrahydro-1H-indeno[1,2-d]imidazol-8-one ꢀ
Antimicrobial activity ꢀ
Cholinesterase enzymes inhibitory activity
Introduction
R. M. Ghalib (&) ꢀ R. Hashim ꢀ S. H. Mehdi ꢀ O. Sulaiman
School of Industrial Technology, Universiti Sains Malaysia,
Minden, 11800 Pulau-Pinang, Malaysia
The area of chemistry that works beyond molecules and
focuses on the chemical systems made up of a discrete
number of assembled molecular subunits or components is
called supramolecular chemistry. Different forces are
responsible for the spatial organization and vary from weak
(intermolecular forces, electrostatic or hydrogen bonding)
to strong (covalent bonding). While traditional chemistry
focuses on the covalent bond, supramolecular chemistry
examines the weaker and reversible noncovalent interac-
tions between molecules. These weak forces can be
hydrogen bonding, metal coordination, hydrophobic forces,
van der Waals forces, p–p interactions and electrostatic
effects. Understanding the non-covalent interactions is
crucial to understand many biological processes from cell
structure to vision that rely on these forces for structure and
function [1–9]. This understanding is important and could
e-mail: raza2005communications@gmail.com
S. F. Alshahateet
Department of Chemistry, Mutah University,
P.O. Box 7, Mutah, Al Karak 61710, Jordan
K.-L. Chan
Discipline of Pharmaceutical Chemistry,
School of Pharmaceutical Sciences, Universiti Sains Malaysia,
11800 Penang, Malaysia
V. Murugaiyah
Discipline of Pharmacology, School of Pharmaceutical Sciences,
Universiti Sains Malaysia, 11800 Penang, Malaysia
A. Jawad
Department of Applied Physics, Zakir Husain College
of Engineering and Technology, AMU, Aligarh 202002, India
123

784
J Chem Crystallogr (2012) 42:783–789
be of great use to predict hopefully the physical properties
and applications of any given crystalline solid compound
and therefore, biological systems are often the inspiration
for supramolecular research [10–22]. In this study, the
antimicrobial derivatives 1 and 2 were prepared, charac-
terized and their antimicrobial activities were examined. In
addition, solid-state structure and the supramolecular
behavior of 1 were investigated and presented in terms of
supramolecular chemistry and crystal engineering
concepts.
3
O
O
O
2
N
HO
4
7
OH
OH
5
6
N1
Diphenyl urea/AcOH
heat, 15 Minutes
8
OH
Ninhydrin
O
1
Diphenyl thiourea/AcOH
heat, 15 Minutes
Experimental
3
Materials and Physical Measurements
S
2
N
HO
4
7
5
6
1
N
Ninhydrin and diphenyl urea were obtained from Sigma-
Aldrich. The solvents and acetic acid were of AR grade and
obtained from Merck. All materials were used without
further purification. The melting point was taken on
Thermo Fisher digital melting point apparatus of IA9000
series and is uncorrected. FTIR spectra were measured by
direct transmittance by means of the KBr pellet technique
using a Nicolet Impact 400 FTIR spectrometer equipped
with a DTGS detector. HR-ESI-MS was recorded on a
8
OH
O
2
Scheme 1 Synthetic route for derivatives 1 and 2
dissolved in acetic acid and then heated over water bath for
15 min (Scheme 1). The conversion was monitored by
TLC. The reaction mixture was dried by using rotary
evaporator at low pressure to give the solid product which
was then recrystallized from alcohol-chloroform (1:1
v/v) mixture to give the transparent crystals of the title
compound 1. Yield (100%), mp 155–156 °C. IR (KBr):
mmax 3341, 3059, 1969, 1896, 1735, 1649, 1596, 1495,
1433, 1287, 1219, 1163, 1063, 947, 909, 840, 755, 689,
1
Finnigan TSQ Quantum Ultra AM Thermo Electron. H
NMR was recorded on Bruker Avance 500 MHz with TMS
as an internal standard and 125 MHz for 13C NMR. Spectra
were recorded in DMSO-d6. Elemental analysis was per-
formed on a Perkin Elmer 2400 Series II Elemental CHNS
analyzer.
Chloramphenicol was purchased from Acros Organics
(New Jersey, USA). Gentamicin and amoxicillin were
purchased from Sigma Aldrich (Steinheim, Germany).
Vancomycin, para iodonitrotetrazolium (INT), acetylcho-
linesterase from electric eel, 5,50-Dithiobis(2-nitrobenzoic
acid), acetylcholine iodide, butyrylcholine esterase from
equine serum, S-butyrylthiocholine chloride and physo-
stigmine were purchased from Sigma (St. Louis, USA).
Amphotericin B was purchased from Himedia (Mumbai,
India). Muller Hinton agar and Potato Dextrose agar were
purchased from Merck (Darmstadt, Germany) and Lab
Scan Analytical Sciences (Bangkok, Thailand), respec-
tively. Dimethyl sulfoxide (DMSO) was purchased from
Fisher Scientific (Leicestershire, UK). All other reagents
used were of analytical grade.
1
647 cm-1. H NMR (DMSO, 500 MHz): d 6.85–6.87 (m,
1H, Ar–H), 7.26–7.64 (a set of signals, 12H, Ar–H), 7.67
(br, 1H, OH), 7.73 (br, 1H, OH), 7.79–7.81 (m, 1H, Ar–H)
ppm. 13C NMR (DMSO, 125 MHz): d 88.9, 89.6, 124.5,
125.5, 126.9, 127.9, 128.2 (2C), 128.8 (2C), 128.9 (2C),
129.1 (2C), 131.2, 132.7, 136.3, 136.4, 136.6, 149.3, 153.6
(C-2, C=O), 195.7 (C-8, C=O) ppm. HR-ESI-MS: m/z
372.243 (M?). Elemental anal. Calcd for C22H16N2O4: C,
70.96; H, 4.33; N, 7.52;. Found: C, 70.46; H, 4.21; N, 7.26.
3a,8a-Dihydroxy-1,3-diphenyl-2-thioxo-2,3,3a,8a-tetra-
hydro-1H-indeno[1,2-d]imidazol-8-one (2) was synthe-
sized in same way except that diphenyl thiourea (2.28 g)
was used in place of diphenylurea (Scheme 1). The reac-
tion mixture was dried by using rotary evaporator at low
pressure to give the solid product which was then recrys-
tallized from alcohol-chloroform (1:1 v/v) mixture to give
the amorphous solid of the title compound 2. Yield (100%),
mp 212–214 °C (decomp). IR (KBr): mmax 3299, 3047,
1963, 1892, 1736, 1598, 1494, 1428, 1377, 1314, 1215,
Synthesis of the Title Compounds 1–2
3a,8a-Dihydroxy-1,3-diphenyl-1,3,3a,8a-tetrahydro-indeno
[1,2-d]imidazole-2,8-dione (1) was synthesized by the
reaction of ninhydrin (1.78 g, 10 mm) with diphenylurea
(2.12 g, 10 mm). Reactants (1:1 molar ratio) were well
1182, 1159, 1055, 946, 896, 776, 737, 693, 662, 619 cm-1
1H NMR (DMSO, 500 MHz): d 6.80–6.82 (m, 1H, Ar–H),
.
123

J Chem Crystallogr (2012) 42:783–789
785
7.32–7.88 (a set of signals, 13H, Ar–H), 7.92 (br, 1H, OH),
7.98 (br, 1H, OH) ppm. 13C NMR (DMSO, 125 MHz): d
91.0, 92.3, 124.1, 125.3, 127.8, 128.0, 128.2 (2C), 128.4
(2C), 130.6 (2C), 130.8 (2C), 131.0, 132.5, 136.3, 136.5,
136.8, 148.3, 179.6 (C-2, C=S), 194.3 (C-8, C=O) ppm.
HR-ESI-MS: m/z 388.0886 (M?). Elemental anal. Calcd
for for C22H16N2O3S: C, 68.02; H, 4.15; N, 7.21; S, 8.25;.
Found: C, 68.0; H, 4.02; N, 7.10; S, 8.04.
Table 1 Numerical details of the solution and refinement of the
crystal structure of 1
Compound
1
Formula
C22H16N2O4
372.37
Formula mass
Space group
P21
˚
a/A
9.5600(4)
9.3119(4)
10.9682(5)
90
˚
b/A
˚
c/A
In Vitro Antimicrobial Activity
a/°
b/°
c/°
111.270(3)
90
The test microorganisms used in this study were as follows:
Streptococcus pneumoniae (ATCC 6303), Staphylococcus
aureus (ATCC 25923), Bacillus subtilis (laboratory strain),
Escherichia coli (ATCC 25922), Klebsiella pneumoniae
(laboratory strain), Pseudomonas aeruginosa (ATCC
27853), Shigella flexneri (ATCC 12022) and Candida albi-
cans (ATCC 10231). For the antimicrobial tests, strains were
grown overnight in an anaerobic chamber at 37 °C under
atmosphere consisting 10% CO2, 10% H2O and 80% N2.
Test samples were prepared in DMSO at final concen-
trations ranged from 0.00097 to 2 mg/mL for the test com-
pounds and 0.00039 to 0.4 mg/mL for positive controls.
Commercial antimicrobials (amoxicillin, vancomycin,
chloramphenicol and gentamicin for bacteria and ampho-
tericin B for Candida albicans) were used as positive con-
trols whereas DMSO was used as negative control.
Minimum inhibitory concentration (MIC) of the test sample
and positive controls was carried out using microdilution
method [23]. The experiment was carried out in triplicate.
3
˚
V/A
909.90(7)
293(2)
T/K
Z
2
F000
388.0
D
calc./g cm-3
1.359
˚
Radiation, k/A
Scan mode
MoKa, 0.7107
h/2h
2hmax./°
Criterion for obs. ref.
27.420
I/r(I) [ 2
3799
No. of reflections (m)
P
P
R = m|DF|/ m|Fo|
0.0558(2909)
0.1517(3799)
1.049
P
P
Rw = [ mw|DF|2/ mw|Fo|2]1/2
P
s = [ mw|DF|2/(m - n)]1/2
graphite monochromated molybdenum radiation (k
˚
0.7107 A). SMART [25] was used for collecting frame
In Vitro Cholinesterase Enzymes Inhibitory Activity
data, indexing reflection, and determination of lattice
parameters. SAINT [25] was used for integration of
intensity of reflections and scaling. A semi-empirical
absorption correction was applied using the program
SADABS [26]. The structure was solved by Direct methods
using the program SHELXS [27].The refinement and all
further calculations were carried out using the program
SHELXL [27]. The H-atoms were included in calculated
positions and treated as riding atoms using SHELXL
default parameters. The non-H atoms were refined aniso-
tropically, using weighted full-matrix least-squares on F2.
Crystallographic data (cif) of the titled compound 1 have
been deposited with the Cambridge Structural Data Centre
(CCDC) with reference number 826750. See http://
www.ccdc.cam.ac.uk/conts/retrieving.html for crystallo-
graphic data in cif or other electronic format. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax:44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.
uk). The crystallographic parameters of crystal structure of
1 are presented in Table 1.
Cholinesterase enzymes inhibitory potential of test samples
was evaluated using Ellman’s microplate assay following
method described by Ahmed and Gilani [24]. Physostig-
mine was used as positive control. Test samples and
physostigmine were prepared in methanol at final concen-
tration of 10%. Each test was conducted in triplicate. A set
of five concentrations was used to estimate the 50%
inhibitory concentration (IC50).
Percentage inhibition was calculated using the following
formula:
Percentage inhibition ¼
Absorbance of control ꢁ Absorbance of test sample
Absorbance of control
ꢂ 100%
Crystal Structure Determination
Reflection data were measured at 293 K with a Bruker
APEX2 CCD diffractometer in h/2h scan mode using
123

786
J Chem Crystallogr (2012) 42:783–789
Table 2 Minimum Inhibitory Concentrations of 1 and 2 and antibacterial drugs against selected microorganism
Strains
Minimum inhibitory concentration (mg/mL)a
1
2
AMX
VAN
CMC
GM
AMP
Gram positive bacteria
B. subtilis
NA
1.0
1.0
0.5
0.5
1.0
0.2
S. pneumoniae
S. aureus
0.00156
0.00625
Gram negative bacteria
K. pneumoniae
S. flexneri
1.0
NA
0.5
NA
1.0
NA
0.5
NA
0.00039
0.1
P. aeruginosa
E. coli
0.025
0.025
Fungus
C. albicans
NA
NA
0.2
a
Only one reference antibiotic was used for each microorganism based on the microbe’s susceptibility
NA not active (MIC values were found to be similar with the blank, DMSO), AMX amoxicillin, VAN vancomycin, CMC chloramphenicol, GM
gentamicin, AMP amphotericin B
80
lesser than that of amoxicillin. Both 1 and 2 showed good
1
2
antibacterial activity against P. aeruginosa with MIC val-
ues 20 times less potent than chloramphenicol. However,
they were less or not active against other test microor-
ganisms (Table 2).
60
40
20
0
In Vitro Cholinesterase Enzymes Inhibitory Activity
Initial cholinesterase enzymes inhibitory activity of 1 and 2
is summarized in Fig. 1. At 100 lg/mL, 2 had a higher
enzyme inhibitory activity than 1 with AChE and BChE
inhibition of 61.84% and 64.61%, respectively compared to
only 7.82% and 17.60%, respectively for 1. Table 3 sum-
marizes the IC50 and selectivity index of 2 and physo-
stigmine. The IC50 determination was not carried out for 1
because it showed weak enzyme inhibitory activity. At
100 lg/mL concentration, 2 has almost similar inhibitory
activity on AChE and BChE. However, comparison of its
IC50 values showed that 2 has almost three times more
potent inhibitory activity on BChE compared to AChE. On
molar basis, 2 was approximately 214 times less potent
than physostigmine against BChE. Interestingly, 2 was
selective towards BChE inhibition in contrast to physo-
stigmine, which has more inhibitory effect on AChE.
AChE
BChE
Fig. 1 Cholinesterase enzymes inhibitory activities of 1 and 2 at
100 lg/mL
Results and Discussion
In Vitro Antimicrobial Activity
In general, 1 and 2 showed antimicrobial activity with MIC
values between 0.5 and 1 mg/mL. 2 had good antimicrobial
activity against B. subtilis with MIC value of only 2.5 times
Table 3 IC50 values for inhibitory activities on cholinesterase enzymes
Sample
AChE inhibition, IC50
BChE inhibition, IC50
Selectivity for
AChEa
lg/mL
lM
lg/mL
lM
BChEb
2
106.70 3.63
0.038 0.007
274.69
1.38 9 10-1
39.31 10.57
0.13 0.02
101.20
4.72 9 10-1
0.37
3.42
2.71
0.29
Physostigmine
a
Selectivity for AChE is defined as IC50(BChE)/IC50(AChE)
Selectivity for BChE is defined as IC50(AChE)/IC50(BChE)
b
123

J Chem Crystallogr (2012) 42:783–789
787
Fig. 2 ORTEP drawing of 1 crystal structure including atom
labeling. Displacement ellipsoids are shown at the 50% probability
level
Fig. 4 One molecule of 1 bifurcates via its oxygen (O4) with
aromatic hydrogens of two molecules of 1 (H20A and H15A)
Fig. 3 Non-centrosymmetric dimer of two molecules of 1 resulted
from bifurcated H4BꢀꢀꢀO2ꢀꢀꢀH3B motif interactions with bond
˚
distances of 1.974 and 1.969 A
Fig. 5 Oxygen–oxygen interactions in form of O4ꢀꢀꢀO2ꢀꢀꢀO3 with
˚
distances of 2.788 and 2.786 A
Acetylcholinesterase (AChE) is the key enzyme
involved in the metabolic hydrolysis of acetylcholine. This
observation led to the introduction of the acetylcholines-
terase inhibitors to prolong the duration of action of ace-
tylcholine and provide symptomatic treatment in AD [28].
In the present study, 2 showed weak AChE inhibitory
activity. Another enzyme, butyrylcholinesterase (BChE),
expressed in selected areas of the central and peripheral
nervous systems is also capable of hydrolysing acetylcho-
line, but its level does not decline, or may even increase in
AD [29]. In addition, BChE has an important role in the
development and progression of AD where it is involved in
formation of b-amyloid plaques. Thus, 2, being a selective
BChE inhibitor have potential use for prevention of further
neurodegeneration as well for symptomatic treatment of
Alzheimer patient.
Structural Study of 3a,8a-Dihydroxy-1,3-diphenyl-
1,3,3a,8a-tetrahydro-indeno[1,2-d]imidazole-2,8-
dione (1)
Solvent free 1 crystallizes in the monoclinic space group
P21. The molecular structure of 1 with atom labeling is
123

788
J Chem Crystallogr (2012) 42:783–789
Fig. 6 Non-centrosymmetric dimer formed between molecules of 1
˚
(N2–H4B and N1–H3B) with distances of 3.445 and 3.382 A
Fig. 8 Weak intermolecular edge-face nitrogen–nitrogen interactions
˚
with contact distances of 5.505 and 5.690 A
O4 and O2–H3B–O3) of 171.25° and 173.71° as shown in
Fig. 3. Another type of oxygen bifurcated is observed
between oxygen atom of one molecule of 1 (O4) with two
aromatic hydrogens (H20A and H15A) of two molecules of
˚
1 with distances of 2.547 and 2.587 A (Fig. 4). Oxygen–
oxygen interaction is also found to play an important role
in stabilizing the crystal structure of 1 by providing a
strong interactions between molecules of 1 with distances
˚
of 2.788 and 2.786 A (O4–O2–O3) as shown in Fig. 5.
Nitrogen atoms have strong influence on the solid-state
packing of 1 by providing different motives of interactions.
Figure 6 shows the non-centrosymmetric dimer that
formed through the double NꢀꢀꢀH interactions (N2–H4B
and N1–H3B) between two molecules of 1 with distances
˚
of 3.445 and 3.382 A. Intermolecular nitrogen–oxygen and
nitrogen–nitrogen interactions are present in solid-state
structure of 1. Figure 7 shows that oxygen atom (O2) of one
molecule is bifurcated with two nitrogen atoms (N1 and N2)
of another molecule to give non-centrosymmetric dimer with
Fig. 7 Intermolecular N1–O2–N2 interactions between two mole-
˚
cules of 1 with distances of 3.649 and 3.382 A
˚
oxygen–nitrogen distances of 3.649 and 3.837 A. Further-
more, very weak intermolecular contacts are observed in
term of edge-face nitrogen–nitrogen interactions with dis-
˚
tances of 5.505 and 5.690 A (Fig. 8).
shown in Fig. 2. The structure and function of biological
molecules is to a large degree determined by hydrogen
bonding. This is the case for proteins, nucleic acids, car-
bohydrates, membranes and also the aqueous medium in
which these components are held [30]. Non-covalent
interactions greatly influence the behavior of compounds.
Oxygen atom (O2) of one molecule of 1 is hydrogen
bonded to the hydrogen atoms of the two hydroxy groups
of another molecule of 1 (H3B and H4B) with bond dis-
Conclusion
Derivative 2 showed good antibacterial activity against B.
subtilis and P. aeruginosa, while derivative 1 showed only
has antibacterial activity against P. aeruginosa. Both of 1
and 2 were inactive against C. albicans. 2 demonstrated
˚
tances of 1.969 and 1.974 A and bond angles (O2–H4B–
123

J Chem Crystallogr (2012) 42:783–789
789
9. Oshovsky GV, Reinhoudt DN, Verboom W (2007) Angew Chem
Int Ed 46(14):2366
10. Alshahateet SF, Bishop R, Craig DC, Scudder ML (2011) Cryst
Growth Des 11:4474–4483
11. Alshahateet SF, Rahman ANMM, Bishop R, Craig DC, Scudder
ML (2002) CrystEngComm 4(97):585–590
12. MacNicol DD, Downing GR (1996) In: MacNicol D, Toda F,
Bishop R (eds) Comprehensive supramolecular chemistry, vol. 6
solid-state supramolecular chemistry: crystal engineering. Perg-
amon Press, Oxford, Ch 14, pp 421–464
good cholinesterase enzyme activity unlike 1 that has weak
inhibitory activity against these enzymes. 2 was found to
be a selective butyrylcholinesterase enzyme inhibitor that
has potential use for prevention of further neurodegenera-
tion as well for symptomatic treatment of Alzheimer
patient. Investigation of the solid-state structure of 1 led to
very interesting supramolecular non-covalent interactions
which greatly influence the behavior of a given compound
such as its bioactivity.
13. Alshahateet SF, Bishop R, Craig DC, Scudder ML (2001)
CrystEngComm 3(48):225–229
14. Alshahateet SF, Bishop R, Craig DC, Scudder ML (2004) Cryst
Growth Des 4:837–844
Supplementary Material
15. Kooli F, Hian PC, Weirong Q, Alshahateet SF, Chen F (2006)
J Porous Mater 13:319–324
16. Alshahateet SF, Bishop R, Craig DC, Scudder ML (2003)
CrystEngComm 3:417–421
17. Alshahateet SF, Bishop R, Craig DC, Scudder ML (2010) Cryst
Growth Des 10:1842–1847
18. Alshahateet SF, Bishop R, Scudder ML, Hu CY, Lau EHE, Kooli
F, Judeh ZMA, Chow PS, Tan RBH (2005) CrystEngComm
7:139–142
19. Alshahateet SF, Bishop R, Craig DC, Scudder ML (2001)
CrystEngComm 3(55):264–269
CCDC-826750 contains the supplementary crystallo-
graphic data for this paper. This data can be obtained free
of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.
html [or from the Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax:
?44(0)1223-336033; email: deposit@ccdc.cam.ac.uk].
Acknowledgments We would like to acknowledge Universiti Sains
Malaysia (USM) for the Postdoctoral Fellowship to Dr. Raza Murad
Ghalib. We would also like to thank Ms Liew Wai Lam, Ms Claira
Arul Aruldass and Mr Mani Maran Marimuthu for their contribution
in the present study.
20. Alshahateet SF, Bishop R, Craig DC, Kooli F, Scudder ML
(2008) CrystEngComm 10:297–305
21. Alshahateet SF, Ong TT, Bishop R, Kooli F, Messali M (2006)
Cryst Growth Des 6(7):1676–1683
22. Alshahateet SF, Bishop R, Craig DC, Scudder ML, Ung AT
(2001) Struct Chem 12:251–257
23. Eloff JN (1998) Planta Med 64:711–713
24. Ahmed T, Gilani AH (2009) Pharmacol Biochem Behav
91:554–559
References
25. Siemens Energy and Automation, Inc (1996) SMART and
SAINT software reference manuals, Version 4.0. Analytical
Instrumentation, Madison, WI
1. Hasenknopf B, Lehn J-M, Kneisel BO, Baum G, Fenske D (1996)
Angew Chem Int Ed 35:1838
2. Day AI (2002) Angew Chem Int Ed 41:275
3. Bravo JA (1998) Eur J Org Chem 1998:2565
4. Anderson S, Anderson HL, Bashall A, McPartlin M, Sanders
JKM (1995) Angew Chem Int Ed 34:1096
5. Freeman WA (1984) Acta Crystallogr B 40:382
6. Schmitt J-L, Stadler A-M, Kyritsakas N, Lehn J-M (2003) Helv
Chim Acta 86:1598
7. Lehn JM (1993) Science 260(5115):1762
8. Lehn J-M (1995) Supramolecular chemistry. Wiley-VCH. ISBN
978-3527293117
¨
26. Sheldrick GM (1996) SADABS. University of Gottingen,
¨
Gottingen
27. Sheldrick GM (2008) Acta Crystallogr A64:112–122
28. Weinstock M, Groner E (2008) Chem-Biol Interact 175:216–221
29. Mesulam M, Guillozet A, Shaw P, Quinn B (2002) Neurobiol Dis
9:88–93
30. Desiraju GR, Steiner T (1999) The weak hydrogen bond in
structural chemistry and biology. Oxford Science Publications,
Oxford
123