Synthesis and structure investigation of novel pyrimidine-2,4,6-trione derivatives of highly potential biological activity as anti-diabetic agent

Article abstract of DOI:10.1016/j.molstruc.2015.06.037

Abstract Synthesis of (±)-1,3-dimethyl-5-(1-(3-nitrophenyl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione (3) is reported. The structure of compound 3 was deduced by using spectroscopic methods, X-ray crystallography, and DFT calculations. The calculated geometric parameters were found to be in good agreement with the experimental data obtained from the X-ray structure. The NBO calculations were performed to predict the natural atomic charges at the different atomic sites and to study the different intramolecular charge transfer (ICT) interactions. The high LP(3)O6 →z BD?(2)O5-N3 ICT interaction energy (165.36 kcal/mol) indicated very strong n → π?electron delocalization while the small LP(2)O → BD?(1)C-H ICT interaction energies indicated that the C-H ... O intramolecular interactions are weak. The ¹H and ¹³C NMR chemical shifts calculated using GIAO method showed good agreement with the experimental data. The calculated electronic spectra of the studied compound using TD-DFT method showed intense electronic transition band at 243.9 nm (f = 0.2319) and a shoulder at 260.2 nm (f = 0.1483) which were due to H-4/H-2/H-1/H → L+2 and H-5 → L electronic excitations, respectively. Compound 3 (IC₅₀ = 305 ± 3.8 μM) was identified as a potent inhibitor of α-glucosidase in vitro and showed several fold more inhibition than the standard drug acarbose (IC₅₀ = 841 ± 1.73 μM). Molecular docking of the synthesized compound was discussed.

Full text of DOI:10.1016/j.molstruc.2015.06.037

Journal of Molecular Structure 1098 (2015) 365e376
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis and structure investigation of novel pyrimidine-2,4,6-trione
derivatives of highly potential biological activity as anti-diabetic agent
Assem Barakat a
,
b
,
*
, Saied M. Soliman , Abdullah Mohammed Al-Majid , Gehad Lotfy ,
b
a
c
d
d
,
e
f
a, f
Hazem A. Ghabbour , Hoong-Kun Fun , Sammer Yousuf , M. Iqbal Choudhary
,
g
Abdul Wadood
a
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
X-Ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang 11800, Malaysia
H.E.J. Research Institute of Chemistry, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan
Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
b
c
d
e
f
g
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 May 2015
Received in revised form
Synthesis of (±)-1,3-dimethyl-5-(1-(3-nitrophenyl)-3-oxo-3-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-
trione (3) is reported. The structure of compound 3 was deduced by using spectroscopic methods, X-ray
crystallography, and DFT calculations. The calculated geometric parameters were found to be in good
agreement with the experimental data obtained from the X-ray structure. The NBO calculations were
performed to predict the natural atomic charges at the different atomic sites and to study the different
intramolecular charge transfer (ICT) interactions. The high LP(3)O6 /z BD*(2)O5eN3 ICT interaction
9
June 2015
Accepted 11 June 2015
Available online 15 June 2015
energy (165.36 kcal/mol) indicated very strong n /
p* electron delocalization while the small LP(2)
Keywords:
O / BD*(1)CeH ICT interaction energies indicated that the CeH … O intramolecular interactions are
weak. The 1H and C NMR chemical shifts calculated using GIAO method showed good agreement with
the experimental data. The calculated electronic spectra of the studied compound using TD-DFT method
showed intense electronic transition band at 243.9 nm (f ¼ 0.2319) and a shoulder at 260.2 nm
(f ¼ 0.1483) which were due to H-4/H-2/H-1/H / Lþ2 and H-5 / L electronic excitations, respectively.
Pyrimidine-2,4,6(1H,3H,5H)-trione
Barbituric acid
DFT computations
13
a-Glucosidase inhibition
Post-prandial hyperglycemia
Molecular docking
Compound 3 (IC50 ¼ 305 ± 3.8
mM) was identified as a potent inhibitor of a-glucosidase in vitro and
showed several fold more inhibition than the standard drug acarbose (IC50 ¼ 841 ± 1.73
mM). Molecular
docking of the synthesized compound was discussed.
©
2015 Elsevier B.V. All rights reserved.
1
. Introduction
antitumor agents. They have high efficacy to form hydrogen-
bonding with drug targets (1e4, Fig. 1) [7e10]. Singh et al. have
evaluated a series of new N-benzyl indole-pyrimidine-2,4,6-trione
hybrid molecules against a panel of 60 human tumor cell lines.
Several of these analogs are also inhibitors of DNA repair and
replication stress response polymerases [11]. Recently, Barakat et al.
[12], synthesized and evaluated some novel zwitterionic adduct
derived from pyrimidine-2,4,6-trione (e.g., compound 5, Fig. 1)
possess anti-oxidant properties.
Nitrogen-containing compounds are privileged heterocyclic
scaffold due to their biological and pharmaceutical activities [1]. For
example, pyrimidine-2,4,6-trione derivatives are known to have as
anti-hypertensive [2], anti-cancer [3], anti-convulsant [4] anti-
inflammatory [5], and anti-psychotic properties [6]. Because of
the biological activities of these compounds, pyrimidine-2,4,6-
triones (PYT) are widely used as a synthons in the design of
Named after Arthur Michael, the conjugate addition of nucleo-
philes to acceptor activated alkene and alkyne substrates is a
recognized strategy for an efficient and versatile construction of
CeC bonds. The reaction produces a large variety of the conjugate
addition products based on a broad range of the Michael donors
*
Corresponding author. Department of Chemistry, College of Science, King Saud
University, P. O. Box 2455, Riyadh 11451, Saudi Arabia.
E-mail address: ambarakat@ksu.edu.sa (A. Barakat).
http://dx.doi.org/10.1016/j.molstruc.2015.06.037
0
022-2860/© 2015 Elsevier B.V. All rights reserved.

366
A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
Fig. 1. Anticancer agents and anti-oxidant bearing pyrimidine-2,4,6-trione moiety.
and acceptor. Depending upon the nature of the nucleophile, many
of its variants, in the form of hetero-Michael reactions, whose
recent examples include, the sulpha-Michael, aza-Michael, oxo-
Michael and phospha-Michael have been developed. The classical
Michael additions are typically base catalyzed that also promotes
Michael adducts efficiently [13e26].
Petroleum ether (PE), hexane, and ethyl acetate were distilled prior
to use, especially for column chromatography. All the major solvents
were dried by using slandered drying techniques mentioned in the
literature. Melting points were measured on a Gallen-kamp melting
point apparatus in open glass capillaries and are uncorrected. IR
Spectra were measured as KBr pellets on a Nicolet 6700 FT-IR
spectrophotometer. The NMR spectra were recorded on a Jeol-400
In view of these reports and our interest in the synthesis of
bioactive heterocyclic compounds [27e32], we report here an
efficient synthesis of 1,3-dimethyl-5-(1-(3-nitrophenyl)-3-oxo-3-
phenylpropyl)pyrimidine 2,4,6(1H,3H,5H)etrione. DFT/B3LYP cal-
culations have also been performed to study the molecular struc-
ture characteristics of the studied compound. The electronic and
spectroscopic properties of the compound have been predicted
using the same level of theory. The TD-DFT calculations were used
to predict and assign the electronic spectra of the studied com-
pound. NBO calculations were performed to predict the natural
atomic charges, and to study the different intramolecular charge
transfer (ICT) interactions occurring in the studied system. The
NMR chemical shifts were calculated using the gauge including
atomic orbital (GIAO) method and used to assign the experimental
results.
1
13
NMR spectrometer. H NMR (400 MHz), and C NMR (100 MHz)
were run in deuterated chloroform (CDCl ). Chemical shifts ( ) are
3
d
referred in terms of ppm and J -coupling constants are given in Hz.
Mass spectrometric analysis was conducted by using ESI mode on
AGILENT Technologies 6410etriple quad LC/MS instrument.
Elemental analysis was carried out on Elmer 2400 Elemental
Analyzer, CHN mode. The X-ray diffraction measurement of com-
pound 3 was collected by using Bruker SMART APEXII D8 Venture
diffractometer. The thermal analysis of the studied compound has
been carried out using TGA Q500 V20.10. The wt% loss has been
ꢀ
measured from the ambient temperature up to 800 C.The elec-
tronic spectrum of the studied compound is measured using Perkin
Elmer, Lambda 35, UV/Vis spectrophotometer.
3 (Ethanol): 205 nm, 243 nm and 266 nm (sh).
2
. Experimental
2.2. 1,3-Dimethyl-5-(1-(3-nitrophenyl)-3-oxo-3-phenylpropyl)
pyrimidine-2,4,6- (1H,3H,5H)-trione (3)
2.1. General remarks
A solution of N,N-dimethyl barbituric acid 1 (1.5 mmol) and
All the glassware was ovenedried before use, and the reactions
enone derivatives 2 (1.5 mmol) in 2 mL of dry CH
into a 50 mL round bottom flask under inert atmosphere. The Et
(1.5 mmol) was then added to the reaction mixture and stirred at
room temperature for up to 1.5e2 h, until TLC showed complete
consumption of both the reactants. After the completion of
2
Cl
2
were charged
NH
were conducted under inert atmosphere. The progress of the reac-
tion was monitored by TLC (Merck Silica Gel 60 Fe254 thin layer
plates). The chemicals were purchased from Aldrich, and Fluka etc,
and were used without further purification, unless otherwise stated.
2

A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
367
reaction, the crud product directly subjected to column chroma-
tography using 100e200 mesh silica gel and ethyl acetate/n-hexane
referenced to the TMS calculations were carried out at the same
level of theory. The natural bond orbital analyses were performed
using the NBO calculations as implemented in the Gaussian 03
package [38] at the DFT/B3LYP level.
(
2:8, v/v) as an eluent to afford the racemic mixture of products 3.
1
3 3
H NMR (400 MHz, CDCl ) d: 3.07 (s, 3H, eNCH ), 3.16 (s, 3H,
eNCH
3
), 3.59 & 3.63 (dd, 1H, J ¼ 18.32 Hz, 5.84 Hz, CH2(a)), 3.98 (d,
1
H, J ¼ 3.68 Hz, CH), 4.05 & 4.10 (dd, 1H, J ¼ 18.32 Hz, 8.08 Hz,
2.6. Homology modeling and molecular docking study of compound
3
CH2(e)), 4.45e4.55 (m,1H, CH), 7.39e7.49 (m, 3H, AreH), 7.56 (d, 2H,
J ¼ 8.80 Hz, AreH), 7.97 (d, 2H, J ¼ 7.36 Hz, AreH), 8.06e8.12 (m, 2H,
AreH); 13C NMR (100 MHz, CDCl
)
d: 28.3, 28.3, 40.5, 42.7, 52.6,
The study was designed to dock compound 3 against a-gluco-
3
(
R)
1
22.3, 123.1, 128.0, 128.7, 129.7, 133.6, 134.3, 136.3, 141.4, 148.3,
sidase enzyme with the following communications; Intel xen-
ꢁ
1
(R)
1
1
6
50.7, 167.3, 167.4, 197.3; IR (KBr, cm
689, 1526, 1449, 1346, 1298, 1270; [Anal. Calcd. for C21
1.61; H, 4.68; N, 10.26; Found: C, 61.49; H, 4.52; N, 10.11]; LC/MS
)
n
max ¼ 3420, 3083, 2953,
on CPU E5620@2.40GHz system having 3.8 GB RAM with the
open 11.4 (X 86_64) operating platform. Protein-Ligand docking
was carried out using the Molecular Operating Environment (MOE
H
19
N
3
O
6
: C,
þ
(
ESI, m/z): [M ], found 409.10, C21
H
19
N
3
O
6
requires 409.13.
2010.11) software package. The three dimensional structure for a-
glucosidase of S. cerevisiae has not been solved up-to yet, although
only few homology models has been reported [39e42]. In the
2.3. Single-crystal X-ray diffraction studies
current study we predict 3D structure for
evisiae by using same protocol as described by (Burke et al.) of
homology modeling [42]. The primary sequence of -glucosidase
a-glucosidase of S. cer-
Compound 3 was obtained as crystals by slow diffusion of
diethyl ether solution of compounds 3 in dichloromethane at room
a
temperature for 24 h. Diffraction data was collected on a Bruker
for S. cerevisiae was retrieved from UniProt (Access code P53341).
Template search was performed using MOE-Search tools against
the PDB implemented in MOE v2010.11. The crystallographic
structure of S. cerevisiae isomaltase (PDB code 3AJ7; Resolution
1.30 Å) with 72.4% of sequence identity with the target was selected
APEX-II D8 Venture area diffractometer, equipped with graphite
ꢀ
monochromatic Cu K
a
radiations at 293 (2) K. Cell refinement and
data reduction were carried out by Bruker SAINT. SHELXS-97
33,34] was used to solve structure. The final refinement was car-
[
ried out by full-matrix least-squares techniques with anisotropic
thermal data for nonhydrogen atoms on 3. All the hydrogen atoms
were placed at calculated positions.
The structure of 3 was determined by X-ray crystal structure
analysis (Bruker AXS GmbH). CCDC- 1024287; contains the sup-
plementary crystallographic data for this compound. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
as a template [43]. The 3D structure of a-glucosidase for S. cerevisiae
was predicted using MOE homology modeling tools. The developed
model was then subjected to energy minimization up to 0.05
gradients.
Before docking, ligands and protein were prepared using MOE
v2010.11. 3D structure of compound 3 was built by using Molec-
ular Builder Module program implemented in MOE and save as a
(.mdb) file for molecular docking. Subsequently, the energy of
compound 3 was minimized up to 0.05 Gradient using MMFF 94x
force field. Energy minimization of the compound 3 was followed
by the preparation of protein for docking purposes. Most macro-
molecular crystal structures contain little or no hydrogen coordi-
nate data due to limited resolution and thus protonation was done
prior to docking using Protonate 3D tools. Protonation was fol-
lowed by energy minimization up to 0.05 Gradient using Amber
99 force field. The compound 3 was docked into the active site of
protein using the Triangular Matching docking method and 30
conformations of compound 3 and protein complex were gener-
ated with docking score (S). The complex was analyzed for in-
teractions and their 3D images were taken by using visualizing
tool PyMol.
2.4. a-Glucosidase inhibition assay
Glucosidase inhibition assay was performed spectrophotomet-
rically. -Glucosidase from Saccharomyces cerevisiae (G0660-
50UN, Sigma Aldrich) was dissolved in phosphate buffer (pH 6.8.,
0 mM). Compound 3 was dissolved in 70% DMSO. In 96-well
a
7
5
plates, 20
m
L of test compound, 20
m
L of enzyme and 135
m
L of
ꢀ
buffer were added, and incubated for 15 min at 37 C. After incu-
bation, 25
Aldrich) was added and change in absorbance was monitored for
0 min at 400 nm. Test compound was replaced with DMSO (7.5%
mL of p-nitrophenyl-a-D-glucopyranoside (0.7 mM, Sigma
3
final) as a control. Acarbose (Sigma Aldrich) was used as a standard
inhibitor.
3. Results and discussion
2.5. Computational study
3.1. Synthesis
All the quantum chemical calculations of the studied compound
were performed by applying DFT method with the B3LYP functional
and 6‒311G (d,p) basis set using Gaussian 03 software [35]. The
input file was taken from the CIF obtained from the X‒ray single
crystal measurement. The geometry was optimized by minimizing
the energies with respect to all the geometrical parameters without
imposing any molecular symmetry constraints. GaussView4.1 [36]
and Chemcraft [37] programs were used to draw the structure of
the optimized geometry. Frequency calculations at the optimized
geometry were aimed out to confirm the optimized structure to be
an energy minimum. The true energy minimum at the optimized
geometry of the studied compound was confirmed by absence of
any imaginary frequency modes. The electronic spectra of the
studied compound were calculated by the TD‒DFT method. The
gauge including atomic orbital (GIAO) method was used for the
The synthetic pathway to the title compound is summarized in
Scheme 1. The starting compounds, N,N-dimethyl barbituric acid
(1) is commercially available, (E)-3-(3-nitrophenyl)-1-phenylprop-
2-en-1-one (2) was obtained by the condensation of m-nitro-
benzaldehyde with acetophenone [25,26]. The reaction of (1) with
2
equimolar amount of enone 2 in DCM using NHEt as a base
afforded the target compound 3 in 93% yield. The desired com-
pound (±) 3 was obtained as a racemic mixture. The compound was
1
13
characterized by a combined application of H, and C and GCeMS
spectroscopy.
3.2. Single e crystal X-ray diffraction study
A
specimen of
C
21
H
19
N
3
O
6
,
approximate dimensions
1
13
NMR calculations. The H and the C isotropic shielding tensors
0.367 mm ꢂ 0.451 mm ꢂ 0.841 mm was used for the X-ray

368
A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
Scheme 1. Michael addition reaction of N,N-dimethyl barbituric acid 1 into enone derivative 2.
crystallographic analysis. The integration of the data using a
3.3. Biological activity evaluation
monoclinic unit cell yielded a total of 28249 reflections to a
ꢀ
maximum
q
angle of 70.13 (0.82 Å resolution), of which 3668 were
Compounds 3 was subjected to in vitro a-glucosidase enzyme
independent (average redundancy 7.701, completeness ¼ 99.8%,
inhibition assay, The results are presented in Table-4.
Compound 3 showed a potent -glucosidase inhibition activity
with IC50 values 305 ± 3.8 M, and was found to be several fold more
M).
R
int ¼ 4.12%, Rsig ¼ 2.19%) and 3296 (89.86%) were greater than
a
2
2
s
(F ). The final cell constants of a ¼ 9.5053(2) Å, b ¼ 12.1670(2) Å,
m
ꢀ
3
c ¼ 17.5962(3) Å,
b
¼ 108.3640(10) , volume ¼ 1931.38(6) Å , are
active than the standard drug, acarbose (IC50 ¼ 840 ± 1.73
m
based upon the refinement of the XYZ-centroids of reflections
Apparently one of the enantiomers of the (±) mixture was
above 20
mission coefficients (based on crystal size) are 0.5250 and 0.7390
Table 1.).
The asymmetric unit of compound 3 contains one molecule
which composed of three rings; two phenyl rings (C8eC13) and
C14eC19) in addition to pyrimidine ring (C1/N2/C2/N1/C3/C4) as
s
(I). The calculated minimum and maximum trans-
responsible of activity in various biological bioassays.
(
3.4. Optimized molecular geometry
The structure of the studied molecule has been optimized using
the B3LYP/6‒311G(d,p) method. The optimized molecular geome-
try is shown in Fig. 4. The studied compound possesses C point
group. Selected optimized geometric parameters (bond lengths and
bond angles) compared with the X-ray results are given in Table 2.
The optimized geometric parameters showed a good agreement
with the structural parameters obtained from the crystallographic
information file (CIF). The calculated CeCeC bond angle values of
(
shown in Fig. 2. These three rings form three different planes, the
1
ꢀ
angles between the two phenyl rings is 30.82 (4) , and the angles
between pyridine ring and the(C8eC13) and (C14eC19) phenyl
ꢀ
ꢀ
rings are 6.70 (2) and 37.56 (3) , respectively. In the crystal; mol-
…
.
ecules are linked via CeH
O interactions to form parallel chains
along the a-axis (Fig. 3, Table 3). Only one form “R” of resulting
racemic product was studied by the single-crystal X-ray diffraction
analysis, but the “S” form exist in equal amount.
ꢀ
the phenyl rings are in the range of 117.9e122.7 (exp.
ꢀ
1
17.6e123.0 ) [44]. The calculations predicted the O1/H44,
O2/H47 and O3/H19 intramolecular distances are 2.262 Å (exp.
.358 Å), 2.260 Å (exp. 2.367 Å) and 2.316 Å (exp. 2.355 Å),
2
Table 1
Experimental details.
respectively. These results indicate the presence of some intra-
molecular O … H interactions between the O-atoms of the pyr-
imidinetrione moiety and the H-atoms of the neighboring CeH
bonds. Moreover, the studied compound has three six member
rings, two are benzene and the third is the pyrimidinetrione. The
calculated CeCeCeC dihedral angles of the two benzene rings are
Crystal data
Chemical formula
21 19 3 6
C H N O
409.39
Monoclinic, P21/c
293
9.5053 (2), 12.1670 (2),
M
r
Crystal system, space group
Temperature (K)
a, b, c (Å)
ꢀ
almost 0 indicating, commonly, the perfectly planar structure of
17.5962 (3)
these rings. In contrast, pyrimidinetrione ring is not planar where
the N7, N8, C10, C11 and C12 atoms are almost lie in the same plane.
The C13 lies above this plane where the C11eN7eC12eC13, and
ꢀ
b
( )
108.364 (1)
1931.38 (6)
4
3
V (Å )
Z
ꢀ
Radiation type
Cu Ka
C11eN8eC10eC13 dihedral angles are in the range 10.4e11.1 .
m
(mmꢁ1)
0.88
Crystal size (mm)
Data collection
Diffractometer
0.84 ꢂ 0.45 ꢂ 0.37
3.5. Natural atomic charge
Bruker APEX-II D8 Venture
diffractometer
Multi-scan SADABS V2012/
Distribution of positive and negative charges has vital role in the
Absorption correction
application of quantum chemical calculations to molecular system
because of atomic charges affect dipole moment, molecular polar-
izability, electronic structure, acidityebasicity behavior and more
lot of properties of molecular system. These electronic properties
have strong relations to the biological activity of compound. The
calculated natural charges (NAC) at the different atomic sites are
given in Table 5. The carbonyl O‒atoms are the most electronega-
tive atomic sites in the molecule. The calculated natural charge
densities at these atoms are in the range ꢁ0.5870 to ꢁ0.6093. The
two oxygen atoms (O5 and O6) of the nitro group are less elec-
tronegative than the carbonyl oxygen. Also, the two N-atoms of the
1
(Bruker AXS Inc.)
T
min, Tmax
0.61, 0.74
28249, 3668, 3296
No. of measured, independent and
observed [I > 2
s
(I)] reflections
R
int
0.041
Refinement
R[F > 2
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
2
2
2
s
(F )], wR(F ), S
0.050, 0.133, 1.03
3668
273
0
H-atom parameters constrained
0.32, ꢁ0.28
Drmax
,
Drmin (e Åꢁ3)

A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
369
Fig. 2. ORTEP diagram of the compound 3. Displacement ellipsoids are plotted at the 50% probability level.
pyrimidinetrione ring are electronrgative. In contrast, the N-atom
positive NAC values.
.6. Molecular electrostatic potential
Electrostatic potential map (MEP) is a very useful three
dimensional diagrams used to visualize the charge distributions
and charge related properties of molecules. The MEP picture is
typically visualized through it values on the molecular electron
density. It is a very useful property for analyzing and predicting
of the nitro group has positive natural charge (0.5164). All the H‒
atoms are electropositive where the most electropositive H‒site is
H4a (0.2974). This H-atom affected strongly by the high electron
withdrawing character of the two C]O groups surrounding it. The
rest of H-atoms have natural atomic charge values in the range of
3
0
.2000e0.2551. In contrast, the C-atoms have negative natural
charges except C1, C2 and C3 which are bonded to O3, O1 and O2
atoms respectively. These carbonyl carbons have the highest
Fig. 3. Crystal packing showing intermolecular CeH…O hydrogen bonds as dashed lines.

370
A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
Table 2
Comparison between the calculated and experimental geometric parameters.
Parameter
X-ray
DFT
Parameter
X-ray
DFT
1.391
1.472
1.387
1.402
1.473
1.482
O1eC2
O2eC3
O3eC1
O4eC7
O5eN3
O6eN3
N1eC2
C2eN1eC3
C2eN1eC21 117.74 (16) 115.75
C3eN1eC21 118.32 (16) 119.00
C1eN2eC2
C1eN2eC20 117.90 (17) 117.14
C2eN2eC20 117.84 (17) 117.75
O5eN3eO6
1.208 (2)
1.210 (2)
1.214 (2)
1.211 (2)
1.216 (3)
1.213 (2)
1.385 (2)
1.210 N1eC3
1.379 (2)
1.464 (3)
1.369 (2)
1.396 (3)
1.465 (3)
1.468 (2)
1.212 N1eC21
1.215 N2eC1
1.220 N2eC2
1.223 N2eC20
1.224 N3eC16
1.398
123.89 (15) 125.17
N2eC1eC4
O1eC2eN1
O1eC2eN2
N1eC2eN2
O2eC3eN1
O2eC3eC4
N1eC3eC4
O4eC7eC6
O4eC7eC8
116.90 (16) 116.89
121.45 (19) 120.83
121.11 (19) 122.00
117.41 (16) 117.15
121.32 (16) 121.44
121.92 (16) 122.00
116.56 (15) 116.45
120.56 (16) 121.19
120.29 (15) 120.33
124.15 (16) 125.03
122.44 (19) 124.72
O5eN3eC16 119.21 (16) 117.75
O6eN3eC16 118.35 (19) 117.53
O3eC1eN2
O3eC1eC4
121.33 (18) 121.44
121.67 (17) 122.00
N3eC16eC15 118.05 (16) 118.63
N3eC16eC17 118.96 (15) 118.70
All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are esti-
mated using the full covariance matrix. The cell e.s.d.'s are taken into account
individually in the estimation of e.s.d.'s in distances, angles and torsion angles;
correlations between e.s.d.'s in cell parameters are only used when they are defined
by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for
estimating e.s.d.'s involving l.s. planes.
Fig. 4. The optimized molecular structure of the studied compound.
be seen from this figure that, negative regions (red) are mainly
localized over the O-atoms. On other hand, the positive regions
(blue) around the N-atom of the nitro group confirms the electron
deficiency of this site. Moreover, the phenyl ring carrying the nitro
group is less reactive toward the electrophilic attack compared to
the other phenyl ring. The blue regions localized over the pyr-
imidinetrione ring indicate its high electron deficiency.
molecular reactive behavior. In this regards, MEP picture has been
used to predict the reactive sites for electrophilic and nucleophilic
attack, and in studies of biological recognition and hydrogen
bonding interactions [45,46]. Moreover, the MEP picture usually
generated by overlapping the VdW radii of all atoms in the mole-
cule so it reflects the molecule boundaries and it allows us to
visualize the size and shape of molecules. MEP has been applied
successfully to the study of interactions that involve a certain op-
timum relative orientation of the reactants. In order to predict the
reactive sites for electrophilic and nucleophilic attack, the molec-
ular electrostatic potential has been plotted for the title compound
and is shown in Fig. 5. This figure provides a visual representation
of the chemically active sites and comparative reactivity of atoms.
Potential increases in the order red < orange < yellow < green <
blue. Regions of negative potential (red) are usually associated with
the lone pair of electronegative atoms while the positive electro-
static potential (blue) corresponds to the electropositive sites. It can
3.7. Nonlinear optical properties
Nonlinear optical materials were used as key materials for
photonic communications which use light instead of electron for
data transmission. With the development of laser technology,
nonlinear optical materials have been extensively applied to in-
dustry, national defense, medicine and research [47,48]. Several
organic materials were used for such applications. These organic
compounds were characterized by their high polarizability (
0
a ) and
low HOMO‒LUMO gap ( E). The and E values of the studied
D
a
0
D
3
compound are calculated to be 261.73 Bohr and 4.772 eV,
respectively. The polarizability of the studied compound is 9 times
higher than urea (28.00 Bohr ). Also, the studied compound has
3
Table 3
lower energy gap (DE) compared to urea (7.66 eV). Based on these
calculations, the studied molecule is considered as a better NLO
material than this reference molecule used in literature [49].
ꢀ
Hydrogen-bond geometry (Å, ).
DdH…A
DdH
H…A
D…A
DdH…A
C4eH4A…O3a
C5eH5A…O2b
C6eH6B…O3
C9eH9A…O6c
C19eH19A…O4
0.9800
0.9800
0.9700
0.9300
0.9300
0.9600
2.4700
2.5900
2.3600
2.5900
2.5100
2.5800
3.415(2)
3.407(2)
3.047(3)
3.492(3)
3.267(2)
3.325(3)
163.00
141.00
128.00
163.00
138.00
135.00
3.8. Frontier molecular orbitals (FMOs)
b
The highest occupied molecular orbital (HOMO) and lowest
unoccupied molecular orbital (LUMO) are called frontier molecular
orbitals. The shapes of their electron densities and energies of have
great interest for chemists and physicists. The shapes of these FMOs
d
C21eH21B…O6
Symmetry codes.
a
ꢁ
xþ1, ꢁyꢁ1, ꢁz.
b
c
ꢁ
x, ꢁyꢁ1, ꢁz.
were used for predicting the most reactive position in
p‒electron
x, yꢁ1, z.
systems and also explained several types of reactions in conjugated
system [50]. Moreover, the energies of the lowest unoccupied
molecular orbital (ELUMO) and the highest occupied molecular
d
ꢁx, ꢁy, ꢁz.
orbital (EHOMO) and their energy gap (
reactivity of the molecule. A molecule having a small frontier
orbital gap ( E) is more polarizable and is generally associated with
a high chemical reactivity and low kinetic stability [51]. Recently
the energy gap between HOMO and LUMO has been used to prove
the bioactivity from intramolecular charge transfer (ICT) [52,53].
DE) reflect the chemical
Table 4
Result of a-glucosidase enzyme inhibition assay on compound 3.
D
Compound
a-glucosidase inhibition (IC50 ± SEM [mM])
3
Std.
305 ± 3.8
Acarbose 840 ± 1.73

A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
371
Table 5
The natural atomic charges calculated at the B3LYP/6-311G(d,p).
Atom
NAC
Atom
NAC
O1
O2
O3
O4
O5
O6
N1
N2
ꢁ0.6025
ꢁ0.6006
ꢁ0.6093
ꢁ0.5870
ꢁ0.3834
ꢁ0.3852
ꢁ0.5011
ꢁ0.4981
0.5164
C11
H11A
C12
H12A
C13
H13A
C14
C15
H15A
C16
ꢁ0.1693
0.2041
ꢁ0.1975
0.2062
ꢁ0.1696
0.2073
ꢁ0.0242
ꢁ0.2015
0.2551
N3
C1
0.7273
0.0682
C2
C3
C4
H4A
C5
H5A
C6
H6A
H6B
C7
C8
C9
H9A
C10
H10A
0.8498
0.7354
C17
H17A
C18
H18A
C19
H19A
C20
H20A
H20B
H20C
C21
H21A
H21B
H21C
ꢁ0.1847
0.2371
ꢁ0.3915
ꢁ0.1857
0.2108
0.2974
ꢁ0.2084
0.2418
ꢁ0.1635
0.2234
ꢁ0.4860
ꢁ0.3548
0.2072
0.2238
0.2284
0.2528
0.5997
ꢁ0.1499
ꢁ0.1470
0.2234
0.2012
ꢁ0.3532
0.2220
0.2000
0.2068
ꢁ0.1972
0.2056
The EHOMO, ELUMO and
D
E values are calculated to be ꢁ7.316, ꢁ2.544
and 4.772, respectively. The HOMO and LUMO pictures are shown
in Fig. 6. It is found that the HOMO level is mainly localized on the
pyrimidinetrione moiety while the LUMO is located mainly on the
benzoyl ring.
For understanding various aspects of pharmacological sciences
including drug design and the possible biological characteristics of
the drug molecules, several new chemical reactivity descriptors
have been proposed. HOMO, which can be thought the outer orbital
containing electrons, tends to give these electrons as an electron
donor and hence the ionization potential is directly related to the
energy of the HOMO. The ionization potential (I) is defined as the
amount of energy required to remove an electron from the neutral
molecule. Therefore, a high ionization potential indicates that the
systems do not lose electrons with facility [54,55]. On the other
hand, LUMO can accept electrons and the LUMO energy is directly
Fig. 6. The ground state isodensity surface plots for the frontier molecular orbitals.
related to electron affinity [56]. The electron affinity (A) is defined
as the energy released when an electron is added to a neutral
molecule. Using HOMO and LUMO orbital energies, the ionization
energy and electron affinity can be expressed as: I ¼ ꢁEHOMO and
A ¼ ꢁELUMO [57]. Moreover, the hardness (
h) is a measure of the
resistance to charge transfer [58] while, the electronegativity is a
measure of the tendency to attract electrons in a chemical bond, as
is defined as the negative of the chemical potential in DFT [58]. The
hardness (
¼ (I-A)/2 and
licity index ( ) measures the stabilization in energy when the
h
) and chemical potential (
m) are given from the relations
h
m
¼ ꢁ (I þ A)/2, respectively [48]. The electrophi-
u
system acquires an additional electronic charge from the environ-
ment. Parr et al. [59] proposed the global electrophilicity power as
2
u
¼
m
/2
h
. Electrophilicity encompasses both the ability of an
electrophile to acquire additional electronic charge and the resis-
tance of the system to exchange electronic charge with the envi-
ronment. It contains information about both electron transfer
(chemical potential) and stability (hardness) and is a better
descriptor of global chemical reactivity. For the title compound, the
ionization potential I ¼ 7.316, electron affinity A ¼ 2.544, global
hardness
trophilicity
h
¼ 2.386, chemical potential
m
¼ ꢁ4.930, global elec-
u
¼ 5.093 eV. It is seen that the chemical potential of
the title compound is negative and it means that the compound is
stable. The hardness signifies the resistance towards the deforma-
tion of electron cloud of chemical systems under small perturbation
encountered during chemical process. Soft systems are large and
highly polarizable, while hard systems are relatively small and
much less polarizable. The low value of chemical potential and high
value of electrophilicity index for 3 favor its electrophilic behavior
Fig. 5. Molecular Electrostatic potentials (MEP) mapped on the electron density sur-
face calculated by the DFT/B3LYP method.
[60].

372
A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
3.9. Electronic spectra and TD-DFT calculations
The lowest energy electronic transition implies the electron
transfer from the highest occupies molecular orbital (HOMO) to the
lowest unoccupied molecular orbital (LUMO). The easiest way, but
the less accurate, to calculate the energy of this transition is to
calculate the energy gap between HOMO and LUMO levels. The
HOMO‒LUMO energy gap (
tronic transition. In the studied compound, the HOMO‒LUMO en-
ergy gap is 4.772 eV. This electron transition belongs mainly to
* excitation which belongs to intramolecular charge transfer from
the pyrimidine moiety to the benzoyl ring.
DE) represents the lowest energy elec-
p
‒
p
The accurate electronic transitions were calculated using the
time‒dependant density functional theory (TD‒DFT). The spin
allowed singletesinglet electronic transitions calculated using the
TD‒DFT method were collected in Table S1 (Supplementary
Information). The calculated electronic spectrum is shown in
Fig. 7. On the basis of calculations, the studied compound showed
intense electronic transition band at 243.9 nm (f ¼ 0.2319) and a
shoulder at 260.2 nm (f ¼ 0.1483). These results showed good
agreement with the observed electronic spectra in ethanol. The
electronic transition band is due to H-4/H-2/H-1/H / Lþ2 elec-
tronic excitations while the shoulder is due to H-5 / L (76%)
transition.
3.10. NMR spectra
The isotropic magnetic shielding (IMS) values calculated using
the GIAO approach at the 6-311G(d,p) level are used to predict the
13
1
C and H chemical shifts (
results are correlated to the experimental NMR data (
solvent. The experimental and theoretical values for H and
dcalc) for the studied compound and the
d
exp) in CDCl
3
1
13
C
Fig. 8. The correlation graphs between calculated and experimental 1H NMR and 13
NMR chemical shifts of the studied compound 3.
C
NMR chemical shifts of the studied compound are given in Table S2
Supplementary Information). According to these results, the
(
calculated chemical shifts are in compliance with the experimental
findings. As shown in Fig. 8, good correlations between the
experimental and the calculated chemical shifts for carbon
energies E(2) deduced from the NBO calculations for the most sig-
nificant intramolecular charge transfer interactions are reported in
2
2
(
R ¼ 0.928) and proton (R ¼ 0.998) were obtained.
(2)
Table 6. The larger the E value, the more intensive is the inter-
action between electron donor and electron acceptor NBOs, i.e. the
greater the extent of conjugation of the whole system [61]. The
energy of these interactions can be estimated by the second‒order
perturbation theory [62]. The ICT interactions formed by the orbital
3
.11. Natural bond orbital (NBO) analysis
The natural bond orbital (NBO) calculations were performed in
order to understand various interactions between the filled NBOs of
one bond and vacant orbitals of another one, which is a measure of
the intramolecular delocalization of electrons. The stabilization
overlap between
of the system upto 26.95, 25.98 and 165.36 kcal/mol respectively,
which are due to BD(2)C16eC17 BD*(2)O5eN3, LP(2)
p / p*, n / s* and n / p* causing stabilization
/
Fig. 7. The calculated electronic spectra of the studied compound 3 using TD-DFT method.

A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
373
O3 / BD*(1)N2eC1 and LP(3)O6 / BD*(2)O5eN3 ICT interactions,
Table 7
The calculated and experimental wavenumbers of the compound 3.
respectively. These results indicate the presence of strong electron
delocalization from LP(3)O6 to the neighboring O5eN3 bond. It is
clear that, the ICT interaction energies due to the electron delo-
calization from the LP(2)O of the carbonyl groups to the BD*(1)CeH
Assignment
Calculated
Experimental
y
(CH, aromatic)
3124e3082, 3077e3062
3082e3081, 3031e2986
2966e2895
1746e1675
1608e1567
1550
1473e1418
1408
1402, 1356, 1351
1354
3083, 3066
2979
2954
1690
1591
1526
1449
1379
y(CHasym, CH3)
are very small indicating weak CeH
…
O
intramolecular
y
y
y
y
(CHsym, CH3)
]
O)
interactions.
(C
C
]
C
(N
e
O, assym)
a
3.12. Vibrational spectra
dCHasymmethyl
d
d
d
y
d
d
y
(CH
,
sciss.)
a
The vibrational frequencies of the titled compound were
CHsymmethyl
(CH
(N
,
e
wag.)
calculated by using the DFT B3LYP/6-311G(d,p) method. Vibrational
mode assignments were made by visual inspection of the modes
animated by using GaussView program [36]. Selected calculated
vibrational frequencies are compared with the experimental
vibrational frequencies (Table 7). The experimental and the pre-
dicted IR spectrum of the titled compound are given in Fig. 9. As can
be seen from Table 6, there is good agreement between the
experimental and calculated scaled IR vibrational frequencies [63].
O, sym)
1334
1347
1299
1210
1271
998
CH aromatic in plane
(CH twist.)
(C N)
1308e1251
1263, 1206
1236
,
e
Ring breathing
985, 984
d
d
CH aromatic out-of-plane
975e745, 688, 670
860
979e740, 688, 670
885
ONO
y
: streching
Mixed with other bending modes.
d
: bending.
a
3.12.1. Aromatic CeH vibrations
The hetero aromatic structure shows the presence of CeH
ꢁ
1
stretching vibrations in the region 3100e3000 cm [64]. In the
present investigation, the IR bands identified for the CeH stretch-
respectively. In the present study, the DFT calculations predicted
ꢁ
1
ꢁ1
)
the in-plane bending modes at 1308e1251 cm (exp. 1299 cm
while the out of plane CeH bending modes are predicted at
ꢁ
1
ing vibrations at 3083 and 3066 cm are calculated at 3124e3082
and 3077e3062 cm , respectively. The bands corresponding to the
in-plane and out-of-plane ring CeH bending vibrations are
ꢁ
1
ꢁ1 ꢁ1
975e745, 688 and 670 cm (exp. 979e740, 688, 670 cm ).
ꢁ1
observed in the region 1400e1000 and 1000e600 cm [65,66],
3.12.2. Aliphatic CeH vibrations
The CeH stretching vibrations of the methyl group occur at
Table 6
lower frequencies than those of the aromatic CeH ring vibrations
65]. The asymmetric stretch is usually at higher wavenumber than
the symmetric one. The asymmetric CeH stretching modes of the
(
2)
The second order perturbation energies E (kcal/mol) of the most important charge
transfer interactions (donoreacceptor) of the studied compound 3 using B3LYP
method.
[
ꢁ1
methyl groups are calculated at 3082e3081 and 3031-2986 cm
Donor NBO (i)
Acceptor NBO (j)
E(2)kcal/mol
ꢁ1
(
exp. 2979 cm ) while the CeH symmetric stretching vibrations
ꢁ
1
ꢁ1
BD(1)C4eH4A
BD(1)C4eH4A
BD(2)C8eC13
BD(2)C8eC13
BD(2)C8eC13
BD(2)C9eC10
BD(2)C9eC10
BD(2)C11eC12
BD(2)C11eC12
BD(2)C14eC15
BD(2)C14eC15
BD(2)C16eC17
BD(2)C16eC17
BD(2)C16eC17
BD(2)C18eC19
BD(2)C18eC19
LP(2)O1
LP(2)O1
LP(2)O2
LP(2)O2
LP(2)O3
LP(2)O3
LP(2)O4
LP(2)O4
LP(2)O5
BD*(2)O2eC3
BD*(2)O3eC1
BD*(2)O4eC7
BD*(2)C9eC10
BD*(2)C11eC12
BD*(2)C8eC13
BD*(2)C11eC12
BD*(2)C8eC13
BD*(2)C9eC10
BD*(2)C16eC17
BD*(2)C18eC19
BD*(2)O5eN3
BD*(2)C14eC15
BD*(2)C18eC19
BD*(2)C14eC15
BD*(2)C16eC17
BD*(1)N1eC2
BD*(1)N2eC2
BD*(1)N1eC3
BD*(1)C3eC4
BD*(1)N2eC1
BD*(1)C1eC4
BD*(1)C6eC7
BD*(1)C7eC8
BD*(1)O6eN3
BD*(1)N3eC16
BD*(1)O5eN3
BD*(1)N3eC16
BD*(2)O5eN3
BD*(2)O1eC2
BD*(2)O2eC3
BD*(2)O1eC2
BD*(2)O3eC1
BD*(1)C20eH20B
BD*(1)C46eH47
BD*(1)C17eH19
8.48
8.36
are calculated at 2966e2895 cm (exp. 2954 cm ). These results
are in line with literature [65,67,68]. The asymmetric and sym-
metric bending vibrations of methyl groups usually appear in the
region 1470e1440 cm and 1390e1370 cm , respectively [69,70].
These bending modes are predicted theoretically and observed
experimentally in their characteristic regions mixed with other
19.33
19.95
18.58
19.47
21.88
22.45
17.87
21.17
21.13
26.95
21.16
17.26
19.28
23.84
25.72
25.78
26.25
19.63
25.98
18.63
19.00
18.58
18.81
13.49
18.72
13.40
165.36
52.98
50.11
52.39
50.78
0.58
ꢁ
1
ꢁ1
vibrations (Table 7). The calculations predicted the CH
2
scissoring,
ꢁ1
ꢁ1
wagging and twisting vibrations at 1408 cm
(1379 cm ),
ꢁ1
ꢁ1
ꢁ1
1354 cm and 1263, 1206 cm (1210 cm ) respectively.
3.12.3. C]O, C]C and CeN vibrations
The aromatic ring C]C stretching vibrations occur in the region
ꢁ1
of 1600e1500 cm [65]. These stretching vibrations are observed
ꢁ1
ꢁ1
at 1608e1567 cm (exp. 1591 cm ). We noted, the aromatic ring
ꢁ
1
ꢁ1
breathing modes calculated at 985 and 984 cm (exp. 998 cm ).
The studied compound has four carbonyl vibrations predicted in
the range 1746e1675 cm (exp. 1690 cm ). Moreover the CeN
ꢁ
1
ꢁ1
stretching vibration band predicted theoretically and observed
ꢁ1
ꢁ1
experimentally at 1236 cm and 1271 cm respectively [71].
LP(2)O5
LP(2)O6
LP(2)O6
LP(3)O6
LP(1)N1
LP(1)N1
LP(1) N2
LP(1) N2
3.12.4. NeO vibrations
The NeO symmetric and asymmetric stretching vibrations of
the aromatic nitro compounds showed strong bands in the regions
ꢁ1
of 1530e1510 and 1360e1335 cm [65]. The FTIR spectrum of the
studied molecule showed these two strong bands at 1526 (calc.
ꢁ1
1550) and 1347 (calc. 1334) cm for the asymmetric and sym-
LP(2)O1
LP(2)O2
LP(2)O3
metric stretching vibrations of the NeO bonds respectively. The
0.60
0.69
ꢁ1
NeO bending vibration is detected at 885 cm which is calculated
ꢁ1
using the DFT method at 860 cm
.

374
A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
Fig. 9. The experimental (lower) and calculated (upper) infrared vibrational spectra of the studied compound.
3.13. Thermogravimetric analysis (TGA)
the active site of the enzyme.
The TGA of the studied compound is performed over the tem-
perature range 25e800 C under a flowing nitrogenatmosphere
4. Conclusion
ꢀ
and the result is shown in Fig. 10. The TGA data showed that the
studied compound is thermally stable up to 181 C then undergo
sublimation without thermal decomposition in fast step leaving
almost 0% residue.
In conclusion, we have synthesized a novel Michael adduct via
Michael addition reaction using diethylamine as a base at room
temperature. The TGA analysis showed high thermal stability of
ꢀ
ꢀ
studied compound upto 181 C. The molecular structure of com-
pound 3 was optimized using the DFT/B3LYP method and 6-
311G(d,p) basis set. The calculated bond distances and bond angles
showed a good agreement with our reported X-ray crystal struc-
ture. The molecular electrostatic potential picture of the studied
compound has been calculated using the same level of theory. The
3
.14. Molecular docking study of compound 3
Exploration of the molecular interaction of compound 3 with a-
glucosidase enzyme was performed through molecular docking
studies using MOE. Fig. 11 illustrated the predicted binding mode of
0
a and HOMO-LUMO energy gap (DE) values indicated that the
compound 3 in the active site of
study it was observed that compound 3 make four interaction
Three hydrogen side chain donor and one arene-cation in-
teractions) with the active site residue (Acidic Asp349, Basic
Arg212 and Arg439) of -glucosidase enzyme (Fig. 11), which may
explain the fact that compound 3 possessed certain level of the
inhibition. Asp349 and Arg212 were found in making H-bond (side
chain donor) with the oxygen of 1,3-dimethylpyrimidine-
a
-glucosidase. From the docking
studied molecule is better NLO material than the urea. In accord
with the experimental data, the TD‒DFT calculated electronic
showed intense electronic transition band at 243.9 nm (f ¼ 0.2319)
(
1
13
and a shoulder at 260.2 nm (f ¼ 0.1483). The GIAO H and C NMR
a
chemical shift values as well IR vibrational spectra correlated well
2
with the experimental data. The correlation coefficients (R ) for
carbon and proton are 0.9957 and 0.9860, respectively. The Lewis
structure NBOs as well as the different ICT interactions in the
studied molecule have been predicted using the NBO calculations.
Compound 3 was also evaluated for its biological activities in
2
,4,6(1H,3H,5H)-trione moiety of the compound 3 and Arg439 was
involved in making 2 interaction, one H-bond (with carbonyl oxy-
gen) and another arene-cation (with phenyl ring) interaction with
various in vitro biological assays. The potent
a-glucosidase

A. Barakat et al. / Journal of Molecular Structure 1098 (2015) 365e376
375
Fig. 10. The TGA curve of the studied compound 3.
Fig. 11. Binding modes of compound 3 in the active site of a-glucosidase. Carbon atoms of the protein and the ligand are indicated in gray and yellow, respectively. Each dotted line
indicates a hydrogen bond. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
inhibitory activity of compounds 3 indicated its potential as a
treatment of possible leads for the treatment of hyperglycemia
associated health disorders. Further studies towards the asym-
metric synthesis of this compound are in process.
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1
[
6] N.R. Madadi, N.R. Penthala, L.K. Brents, B.M. Ford, P.L. Prather, P.A. Crooks,
The authors would like to extend their sincere appreciation to
the Deanship of Scientific Research at king Saud University for its
funding this Research group NO (RG -257-1435-1436).
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