Synthesis, quantum chemical, in vitro acetyl cholinesterase inhibition and molecular docking studies of four new coumarin based pyrazolylthiazole nuclei

Article abstract of DOI:10.1016/j.molstruc.2018.05.017

Four new 3-(2-(3-Phenyl-5-substituted phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-2-one derivatives (1–4) were synthesized and fully characterized by spectroscopic techniques. The final structures of all chromenone analogues (1–4) were confirm

Full text of DOI:10.1016/j.molstruc.2018.05.017

Accepted Manuscript
Synthesis, quantum chemical, in vitro acetyl cholinesterase inhibition and molecular
docking studies of four new coumarin based pyrazolylthiazole nuclei
Murtaza Madni, Muhammad Naeem Ahmed, Shahid Hameed, Syed Wadood Ali
Shah, Umer Rashid, Khurshid Ayub, M.Nawaz Tahir, Tariq Mahmood
PII:
S0022-2860(18)30573-8
10.1016/j.molstruc.2018.05.017
MOLSTR 25189
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 18 November 2017
Revised Date: 9 April 2018
Accepted Date: 6 May 2018
Please cite this article as: M. Madni, M.N. Ahmed, S. Hameed, S.W. Ali Shah, U. Rashid, K. Ayub, M.N.
Tahir, T. Mahmood, Synthesis, quantum chemical, in vitro acetyl cholinesterase inhibition and molecular
docking studies of four new coumarin based pyrazolylthiazole nuclei, Journal of Molecular Structure
(2018), doi: 10.1016/j.molstruc.2018.05.017.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis, quantum chemical, in vitro acetyl cholinesterase inhibition and
molecular docking studies of four new coumarin based pyrazolylthiazole nuclei
a
b
a*
Murtaza Madni , Muhammad Naeem Ahmed Shahid Hameed , Syed Wadood Ali
,
c
d
d
e
d*
Shah , Umer Rashid , Khurshid Ayub , M. Nawaz Tahir , Tariq Mahmood
a
Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Department of Chemistry, The University of Azad Jammu and Kashmir Muzaffarabad, 13100
Pakistan.
b
c
Department of Pharmacy, University of Malakand, KPK, Pakistan.
d
Department of Chemistry, COMSATS Institute of Information Technology, University Road,
Tobe Camp, 22060, Abbottabad, Pakistan.
e
Department of Physics, University of Sargodha, Sargodha, Pakistan.
*
To whom correspondence should be addressed: E-mail: mahmood@ciit.net.pk (T. M) and
shameed@qau.edu.pk (S. H).
1

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Abstract
Four new 3-(2-(3-Phenyl-5-substituted phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-
-one derivatives (1-4) were synthesized and fully characterized by spectroscopic techniques. The
2
final structures of all chromenone analogues (1-4) were confirmed by single crystal X-ray
diffraction analysis. Quantum chemical studies were performed to compare the results from the
theoretical studies with the experimental (X-ray as well as spectroscopic) ones. The theoretically
simulated geometric parameters and other spectroscopic properties agreed nicely with the
experimental data. All compounds were evaluated for biological activity (acetyl cholinesterase
inhibition potential). Compound 3 emerged as the most potent derivative in acetylcholine esterase
(
AChE) inhibition assay with IC =27.29 µM. The IC of compound 3 is greater than the standard
50 50
drug galantamine (IC =44.02 µM). To rationalize the potencies, molecular docking studies were
5
0
also carried out. These docking results revealed a good correlation between binding energies
values and in vitro AChE inhibition assay.
Keywords: Coumarin; X-ray; DFT; Acetyl cholinesterase; Molecular docking
2

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1
. Introduction
Thiazole scaffold is a basic unit of a large number of natural and synthetic molecules having wide
spread biological applications. The famous reported biological applications of thiazole containing
molecules include antibacterial, antifungal, antiviral, anticancer, antiparkinsonian, and anti-
inflammatory activities [1–4]. The importance of the thiazole moiety is also reflected by its
presence in large number of marketed drugs as an active group [5]. Besides thiazole, pyrazole is
also a biologically important structural motif. Several cyclooxygenase-2 (COX-2) inhibitors
possess pyrazole and pyrazoline nuclei as key moieties in their chemical structures [6–8]. In
literature, many pyrazoline containing compounds e.g. mefobutazone, kebuzone, phenylbutazone
[9] and ramifenazone [10] are reported to have potent anti-inflammatory activity.
The importance of coumarin moiety is very well reflected by its presence in many antibiotics.
Moreover antibacterial activity of coumarins against Gram-positive bacteria is also reported in the
literature [11–13]. Dicoumarol and warfarin contain coumarin moiety and are used as
anticoagulant of blood in different organs (veins, lungs and heart) of living beings [14]. Apart
from the pharmacological properties, substituted coumarin derivatives also find applications in
dyes due to their unique optical and photophysical properties [15]. Coumarin-thiazoles based dyes
are used as fluorescence labels [16,17], optical brighteners [18,19], non-linear optical materials
[20], solar energy absorbers, laser dyes and as two-photon absorption (TPA) materials [21]. 3-
Substituted pyrazolyl thiazolyl based coumarin dyes have also been used as fluorescent
brightening agents [22], red, green and blue dopants in organic light-emitting diodes (OLEDs)
[23,24].
Neurodegenerative diseases (NDs) in developed countries are becoming big threat to the general
population. The researchers are struggling for pharmacological cures of NDs [25]. Alzheimer's
3

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disease (AD), the common form of dementia, is one of the neurodegenerative diseases (NDs).
Some of the major effects of AD include confusion, petulance, memory loss, anger and the
absence of potency in body [26]. During the last decade, treatment plan for AD has been focused
on the improvement of cholinergic neurotransmission in the brain, which is based on the
‘cholinergic hypothesis’. According to this hypothsis, one of the rational and operative methods
to treat the AD disease is to raise the acetylcholine (ACh) level through inhibition of
acetylcholinesterase (AChE) [26,27]. A few compounds (medicine) for increasing acetylcholine
levels in the brain include tacrine, donepezil, rivastigmine and galantamine [28]. The central
cholinergic pathways have vital role in memory processes and their damage can be reduced by
the improvement of acetylcholine (Ach) levels in brain through AChE inhibitors [29,30].
Synthetic organic compounds with neurobiological action may be possible targets for drug
discovery, in this regard [31,32]. Recently, medicinally important coumarin derivatives bearing
heterocyclic rings e.g. thiazole, pyrazolyl and thiazole have been reported in literature, in this
regard [33–36]. Keeping in view the importance of pyrazolyl and coumarin moieties as useful
materials in drug research and in continuation of our previous work on pyrazolylthiazole
derivatives [37] and density functional theory investigations of organic compounds [38–41],
herein we report the synthesis, structural properties, density functional theory (DFT) studies,
acetylcholineesterase inhibition and molecular docking studies of four new coumarin based
pyrazolylthiazole derivatives.
2
. Material and methods
2
.1 Experimental
4

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Substituted benzaldehydes, acetophenone, salicyaldehyde and ethyl acetoacetate were purchased
from Sigma-Aldrich and Fluka. The reactions were performed in 100 mL 2-neck round bottom
flask having teflon stirring bar, and the progress of the reaction was monitored through thin layer
chromatography (TLC). The melting points were determined on a Yanaco melting point apparatus
and are reported as uncorrected. FT-IR spectra of all four derivatives were recorded on a Nicolet
1
13
FT-IR 5DX spectrophotometer. H and C-NMR spectra were scanned on a JEOL-ECA in CDCl
3
with proton and carbon resonances at 400 and 100 MHz, respectively. TMS was used as an
internal standard and J values are reported in Hz.
2
.2 Synthesis
The synthesis of compounds (1-4) was achieved by following the synthetic scheme provided in
Fig. 1.
2
.2.1 General Procedure for the synthesis,of coumarin based pyrazolylthiazole nuclei (1-4)
According to the reported literature procedure [42], acetophenone and appropriate benzaldehydes
were condensed to their respective substituted chalcones by treating them with 60% KOH in
ethanol. In the next step, 3-Phenyl-5-substituted phenyl-4,5-dihydropyrazole-1-carbothioamide
were synthesized by reacting substituted chalcones with thiosemicarbazide [43]. Finally,
substituted 3,5-diphenyl-4,5-dihydropyrazole-1-carbothioamides (2 mmol) was added to a
suspension of 3-(2-bromoacetyl)-2H-chromen-2-one (2 mmol) in ethanol (10 mL). The resultant
mixture was stirred vigorously under reflux for 2 hours at room temperature. Then, the reaction
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mixture was poured in ice cold water. Precipitates were filtered and recrystallized from
chloroform:ethanol (3:1) mixture to afford excellent yields of desired compounds.
2
.2.1.1 3-(2-(5-(3-Bromophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-2-
one (1).
°
-1
Pale yellow solid; m.p. 230 C, yield = 85%, FT-IR (ATR, cm ): ν 3123, 1709, 1606, 1545,
max
1
1
485, 1443, 1316, 1247, 1172, 1132, 1087, 962, 752; H-NMR (400 MHz, CDCl ): δ 3.38 (1H,
3
dd, J = 7.5Hz, J
= 17.4Hz, CH pyrazoline), 3.95 (1H, dd, Jtrans = 12Hz, Jgem = 17.4Hz, CH-
cis
gem.
pyrazoline), 5.54 (1H, dd, J = 7.5Hz, J
= 12Hz, CH-pyrazoline), 7.25-7.85 (14H, m, Ar), 8.19
cis
trans
1
3
(
1H, s, CH-thiazole); C-NMR (100 MHz, CDCl
3
): δ 43.4, 64.4, 111.8, 116.2, 119.7, 121.2,
1
1
2
22.4, 124.4, 125.0, 126.4, 128.3, 128.7, 130.0, 130.5, 130.7, 130.9, 131.0, 131.0, 138.6, 144.0,
44.3, 151.8, 152.7, 159.7, 164.0.
.2.1.2 3-(2-(5-(3-Methoxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-2-
one (2).
°
-1
Pale yellow solid, m.p. 265-266 C, yield = 87%, FT-IR (ATR, cm ): ν
3145, 1705, 1603,
max
1
1
554, 1487, 1380, 1317, 1265, 1134, 1053, 1010, 751; H-NMR (400 MHz, CDCl ): δ 3.38 (1H,
3
dd, J = 7.5Hz, J = 17.4Hz, CH-pyrazoline), 3.83 (3H, s, OCH ), 3.93 (1H, dd, J = 12Hz,
trans
cis
gem
3
Jgem = 17.4Hz, CH-pyrazoline), 5.59 (1H, dd, Jcis = 7.5Hz, Jtrans = 12Hz, CH-pyrazoline), 6.84-
1
3
7
1
1
.83 (14H, m, Ar), 8.23 (1H, s, CH-thiazole); C-NMR (100 MHz, CDCl ): δ 43.5, 55.3, 64.9,
3
11.6, 112.8, 116.2, 118.8, 119.7, 121.2, 124.3, 126.4, 128.1, 128.7, 129.8, 129.9, 130.9, 131.3,
38.6, 143.3, 144.3, 151.9, 152.7, 159.7, 159.8, 164.1.
2
.2.1.3 3-(2-(3-Phenyl-5-p-tolyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-2-one (3).
6

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°
-1
Pale yellow solid, m.p. 250 C, yield = 88%, FT-IR (ATR, cm ): νmax 3141, 1718, 1550, 1390,
1
1
249, 1174, 1134, 1043, 1005, 752; H-NMR (400 MHz, CDCl ): δ 3.32 (3H, s, CH ), 3.36 (1H,
3
3
dd, J = 7.2Hz, J = 17.4Hz, CH-pyrazoline), 3.92 (1H, dd, Jtrans = 12Hz, Jgem = 17.4Hz, CH-
cis
gem
pyrazoline), 5.61 (1H, dd, J = 7.2Hz, J
= 12Hz, CH-pyrazoline), 7.19-7.82 (14H, m, Ar), 8.24
cis
trans
1
3
(
1H, s, CH-thiazole); C-NMR (100 MHz, CDCl ): δ 21.1, 43.6, 64.7, 111.6, 116.2, 119.8, 121.3,
3
1
1
24.3, 126.4, 126.6, 128.0, 128.7, 129.3, 129.8, 130.8, 131.4, 137.5, 138.5, 138.7, 144.3, 151.8,
52.7, 159.6, 164.1.
2
.2.1.4 3-(2-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-2-
one (4).
-1
Pale yellow solid; m.p. 242˚C, Yield = 85%; FT-IR (ATR, cm ): νmax 3153, 1712, 1604, 1552,
1
1
6
1
512, 1330, 1242, 1118, 1027, 1004, 754; H-NMR (400 MHz, CDCl
3
): δ 3.42 (1H, dd, Jcis
=
=
.9Hz, Jgem = 18Hz, CH-pyrazoline), 3.72 (3H, s, OCH
8Hz, CH-pyrazoline), 5.65 (1H, dd, J = 6.9Hz, J
3
), 4.06 (1H, dd, Jtrans = 12Hz, Jgem
= 12Hz, CH-pyrazoline), 6.95-7.84 (14H,
trans
cis
1
3
m, Ar), 8.32 (1H, s, CH-thiazole); C-NMR (100 MHz, CDCl ): δ 43.3, 55.5, 64.3, 111.5, 114.3,
3
1
1
16.3, 119.5, 120.9, 125.2, 126.9, 128.9, 129.1, 129.3, 130.5, 131.4, 132.1, 133.9, 138.8, 144.3,
52.7, 153.7, 159.0, 159.2, 164.0.
2
.3 Crystal structure determination
Suitable crystals having proper size and shape of all synthesized compounds (1-4), were selected
and analyzed by X-ray diffraction technique. Suitable crystal of each compound was coated with
paratone oil and mounted on a glass fiber. All measurements were made on Bruker Kappa Apex-
7

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o α
IICCD diffractometer with graphite monochromator using M -K radiation source. All structures
were solved by direct method and refined by using SHELXL 2013 (Sheldrick, 2013) [44]. The
figures were plotted with ORTEP II program [45]. The CIF files of compounds (1-4) have been
assigned CCDC numbers 1009293, 1009294 981486, and 1009299 and can be obtained free of
,
charge on application to CCDC 12 Union Road, Cambridge CB21 EZ, UK. (Fax: (+44) 1223 336-
0
33: data_request@ccdc.cam.ac.uk).
2
.4 Computational methods
DFT studies were performed with Gaussian 09 software [46]. Visualization of geometries and
graphics were performed with GaussView 05 [47]. The geometries of all compounds (1-4) were
optimized at hybrid B3LYP method along with 6-31G(d,p) basis set. B3LYP method is quite
reliable for the structural properties of organic compounds, due to its nice balance between cost
and accuracy [48–52]. These structures were confirmed as true minima through frequency analysis
at the same level (no imaginary frequency). Furthermore, the results from frequency simulations
were used for theoretical vibrational analysis. TD-DFT calculations for absorption spectra were
performed at CAM-B3LYP/6-31G(d,p) level in DMSO solvent through CPCM model. Twenty
excited states (10 each for singlet & triplet) were considered for the computation of absorption
spectra of all compounds. Frontier molecular orbitals (FMOs) and molecular electrostatic potential
(MEP) analyses were performed at B3LYP/6-31G(d,p) level of theory.
2
.5 Determination of in-vitro AChE inhibitory activity
8

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AChE (Electric eel type-VI-S, Sigma-Aldrich GmbH USA, code 1001596210), Acetylthiocholine
iodide (Sigma-Aldrich UK, code 101303874), DTNB (Sigma Aldrich Germany, code 101261619),
Galantamine hydrobromide Lycoris sp. (Sigma-Aldrich France, code G1660) and all the other
chemicals used were of analytical grade. Galantamine was used as a reference drug.
The synthesized compounds (1-4) were dissolved in 0.1M phosphate buffer of pH 8.0
(
KH PO /K HPO ). The reaction mixture consisted of appropriate amount of DTNB (Ellman’s
2 4 2 4
reagent), test compounds and 0.03 U/mL of enzymes (AChE). The mixture was pre-incubated at
o
3
0 C for 10 minutes and after that 1mM of ATCI was added and incubated again for further 15
minutes. The enzymatic hydrolysis was monitored at 412nm using lQuant microplate
spectrophotometer (MQX200, BioTek USA). All reactions were repeated in triplicate. The IC50
values were determined by plotting the inhibition against the sample solution concentrations [53].
2
.6 Molecular docking
Molecular docking studies were carried out using X-ray crystal structure of TcAChE (PDB code
EVE) co-crystalized with E2020. The structures of the compounds were drawn using
1
MarvinSketch 16.5.2 [54]. Optimized structures of all compounds (1-4) from DFT studies were
used for docking studies. For the enzyme, downloaded from PDB, solvation parameters and
Kollman charges for all the atoms were assigned. AutoDock Tools (ADT) were used to create
PDBQT file for both ligand and enzyme. A grid parameter file was generated using ADT. A cubic
grid box of 40 Å (x, y, z) with a spacing of 0.375 Å was created. The grid map was created and
centered in the active site region where E2020 (native ligand) was embedded (X=2.858421;
Y=64.578837; Z=67.967228). As a first step, the reliability of docking algorithm was confirmed
9

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by re-docking of co-crystalized ligand E2020 in the 1EVE pocket. The RMSD between the co-
crystallized and re-docked conformation is 1.34 Å. The RMSD value of <2.0 Å is considered
accurate in predicting binding orientation of ligand. To evaluate the lowest binding energy,
docking studies were carried out using AutDock and a Lamarckian genetic algorithm (LGA) [55].
The maximum number of energy evaluations of the (LGA) run was 2500,000 and the maximum
number of evaluations were set to 27,000. Other parameters were set to default values of
AutoDock 4.2. The view of the docking results and analysis of their surface with graphical representations
were done using AutoDock and discovery studio visualizer [56].
3
. Results and discussion
The reaction sequence employed for the synthesis of target heterocycles is outlined in the Fig.1.
Treatment of substituted chalcones, prepared by the reaction of acetophenone and substituted
benzaldehydes under basic conditions, with thiosemicarbazide in the presence of NaOH afforded
3
-Phenyl-5-substituted phenyl-4,5-dihydropyrazole-1-carbothioamide which on reaction with 3-
(2-bromoacetyl)-2H-chromen-2-one furnished the target compounds (1-4). The analytical and
spectral data of the molecules 1-4 was fully in agreement with the proposed structure. In the IR
spectra, the appearance of absorption band for the carbonyl of lactone moiety in the range of 1718-
-1
-1
1
705 cm and disappearance of doublet for NH stretching in the range of 3500-3300 cm
2
confirmed the formation of derivatives (1-4) and agree well with the reported values in literature
1
[
57]. In H NMR spectra, a singlet in the range δ 8.19–8.32 ppm assigned to CH proton of the
thiazole, confirmed successful synthesis of desired compounds 1-4. The protons in pyrazoline ring
appeared as doublet of doublet in the range of 3.32-5.65 ppm also supported the synthesis [58,59].
1
3
In the C NMR spectra, the low field resonance in the region of 164.1-164.0 and 159.8-159.2
1
0

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were assigned to C=O of coumarin and C=N of thiazole moiety respectively. The other
substituents and aromatic carbons were also fully analyzed (cf. Experimental section).
3
.1 Molecular structure
The ORTEP plots of all compounds (1-4) are shown in Fig. 2, and structural refinement
parameters are given in Table 1. The molecular formulas of the compounds (1-4) are
[
C H BrN O S], [C H N O S], [C H N O S] and [C H N O S], respectively. The
27 18 3 2 28 21 3 3 28 21 3 2 28 21 3 3
compound (1) crystallized in orthorhombic crystal system having space group Pca2 . Packing
1
diagram (Fig. 3) shows that it consists of two independent molecules. In the first molecule, the
chromen-2-one moiety A (C1-C9/O1/O2), 1,3-thiazol ring B (C10-C12/N1/S1), the pyrazol ring C
(
C13/C20/C21/N2/N3), the 3-bromophenyl D (C14-C19/BR1) and the benzene ring E (C22-C27)
atomic labelling is in accordance with the ORTEP plot Fig. 2) are planar with r. m. s. deviation of
(
0
.0208, 0.0114, 0.0147, 0.0273 and 0.0041 Å, respectively. The dihedral angle between A/B, A/C,
A/D, A/E, B/C, B/D, B/E, C/D, C/E and D/E are 12.6(4)°, 8.4(4)°, 75.4(2)°, 3.5(5)°, 8.5 (5)°,
7.4(3)°, 11.8(5)°, 79.8(3)°, 5.5(6)° and 75.6(3)°, respectively. In the second molecule, the
8
chromen-2-one moiety F (C28-C36/O3/O4), 1,3-thiazol ring G (C37-C39/N4/S2), the pyrazol ring
H (C40/C47/C48/N5/N6), the 3-bromophenyl I (C41-C46/BR2) and the benzene ring J (C49-C54)
are planar with r. m. s. deviation of 0.0340, 0.0029, 0.0160, 0.0218 and 0.0069 Å, respectively.
The dihedral angle between F/G, F/H, F/I, F/J, G/H, G/I, G/J, H/I, H/J and I/J are 9.1(4)°, 6.6(4)°,
8
3.6(2)°, 1.7(5)°, 10.0 (5)°, 83.3(3)°, 9.5(5)°, 84.3(3)°, 5.0(6)° and 83.2(3)°, respectively. The
2
molecules exists in dimer form due to C-H…O interactions with R (12) ring, where CH is of the
2
thiazol ring and O-atoms are of the carbonyl groups. Those are further interlinked due to C-H…O
bonding where H is from the dihydro carbon of the pyrazol ring and O-atom is of carbonyl group.
1
1

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The presence of π-π interactions in the range 2.319(5)-3.582(2) Å and C-H…π interactions among
different moieties collectively play important role in stabilizing the molecules.
The compound 2, crystallized with monoclinic crystal system and P2 /c space group. The
1
chromen-2-one moiety A (C1-C9/O1/O2), 1,3-thiazol ring B (C10-C12/N1/S1), the pyrazol ring C
(C13/C21/C22/N2/N3), the 3-methoxyphenyl moiety D (C14-C20/O3) and the benzene ring E
(C23-C28) in 2 are planar with r. m. s. deviation of 0.0403, 0.0027, 0.0343, 0.0218 and 0.0010 Å,
respectively. The dihedral angle between rings A/B, A/C, A/D, A/E, B/C, B/D, B/E, C/D, C/E and
D/E are 6.70(7)°, 1.58(9)°, 86.15(5)°, 1.42(8)°, 7.56(10)°, 88.80(7)°, 8.02(10)°, 84.60(7)°,
1
.89(10)° and 85.57(7)°, respectively. The molecules are dimerized due to C-H…O interactions
2
2
with R (28) rings, where CH of the benzene ring in the chromen-2-one moiety and O-atom is of
methoxy group. The π-π interactions are in the range 2.4842(10)-3.4805(10) Å. Moreover, some
C-H…π interactions are also present and collectively with π-π interactions play important role in
stabilizing the molecules.
The compound 3 has triclinic crystal system and P-1 space group. Again in 3, the chromen-2-one
moiety A(C1-C9/O1/O2), 1,3-thiazol ring B(C10-C12/N1/S1), the pyrazol ring
C
(C13/C21/C22/N2/N3), the 4-methylphenyl moiety D (C14-C20) and the benzene ring E (C23-
C28) are planar with r. m. s. deviation of 0.0256, 0.0017, 0.0368, 0.0098 and 0.0021 Å,
respectively. The dihedral angles between A/B, A/C, A/D, A/E, B/C, B/D, B/E, C/D, C/E and D/E
are 9.30(8)°, 7.88(10)°, 76.69(5)°, 5.71(10)°, 6.76(12)°, 82.44(5)°, 15.00(11)°, 75.71(6)°,
1
2.28(12)° and 72.82(6)°, respectively. The individual molecules in 3, are dimerized due to C-
2
H…O interactions with R (12) ring, where CH is of the thiazol ring and O-atom is of the
2
carbonyl group. The dimmers are further interlinked due to C-H…O bonding where H is from the
1
2

ACCEPTED MANUSCRIPT
dihydro carbon of pyrazol ring and O-atom is of the carbonyl group. There are π-π interactions are
observed in the range of 2.5088(8)-4.40952(8) Å between the coumarin moieties.
Similarly in 4, the chromen-2-one moiety A(C1-C9/O1/O2), 1,3-thiazol ring B(C10-C12/N1/S1),
the pyrazol ring C(C13/C21/C22/N2/N3), the 4-methoxyphenyl moiety D (C14-C20/O3) and the
benzene ring E (C23-C28) are planar with r. m. s. deviation of 0.0134, 0.0011, 0.0468, 0.0180 and
0
.0036 Å, respectively. The dihedral angle between A/B, A/C, A/D, A/E, B/C, B/D, B/E, C/D,
C/E and D/E are 2.47(8)°, 3.54(8)°, 86.73(7)°, 0.80(9)°, 4.47(9)°, 87.44(10)°, 2.45(10)°,
8
3
9.98(11)°, 4.33(10)° and 86.02(10)°, respectively. There π-π interactions in the range of
.430(2)-4.146(2) Å. Moreover, some C-H…π interactions are present which collectively with π-π
interaction play important role in stabilizing the molecules.
3
.2 DFT Optimized geometries
The geometries of all four compounds have been optimized (Fig. 4) through DFT methods to
compare the geometric parameters (bond lengths and bond angles) obtained theoretically with the
X-ray diffraction results. The input geometries are taken from the X-ray structures. The important
X-ray geometric parameters of all compounds (1-4) are given in Tables 2-3 (bond lengths) and
Tables 4-5 (bond angles). The computed geometric parameters of bond lengths and bond angles
are summarized in Table 3 and Table 5, respectively. The data given in the Tables, indicate that
the X-ray geometric parameters have shown strong agreement with the theoretical results.
The X-ray values of important bond lengths involving hetro atoms such as Br1—C1, S1—C17,
S1—C16, O1—C20, O2—C21, O2—C20, N1—C9, N1—N2, N2—C16, N2—C7, N3—C16,
N3—C18 (atomic labelling is in accordance with Fig. 2) in 1 are 1.90, 1.72, 1.74, 1.20, 1.36, 1.38,
1
3

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1
.28, 1.38, 1.36, 1.48, 1.28 and 1.42Å, respectively. Whereas the corresponding theoretical values
are 1.91, 1.74, 1.76, 1.21, 1.36, 1.38, 1.29, 1.37, 1.37, 1.48, 1.29 and 1.39Å respectively. In
compound 2, the important bonds such as S1—C11, S1—C12, O1—C9, O2—C1, O2—C9, O3—
C18 O3—C20, N1—C12, N1—C10, N2—C12, N2—N3, N2—C13, N3—C22 determined
experimentally are 1.71, 1.73, 1.20, 1.37, 1.37, 1.37, 1.40, 1.29, 1.38, 1.34, 1.37, 1.47 and 1.28Å,
respectively. The simulated values of these bonds are 1.74, 1.76, 1.21, 1.39, 1.39, 1.36, 1.42, 1.29,
1
.38, 1.37, 1.37, 1.48 and 1.29Å, respectively. Again, in compound 3 and 4 the basic skeleton is
similar, only difference exists in the substituent on one aromatic ring. The experimental (X-ray)
and simulated bond lengths of both compounds are in strong agreement with each other (for
detailed values see Table 2 and Table 3).
The experimental and simulated values of all prominent bond angles of compounds (1-4) are
narrated in Table 4 and 5, respectively. The comparative analysis shows that excellent correlation
exists among experimental and theoretical values of bond angles of all compounds. In compound
1
, the experimental values of important bond angles such as C17—S1—C16, C21—O2—C20,
C9—N1—N2, C16—N2—N1, C16—N2—C7, N1—N2—C7, C16—N3—C18, C6—C1—Br1,
C2—C1—Br1, N1—C9—C8, N1—C9—C10, N3—C16—N2, N3—C16—S1, N2—C16—S1,
C17—C18—N3, N3—C18—C19, O1—C20—O2, O1—C20—C19, O2—C20—C19, O2—
C21—C27 and O2—C21—C22 are 88.0, 122.7, 106.8, 120.6, 123.3, 114.1, 110.1, 118.0, 120.5,
o
1
14.8, 122.1, 123.3, 116.1, 120.5, 113.8, 116.4, 116.3, 126.5, 117.2, 116.9 and 121.7 ,
respectively. The theoretical values of these bond angles are 87.7, 123.5, 109.3, 119.1, 122.7,
1
1
13.5, 110.5, 119.1, 119.1, 112.8, 122.2, 123.1, 115.6, 121.1, 115.2, 117.3, 116.2, 126.7, 116.6,
o
17.6 and 120.7 , respectively. Similarly, the experimental and theoretical bonds angles values in
compounds 2, 3 and 4 also corroborated nicely to each other.
1
4

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3
.3 Vibrational analysis
Since last few years, the DFT calculations have been extensively used to compare and validate the
experimental vibrational spectrum [60–62]. The experimental FT-IR of all compounds were
recorded under neat conditions and theoretical vibrational frequencies were extracted from the
frequency analysis. The calculated vibrational spectrum of compound 2 is compared with the
experimental spectrum in the Fig. 5. The calculated vibrational spectra of compounds 1, 3 and 4
along with experimental spectra are given in Fig. S9 (supplementary information). The
comparative analysis of prominent experimental and theoretical vibrations of all compounds is
given in Table 6. In order to minimize the error, 0.9627 scaling factor was used, which is
recommended for B3LYP/6-31G(d,p) level of theory [63,64]. The basic skeleton is same
(compounds 1-4), the only difference exists in the substituents on one aromatic ring. Therefore,
the theoretical and experimental stretching/bending vibrations of prominent functional groups
show similar kind of trends in vibrational spectra and correlate to each other nicely
(experimentally as well as theoretically). The calculated prominent CHarom. symmetric/asymmetric
-1
-1
-1
stretching vibrations of compounds 1, 3 and 4 are 3089 cm and 3080 cm , of 2 are 3089 cm ,
-1
-1
-1
-1
3
080 cm , 2967 cm and 2906 cm . Their respective experimental values are 3123cm (1), 3145
-1
-1
-1
cm (2), 3141 cm (3) and 3153 cm (4) respectively, which agree well with the computed
values. Experimental value of stretching vibrations of C=O for compounds 1, 2, 3 and 4 are 1709
-1
-1
-1
-1
cm , 1705 cm , 1718 cm and 1712 cm , respectively. The theoretical stretching value for the
-1
carbonyl functional group is 1748 cm in all four compounds. The experimental
symmetric/asymmetric stretching vibrations of C=N functional group in all compounds (1-4) are
1
5

ACCEPTED MANUSCRIPT
-1
in the range 1545-1300 cm and showed an excellent correlation with the theoretical values,
-1
(
1550-1300 cm ). Apart from the stretching vibrations, number of bending vibrations of CH , CH
3 2
and aromatic CH groups are analyzed which also show nice correlation between theory and
experiment (for individual values see Table 6). The experimental S-CH stretching vibrations are
-1
-1
-1
-1
7
52 cm , 751 cm , 752 cm and 754 cm for compound 1, 2, 3 and 4 respectively, whereas the
-1
theoretical bending vibrations appear at 751 cm in all compounds (1-4).
3
.4 Absorption studies and frontier molecular orbitals (FMOs) analysis
The experimental absorption maxima of all four compounds (1-4) were recorded in dimethyl
sulfoxide (DMSO) solvent. The corresponding simulated absorption spectra were calculated by
using time dependent (TD) calculation at CAM-B3LYP/6-31G(d,p) level of theory in DMSO by
using conductor-like polarizable continuum model (CPCM). The experimental as well as
theoretical absorption spectra of all compounds are shown in Fig. 6. In all compounds, almost
similar chromophoric groups are present, therefore similar trends are observed in absorption
maxima. The experimental absorption maxima are 352 nm (1), 354 nm (2), 352 nm (3) and 355
nm (4), respectively. Theoretically measured absorption maxima of all four derivatives (1-4) are
3
31 nm, 332 nm, 333 nm and 334 nm, respectively and correlated nicely with the experimental
results. The differences are attributed to the errors associated with function in properly calculating
the absorption spectrum.
Frontier molecular orbital (FMOs) analysis by using quantum chemical methods can be used to
explain the molecular transitions and reactivity of compounds. The frontier molecular orbital
analysis of all four compounds has been analyzed for correlation of theoretical and experimental
1
6

ACCEPTED MANUSCRIPT
absorption spectra. In case of 1, the corresponding HOMO and LUMO energies are -5.26 eV and -
1
.83 eV, respectively. The HOMO-LUMO gap is 3.43 eV, corresponds to 361 nm which is in
excellent agreement the experimental transition at 352 nm. In compound 2, the HOMO and
LUMO energies are -5.12 eV and -1.73 eV, respectively. The HOMO-LUMO gap is 3.39 eV,
which corresponds to transitions at 365 nm, which is again in complete agreement with
experimental absorption maxima (354 nm). Similarly, in 3, the corresponding HOMO (-5.13 eV)
and LUMO (-1.76 eV) energies and HOMO-LUMO gap (3.37 eV) corroborated nicely with the
experimental absorption maximum. The similar trend is observed for compound 4. The HOMO-
LUMO gap (3.34 eV) is in nice agreement with the experimental absorption band. The absorption
maxima in all compounds reflect that molecular transitions are due to π to π* (HOMO to LUMO)
transitions of electrons. The HUMO and LUMO surfaces of all compounds are studied to
understand the distribution of isodensities, and similar kind of trend is observed (For FMOs
surfaces see the supplementary information Fig. S10).
3
.5 Molecular electrostatic potential analysis
Molecular electrostatic potential analysis of all compounds was performed by using optimized
geometries at B3LYP/6-31G(d,p) level of theory, and surfaces are shown in Fig. 7. From MEP
surfaces it is observed that the –ve potential is concentrated on the coumarin moiety whereas the
rest of the skeleton in all compounds is neutral. This reflects that all compounds are nucleophilic
in nature. The dispersion of potential in ranges from -0.05796 to 0.05796 in 1, -0.06007 to
0
.06007 in 2, -0.05939 to 0.05939 in 3 and -0.0591 to 0.0591 esu in 4, respectively. The maximum
dispersion is observed in 2, which reflects that 2 has more affinity for electropositive charge.
1
7

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3
.6 Acetyl Cholinesterase (AChE) inhibition potential
To find out the therapeutic potential of the thiazoles derivatives bearing coumarin moiety in the
treatment of AD, the inhibitory response of compounds 1–4 together with the reference standard
galantamine against AChE was evaluated as per Ellman's protocol by determining the rate of
acetylthiocholine in the presence of the inhibitor. All compounds proved to be immensely active
toward AChE in low micromolar range of IC50 values. The in-vitro AChE inhibitory response
(
IC50 values) of the target compounds are summarized in Table 7. From the data, it is notable that
among the four compounds tested, compound 3 exhibited the highest inhibitory activity toward
AChE, which is even higher than galantamine (44.02 µM), a standard drug. Compound 3, emerged
as potent compound with IC value of 27.29 ± 0.42 ꢀM, followed by compound 1 with IC value
5
0
50
of 70.94 ± 0.29 µM. The compounds 2 and 4 showed poor inhibition with IC50 values of 3461.43
µM and 1113 µM respectively.
3
.7 Molecular docking studies
To evaluate the binding affinity of the experimentally tested compounds, docking studies were
carried out using AutoDock 4.2 [65]. Molecular docking studies were carried out using X-ray
crystal structure of TcAChE (PDB code 1EVE) [66]. Three dimensional (3D) modelled molecular
surface of compound 3 (IC =27.29 µM) into the binding site of 1EVE is shown in Fig. 8. The
5
0
visual inspection of the lowest energy docked pose of compound 3 showed that the coumarin ring
is oriented toward the catalytic anionic site (CAS) and forms strong bifurcated π-π stacking
1
8

ACCEPTED MANUSCRIPT
interactions with indole ring of Trp84. 3-Methoxyphenyl ring establishes π-π stacking interactions
with peripheral anionic site (PAS) residues Trp279 at the entry of the active site gorge. Another
important PAS residue Tyr121 forms four types of interactions with compound 3. Two hydrogen
bonding interactions were also observed between the carbonyl oxygen of coumarin and OH of
Tyr121. The phenyl ring of Tyr121 also forms one π-π T-shaped interactions with the thiazole ring
and one π-sulphur interaction with its sulphur atom. A π-non-bonding electron interaction was also
observed between OH of Tyr121 and thiazole ring π-system. Tyr70 is another PAS residue, which
forms π-sulphur interaction with its sulphur atom of the thiazole (Fig. 9). The free energy of
-1
binding for compound 3 is -11.92 kcal mol .
4
. Conclusions
Four new 3-(2-(3-Phenyl-5-substituted phenyl-4,5-dihydropyrazol-1-yl)thiazol-4-yl)-2H-chromen-
-one 1-4 containing coumarin, 2-pyrazoline clubbed with 1,3-thiazole scaffold were synthesized
2
in very good yield. Characterization of final structures was achieved with help of spectroscopic
and X-ray diffraction analyses. Calculated bond lengths and bond angles of all compounds
correlated very nicely with the X-ray values. The experimental and theoretical vibrations of all
prominent functional groups in all compounds are in good agreement with each other. The FMOs
analysis proved that electronic transitions are mainly due to π to π* transitions. The low band gap
reflects that compounds are reactive and kinetically less stable. The ESP analysis reveals that all
four compounds (1-4) are nucleophilic in nature. The maximum dispersion of potential is observed
in 2 ( -0.06007 to 0.06007 esu). Compound 3 exhibited inhibitory activity toward AChE almost
equal galantamine, a standard drug and emerged as potent compound with IC50 value of 27.29 ±
1
9

ACCEPTED MANUSCRIPT
0
.42 ꢀM. Molecular docking studies proved that the free energy of binding is maximum
-1
compound 3 (-11.92 kcal mol ).
Acknowledgements
The authors highly acknowledge Higher Education Commission of Pakistan (Grant no. 20-
3
013/NRPU/R&D/HEC/14/525), QAU Islamabad, COMSATS Abbottabad and University of
Azad Jammu and Kashmir for financial support.
Supplementary material
Cartesian co-ordinates of optimized geometries and cif files of all four compounds (1-4) are
1
13
provided in supporting information. Experimental H, C-NMRs are also pasted in supporting
information as Fig. S1-S8. The combined experimental and theoretical IRs of compounds 1, 3 and
4
are provided in Fig. S9 and HOMO-LUMO surfaces are given in the Fig. S10. Supplementary
data associated with this article can be found, in the online version, at http://dx.doi.org/
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