Synthesis of imidazole-pyrazole conjugates bearing aryl spacer and exploring their enzyme inhibition potentials

Article abstract of DOI:10.1016/j.bioorg.2021.104686

Developing improved enzyme inhibitors is an effective therapy to counter various diseases. Aiming to build up biologically active templates, a new series of bis-diazoles conjugated with an aryl linker was designed and prepared through a convenient synthetic approach. Synthesized derivatives 6(a-m), having different substitutions at the 2^nd position of the imidazole nucleus, depict the scope of present study. These compounds were characterized through spectroscopic methods and further examined for their in vitro enzyme inhibitory potentials against two selected enzymes: α-glucosidase and lipoxygenase (LOX). Overall, this series was found to be effective against α-glucosidase and moderately active against LOX enzyme. Compound 6k was the most potent α-glucosidase inhibitor with IC₅₀ = 54.25 ± 0.67 μM as compared to reference drug acarbose (IC₅₀ = 375.82 ± 1.76 μM). The docked conformation revealed the involvement of substituent's heteroatoms with amino acid residue Gly280 through hydrogen bonding. The most active LOX inhibitor was 6a with IC₅₀ = 41.75 ± 0.04 μM as compared to standard baicalein (IC₅₀ = 22.4 ± 1.3 μM). Docking model of 6a suggested the strong interaction of imidazole's nitrogen with iron atom of the active pocket of enzyme. Other features like lipophilicity, bulkiness of compounds, pi-pi interactions and/or pi-alkyl interactions also affected the inhibiting potentials of all prepared scaffolds.

Full text of DOI:10.1016/j.bioorg.2021.104686

Bioorganic Chemistry 108 (2021) 104686
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis of imidazole-pyrazole conjugates bearing aryl spacer and
exploring their enzyme inhibition potentials
,b,
Faryal Chaudhrya *, Wardah Shahidc, Mariya al-Rashidad, Muhammad Ashrafc,
,
,c
Munawar Ali Munawara *, Misbahul Ain Khana
a Institute of the Chemistry, Quaid-e-Azam Campus, University of the Punjab, Lahore 54590, Pakistan
b Department of Chemistry, Kinnaird College for Women Lahore, 93-Jail Road, Lahore 54000, Pakistan
c Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan
d Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan
A R T I C L E I N F O
A B S T R A C T
Keywords:
Developing improved enzyme inhibitors is an effective therapy to counter various diseases. Aiming to build up
biologically active templates, a new series of bis-diazoles conjugated with an aryl linker was designed and
prepared through a convenient synthetic approach. Synthesized derivatives 6(a-m), having different sub-
stitutions at the 2nd position of the imidazole nucleus, depict the scope of present study. These compounds were
characterized through spectroscopic methods and further examined for their in vitro enzyme inhibitory potentials
α
-Glucosidase
Imidazole
Lipoxygenase
Molecular Docking
Pyrazole
against two selected enzymes:
effective against -glucosidase and moderately active against LOX enzyme. Compound 6k was the most potent
-glucosidase inhibitor with IC50 = 54.25 ± 0.67 µM as compared to reference drug acarbose (IC50 = 375.82 ±
α-glucosidase and lipoxygenase (LOX). Overall, this series was found to be
α
α
1.76 µM). The docked conformation revealed the involvement of substituent’s heteroatoms with amino acid
residue Gly280 through hydrogen bonding. The most active LOX inhibitor was 6a with IC50 = 41.75 ± 0.04 µM
as compared to standard baicalein (IC50 = 22.4 ± 1.3 µM). Docking model of 6a suggested the strong interaction
of imidazole’s nitrogen with iron atom of the active pocket of enzyme. Other features like lipophilicity, bulkiness
of compounds, pi-pi interactions and/or pi-alkyl interactions also affected the inhibiting potentials of all pre-
pared scaffolds.
1. Introduction
inhibitors have become of special interest in drug design and discovery
[12]. Diazoles are privileged pharmacophores for the development of
In recent years, diazolic core has attracted attention of synthetic
chemists because of its manifold applications. Among diazolic ana-
logues; pyrazole and imidazole have constituted structural make up of
natural products [1], photochromic compounds [2], frame works having
optical properties [3], agrochemicals [4] and also displayed excellent
catalytic potentials [5]. Heravi and Zadsirjan recently reviewed some
leading drugs where such nitrogen based heterocyles were considered as
the foundation of many marketed medicines such as ondansetron, los-
artan, apixaban, celecoxib and sildenafil [6]. These nitrogen containing
motifs facilitate in pharmaceutics as anti-inflammatory [7], anticancer
[8], antimicrobial [9], antidiabetic [10], antioxidant agents [11].
Enzymes are often highlighted by experimental evidences as the
validated potential drug targets. In the past few decades, enzyme
new enzyme inhibitors because of their tendency to form hydrogen
bonds. Some exclusive templates of pyrazole and/or imidazole moieties
have recently been designed to target enzymes like mushroom tyrosi-
nase [13], α-amylase [14], carbonic anhydrase [15], DNA gyrase [16],
nucleotide pyrophosphatase [17], cyclooxygenase [18] to cope with
different diseases. One such identified target is
α-glucosidase which
plays a significant role in controlling a well known metabolic disease:
diabetes mellitus type 2. The dilemma of this disease is that it may cause
several other complications in body such as heart disease and kidney
failure. Various research reports have emphasized that postprandial
glucose regulation can control diabetes and inhibition of α-glucosidase is
one of the useful therapies. Recently, different heterocycles have been
documented as excellent -glucosidase inhibitors that may lead to
α
* Corresponding authors at: Institute of the Chemistry, Quaid-e-Azam Campus, University of the Punjab, Lahore 54590, Pakistan (F. Chaudhry; M.A. Munawar);
Department of Chemistry, Kinnaird College for Women Lahore, 93-Jail Road, Lahore 54000, Pakistan (F. Chaudhry).
E-mail addresses: faryal.chaudhry@kinnaird.edu.pk, frylchaudhry@yahoo.com (F. Chaudhry), mamunawar.chem@pu.edu.pk (M. Ali Munawar).
https://doi.org/10.1016/j.bioorg.2021.104686
Received 26 October 2020; Received in revised form 10 January 2021; Accepted 22 January 2021
Available online 3 February 2021
0045-2068/© 2021 Elsevier Inc. All rights reserved.

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
clinical trials [19–21].
2. Results and discussion
A non-heme iron-containing class of metalloenzymes is lipoxygenase
(LOX) that can be isolated from plants and animals. LOXs isoenzymes
(most commonly 5-LOX, 12-LOX and 15-LOX) differ in their substrate
specificity and mode of interaction at their binding sites. This class of
enzymes exhibits multi-faceted biological functions such as production
of biological mediators in signaling pathways and mobilization of lipids
by oxidizing esters etc. LOX isoforms catalyze the peroxidation of
arachidonic and linoleic acids to generate hydroperoxy fatty acids which
further metabolize and produce lipoxins and leukotrienes. Scientists
have established claims that LOX metabolites promote different human
diseases such as initiation and/or progression of inflammation, athero-
sclerosis, oxidative stress in Alzheimer’s patients, diabetes, cardiovas-
cular diseases and development of different forms of cancer. Therefore,
LOXs have been hypothesized as important therapeutic targets for both
redox and non-redox inhibiting agents [22–26]. In this respect, different
natural and synthetic pharmacophores have been documented [27–29].
2.1. Chemistry
Previously, we have synthesized directly linked imidazole-pyrazole,
imidazole-indole and pyrazole-pyridazine hybrids which were found to
be good enzyme inhibitors [37–41]. Literature reveals the significant
role of spacers in enhancing the bioactivity of molecules [43]. Thus, a
series of arylidenes was designed before and those products exhibited
encouraging results [42]. In continuation, present project was designed
where a benzene spacer is used between pyrazole and imidazole rings
and to study the enzyme inhibition potencies of this linking pattern.
Initially, precursor 2 was prepared by following the reported pro-
tocols [44]. Further, a convenient one pot multi-component approach
was adopted to react substrate 2 with substituted aldehdyes 3(a-m),
benzil (4) and ammonium acetate (5). After purifying through column
chromatography, products 6(a-m) were subjected to NMR studies to
identify their structures and purity. Moreover, elemental analyses re-
sults also validated our findings. The scope of the present study is
depicted in structural diversity generated by the modifications in R1
with different substitutions. All products 6(a-m) were obtained in good
yields (Scheme 1).
Some pyrazole and imidazole engineered
α-glucosidase and LOXs
inhibiting agents have been reported as promising drug candidates
[30–34]. Recently, Cornec’s group identified substituted imidazoles as
potential inhibiting agents of LOX pathways to deal with neurodegen-
erative diseases [35]. Similarly, purine-pyrazole incorporated hybrids
are reported as potent LOX inhibitors with anticancer potentials [36].
To meet the requirement of effective novel enzyme inhibitors, we
have been involved in designing different combinations of heterocyclic
compounds [37–42]. Herein, an aryl linker is used to connect both
diazolic moieties (pyrazole and imidazole) in one molecular template 6
(a-m) (Fig. 1). These compounds were later screened out against two
To illustrate general signals of 1H NMRs, a magnified view of 1H
NMR of 6a is given in Fig. 2 where methyl protons appeared as two
singlets. The methyl protons, present at the 3rd position of pyrazole,
were spotted at δ 2.27 ppm whereas methyl group present at the 5th
position of pyrazole ring appeared little upfield at δ 2.26 ppm. The signal
for H-4 of pyrazole ring was found at δ 5.99 ppm as singlet. The benzene
linker has two characteristic doublets with J value of 8.5 Hz. The aryl
protons nearest to pyrazole appeared upfield at δ 7.10 ppm and the other
two protons, adjacent to imidazole ring appeared at δ 7.35 ppm. Other
compounds 6(b-m) also showed the similar spectral patterns. Beside
these distinguishing signals, presence of substituents was also confirmed
from respective spectra. The 13C NMRs possessed all characteristic sig-
nals as well. The most prominent signals were of: two methyl carbons
around δ 112 ppm and δ 113 ppm, CH-4 of pyrazole in between δ
enzymes (α-glucosidase and LOX) to evaluate the enzyme inhibition
potentials of this new class of compounds and results were compared
with standard drugs. To the best of our knowledge, this structural
framework is not explored yet.
Fig. 1. Rationale of current research plan.
2

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
Scheme 1. Synthetic approach towards new series of imidazole-pyrazole hybrids.
each compound of this series 6(a-m). The experimentally found CHN
percentages were also promising when compared with the calculated
ones.
2.2. Biological activities
2.2.1. In vitro enzymes inhibition studies
Channar et al. have explored enzyme inhibitory potentials of some
related 3,5-dimethylpyrazoles and investigated the effects of different
substituents in the N-phenyl ring of pyrazole nucleus over their enzyme
inhibition strengths [46]. Herein, we have prepared a comparable series
of novel substituted imidazole-pyrazole hybrids 6(a-m) which after
structure elucidation was tested for their α-glucosidase and LOX inhi-
bition potencies (Table 1). In search of potent enzyme inhibitors, we
have investigated the effect of different substitutions at the 2nd position
of imidazole moiety on the inhibiting efficiencies of synthesized mole-
cules. For this purpose, α-glucosidase (from Saccharomyces cerevisiae)
and LOX (from Glycine max) enzymes were selected for current enzyme
inhibition studies. Acarbose was used as the standard drug for α-gluco-
sidase inhibition which displayed activity with IC50 375.82 ± 1.76 µM.
Meanwhile, baicalein (with IC50 22.4 ± 1.3 µM) was used as standard
inhibitor for LOX inhibition study.
Fig. 2. Important signals in 1H NMR spectrum of compound 6a.
2.2.2. Inhibition of α-Glucosidase
Inhibition of α-glucosidase enzyme is one of the useful methods to
107–109 ppm whereas C-2 of imidazole ring appeared downfield around
δ 140 ppm.
reduce post-prandial increase in blood glucose level of diabetic patients.
Azimi’s research group has recently proposed few pyrazole core based
These aryl decorated scaffolds were quite stabilized; therefore, mo-
lecular ion peaks were spotted in mass spectra of all compounds. As an
example of fragmentation pattern; Fig. 3 is signifying key fragmenta-
tions observed in EI-MS spectrum of 6j. Most probably, loss of CH3
radical, PhCN, CH3CN and NH(CH3)2 molecules have been involved. The
skeletal rearrangement (SR) of fragment m/z 192 lead to two interesting
ions; at m/z 190 and m/z 165 [45] and these fragments were observed in
molecules as significant α-glucosidase inhibitors [47]. Herein, structural
variety (at the Ar3 ring) of synthesized series and the inhibition results of
products helped us to identify the general features that probably control
inhibiting potencies of these compounds. Overall compounds have dis-
played moderate to excellent inhibition data (Fig. 4). By comparing the
results of 6a and 6b, the compound 6a with IC50 105.17 ± 0.94 µM has
exhibited better inhibition potential than of 6b with IC50 213.32 ± 1.38
3

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
Fig. 3. Plausible EI-MS fragmentation pattern of compound 6j.
µM. Perhaps, transferring to bulky naphthyl group has reduced the ac-
tivity. The derivatives 6c, 6d and 6e, substituted with the moderate
halogen atoms, also found to be good inhibitors. Among these, fluoro
substituted 6c (IC50 179.61 ± 1.31 µM) executed the best results
amongst 6c, 6d and 6e.
in analog 6l, there was marked decline in the activity. It is the most
probable; the hydroxyl group is involved in intramolecular hydrogen
bonding thus reducing the inhibiting potency. The presence of electron
withdrawing group, such as nitro, usually improves the activity [47]. In
present series, however, substitution of nitrile 6g or nitro 6h groups at
the para position of Ar3 ring reduced the activity. Compound 6m has
shown better results because of the presence of 1,3-benzodioxole
moiety.
Further, the para-hydroxyl (6f) and para-methoxy (6g) groups con-
taining compounds displayed good inhibition profiles with IC50 224.91
± 1.56 µM and IC50 379.51 ± 2.54 µM, respectively. It has been pro-
posed that the presence of both hydroxyl and methoxyl groups are
possibly involved in hydrogen bonding with the active site of the
enzyme and thus improving the inhibiting potential. By looking at the
structural features of the most potent agent 6k (IC50 54.25 ± 0.67 µM),
the presence of para-hydroxyl and meta-methoxyl groups in ring Ar3 are
seemed to be synergistically engaged in substantially enhancing the
activity. Conversely, the shifting of hydroxyl group to ortho position, as
2.2.3. Inhibition of LOX
We explored the LOX inhibition of indole-imidazole hybrids previ-
ously [37]. In the present study, we aimed to engineer novel hetaryl
conjugates with different substituents to observe the effects of such
structural variations on the bioactivity. Towards this aim, compound 6a
was tested first and showed the best results with IC50 41.75 ± 0.04 µM.
4

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
in the cavity [47,49]. Here it was observed that one of the nitrogen
atoms of the imidazole ring was making a hydrogen bond with Asn246,
while one of the nitrogen atoms of the pyrazole ring was making a
hydrogen bond with Gly280. One of the phenyl rings attached to the
imidazole ring was making a pi-pi T-shaped interaction with Trp242.
The phenyl ring, attached to the nitrogen atom of the imidazole ring was
making a pi-pi stacked interaction with His245. Fig. 5 also shows docked
conformation of most active inhibitor 6k. Apparently, the change in
observed potency was due to different snug fit orientation. The amino
acid Gly280 was acting as a hydrogen bond donor (towards the oxygen
atom of the methoxy group), and as a hydrogen bond acceptor (towards
the hydroxyl group). One of the phenyl groups attached to the imidazole
ring was making a pi-alkyl interaction with Pro309. The pyrazole ring
was also making a pi-alkyl interaction with Ala326.
Table 1
α
-Glucosidase (6a, 6k) and LOX inhibition activities of diazolic conjugates 6(a-
m).
Compound
α-Glucosidase
LOX
Inhibition (%) at
0.5 mM
IC50 (µM)
Inhibition (%) at
0.25 mM
IC50 (µM)
6a
6b
6c
6d
6e
6f
98.54 ± 1.93
88.94 ± 2.45
98.78 ± 2.78
98.76 ± 1.87
98.19 ± 1.87
82.84 ± 2.37
94.66 ± 1.53
105.17 ±
0.94
99.61 ± 0.93
94.91 ± 1.14
68.28 ± 1.08
91.86 ± 1.87
78.89 ± 1.05
28.81 ± 1.11
82.82 ± 1.21
41.75 ±
0.04
213.32 ±
1.38
52.82 ±
0.03
179.61 ±
1.31
121.35 ±
0.96
184.61 ±
0.95
132.25 ±
1.08
194.81 ±
1.29
153.28 ±
0.93
224.91 ±
1.56
NA
2.3.2. Docking of LOX inhibitors
Compound 6a was the most active LOX inhibitor (IC50 = 41.75 ±
0.04 µM), closely followed by compounds 6b and 6m (having almost
same inhibition activities, IC50 = 52.82 ± 0.03, and 53.36 ± 0.02 µM,
respectively). Hence, these compounds were selected for the docking
studies. The enzyme crystal structure was downloaded from the PDB
(PDB ID: 3V99). Fig. 6 shows docked conformation of 6a. For this
compound, no hydrogen bonded interactions were observed; instead,
two of the most important interactions observed were hydrophobic in-
teractions and the interaction of the imidazole nitrogen with the Fe atom
of the enzyme’s active site.
6g
379.51 ±
2.54
239.36 ±
0.96
6h
6i
11.76 ± 2.11
97.19 ± 2.35
NA
26.41 ± 1.12
55.34 ± 1.41
NA
245.33 ±
1.75
245.86 ±
1.12
6j
91.73 ± 1.32
97.89 ± 1.54
203.54 ±
2.11
67.89 ± 1.05
75.58 ± 1.63
75.23 ±
0.03
6k
54.25 ±
0.67
61.97 ±
1.15
6l
35.57 ± 2.22
95.94 ± 2.13
NA
26.31 ± 1.08
97.13 ± 0.87
NA
6m
182.73 ±
1.19
53.36 ±
0.02
Acarbosea
65.73 ± 1.93
375.82 ±
1.76
–
–
Among hydrophobic interactions, the pi-alkyl interactions between
Leu368 and the phenyl group attached to the imidazole ring. Gedawy
et al. have proposed comparable hydrophobic interactions between
Leu368 and aryl ring of pyrazole sulfonamides [50]. Other observed
interactions were among phenyl ring (also substituted on imidazole
ring) and Ala672, and between Ala410 and the phenyl ring attached to
the nitrogen atom of the imidazole ring. Ala410 was also making a pi-
alkyl interaction with the pyrazole ring, as well as making hydropho-
bic interactions with the methyl groups attached to the pyrazole ring.
Compounds 6b and 6m showed almost similar inhibition patterns
with different binding modes. The docked conformations and binding
site interactions of 6b revealed that the nitrogen atom of the imidazole
ring was making a hydrogen bond with Phe177. A number of pi-alkyl
interactions were observed, one of the phenyl rings attached to the
imidazole ring was making a pi-alkyl interaction with Ala410, while the
two methyl groups attached to the pyrazole ring were also making pi-
alkyl interactions with Leu607 and Ala672. For compound 6m, two
oxygen atoms of the benzodioxole ring were hydrogen bonded with
Asn554 and Gln557. Again hydrophobic interactions were observed to
be of importance in imparting stability to the enzyme-inhibitor complex.
Ala410 was making a pi-sigma and a pi-alkyl interaction with two
phenyl rings attached to the imidazole ring. Another pi-sigma interac-
tion was observed between Leu607 and the remaining phenyl group
attached to the imidazole ring. Leu607 was also making a pi-alkyl
interaction with the pyrazole ring, while one of the methyl groups
attached to the pyrazole ring. Overall results are in agreement with the
documented reports where methyl groups gave flexibility in bond
rotation, heteroatoms formed hydrogen bonds to give stability and the
heterocyclic/aromatic pi-rings involved in aromatic interactions
[47–50].
Baicaleinb
cNA: Not active.
–
–
93.79 ± 1.27
22.4 ± 1.3
a
b
Acarbose (0.5 mM) used as positive control for
α
-glucosidase inhibition.
Baicalein (0.25 mM) used as positive control for LOX inhibition.
Efforts were made to introduce further structural modifications in Ar3
ring with different functionalities. Extending the phenyl to naphthyl
group (compound 6b) has also displayed better results (IC50 52.82 ±
0.03). Apparently, the presence of phenyl rings was more favorable for
enzyme inhibition. In literature, some dihydropyrazoles were screened
for LOX inhibition activity. The chloro and para-tolyl analogues were the
most active [48]. However, substitutions of halogens in Ar3 ring were
not much effective for us to reduce the enzyme activities. Hence, com-
pounds 6c, 6d, and 6e have exhibited moderate inhibition. As a next
step, replacement with electron rich or poor groups 6(f-i) did not
improve their potencies either. However, 6j with -N(CH3)2 substitution
improved its activity to (IC50 75.23 ± 0.03). To further explore, the
presence of methoxyl group at the meta position and hydroxyl at the
para position of Ar3 in compound 6k apparently enhanced the activity to
IC50 61.97 ± 1.15, though, 6l was found to be inactive. Another deriv-
ative 6m has also displayed excellent inhibition profiles (IC50 53.36 ±
0.02) which partially can be justified that possibly the oxygen atoms are
participating to make additional H-bonds with amino acid residues of
enzyme. Overall, results signify compound 5a to be the most potent
inhibitor of the series (Fig. 4). Docking of lead inhibitors further
explained the observed relationships.
2.3. Molecular docking studies
3. Conclusion
2.3.1. Docking of
For
α-Glucosidase inhibitors
α
-glucosidase docking studies, two of the most active inhibitors
In conclusion, a novel series of phenyl bridged imidazole-pyrazole
scaffolds 6(a-m) was designed and synthesized. Unlike our previous
findings where anilines were used to produce varied N-substitutions in
imidazole ring, herein, a variety of substituted aldehydes were exploited
to investigate the enzyme inhibitory effects of different substitutions at
the 2nd position of imidazole ring. The chemical structures were pro-
posed on the basis of observed spectral data. Later, these compounds
6k (IC50 = 54.25 ± 0.67 µM) and 6a (IC50 = 105.17 ± 0.94 µM) were
selected. A number of non-bonded interactions were observed (Table 2).
Compound 6a was the second most active inhibitor, its docked confor-
mation and binding site interactions are shown in Fig. 5.
In accordance to the literature, nitrogen atoms have usually made
hydrogen bonds at the enzyme’s binding sites to make ligand fitted well
5

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
Fig. 4. Comparative enzyme inhibition potentials of compounds 6(a-m) against
α
-glucosidase (IC50 values in pink) and LOX (IC50 values in green). (For interpre-
tation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
were tested for their enzyme inhibition potentials. Preliminary
screening studies were carried out against -glucosidase and LOX en-
zymes. Overall decreasing order of -glucosidase inhibition was: 6k >
6a > 6c > 6m > 6d > 6e > 6j > 6b > 6f > 6i > acarbose > 6g > 6l > 6h.
These results suggest that modifications in Ar3 ring most probably
α
affected the enzyme activity. However, this series displayed moderate
inhibitory effects against LOX enzyme with IC50 between 41.75 and
245.86 µM. Compounds 6a, 6b and 6m can be considered as good lead
α
6

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
on heating. Afterwards, equivalent amounts (2.7 mmol) of substituted
aldehyde 3(a-m), benzil (4) and ammonium acetate (5) were added to
the solution. The reaction mixture was refluxed for about 6 hrs and
monitored through TLC. After reaction completion, the reaction con-
tents were poured into cold water and neutralized with sodium car-
bonate solution to afford crude product 6(a-m) which was further
purified through column chromatography over silica gel by using n-
hexane:ethyl acetate (in 8:2 ratio). These newly synthesized compounds
6(a-m) were characterized by physical and spectral means.
Table 2
Binding free energies and non-bonded interactions of α-glucosidase inhibitors
(6a, 6k) and LOX inhibitors (6a, 6b, 6m) with their respective receptors.
Ligand
Binding
free
Hydrophobic
interactions
Hydrogen
bond
Hydrogen
bond
Other
interactions
and distance
(Å)
energy
(kJ/
interactions
distance
(Å)
mol)
α
6a
-Glucosidase Inhibitors
ꢀ 13
His245 (pi-pi
stacked),
Asn246,
Gly280
1.74, 2.33
1.73, 1.83
_
_
4.2.2. 3,5-Dimethyl-1-(4-(2,4,5-triphenyl-1H-imidazol-1-yl)phenyl)-1H-
pyrazole (6a)
Trp242 (pi-pi
T-shaped)
White solid; m.p. 190–192 ◦C; Yield 73%; FTIR (νmax-cmꢀ 1; neat):
6k
ꢀ 29
Pro306 (pi-
alkyl), Ala326
(pi-alkyl)
Gly280 (H-
bond
3055–2970 (C H), 1602 (C N), 1560 (C C); 1H NMR (CDCl3, 500
–
–
–
–
–
acceptor),
Gly280 (H-
bond
MHz), δ: 2.26 (s, 3H; CH3-5 Pyrazole), 2.27 (s, 3H; CH3-3 Pyrazole), 5.99
(s, 1H; H-4 Pyrazole), 7.10 (d, 2H, J = 8.5 Hz; Ar-2H Pyrazole),
7.14–7.16 (m, 2H; Ar2-2H), 7.19–7.22 (m, 1H; Ar2-H), 7.24–7.29 (m,
8H; Ar1-3H, Ar2-2H & Ar3-3H), 7.35 (d, 2H, J = 8.5 Hz; Ar-2H Imid-
donor)
LOX Inhibitors
azole), 7.46–7.48 (m, 2H; Ar1-2H), 7.61 (d, 2H, J = 7.4 Hz; Ar3-2H); 13
C
6a
ꢀ 25
Ala410 (alkyl
and pi-alkyl),
Ala672 (pi-
alkyl),
_
_
Lig-Fe2+
(2.22)
NMR (CDCl3, 75 MHz), δ: 12.76 (CH3-5 Pyrazole), 13.59 (CH3-3 Pyr-
azole), 107.88 (CH-4 Pyrazole), 124.75, 126.92, 127.57, 128.31,
128.36, 128.64, 128.70, 129.07, 129.21, 130.05, 130.38, 130.90,
131.25, 134.02, 135.56, 138.25, 139.57, 139.72, 147.01 (C-2 Imid-
azole), 149.72 (C-3 Pyrazole); MS (ESI): m/z (%) 467.2 ([M + H]+, 100),
489.2 ([M + Na]+, 25.1); Anal. Calcd. For C32H26N4: C, 82.38; H, 5.62;
N, 12.01%. Found: C, 82.29; H, 5.46; N, 11.93%.
Leu368 (pi-
alkyl)
6b
6m
ꢀ 23
ꢀ 24
Leu607
Phe177
1.93
_
_
(alkyl),
Ala672
(alkyl),
Ala410 (pi-
alkyl)
4.2.3. 3,5-Dimethyl-1-(4-(2-(naphthalen-1-yl)-4,5-diphenyl-1H-imidazol-
1-yl)phenyl)-1H-pyrazole (6b)
Ala410 (pi-
sigma and pi-
alkyl),
Asn554,
Gln557
1.63, 2.44
White solid; m.p. 183–185 ◦C; Yield 70%; FTIR (νmax-cmꢀ 1; neat):
3050–2955 (C H), 1600 (C N), 1555 (C C); 1H NMR (CDCl3, 500
–
–
–
–
–
Leu607 (pi-
sigma, pi-
alkyl and
alkyl), Ala606
(alkyl),
MHz), δ: 2.09 (s, 3H; CH3-5 Pyrazole), 2.21 (s, 3H; CH3-3 Pyrazole), 5.91
(s, 1H; H-4 Pyrazole), 6.94 (d, 2H, J = 8.2 Hz; Ar-2H Pyrazole), 7.11 (d,
2H, J = 8.2 Hz; Ar-2H Imidazole), 7.21–7.28 (m, 8H; Ar1-3H, Ar2-5H),
7.32–7.35 (m, 1H; H-7 Ar3), 7.38–7.40 (m, 1H; H-6 Ar3), 7.44–7.46 (m,
2H; H-1 & H-2 Ar3), 7.67 (d, 2H, J = 7.4 Hz; Ar1-H), 7.81–7.82 (m, 2H;
H-4 & H-5 Ar3), 8.13–8.14 (m, 1H; H-8 Ar3); 13C NMR (CDCl3, 125
MHz), δ: 12.54 (CH3-5 Pyrazole), 13.52 (CH3-3 Pyrazole), 107.64 (CH-4
Pyrazole), 124.39, 124.82, 126.17, 126.19, 126.84, 126.90, 127.65,
127.98, 128.30, 128.32, 128.39, 128.74, 129.67, 129.72, 129.94,
130.57, 131.18, 132.75, 133.72, 134.28, 135.24, 138.21, 139.16,
139.49, 146.33 (C-2 Imidazole), 149.53 (C-3 Pyrazole); MS (ESI): m/z
(%) 517.2 ([M + H]+, 100), 539.2 ([M + Na]+, 42.2); Anal. Calcd. For
C36H28N4: C, 83.69; H, 5.46; N, 10.84%. Found: C, 83.51; H, 5.38; N,
10.91%.
for finding effective LOX inhibitors. Docking conformations helped to
recognize key interactions of the potent ligands of the series with the
active sites of enzymes. This study has led to the discovery of core
structure which would help in the development of potent drugs.
4. Experimental
4.1. Materials
Chemicals were purchased from Sigma-Aldrich and for thin layer
chromatography (TLC), DC-Alufolien Silica Gel 60 F254 Merck was used.
Melting points were determined over Gallen Kamp. Agilent Technolo-
gies Cary 630 FTIR spectrophotometer was used to run FTIR spectra. For
1H (13C) NMR spectra, Bruker Avance Instruments of 300 (75), 400
(100) or 500 (125) MHz were used. The analysis was carried out by
dissolving compounds in CDCl3/DMSO‑d6. The MS were recorded on
JEOL JMS 600H or FTMS spectrometer. The CHN data was found out
through Perkin Elmer 2400 Series II CHN/S Analyzer. Initial reactants 1
and 2 were synthesized following reported methods. Condensation re-
action between 4-nitrophenylhydrazine hydrochloride and 2,4-petane-
dione in methanol afforded the initial precursor 1. Further, nitro
group was reduced to amine with the help of Sn/HCl to generate reac-
tant 2. Their physiochemical properties were also comparable with the
literature reports [44].
4.2.4. 1-(4-(2-(4-Fluorophenyl)-4,5-diphenyl-1H-imidazol-1-yl)phenyl)-
3,5-dimethyl-1H-pyrazole (6c)
White solid; m.p. 178–180 ◦C; Yield: 71%; FTIR (νmax-cmꢀ 1; neat):
3056–2970 (C H), 1599 (C N), 1560 (C C); 1H NMR (CDCl3, 500
–
–
–
–
–
MHz), δ: 2.27 (s, 3H; CH3-5 Pyrazole), 2.27 (s, 3H; CH3-3 Pyrazole), 6.00
(s, 1H; H-4 Pyrazole), 6.96 (t, 2H, J = 8.7 Hz ; Ar3-2H), 7.09 (d, 2H, J =
8.6 Hz; Ar-2H Pyrazole), 7.14 (dd, 2H, J = 7.8, 2.0 Hz; Ar2-2H),
7.18–7.21 (m, 1H; Ar2-1H), 7.22–7.27 (m, 5H; Ar1-3H & Ar2-2H), 7.37
(d, 2H, J = 8.6 Hz; Ar-2H Imidazole), 7.45 (dd, 2H, J = 8.7, 5.4 Hz; Ar3-
2H), 7.59 (d, 2H, J = 7.2 Hz; Ar1-2H); 13C NMR (CDCl3, 125 MHz), δ:
12.80 (CH3-5 Pyrazole), 13.59 (CH3-3 Pyrazole), 107.98 (CH-4 Pyr-
azole), 115.49 (d, 2C, J (13C-19F) = 22.7 Hz, CH-3 Ar3 & CH-5 Ar3),
124.80, 126.47, 126.96, 127.51, 128.34, 128.41, 128.67, 129.06,
130.35, 130.95, 131.08 (d, 2C, J (13C-19F) = 8.3 Hz, CH-2 Ar3 & CH-6
Ar3), 131.23, 134.06, 135.43, 138.36, 139.57, 139.85 146.14 (C-2
Imidazole), 149.82 (C-3 Pyrazole), 162.94 (d, 2C, J (13C-19F) = 249.2
Hz, C-F); MS (ESI): m/z (%) 485.2 ([M + H]+, 100), 507.1 ([M + Na]+,
58.0); Anal. Calcd. For C32H25FN4: C, 79.32; H, 5.20; N, 11.56%. Found:
C, 79.24; H, 5.09; N, 11.60%.
4.2. Synthetic method
4.2.1. General procedure for the preparation of compound 6(a-m)
The reactant 2 (2.7 mmol) was first dissolved in acetic acid (15 mL)
7

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
Fig. 5. Docked conformations of α-glucosidase inhibitors 6a and 6k.
4.2.5. 1-(4-(2-(4-Chlorophenyl)-4,5-diphenyl-1H-imidazol-1-yl)phenyl)-
3,5-dimethyl-1H-pyrazole (6d)
7.17–7.18 (m, 1H; Ar1-1H), 7.22–7.25 (m, 5H; Ar-2H Imidazole & Ar2-
3H), 7.31 (d, 2H, J = 8.5 Hz; Ar3-2H), 7.35–7.38 (m, 4H; Ar1-2H & Ar3-
2H), 7.56 (d, 2H, J = 7.3 Hz; Ar1-2H); 13C NMR (CDCl3, 125 MHz), δ:
12.68 (CH3-5 Pyrazole), 13.45 (CH3-3 Pyrazole), 107.86 (CH-4 Pyr-
azole), 122.81 (C-Br), 124.67, 126.78, 127.32, 128.19, 128.26, 128.52,
128.89, 129.29, 130.23, 130.36, 131.08, 131.14, 131.42, 134.10,
135.32, 138.67, 139.42, 139.78, 145.80 (C-2 Imidazole), 149.69 (C-3
Pyrazole); MS (EI): m/z (%) 544.0 (M+, 100), 546.0 ([M + 2]+, 100);
Anal. Calcd. For C32H25BrN4: C, 70.46; H, 4.62; N, 10.27%. Found: C,
70.31; H, 4.53; N, 10.16%.
White solid; m.p. 185–187 ◦C; Yield 68%; FTIR (νmax-cmꢀ 1; neat):
3052–2950 (C H), 1590 (C N), 1555 (C C); 1H NMR (CDCl3, 300
–
–
–
–
–
MHz), δ: 2.28 (s, 6H; 2 × CH3 Pyrazole), 6.00 (s, 1H; H-4 Pyrazole), 7.10
(d, 2H, J = 8.8 Hz; Ar-2H Pyrazole), 7.12–7.15 (m, 2H; Ar2-2H),
7.22–7.28 (m, 8H; Ar1-3H, Ar2-3H & Ar3-2H), 7.37–7.42 (m, 4H; Ar-2H
Imidazole & Ar3-2H), 7.59 (dd, 2H, J = 8.2, 1.8 Hz; Ar1-2H); 13C NMR
(CDCl3, 75 MHz), δ: 12.84 (CH3-5 Pyrazole), 13.60 (CH3-3 Pyrazole),
108.04 (CH-4 Pyrazole), 124.82, 127.05, 127.53, 128.36, 128.49,
128.66, 128.69, 129.02, 130.18, 130.36, 131.22, 133.87, 134.85 (C-Cl),
135.29, 138.47, 139.58, 139.97, 145.85 (C-2 Imidazole), 149.85 (C-3
Pyrazole); MS (ESI): m/z (%) 501.1 ([M + H]+, 100), 502.1 ([M + 2]+,
31.2), 503.2 ([M + H + 2]+, 29.1), 523.1 ([M + Na]+, 6); Anal. Calcd.
For C32H25ClN4: C, 76.71; H, 5.03; N, 11.18%. Found: C, 76.59; H, 4.91;
N, 11.26%.
4.2.7. 4-(1-(4-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4,5-diphenyl-1H-
imidazol-2-yl)phenol (6f)
White solid; m.p. 234–236 ◦C; Yield 65%; FTIR (νmax-cmꢀ 1; neat):
–
–
–
–
3160 (br., OH), 3078–2924 (C H), 1611 (C N), 1556 (C C), 1235
–
1
–
(C O); H NMR (DMSO‑d6, 400 MHz), δ: 2.14 (s, 3H; CH3-5 Pyrazole),
2.23 (s, 3H; CH3-3 Pyrazole), 6.05 (s, 1H; H-4 Pyrazole), 6.68 (d, 2H, J =
8.4 Hz; Ar3-2H), 7.15–7.17 (m, 1H; Ar2-1H), 7.21–7.23 (m, 6H; Ar-2H
Pyrazole & Ar2-4H), 7.30–7.31 (m, 5H; Ar1-3H & Ar3-2H), 7.42 (d,
2H, J = 8.4 Hz; Ar-2H Imidazole), 7.49 (d, 2H, J = 7.4 Hz; Ar1-2H), 9.67
(br. s, 1H; OH); 13C NMR (DMSO‑d6, 100 MHz), δ: 12.20 (CH3-5 Pyr-
azole), 13.20 (CH3-3 Pyrazole), 107.56 (CH-4 Pyrazole), 114.98,
121.10, 124.07, 126.31, 128.09, 128.31, 128.44, 129.44, 129.83,
4.2.6. 1-(4-(2-(4-Bromophenyl)-4,5-diphenyl-1H-imidazol-1-yl)phenyl)-
3,5-dimethyl-1H-pyrazole (6e)
White solid; m.p. 180–182 ◦C; Yield 71%; FTIR (νmax-cmꢀ 1; neat):
3050–2957 (C H), 1603 (C N), 1559 (C C); 1H NMR (CDCl3, 500
–
–
–
–
–
MHz), δ: 2.26 (s, 6H; 2 × CH3), 5.98 (s, 1H; H-4 Pyrazole), 7.08 (d, 2H, J
= 8.6 Hz; Ar-2H Pyrazole), 7.12 (d, 2H, J = 6.4, 1.5 Hz; Ar2-2H),
8

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
Fig. 6. Docked conformations of LOX inhibitors 6a, 6b and 6m.
–
130.49, 130.53, 131.12, 134.49, 135.15, 136.48, 139.19, 139.30,
146.51 (C-2 Imidazole), 148.27 (C-3 Pyrazole), 157.66 (C-OH); MS (EI):
m/z (%) 482.1 (M+, 100); Anal. Calcd. For C32H26N4O: C, 79.64; H, 5.43;
N, 11.61%. Found: C, 79.45; H, 5.38; N, 11.62%.
2.23 (s, 3H; CH3-3 Pyrazole), 3.72 (s, 3H; OCH3), 6.06 (s, 1H; H-4
Pyrazole), 6.87 (d, 2H, J = 8.7 Hz; Ar3-2H), 7.17–7.18 (m, 1H; Ar2-1H),
7.22–7.25 (m, 4H; Ar-2H Pyrazole & Ar2-2H), 7.30–7.36 (m, 7H; Ar1-3H,
Ar2-2H & Ar3-2H), 7.44 (d, 2H, J = 8.5 Hz; Ar-2H Imidazole), 7.49 (d,
2H, J = 7.6 Hz; Ar1-2H); 13C NMR (DMSO‑d6, 100 MHz), δ: 12.24 (CH3-5
–
4.2.8. 1-(4-(2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazol-1-yl)
Pyrazole), 13.20 (CH3-3 Pyrazole), 55.11 ( OCH3), 107.62 (CH-4 Pyr-
phenyl)-3,5-dimethyl-1H-pyrazole (6g)
azole), 113.67, 122.67, 124.04, 126.32, 126.38, 128.11, 128.37,
128.45, 129.45, 129.71, 130.40, 130.80, 131.12, 134.42, 135.03,
136.61, 139.28, 139.33, 146.07 (C-2 Imidazole), 148.30 (C-3 Pyrazole),
159.27 (C-OCH3); MS (EI): m/z (%) 496.1 (M+, 100); Anal. Calcd. For
White solid; m.p. 201–203 ◦C; Yield 70%; FTIR (νmax-cmꢀ 1; neat):
3
–
–
–
–
3052–2948 (C H), 1609 (C N), 1563 (C C), 1252 (Ar -O), 1025
–
1
–
(C O); H NMR (DMSO‑d6, 400 MHz), δ: 2.14 (s, 3H; CH3-5 Pyrazole),
9

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
–
C33H28N4O: C, 79.81; H, 5.68; N, 11.28%. Found: C, 79.92; H, 5.61; N,
11.32%.
Pyrazole), 13.40 (CH3-3 Pyrazole), 55.81 ( OCH3), 107.73 (CH-4 Pyr-
azole), 111.95, 114.11, 122.15, 122.37, 124.57, 126.61, 127.40,
128.07, 128.12, 128.44, 128.71, 129.00, 130.37, 130.43, 131.10,
134.20, 135.78, 138.05, 139.38, 146.27 (C-2 Imidazole), 146.44 (C-
OCH3), 147.10 (C-3 Pyrazole), 149.57 (C-OH); MS (ESI): m/z (%) 512.3
(M + H+, 100); Anal. Calcd. For C33H28N4O2: C, 77.32; H, 5.51; N,
10.93%. Found: C, 77.27; H, 5.44; N, 11.01%.
4.2.9. 4-(1-(4-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4,5-diphenyl-1H-
imidazol-2-yl)benzonitrile (6h)
White solid; m.p. 261–263 ◦C; Yield 77%; FTIR (νmax-cmꢀ 1; neat):
3060–2930 (C H), 2229 (C N), 1602 (C N), 1560 (C C); 1H NMR
–
–
–
–
–
–
–
–
(CDCl3, 500 MHz), δ: 2.26 (s, 3H; CH3-5 Pyrazole), 2.27 (s, 3H; CH3-3
Pyrazole), 5.99 (s, 1H; H-4 Pyrazole), 7.11 (d, 2H, J = 8.7 Hz; Ar-2H
Pyrazole), 7.12–7.14 (m, 2H; Ar2-2H), 7.20–7.27 (m, 6H; Ar1-3H &
Ar2-3H), 7.40 (d, 2H, J = 8.7 Hz; Ar-2H Imidazole), 7.52 (d, 2H, J = 8.5
Hz; Ar3-2H), 7.56 (dd, 2H, J = 7.0, 1.0 Hz; Ar1-2H), 7.57 (d, 2H, J = 8.5
Hz; Ar3-2H); 13C NMR (CDCl3, 125 MHz), δ: 12.71 (CH3-5 Pyrazole),
4.2.13. 5-Bromo-2-(1-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4,5-
diphenyl-1H-imidazol-2-yl)phenol (6l)
White solid; m.p. 192–194 ◦C; Yield 58%; FTIR (νmax-cmꢀ 1; neat):
1
–
–
–
–
3064 (br., OH), 3050–2921 (C H), 1604 (C N), 1578 (C C); H NMR
–
(CDCl3, 500 MHz), δ: 2.28 (s, 3H; CH3-5 Pyrazole), 2.35 (s, 3H; CH3-3
Pyrazole), 6.01 (s, 1H; H-4 Pyrazole), 6.56 (d, 1H, J = 2.4 Hz; Ar3-1H),
6.94 (d, 1H, J = 8.8 Hz; Ar3-1H), 7.16 (dd, 2H, J = 7.9, 1.5 Hz; Ar2-2H),
7.20 (t, 1H, J = 4.0, 2.5 Hz; Ar1-1H), 7.22 (t, 1H, J = 2.5, 1.5 Hz; Ar2-
1H), 7.23–7.28 (m, 7H; Ar-2H Pyrazole, Ar1-2H, Ar2-2H & Ar3-1H), 7.49
(d, 2H, J = 8.7 Hz; Ar-2H Imidazole), 7.49–7.51 (m, 2H; Ar1-2H), 13.41
(br. s, 1H; OH); 13C NMR (CDCl3, 125 MHz), δ: 12.68 (CH3-5 Pyrazole),
13.45 (CH3-3 Pyrazole), 107.89 (CH-4 Pyrazole), 109.55, 114.36,
119.52, 125.60, 126.88, 127.25, 128.33, 128.45, 128.79, 128.90,
129.13, 129.16, 130.78, 131.22, 132.49, 132.66, 135.08, 135.59,
139.85, 140.68, 143.63 (C-2 Imidazole), 149.84 (C-3 Pyrazole), 157.52
(C-OH); MS (ESI): m/z (%) 561.2 ([M + H]+, 98.1), 563.2 ([M + H +
2]+, 100); Anal. Calcd. For C32H25BrN4O: C, 68.45; H, 4.49; N, 9.98%.
Found: C, 68.38; H, 4.45; N, 9.83%.
–
–
13.42 (CH3-3 Pyrazole), 108.03 (CH-4 Pyrazole), 111.66 (C-C N),
–
–
–
118.52 (C N), 124.76, 127.01, 127.24, 128.24, 128.50, 128.58,
–
128.80, 128.97, 129.82, 131.02, 131.96, 132.11, 133.76, 134.52,
134.95, 139.25, 139.41, 140.10 (C-2 Imidazole), 144.64, 149.82 (C-3
Pyrazole); MS (EI): m/z (%) 491.2 (M+, 100); Anal. Calcd. For C33H25N5:
C, 80.63; H, 5.13; N, 14.25%. Found: C, 80.66; H, 5.06; N, 14.13%.
4.2.10. 3,5-Dimethyl-1-(4-(2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazol-
1-yl)phenyl)-1H-pyrazole (6i)
Yellow solid; m.p. 202–204 ◦C; Yield 78%; FTIR (νmax-cmꢀ 1; neat):
1
–
–
–
–
3059–2940 (C H), 1601 (C N), 1555 (C C), 1517 & 1350 (NO ); H
–
2
NMR (CDCl3, 300 MHz), δ: 2.29 (s, 3H; CH3-5 Pyrazole), 2.31 (s, 3H;
CH3-3 Pyrazole), 6.02 (s, 1H; H-4 Pyrazole), 7.15–7.17 (m, 4H; Ar-2H
Pyrazole & Ar2-2H), 7.24–7.28 (m, 6H; Ar1-3H & Ar2-3H), 7.45 (d,
2H, J = 8.7 Hz; Ar-2H Imidazole), 7.60 (d, 2H, J = 6.6 Hz; Ar1-2H), 7.68
(d, 2H, J = 8.7 Hz; Ar3-2H), 8.12 (d, 2H, J = 8.7 Hz; Ar3-2H); 13C NMR
(CDCl3, 125 MHz), δ: 12.78 (CH3-5 Pyrazole), 13.43 (CH3-3 Pyrazole),
108.15 (CH-4 Pyrazole), 123.50, 124.59, 124.76, 127.33, 127.38,
128.32, 128.68, 128.74, 128.80, 129.38, 130.99, 132.37, 132.93,
134.48, 135.52, 138.84, 139.44, 140.33 (C-2 Imidazole), 144.15 (Ar3-C-
NO2), 147.32 (C-3 Pyrazole), 149.90 (Ar3-C-Imidazole); MS (EI): m/z
(%) 511.0 (M+, 100); Anal. Calcd. For C32H25N5O2: C, 75.13; H, 4.93; N,
13.69%. Found: C, 75.02; H, 4.74; N, 13.71%.
4.2.14. 1-(4-(2-(Benzo[d][1,3]dioxol-5-yl)-4,5-diphenyl-1H-imidazol-1-
yl)phenyl)-3,5-dimethyl-1H-pyrazole (6m)
White solid; m.p. 182–184 ◦C; Yield 70%; FTIR (νmax-cmꢀ 1; neat):
3056–2984 (C H), 1601 (C N), 1558 (C C), 1034 (C O); 1H NMR
–
–
–
–
–
–
(DMSO‑d6, 400 MHz), δ: 2.14 (s, 3H; CH3-5 Pyrazole), 2.22 (s, 3H; CH3-3
Pyrazole), 6.01 (s, 2H; CH2), 6.06 (s, 1H; H-4 Pyrazole), 6.85 (d, 1H, J =
8.0 Hz; Ar3-1H), 6.89 (d, 1H, J = 8.0 Hz; Ar3-1H), 6.93 (s, 1H; Ar3-1H),
7.17–7.18 (m, 1H; Ar2-1H), 7.22–7.26 (m, 4H; Ar-2H Pyrazole & Ar2-
2H), 7.30–7.35 (m, 5H; Ar1-3H & Ar2-2H), 7.44 (d, 2H, J = 8.4 Hz; Ar-
2H Imidazole), 7.49 (d, 2H, J = 7.5 Hz; Ar1-2H); 13C NMR (DMSO‑d6,
100 MHz), δ: 12.20 (CH3-5 Pyrazole), 13.19 (CH3-3 Pyrazole), 101.29
4.2.11. 4-(1-(4-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4,5-diphenyl-1H-
imidazol-2-yl)-N,N-dimethylaniline (6j)
–
(
CH2), 107.60 (CH-4 Pyrazole), 108.09, 108.50, 122.63, 124.11,
White solid; m.p. 174–176 ◦C; Yield 66%; FTIR (νmax-cmꢀ 1; neat):
126.33, 126.42, 128.11, 128.41, 128.46, 129.46, 130.31, 130.94,
131.11, 134.32, 134.94, 136.58, 139.32, 145.86 (C-2 Imidazole),
147.05 (C-3 Pyrazole), 147.41, 148.31; MS (EI): m/z (%) 510.2 (M+,
100); Anal. Calcd. For C33H26N4O2: C, 77.63; H, 5.13; N, 10.97%. Found:
C, 77.71; H, 5.11; N, 11.16%.
3053–2930 (C H), 1606 (C N), 1570 (C C), 1359 (C N); 1H NMR
–
–
–
–
–
–
(DMSO‑d6, 400 MHz), δ: 2.14 (s, 3H; CH3-5 Pyrazole), 2.24 (s, 3H; CH3-3
Pyrazole), 2.88 (s, 6H; -N(CH3)2), 6.06 (s, 1H; H-4 Pyrazole), 6.60 (d,
2H, J = 8.6 Hz; Ar3-2H), 7.15–7.17 (m, 1H; Ar2-1H), 7.23–7.25 (m, 6H;
Ar-2H Pyrazole & Ar2-4H), 7.29–7.32 (m, 5H; Ar1-3H & Ar3-2H), 7.44
(d, 2H, J = 8.3 Hz; Ar-2H Imidazole), 7.49 (d, 2H, J = 7.5 Hz; Ar1-2H);
13C NMR (DMSO‑d6, 100 MHz), δ: 12.27 (CH3-5 Pyrazole), 13.21 (CH3-3
Pyrazole), 39.71 (-N(CH3)2), 107.60 (CH-4 Pyrazole), 111.38, 117.52,
124.00, 126.25, 126.30, 128.07, 128.24, 128.41, 129.08, 129.49,
130.36, 130.59, 131.15, 134.59, 135.37, 136.40, 139.16, 139.31,
4.3. Enzyme inhibition assays
To determine the inhibition of selected enzymes, we used our pre-
viously reported protocols [37,38]. Study of
α-glucosidase inhibition
was carried out with respective enzyme isolated from Saccharomyces
cerevisiae (Cat No. 5003-1KU Type I, Sigma USA) while the positive
control was acarbose. For LOX inhibition, lipoxygenase enzyme isolated
from Glycine max (Sigma, USA) was used and baicalein was the positive
control. Compounds were dissolved in HPLC grade methanol and assays
were carried out with different sample dilutions and run in triplicates.
After calculating the inhibitory percentages, IC50 values were deter-
mined with the help of EZ-Fit Enzyme Kinetics Software from Perrella
Scientific Inc.
–
146.79 (C-2 Imidazole), 148.27 (C-3 Pyrazole), 149.98 (C N(CH3)2);
MS (EI): m/z (%) 509.1 (M+, 100); Anal. Calcd. For C34H31N5: C, 80.13;
H, 6.13; N, 13.74%. Found: C, 79.95; H, 6.08; N, 13.73%.
4.2.12. 4-(1-(4-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4,5-diphenyl-1H-
imidazol-2-yl)-2-methoxyphenol (6k)
White solid; m.p. 228–230 ◦C; Yield 60%; FTIR (νmax-cmꢀ 1 neat):
;
–
–
–
–
–
3057 (br., OH), 3040–2933 (C H), 1605 (C N), 1596 (C C), 1269 &
1033 (Ar3-O-CH3); 1H NMR (CDCl3, 500 MHz), δ: 2.24 (s, 3H; CH3-5
–
Pyrazole), 2.25 (s, 3H; CH3-3Pyrazole), 3.77 (s, 3H; OCH3), 5.74 (br. s,
4.4. Molecular docking
1H; OH), 5.97 (s, 1H; H-4 Pyrazole), 6.70 (d, 1H, Jab = 8.3 Hz; Ar3-1H),
6.74 (dd, 1H, Jab = 8.3 & Jbc = 1.8 Hz; Ar3-1H), 7.09 (d, 2H, J = 8.7 Hz;
Ar-2H Pyrazole), 7.12 (dd, 1H, J = 7.6, 1.5 Hz; Ar2-1H), 7.15 (d, 1H, J =
1.8 Hz; Ar3-1H), 7.17–7.18 (m, 1H; Ar2-1H), 7.21–7.24 (m, 5H; Ar1-3H
& Ar2-2H), 7.34 (d, 2H, J = 8.7 Hz; Ar-2H Imidazole), 7.57 (dd, 2H, J =
7.2, 1.4 Hz; Ar-2H); 13C NMR (CDCl3, 125 MHz), δ: 12.58 (CH3-5
The crystal structure data of α-glucosidase from Saccharomyces cer-
evisiae is not yet available in protein data bank (PDB). Previously, we
built its homology model, validated and reported [38–40,42]. Herein,
this model was utilized for the docking studies. Whereas for LOX studies,
the crystal structure was downloaded from the PDB (PDB ID: 3V99) and
10

F. Chaudhry et al.
Bioorganic Chemistry 108 (2021) 104686
evaluation of new pyrazole-triazolopyrimidine hybrids as potent
inhibitors, Bioorg. Chem. 93 (2019), 103307.
α-glucosidase
docking was performed on BioSolveIT’s LeadIT software [51]. The
detailed studies regarding binding interactions were carried out with the
most favorable conformations possessing the lowest binding energies.
Discovery Studio Visualizer 3.5 was used for visualization of docked
structures.
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Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
c) S. Kandasamy, P. Subramani, S. Subramani, J.M. Jayaraj, G. Prasanth,
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Acknowledgements
F.C. is highly grateful to the Higher Education Commission of
Pakistan (HEC) for their financial support during her research projects.
A part of this research study was carried out from NRPU-4950 funded
project to M.A. wherein W.S. worked as research assistant.
anti-diabetic agents: in vitro α-glucosidase inhibition, kinetic, and in silico studies,
Bioorg. Med. Chem. Lett. 29 (2019) 713–718.
[13] P.A. Channar, A. Saeed, F.A. Larik, B. Batool, S. Kalsoom, M.M. Hasan, M.F. Erben,
H.R. El-Seedi, M. Ali, Z. Ashraf, Synthesis of aryl pyrazole via Suzuki coupling
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Appendix A. Supplementary material
[14] R. Rafique, K.M. Khan, S. Chigurupati, A. Wadood, A.U. Rehman, A. Karunanidhi,
S. Hameed, M. Taha, M. Al-Rashida, Synthesis of new indazole based dual
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bioorg.2021.104686.
inhibitors of α-glucosidase and α-amylase enzymes, their in vitro, in silico and
kinetics studies, Bioorg. Chem. 94 (2020), 103195.
[15] F. Turkan, A. Çetin, P. Taslimi, M. Karaman, I. Gulçin, Synthesis, biological
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anhydrase and acetylcholinesterase inhibitors, Bioorg. Chem. 86 (2019) 420–427.
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benzo-indole pyrazole schiff base derivatives with antibacterial activity targeting
DNA gyrase, Bioorg. Chem. 99 (2020), 103807.
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