Synthesis, molecular docking and radical scavenging activity of 1,2,4,5-tetrasubstituted imidazole derivatives

Article abstract of DOI:10.14233/ajchem.2019.22107

A series of 1,2,4,5-tetrasubstituted imidazoles (2a-g) were synthesized using 1,2-diketone, 1-naphthaldehyde, substituted aromatic amine and ammonium acetate in the presence of ceric ammonium nitrate as a catalyst. The synthesized compounds were character

Full text of DOI:10.14233/ajchem.2019.22107

Asian Journal of Chemistry; Vol. 31, No. 11 (2019), 2448-2452
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22107
Synthesis, Molecular Docking and Radical Scavenging
Activity of 1,2,4,5-Tetrasubstituted Imidazole Derivatives
1,2
1,*
3
4
SOMASHEKARA BHADRACHAR , GIRIYAPURA R.VIJAYAKUMAR , KITTAPPA M. MAHADEVAN and THIPPESWAMY BASAVARAJA
1Department of Chemistry, University College of Science, Tumkur University, Tumkur-572103, India
2Department of Chemistry, Smt. Indira Gandhi Government First Grade Women′s College, Sagar-577401, India
3Department of Chemistry, Kuvempu University, P.G. Centre, Kadur-577548, India
4Department of Chemistry, Government Science College, Chithradurga-577501, India
*Corresponding author: E-mail: vijaykumargr18@gmail.com
Received: 30 March 2019;
Accepted: 3 May 2019;
Published online: 28 September 2019;
AJC-19567
A series of 1,2,4,5-tetrasubstituted imidazoles (2a-g) were synthesized using 1,2-diketone, 1-naphthaldehyde, substituted aromatic amine
and ammonium acetate in the presence of ceric ammonium nitrate as a catalyst. The synthesized compounds were characterized by FT-IR,
1H NMR, Mass spectra and explored for their antioxidant activity by DPPH free radical scavenging assay method.Among the synthesized
compounds 2a, 2e and 2f exhibit good antioxidant activities. Molecular docking study was also been performed to know the possible
interactions between the synthesized compound and antioxidant receptor 3MNG.
Keywords: 1,2,4,5-Tetrasubstituted imidazoles, Ceric ammonium nitrate, Antioxidant activity, Molecular docking.
dysfunction, immune system decline, atherosclerosis and cancer.
Many methods have been reported for the synthesis of 1,2,4,5-
tetrasubstituted imidazole derivatives which includes conven-
tional methods and solvent free microwave assisted synthesis.
In recent years, extensive work has been carried out on the
development of methods for the efficient synthesis imidazole
derivatives. Particularly, four component one-pot synthesis
involving aldehyde, 1,2-diketone, primary amines and ammonium
acetate in acetic acid and in the presence of variety of catalysts
such as FeCl3/I2 [12], nanocrystalline MgAl2O4 [13], InCl3·3H2O
[14], Ph3P/CCl4 [15], p-toluene sulfonic acid [16], nano-TiCl4
·SiO2 [17], ZnO nanorods [18], Co3O4 nanoparticles [19], SBA-
Pr-SO3H [20], silica supported SbCl3 [21], sodium benzene-
sulfonate [22], ceric ammonium nitrate [23], Fe3+-K10 [24],
sodium dihydrogen phosphate [25], L-proline [26], erbium
triflate [27] and molecular iodine under solvent free condition
[28].
INTRODUCTION
Imidazole and its analogues are important class of com-
pounds and being the constituent of many naturally occur-
ring substances and drugs. Compound containing imidazole
moieties have attracted many medicinal chemists due to their
wide range of biological applications. Literature review revealed
that many new imidazole containing drugs have been synthe-
sized and explored their biological activity. The series of 1,2,
4,5-tetrasubstituted imidazoles acts as an anti-bacterial agent
[1], antifungal agents [2], antioxidant agents [3], anti-inflam-
matory agents [4], analgesic agents [5], antiviral agents [6],
anti-tuberculosis agents [7], anticonvulsant agents [8], anti-
cancer agents [9], antiurease [10] and alsoATP-mimetic inhibitors
of P38 MAP Kinase [11].
The development of new antioxidant agents has been very
important because free radicals produced by various endogen-
eous process controls crucial cellular metabolism and mediate
many critical biochemical reactions and induce physiological
effects. The antioxidants play an important role in the treat-
ment of many chronic and degenerative diseases such as brain
Considering the bioprofile and synthetic methods, a series
of 1,2,4,5-tetrasubstituted imidazoles were synthesized and
screened for their antioxidant activity by DPPH free radical
scavenging assay method.A molecular docking study was also
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Vol. 31, No. 11 (2019)
Synthesis and Radical Scavenging Activity of 1,2,4,5-Tetrasubstituted Imidazole Derivatives 2449
carried out to understand the interaction sites of receptor with
the synthesized molecules.
1-(4-Methylphenyl)-4,5-bis(4-methylphenyl)-2-(naphth-
alen-1-yl)-1H-imidazole (2b): Pale brown solid;Yield: 89.40
%; m.f.: C34H28N2; m.p.: 216-218 ºC; IR (KBr, λmax, cm-1):
3044.09 (Ar-H), 2918.73 (C-CH3), 1607.38 (C=N), 1585.20
EXPERIMENTAL
1
All reagents used in the synthesis were purchased from
Sigma-Aldrich, USA. Solvents were purchased from S.D. Fine
Chemicals, India and distilled once before usage. The progress
of the reaction and purity of the samples were checked by TLC
using mobile phase petroleum ether and ethyl acetate (4:1).
For TLC stationary phase, silica gel coated aluminum sheets
(silica gel 60 F254) procured from Merck, India were employed.
Yields were recorded after isolation of the products. IR spectra
of the products were obtained on a JASCO FTIR4100 spectro-
photometer using KBr pellet method. 1H NMR spectra were
recorded using JEOL 500 MHz instrument by using TMS as
internal standard and chemical shift values are expressed in δ
ppm. Shimadzu LC-2010EV with ESI probe was used for
recording mass of the sample. Melting points of the synthesized
compounds were determined by open capillary method by using
Mvtec melting point apparatus and are uncorrected.
Synthesis of 1,2,4,5-Tetrasubstituted imidazole derivatives
(2a-g):A mixture of 1-naphthaldehyde (10 mmol), 1,2-diketone
(10 mmol), ammonium acetate (50 mmol), aromatic amine
(10 mmol) and ceric ammonium nitrate (10 mol %) as catalyst
were taken in a round bottom flask. Methanol (20 mL) was
added as a solvent and the reaction mixture was refluxed for 10-
12 h. The progress of the reaction was monitored by TLC using
petroleum ether and ethyl acetate (4:1) as eluent.After comple-
tion of the reaction, the mixture was poured into ice-cold water
and the solid obtained was filtered and dried (Scheme-I). The
crude solid product was then subjected to purification by column
chromatography.
(C=C), 1335.46 (C-N); H NMR (500 MHz,CDCl3) δ ppm:
2.16 (s, 3H, -CH3), 2.320 (S, 3H, -CH3), 2.328 (s, 3H, -CH3),
6.75 (d, J1 = 8.3 Hz, 2H, ArH), 6.82 (d, J1 = 7.6 Hz, 2H, ArH),
7.05-7.46 (m, 10H, ArH), 7.54 (d, J1 = 8.3 Hz, 2H, ArH), 7.81
(m, 2H, ArH), 8.20 (q, J1 = 3.2 Hz, 1H, ArH); MS (ESI) m/z:
465.01 (M+), calcd: 464.22.
1-(4-Bromophenyl)-2-(naphthalen-1-yl)-4,5-diphenyl-
1H-imidazole (2c): Brown solid;Yield: 83.24 %; m.f.:C31H21N2 Br;
m.p.: 155-157 ºC; IR (KBr, λmax, cm-1): 3057.58 (Ar-H),1598.70
1
(C=N),1556.27 (C=C), 1363.36 (C-N), 776.20 (C-Br); H
NMR (500 MHz, CDCl3) δ ppm: 6.72-7.64 (m, 21H, ArH);
MS (ESI) m/z: 501.13 (M+), calcd: 500.08
1-(2-Chlorophenyl)-4,5-bis(4-methylphenyl)-2-(naphth-
alen-1-yl)-1H-imidazole (2d): Off white solid; Yield: 68.28
%; m.f.: C33H25N2Cl; m.p.: 227-228 ºC; IR (KBr, λmax, cm-1):
3047.94 (Ar-H), 1613.16 (C=N), 1583.27 (C=C), 1336.43 (C-N),
670.14 (C-Cl); 1H NMR (500 MHz, CDCl3) δ ppm: 2.32 (s,
3H, -CH3), 2.34 (s, 3H, -CH3), 6.73 (td, J1 = 5.9 Hz, J2 = 3.4
Hz, 2H, ArH), 7.0-7.54 (m, 12H, ArH), 7.5 (d, J1 = 8.3 Hz, 2H,
ArH), 7.83 (td, J1 = 5.3 Hz, J2 = 3.4 Hz, 2H, ArH), 8.14 (t, J1
= 4.8 Hz, 1H, ArH); MS (ESI) m/z: 485.21 (M+), calcd:484.17.
1-(4-Hydroxyphenyl)-2-(naphthalen-1-yl)-4,5-diphenyl-
1H-imidazole (2e): Brown solid; Yield: 80.22 %; m.f.:
C31H22N2O; m.p.: 305-308 ºC; IR (KBr, λmax, cm-1): 3061.15
1
(Ar-H), 1612.86 (C=N),1596.27 (C=C),1336.18 (C-N); H
NMR (500 MHz, CDCl3) δ ppm: 1.70 (s,1H, OH), 6.32 (t, J1 =
10.0 Hz, 2H, ArH), 6.6 (d, J1 = 9.0 Hz, 2H, ArH), 7.1-7.5 (m,
14H, ArH), 7.6 (d, J1 = 7.6 Hz, 2H, ArH), 8.07 (d, J1 = 8.3 Hz,
1H, ArH); MS (ESI) m/z: 439.20 (M+), calcd:438.17.
2-(Naphthalen-1-yl)-1,4,5-triphenyl-1H-imidazole (2f):
Off white solid; Yield: 75.81 %; m.f.: C31H22N2; m.p.: 168-
169 ºC; IR (KBr, λmax, cm-1): 3055.66 (Ar-H), 1621.86 (C=N),
1596.77 (C=C), 1332.57 (C-N); 1H NMR (500 MHz, CDCl3)
δ ppm: 6.88-7.20 (m, 8H, ArH), 7.24 (t, J1 = 4.5 Hz, 2H,ArH),
7.27-7.47 (m, 7H, ArH), 7.6 (d, J1 = 6.9 Hz, 2H, ArH), 7.79
(m, 2H, ArH), 8.20 (t, J1 = 4.8 Hz, 1H, ArH); MS (ESI) m/z:
423.16 (M+), calcd:422.18.
1-(4-Methylphenyl)-2-(naphthalen-1-yl)-4,5-diphenyl-1H-
imidazole (2a): Off white solid;Yield: 76.18 %; m.f.: C32H24N2;
m.p.:162-163 ºC; IR (KBr, λmax, cm-1): 3051.80 (Ar-H), 2998.77
(C-CH3), 1598.70 (C=N), 1580.38 (C=C),1336.43 (C-N); 1H
NMR (500 MHz,CDCl3) δ ppm: 2.14 (s, 3H, -CH3), 6.76 (d,
J1 = 8.3 Hz, 2H, ArH), 6.81 (d, J1 = 8.3 Hz, 2H,ArH), 7.20 (m,
3H, ArH), 7.25 (t, J1 = 7.2 Hz, 6H, ArH), 7.31-7.80 (m, 7H,
ArH), 8.20 (q, J1 = 4.4 Hz, 1H, ArH); MS (ESI) m/z: 437.21
(M+), calcd: 436.19.
R
O
H
NH2
R1
O
N
R
i
R
R
+
+
Reflux
N
O
R1
R2
1
i. CH3COONH4, Ceric ammonium nitrate, Methanol
R2
2a: R = H, R1 = H, R2 = CH3
2b: R = CH3, R1 = H, R2 = CH3
2c: R = H, R1 = H, R2 = Br
2d: R = CH3, R1 = Cl, R2 = H
2e: R = H, R1 = H, R2 = OH
2f: R = H, R1 = H, R2 = H
2g: R = CH3, R1 = H, R2 = Br
2a-g
Scheme-I: General synthesis of 1,2,4,5-tetrasubstituted imidazole analogues

2450 Bhadrachar et al.
Asian J. Chem.
1-(4-Bromophenyl)-4,5-bis(4-methylphenyl)-2-(naphth-
alen-1-yl)-1H-imidazole (2g): Pale brown; Yield: 79.10 %;
m.f.: C33H25N2Br; m.p: 225-228 ºC; IR (KBr, λmax, cm-1): 3048.91
(Ar-H), 2943.80 (C-CH3), 1613.16 (C=N), 1588.09 (C=C),
1335.46 (C-N), 773.31 (C-Br); 1H NMR (500 MHz, CDCl3) δ
ppm: 2.30 (s, 3H, -CH3), 2.32 (s, 3H, -CH3), 6.72-7.64 (m, 16H,
ArH) 7.75 (m, 2H, ArH, 8.18 (q, 1H, ArH); MS (ESI) m/z:
529.18 (M+), calcd:528.11.
was measured at 517 nm using butylated hydroxy anisole (BHA)
as a reference standard. Free radical scavenging activities were
calculated using the following formula:
Control OD−Sample OD
Free radical scavenging (%) =
×100
Sample OD
RESULTS AND DISCUSSION
The synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives
(2a-g) involves four components one pot reaction of 1-naphthal-
dehyde, aromatic amine, benzil analogue and ammonium acetate
in presence of ceric ammonium nitrate as a catalyst. Methanol
was found to be good solvent for the synthesis and product
yield in the range 68.28 to 89.40 % has been achieved after the
isolation. The structures of the synthesized compounds were
established on the basis of FT-IR, 1H NMR and mass spectral
data.All the title compounds showed a characteristic absorption
bands in the range between 1613-1595 cm-1 for C=N, 1337-
1332 cm-1 for C-N and 1598-1583 cm-1 for C=C stretching frequ-
Molecular docking study: in silico Molecular docking
study was performed by previously reported methods and using
receptor PDB ID: 3MNG, which obtained from RCSB Protein
Data Bank [29]. The receptor structure was prepared prior to
use in docking study using protein preparation module of HEX
modeling package 8.0. During the protein preparation, all
hetero and water molecules were removed from the crystal
structure except water molecules within 5 Å from the ligand.
All the molecules docked at the binding sites of the receptor
structures. The 3D structure of each ligand with the receptor
and binding interactions were visualized to optimization quality
by discovery studio 3.2. The in silico molecular docking scores
give useful information concerning the capability of the newly
synthesized compounds to bind the active sites of the receptor.
Thus the obtained docking score values guided us for performing
antioxidant activity by DPPH assay method.
Free radical scavenging activity by DPPH assay method:
Free radical scavenging activities of 1,2,4,5-tetrasubstituted
imidazoles (2a-g) were determined as per the reported method
[30]. Compounds have been dissolved first in DMSO and diluted
with methanol to get the concentrations 50, 100, 150, 200, 500
and1000 µg/mL. Methanolic solution (0.1mM, 5 mL) of 1,1-
diphenyl-2-picryl hydrazyl was added to the above stock solutions
and shaken vigorously. The solutions were allowed to stand at
room temperature for 20 min. The absorbance of the samples
1
encies of imidazole ring. H NMR spectrum supported the
structures of 1,2,4,5-tetrasubstituted imidazole derivatives and
exhibits a multiplet between 6.32-8.20 ppm for aromatic protons.
Further, the structures were confirmed from the mass analysis
in which the calculated mass values were well correlated with
the observed data.
The molecular docking of the synthesized compounds (2a-g)
was done with antioxidant receptor (PDB ID: 3MNG). The
binding energies of the compounds 2a-g with the receptors
were calculated using computational docking studies with HEX
8.0 engine. These docking energy values and possible interactions
are listed in Table-1. The antioxidant docking results showed
that there are possible good interactions between 2a, 2e and
2f. The compound 2e showed a stronger interaction with 3MNG
TABLE-1
BINDING INTERACTION OF LIGANDS OF 3MNG WITH COMPOUNDS 2a-g
Docking
score
(Kcal/mol)
Ligand interaction
Compounds
Hydrogen bond
Alkyl-alkyl
π-Lonepair
π-Alkyl
LEU 97, CYS 72, PHE 128,
GLY38, MET130, ALA, 71,
HE37, GY38
VAL 35, ARG 127,
VAL39, LEU 73, CYS 72
VAL 35, LEU 36, MET
130
-291.56
-289.42
-277.43
-280.48
-298.42
-292.09
PHE 128
2a
2b
2c
2d
2e
2f
SER 74, LEU 97, ARG95,
VAL70, MET 130, LEU36,
VAL 71, ARG 95, CYS72
ARG 95, LEU 36, VAL94,
LEU73, LEU125, PHE 55,
VAL 94, CYS 72
LEU 73, PHE 37
CYS72, PHE 37, ALA 71
LEU 127, LEU 110, ARG
95, VAL 35, PHE55, VAL
70, VAL 94
CYS72, PHE37,
GLY38
PHE 37, PHE128, SER
129
LEU 36, LEU110,
ALA71, CYS72, VAL70
PHE 15, ALA 98, VAL 39,
LEU73, CYS72, ARG 95,
SER 74, LEU 97, GLY38
CYS72, PHE 37, PHE
55, ASP99,
SER 74, MET 130
ASN 76, LYS 126,
LEU110, ASN 141, SER
129
VAL 35, LEU 36, GLY 38
PHE 37, CYS 72, SER74
ALA 71, VAL 35, CYS 72,
ARG 95, LEU 97, VAL 70,
VAL 35
ALA 98, PHE 37, ALA
71, CYS 72, ARG 95, SER
74
SER 129, LEU 36, PHE
37, LEU 125, LEU 110
SER 74, PHE 128, SER
129, LEU 36
ILE 9, VAL 14, PHE 15,
LEU 25, PHE 29, VAL 35,
SER 74, LEU 97
LEU 125, VAL131,
ARG127, PHE 128, SER
129, MET 130
LEU 36, PHE 37, GLY
38, VAL 39
CYS 47, HIS 51, PHE 55,
ALA 71, CYS 72, LEU 73
ALA71, CYS 72, LEU 73,
SER 74, VAL 75, TRP 84,
LEU 96, LEU 97
MET30, SER 129, GLY
38, LEU 25
PHE 37, SER 129, LEU
36, ALA 71
VAL 94, SER 129, LEU
36
-288.48
-183.02
2g
Standard
(BHT)a
–
–
–
–

Vol. 31, No. 11 (2019)
Synthesis and Radical Scavenging Activity of 1,2,4,5-Tetrasubstituted Imidazole Derivatives 2451
TABLE-2
receptor with lowest binding energy −298.42 kcal mol-1. The
compounds 2a, 2e and 2f are hydrogen bonded to LEU97,
CYS72, PHE128, GLY38, MET130, ALA71 and GLY 38 as
shown in Fig. 1.
The antioxidant activity of the title compounds was studied
by using DPPH scavenging assay method. The results of the
activity of compounds 2a-g are presented in Table-2. The anti-
oxidant activity has been compared with reference standard
BHA, compounds 2a, 2e and 2f exhibit good antioxidant activity
and moderate activity with respect to others.
PERCENTAGE OF FREE RADICAL SCAVENGIG
ACTIVITIES OF COMPOUNDS 2a-g
Concentration (µg/mL)
Compd.
50
100
150
33.5
200
500
1000
35.31
29.38
19.42
20.66
69.96
36.5
27.41
19.34
14.24
24.03
29.55
28.56
27.73
27.98
32.26
20.25
18.6
35.64
22.72
17.45
21.15
41.32
33.09
31.11
95.47
33.99
25.84
17.53
21.48
50.95
34.65
31.77
100
2a
2b
2c
2d
2e
2f
2g
BHA
21.15
17.28
20.82
37.94
33
20.33
34.16
33.58
31.11
42.8
Conclusion
32.26
60.08
32, 51
100
In this study, the synthesis of 1,2,4,5-tetrasubstituted imid-
azoles from one-pot synthesis using 1-naphthaldehyde, aromatic
2a
Interactions
Unfavourable bump
Pi-Sulfur
Pi-Pi Stacked
Alkyl
Pi-Alkyl
Pi-Lone pair
(b)
(a)
2e
Interactions
van der Waals
Pi-Pi Stacked
Pi-Alkyl
Unfavourable bump
(b)
(a)
2f
Interactions
van der Waals
Pi-Sulfur
Pi-Pi Stacked
Pi-Alkyl
Unfavourable bump
Carbon Hydrogen bond
(b)
(a)
Fig. 1. (a) Three dimension and (b) Two dimension binding interaction of the compounds 2a, 2e, 2f with ligands of receptor 3MNG

2452 Bhadrachar et al.
Asian J. Chem.
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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