Synthesis and analgesic activity of some 1-benzyl-2-substituted-4,5-diphenyl-1H-imidazole derivatives

Article abstract of DOI:10.1016/S0014-827X(01)01076-X

In this study, derivatives of 1-benzyl-2-substituted-4,5-diphenyl-1H-imidazole were synthesized and their analgesic activity assayed in two tests. 1,2,4,5-Tetrasubstituted imidazole compounds were obtained by the treatment of purified imidazole compounds with benzyl chloride in the presence of sodium hydride. The structure elucidation of the compounds was performed by IR, ¹H-NMR and mass spectroscopic data and elemental analysis results. Generally the prepared compound exhibited only moderate analgesic activity in mice at the dose of 100 mg/kg i.p.; however, a few of them exhibited good activity, almost equivalent to that of morphine at 1 mg/kg i.p. was observed. At the above dosage, no toxicity was observed for all compounds. Copyright

Full text of DOI:10.1016/S0014-827X(01)01076-X

www.elsevier.nl/locate/farmac
Il Farmaco 56 (2001) 285–290
Synthesis and analgesic activity of some
1-benzyl-2-substituted-4,5-diphenyl-1H-imidazole derivatives
8
:
Umit Uc¸ucu, Nalan Gu¨ndog˘du Karaburun *, Ilhan Is¸ikdag˘
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Uni6ersity of Anadolu, 26470 Eskis¸ehir, Turkey
Received 9 June 2000; accepted 10 January 2001
Abstract
In this study, derivatives of 1-benzyl-2-substituted-4,5-diphenyl-1H-imidazole were synthesized and their analgesic activity
assayed in two tests. 1,2,4,5-Tetrasubstituted imidazole compounds were obtained by the treatment of purified imidazole
compounds with benzyl chloride in the presence of sodium hydride. The structure elucidation of the compounds was performed
1
by IR, H-NMR and mass spectroscopic data and elemental analysis results. Generally the prepared compound exhibited only
moderate analgesic activity in mice at the dose of 100 mg/kg i.p.; however, a few of them exhibited good activity, almost
equivalent to that of morphine at 1 mg/kg i.p. was observed. At the above dosage, no toxicity was observed for all compounds.
© 2001 Elsevier Science S.A. All rights reserved.
Keywords: 1,2,4,5-Tetrasubstituted imidazole; Analgesic activity
1. Introduction
diphenyl imidazole compounds were stirred with NaH
in THF and refluxed by the addition of the benzyl
chloride for 3–45 h (Scheme 1).
Imidazole nucleus forms the main structure of some
well-known components of human organisms, i.e. the
amino acid histidine, Vit-B12, a component of DNA
base structure and purines, histamine and biotin. It is
also present in the structure of many natural or syn-
thetic drug molecules, i.e. cimetidine, azomycin and
metronidazole. Literature findings, especially on its
analgesic [1] and anti-inflammatory [2,3] activities, has
prompted us to synthesize similar compounds.
The structure elucidation of the prepared compounds
1
was performed by IR, H-NMR and mass spectral data
and elemental analyses.
3. Experimental
3.1. Chemistry
Melting points of the compounds were determined
using Stuart Scientific Smpl Melting Point apparatus
and were reported uncorrected. Thin-Layer-Chro-
matography was performed on silica gel 60 GF254 and
silica gel 60 G (Merck) (15:25) plates and spots were
visualized by UV lamp. IR spectra were detected in
KBr pellets using a Schimadzu-435 spectrophotometer.
2. Chemistry
For the syntheses of 2-substituted-4,5-diphenyl imi-
dazole derivatives, benzil and aldehyde derivatives were
reacted with ammonium acetate in glacial acetic acid as
described previously [4]. The obtained 2-substituted-4,5-
1
The H-NMR spectra were recorded in DMSO-d6 by
Jeol-JNM-EX90A spectrometers using tetramethylsi-
lane as an internal standard. Elemental analyses were
performed by Carlo-Erba 1106 Analyser and results for
C, H, N were within 90.4% of calculated values. All
the chemicals and solvents used in this study were of
analytical grade (Merck, Sigma and Aldrich).
* Corresponding author.
E-mail address: ngundogd@anadolu.edu.tr (N.G. Karaburun).
0014-827X/01/$ - see front matter © 2001 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(01)01076-X

8
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U. Uc¸ucu et al. / Il Farmaco 56 (2001) 285–290
Scheme 1.
3.1.1. General procedure for the synthesis of
mary testing the test was repeated with a group of six
animals. The analgesic activity was determined by me-
chanical (Tail-Clip) and thermal (52.5°C hot water)
methods as described previously [11,12]. A control re-
sponse was also obtained by the intraperitonial admin-
istration of DMSO alone. Injection volumes were not
more than 0.1 ml at each case. Latencies were measured
after 30 min of intraperitonial injections of compounds
at doses of 100 mg/kg and percent variation was calcu-
lated respect to control response. In order to avoid
irreversible damage to the tail structures of animals, a
maximum latency of 15 s was imposed for Tail-Clip
test, if no response occurred within that time (cutoff
time). The mean latency was calculated for each com-
pound. Using the latency, analgesia determined by both
mechanical and thermal methods was expressed as a
percentage of maximum effect where [12]:
1-benzyl-2-substituted-4,5-diphenyl-1H-imidazoles
2-Substituted-4,5-diphenyl imidazoles (0.01 mol) [4]
were stirred with 0.015 mol NaH in THF and refluxed
by the addition of the benzyl chloride (0.015 mol) for
3–45 h. The content of the reaction vessel was evapo-
rated. Residue was washed with water, dried and re-
crystallized from ethanol. Melting points and yields are
collected in Table 1. Spectral data of the compounds
are given in Table 2.
3.2. Pharmacology
3.2.1. Materials
For toxicity and analgesic activity tests, all com-
pounds were dissolved in dimethylsulfoxide (DMSO).
Morphine sulfate as opioid agonist and naloxone hy-
drochloride as opioid antagonist were used as pharma-
cological standards, similarly dissolved in DMSO.
postdrug latency−predrug latency
ꢀ
n
% Analgesia=
cutoff time−predrug latency
3.2.2. Acute lethal toxicity
×100
(1)
The method of Lorke [10] was used for acute lethal
toxicity tests. No mortality was observed after the
injection of a dose of 100 mg/kg. Therefore, only a
predictive LD50 value for each compound was calcu-
lated, i.e. LD50\100 mg/kg i.p.
The reference drugs, morphine sulfate and naloxone
hydrochloride, were used i.p. at doses of 1 and 0.4
mg/kg, respectively.
3.2.4. Analysis of data
3.2.3. Analgesic acti6ity
Results were expressed as means9standard error of
means. Statistical significance relative to controls were
determined by Tukey’s HSD test, with PB0.05. Statis-
tical calculations have been performed by Minitab
statistic program package (version 11.12).
Analgesic activity experiments were carried out using
Swiss albino mice of both sexes weighing 23–36 g. For
primary testing three animals were injected i.p. with
each compound; for the active compounds of the pri-

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U. Uc¸ucu et al. / Il Farmaco 56 (2001) 285–290
287
Table 1
Some characteristics of the compounds
Compound R1
Yield (%)
Experimental m.p. (°C)
Literature m.p. (°C)
Formula
Molecular mass
1
2
3
4
5
6
7
8
9
H
CH3
Ph
Ph–o-OH
Ph–m-OH
Ph–p-OH
Ph–o-OCH3
Ph–m-OCH3
Ph–p-OCH3
Ph–o-NO2
42
40
42
41
45
43
62
42
87
74
116
120
117–8 [5]
137–8 [5]
164 [6]
–
–
–
–
–
–
–
C22H18N2
C23H20N2
C28H22N2
C28H22N20 402.48
C28H22N20 402.48
310.38
324.41
386.48
160–2
147–8
130
134–5
187–90
128–9
153–5
166–7
C28H22N20 402.48
C29H24N2O 416.50
C29H24N2O 416.50
C29H24N2O 416.50
C28H21N3O2 431.47
10
11
12
Ph–m-NO2
Ph–p-NO2
47
63
115–6
–
–
C28H21N3O2 431.47
168–71
C28H21N3O2 431.47
13
14
Ph–p-N(CH3)2
Ph–3,4-(OCH2O)
52
82
155–7
148–50
–
–
C30H27N3
C29H22N2O2 430.49
429.54
15
16
17
Ph–o-Cl
Ph–m-Cl
Ph–p-Cl
48
54
49
144–7
152–4
162–6
–
–
–
C
28H21N2Cl 420.92
C28H21N2Cl 420.92
28H21N2Cl 420.92
C
18
19
20
21
Ph–o-CH3
Ph–m-CH3
Ph–p-CH3
Ph–o-Br
53
47
92
62
123–5
135–7
163–6
140–2
124–5 [7]
–
162 [8]
–
C29H24N2
C29H24N2
C29H24N2
400.50
400.50
400.50
C
28H21N2Br 465.37
C28H21N2Br 465.37
28H21N2Br 465.37
22
23
Ph–m-Br
Ph–p-Br
87
64
155–7
170–4
–
–
C
24
25
2-Furyl
Ph–m-OCH3, p-OH
52
45
156–8
243–7
156–7 [9]
–
C26H20N2O 376.44
C29H24N2O2 423.50
26
Ph–m,p-(OCH3)2
42
168
–
C30H26N2O2 446.53
27
28
Ph–o,p-(CH3)2
Ph–o,m,p-(OCH3)3
72
65
160–3
132–4
–
–
C
30H26N2
414.53
C31H28N2O3 476.55
4. Results and discussion
tivity. Better results were obtained at the Tail-
Clip algesic test, with about one third of assayed
compounds giving a moderate or good response.
Particularly compounds 4 and 10 ranged not far from
morphine. All compounds tested in the present
study were also found to have low lethal toxicity,
since their LD50 values were greater than 100 mg/kg
i.p.
4.1. Pharmacology
Results of Tail-Clip and thermal analgesic tests
were presented in Table 3. At the thermal algesic
test all compounds gave a rather poor response;
only compounds 21 and 25 exhibited a moderate ac-

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U. Uc¸ucu et al. / Il Farmaco 56 (2001) 285–290
288
Table 2
Spectral data of the compounds
Compound
IR (KBr, cm−1
)
1H-NMR (90 MHz) (DMSO-d6) l(ppm)
EI-MS (m/z)
1
2
3
4
1625, 1493 (CꢀN and CꢀC), 1357 (C–N),
722, 695 (monosubstituted benzene)
1599, 1521, 1493 (CꢀN and CꢀC), 1362 (C–N),
739, 694 (monosubstituted benzene)
1601, 1478, 1447 (CꢀN and CꢀC), 1350 (C–N),
770, 695 (monosubstituted benzene)
3408 (O–H), 1621, 1582, 1527 (CꢀN and CꢀC),
1390 (C–N), 1314, 1156 (C–O), 1225 (O–H), 774
(1,2-disubstituted benzene), 745, 695
5.14 (2H, s, –CH2–), 6.99–7.54 (15H, m,
Ar–H), 8.04 (1H, s, imidazole C2–H)
2.38 (3H, s, imidazole C2–CH3), 5.08 (2H,
s, –CH2–), 6.95–7.55 (15H, m, Ar–H)
5.15 (2H, s, –CH2–), 6.68–7.71 (20H, m,
Ar–H)
310, 219, 165, 116, 103, 91
(%100), 89, 77, 65
386, 295, 192, 165, 103, 91
(%100), 89, 77, 65
5.38 (2H, s, –CH2–), 7.18–8.20 (19H, m,
Ar–H), 11.696 (1H, s, OH)
(monosubstituted benzene)
5
6
3370 (O–H), 1601, 1495, 1446 (CꢀN and CꢀC),
5.11 (2H, s, –CH2–), 6.81–7.62 (19H, m,
1387 (C–N), 1268 (C–O), 1223, 1117 (O–H), 952, Ar–H), 11.65 (1H, s, OH)
861, 793 (1,3-disubstituted benzene), 732, 693
(monosubstituted
benzene)
3696 (O–H), 1607–1439 (CꢀN and CꢀC),
1383 (C–N), 1316–1228 (C–O), 1197–1128 (O–H), J=8.90, Ar–H C3–C5 of p-OH phenyl),
5.25 (2H, s, –CH2–), 7.16–7.26 (2H, d,
831 (1,4-disubstituted benzene),
735, 694 (monosubstituted benzene)
7.31–7.71 (15H, m, Ar–H), 8.08–8.17 (2H,
d, J=8.79, Ar–H C2–C6 of p-OH
phenyl), 12.58 (1H, s, OH)
7
8
9
1603–1441 (CꢀN and CꢀC), 1354 (C–N),
1253–1020 (C–O–C), 748 (1,2-disubstituted
benzene), 770, 702 (monosubstituted
benzene)
1600–1426 (CꢀN and CꢀC), 1351 (C–N),
1226, 1051 (C–O–C), 952, 886, 793
(1,3-disubstituted benzene), 724, 694
(monosubstituted benzene)
3.36 (3H, s, OCH3), 4.89 (2H, s, –CH2–),
7.05–7.40 (19H, m, Ar–H)
3.66 (3H, s, OCH3), 5.15 (2H, s, –CH2–),
6.75–7.51 (19H, m, Ar–H)
1605–1447 (CꢀN and CꢀC), 1349 (C–N),
1244, 1174, 1072 (C–O–C), 836 (1,4-disubstituted 6.69–7.50 (15H, m, Ar–H), 6.93–7.03 (2H, 77, 65
3.76 (3H, s, OCH3), 5.12 (2H, s, –CH2–), 416, 325, 103, 91 (%100), 89,
benzene), 770, 694 (monosubstituted benzene)
d, J=8.90, Ar–H C3–C5 of p-OCH3
phenyl), 7.52–7.62 (2H, d, J=8.90, Ar–H
C2–C6 of p-OCH3 phenyl)
10
1601, 1573 (CꢀN and CꢀC), 1523, 1355 (NꢀO),
5.02 (2H, s, –CH2–), 6.71–8.16 (19H, m,
1326 (C–N), 750 (1,2-disubstituted benzene), 729, Ar–H)
696 (monosubstituted
benzene)
11
12
1612, 1575 (CꢀN and CꢀC), 1523, 1349 (NꢀO),
1308 (C–N), 953, 812, 775 (1,3-disubstituted
benzene), 740, 700 (monosubstituted benzene)
1598–1549 (CꢀN and CꢀC), 1517, 1339
(NꢀO), 1291 (C–N), 772 (1,4-disubstituted
benzene), 732, 696 (monosubstituted
benzene)
5.22 (2H, s, –CH2–), 6.77–8.46 (19H, m,
Ar–H)
5.24 (2H, s, –CH2–), 6.72–7.53 (15H, m,
Ar–H), 7.92–8.02 (2H, d, J=9.13, Ar–H
C2–C6 of p-NO2 phenyl), 8.21–8.31 (2H,
d, J=9.01, Ar–H C3–C5 of p-NO2
phenyl)
13
14
1679–1490 (CꢀN and CꢀC), 1335 (C–N),
813 (1,4-disubstituted benzene), 763, 695
(monosubstituted benzene)
1622–1452 (CꢀN and CꢀC), 1353, 1330
(C–N), 1252, 1221, 1035 (C–O–C cyclic
ether), 876, 813 (1,2,4-trisubstituted
benzene), 762, 699 (monosubstituted
benzene)
3.00 (6H, s, N(CH3)2), 5.21 (2H, s,
–CH2–), 6.76–8.06 (19H, m, Ar–H)
5.12 (2H, s, –CH2–), 6.05 (2H, s,
–OCH2O–), 6.69–7.50 (18H, m, Ar–H)
15
16
1600–1460 (CꢀN and CꢀC), 1350 (C–N),
1069 (C–Cl), 760 (1,2-disubstituted
benzene), 777, 695 (monosubstituted
benzene)
1598–1453 (CꢀN and CꢀC), 1362–1329
(C–N), 1071 (C–Cl), 911, 830, 790
(1,3-disubstituted benzene), 756, 693
(monosubstituted benzene)
4.90 (2H, s, –CH2–), 6.67–7.57 (19H, m,
Ar–H)
5.16 (2H, s, –CH2–), 6.71–7.70 (19H, m,
Ar–H)

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289
Table 2 (Continued)
Compound
IR (KBr, cm−1
)
1H-NMR (90 MHz) (DMSO-d6) l(ppm)
EI-MS (m/z)
17
1600–1415 (CꢀN and CꢀC), 1357, 1333
(C–N), 1086 (C–Cl), 775 (1,4-disubstituted
benzene), 760, 692 (monosubstituted benzene)
1601–1445 (CꢀN and CꢀC), 1351 (C–N), 758
(1,2-disubstituted benzene), 775, 692
(monosubstituted benzene)
1603–1453 (CꢀN and CꢀC), 1356 (C–N),
913, 870, 805 (1,3-disubstituted benzene), 736,
693 (monosubstituted benzene)
1599–1450 (CꢀN and CꢀC), 1348 (C–N),
766 (1,4-disubstituted benzene), 730, 700
(monosubstituted benzene)
1601–1440 (CꢀN and CꢀC), 1355, 1334
(C–N), 1069 (C–Br), 750 (1,2-disubstituted
benzene), 771, 692 (monosubstituted
benzene)
5.15 (2H, s, –CH2–), 6.79–7.74 (19H, m, Ar–H)
18
19
20
21
2.19 (3H, s, CH3), 4.89 (2H, s, –CH2–),
6.52–7.51 (19H, m, Ar–H)
2.39 (3H, s, CH3), 5.23 (2H, s, –CH2–),
6.78–7.55 (19H, m, Ar–H)
2.40 (3H, s, CH3), 5.23 (2H, s, –CH2–),
6.77–7.68 (19H, m, Ar–H)
4.88 (2H, s, –CH2–), 6.69–7.75 (19H, m, Ar–H)
22
1598–1453 (CꢀN and CꢀC), 1362 (C–N),
1068 (C–Br), 886, 818, 790 (1,3-disubstituted
benzene), 724, 693 (monosubstituted
benzene)
5.16 (2H, s, –CH2–), 6.73–7.83 (19H, m, Ar–H)
23
24
25
1620–1445 (CꢀN and CꢀC), 1357 (C–N),
1068 (C–Br), 829 (1,4-disubstituted benzene),
774, 692 (monosubstituted benzene)
1599, 1492 (CꢀN and CꢀC), 1335 (C–N),
1025 (C–O furyl), 762, 695 (monosubstituted
benzene)
3845 (O–H), 1600, 1543, 1509 (CꢀN and
CꢀC), 1350 (C–N), 1257, 1219 (O–H), 1177,
1141 (C–O Ar–O–CH3), 1069, 1027 (C–O
Ar–OH), 912, 763 (1,2,4-trisubstituted
benzene), 730, 694 (monosubstituted
benzene)
5.15 (2H, s, –CH2–), 6.796–7.811 (19H, m,
Ar–H)
4.89 (2H, s, –CH2–), 6.87–7.67 (18H, m, Ar–H)
3.52 (3H, s, OCH3), 5.17 (2H, s,–CH2–),
6.82–7.65 (18H, m, Ar–H), 12.54 (1H, s, OH)
26
1691, 1528 (CꢀN and CꢀC), 1352, 1322
(C–N), 1174, 1143, 1020 (C–O Ar–O–CH3),
915, 807 (1,2,4-trisubstituted benzene), 728,
697 (Monosubstituted benzene)
3.21 (3H, s, OCH3), 3.59 (3H, s, OCH3), 5.13
(2H, s, –CH2–), 7.12–7.40 (18H, m, Ar–H)
27
28
1599–1470 (CꢀN and CꢀC), 1347 (C–N),
915, 796 (1,2,4-trisubstituted benzene), 728,
691 (Monosubstituted benzene)
1602–1449 (CꢀN and CꢀC), 1353 (C–N),
1291, 1228, 1094 (C–O–C), 868
2.36 (3H, s, CH3), 2.49 (3H, s, CH3), 5.08 (2H,
s, –CH2–), 6.78–7.65 (18H, m, Ar–H)
3.73–3.81 (9H, t, OCH3), 4.92 (2H, s, –CH2–),
6.62–7.44 (17H, m, Ar–H)
(1,2,3,4-tetrasubstituted benzene), 757, 694
(Mono substituted benzene)
Acknowledgements
Research Center for spectral analyses of the com-
pounds. We acknowledge the members of Anadolu
University, Department of Pharmacology for pharma-
cological tests.
We are grateful to the facilities of Eskisehir Anadolu
University Medicinal and Aromatic Plant and Drug
.

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290
Table 3
Analgesic activities of the compounds
Compound
Thermal algesic test
Mechanical (Tail-Clip) algesic test
% Analgesia
Standard error
% Analgesia
Standard Error
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
5.02
−9.38
8.31
17.23
12.19
2.93
−0.99
14.55
−6.06
9.21
8.30
4.58
2.99
16.80
10.60
2.46
2.98
16.20
6.35
7.05
3.24
6.19
8.97
0.53
10.00
3.57
8.30
5.20
5.92
3.05
13.30
6.82
3.62
2.38
7.75
2.56
6.16
6.15
17.40
2.25
28.03
–
14.22
46.15
−4.10
2.23
36.20
–
9.10
21.01
6.32
1.95
3.03
8.49
16.70
16.70
20.80
17.40
3.85
4.95
2.38
11.90
5.30
11.40
15.80
0.65
2.38
4.76
5.98
5.13
20.50
6.44
3.98
3.01
17.00
10.00
−0.91
8.49
20.20
45.51
35.60
15.44
3.85
0.79
6.09
−4.84
19.76
−13.89
3.57
12.10
10.32
−0.03
8.26
26.41
14.70
−3.51
2.38
22.74
−2.56
8.83
2.20
2.38
23.81
−5.37
13.10
28.85
0.70
2.38
4.76
7.86
−5.13
35.49
2.20
−5.27
−5.76
67.20
18.00
3.02
70.20
12.40
Morphine
Morphine+naloxone
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