Synthesis of novel tetrahydroimidazole derivatives and studies for their biological properties

Article abstract of DOI:10.1016/S0223-5234(01)01256-9

Ethylenediamine was reacted with suitable aromatic aldehydes in order to prepare their respective diSchiff bases. These compounds were then reduced to give the corresponding tetrahydrodiSchiff bases, which were low melting in nature. Finally, these derivatives were condensed with different aromatic aldehydes to give the desired tetrahydroimidazoles. The structures of all these compounds were established on the basis of spectral data. These novel tetrahydroimidazoles showed promising anti-inflammatory and analgesic activity. The compounds were also screened for their anti-bacterial property against Staphylococcus aureus and Escherichia coli.

Full text of DOI:10.1016/S0223-5234(01)01256-9

Eur. J. Med. Chem. 36 (2001) 651–658
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01256-9/FLA
Original article
Synthesis of novel tetrahydroimidazole derivatives and studies for their
biological properties
Vibha Sharma*, M.S.Y. Khan
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi, India
Received 19 June 2000; revised 18 June 2001; accepted 19 June 2001
Abstract – Ethylenediamine was reacted with suitable aromatic aldehydes in order to prepare their respective diSchiff bases. These
compounds were then reduced to give the corresponding tetrahydrodiSchiff bases, which were low melting in nature. Finally, these
derivatives were condensed with different aromatic aldehydes to give the desired tetrahydroimidazoles. The structures of all these
compounds were established on the basis of spectral data. These novel tetrahydroimidazoles showed promising anti-inflammatory
and analgesic activity. The compounds were also screened for their anti-bacterial property against Staphylococcus aureus and
´
Escherichia coli. © 2001 Editions scientifiques et me´dicales Elsevier SAS
diSchiff base / tetrahydrodiSchiff base / tetrahydroimidazole / anti-inflammatory / analgesic
1. Introduction
except that derived from salicylaldehyde were semi-
solid in character, Finally these derivatives were con-
densed with aromatic aldehydes to give new
functional derivatives of N,N%-di-aryl-methyl-2-(4-di-
ethylamino phenyl) tetrahydroimidazole and N,N%-di-
4-diethylamino benzyl-2-(aryl) tetrahydroimidazole
derivatives.
A diversity of useful biological effects is possessed
by heterocyclic compounds containing the five-mem-
bered imidazole nucleus. A variety of drugs from
anti-microbials (metronidazole, ketocanazole), car-
diovascular (clonidine, naphazoline), centrally active
(benperidol, fenmetozole) to anti-cancer (dacarbazine,
misonidazole) are examples of this. The ring system
itself is primarily a molecular scaffold upon which
characteristic pharmacophores for various receptors
are assembled. In view of the wide spectrum of useful
biological activities of imidazole compounds further
exploratory synthesis of compounds built up on imi-
dazole skeleton was done. Present studies were
devoted to the syntheses and pharmacological evalua-
tion of tetrahydroimidazoles. These compounds have
been an area of considerable recent research [1–8]. In
the study, aromatic aldehydes were reacted with
ethylenediamine to give their respective diSchiff bases,
which were reduced with sodium borohydride to form
tetrahydrodiSchiff bases, All tetrahydrodiSchiff bases
2. Chemistry
The synthesis of N,N%-di-aryl-methyl-2-(4-diethyl-
amino phenyl) tetrahydroimidazole and N,N%-di-4-di-
ethylamino benzyl-2-(aryl) tetrahydroimidazole has
been carried out following the steps shown in figure 1.
In the first step, aromatic aldehydes were reacted
with ethylenediamine to give their respective diSchiff
bases, 1, 4, 7, 10, 13, 16, 19, 22, 25, 28 and 31.
Reduction of the diSchiff bases by sodium borohy-
dride (step II) gave tetrahydrodiSchiff bases 2, 5, 8,
11, 14, 17, 20, 23, 26, 29 and 32. The compounds
obtained were viscous in nature except the compound
29, which was crystalline. The tetrahydrodiSchiff
bases were condensed with different aromatic alde-
hydes in step III to obtain the desired tetrahydroimi-
* Correspondence and reprints
E-mail address: vibhasharma@worldnet.att.net (V. Sharma).

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V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
dazole derivatives 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33,
34, 35, 36 and 37. For step III, two methods were
followed as described in Section 5. Physico-chemical
data for the synthesized compounds are summarized
in tables I and II.
pounds with significant activity were 6, 15, and 30.
These compounds were compared with the standard
indomethacin at a dose of 20 mg kg−1 i.p.
4.2. Analgesic activity
The synthesized compounds were tested for their po-
tential analgesic effect by comparing with aspirin at a
dose of 25 mg kg−1 i.p. at three time points. Compound
21 showed maximum activity at 30 and 60 min. The
compounds 35, 12, 18, 9 and 37 showed significant good
activity as compared to the standard.
3. Pharmacology
The synthesized tetrahydroimidazole derivatives
were tested for their anti-inflammatory and analgesic
potential. The anti-inflammatory activity of the com-
pounds as measured by their ability to inhibit car-
rageenan-induced edema in rats, is given in table III.
The compounds were evaluated for their analgesic
activity by tail immersion method in mice at three
time points. These derivatives were also casually
tested for any hint of potential anti-bacterial activity
against ATCC strains of Staphylococcus aureus and
Escherichia coli at a dose of 100 mg mL−1, as reported
in table III.
4.3. Anti-bacterial activity
Twelve compounds of tetrahydroimidazole series were
screened for their anti-bacterial activity against ATCC
strains of both S. aureus and E. coli bacteria. Com-
pound 36 showed good activity against both the strains
while other tested compounds exhibited a degree of
microbial inhibition against S. aureus. The compounds
were compared with norfloxacin at the concentration of
100 mg mL−1 with dimethyl formamide (DMF) as
control.
4. Results and discussion
4.1. Anti-inflammatory activity
5. Experimental protocols
Fourteen compounds were screened for their anti-in-
flammatory activity. Percent inhibition was computed
by comparing individual values in treatment groups to
the mean value of the control group. The compound 21
showed maximum percentage reduction in edema vol-
ume followed by compounds 9 and 37. Other com-
5.1. Chemistry
Melting points of all the compounds were taken on a
liquid paraffin bath in open capillary tubes and are
uncorrected. Purity of the compounds was tested on thin
Figure 1. Steps involved in the synthesis of tetrahydroimidazole.

V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
Table 1. Physico-chemical data of diSchiff and tetrahydrodiSchiff compounds.
653
layer chromatography (TLC) plates (silica gel G.E.
Merck) in the solvent system benzene–ethanol (8:2).
The spots were located under UV light and/or by expo-
on 60, 90 or 300 MHz instruments using Me4Si as an
internal standard. The chemical shift values have been
recorded in l values. Mass spectra of the compounds
were recorded on JEOL JMS-D 300 instruments.
1
sure to iodine vapors. H-NMR spectra were recorded

654
V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
Table II. Physico-chemical data of tetrahydroimidazoles.
Compound R, R%
R%%
Yield (%)
M.P. (°C)
Formula
3
Phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
2-methoxy phenyl
65
77
76
70
78
70
79
70
70
62
69
76
78
76
79
80-2
146
102
148
126
100
140
86
104
156
60
68
98-102
80
C27H33N3
6
2-methoxy phenyl
4-methoxy phenyl
3,4,5-trimethoxy phenyl
2-chloro phenyl
4-chloro phenyl
4-dimethyl amino phenyl
2-thienyl
3, 4-methylene dioxy phenyl
2-hydroxy phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
4-diethylamino phenyl
C29H37N3O2
C29H37N3O2
C33H45N3O6
C27H31N3Cl2
C27H31N3Cl2
C31H43N5
C23H29N3S2
C29H33N3O4
C27H33N3O2
C32H44N4O
C31H41N4Cl
C31H41N4Cl
C32H42N4O2
C33H47N5
9
12
15
18
21
24
27
30
33
34
35
36
37
2-chloro phenyl
4-chloro phenyl
3, 4-methylene dioxy phenyl
4-dimethyl amino phenyl
80
Table III. Anti-inflammatory, analgesic and anti-bacterial properties of tetrahydroimidazoles.
Compound Anti-inflammatory activity
Percentage inhibition against
Analgesic activity
Tail flick latency
Anti-bacterial activity
Cup plate method
carrageenan induced edema
At 60 min
At 180 min
At 30 min
At 60 min
At 120 min
Escherichia
coli (ATCC) (ATCC)
Staphylococcus aureus
3
0
60
90
20
68
15
93
63
15
65
50
47
48
87
40
4
75
82
7
61
0
96
46
10
64
50
7
77
93
64
3.2591.5
3.3391.5
593.56
2.2590.5
3.591.3
2.891.26
2.7590.957
3.191.64
3.7591.5
2.7591.26
4.2590.95
3.7591.5
3.2591.26
3.7591.5
3.091.15
2.2590.96
4.2594.72
2.7590.95
3.090.82
5.291.3
++
++
++
+
+
NS
NS
++
+
−
+
+++
+++
++
+++
+++
NS
6
9
593.37
12
6.2590.96
3.2590.95
4.090.82
5.2591.26
4.2590.96
4.590.58
3.2591.5
3.2591.26
5.092.8
3.590.58
2.590.58
5.092.2
7.6796.66
3.590.58
3.891.7
3.591.73
2.2591.5
7.592.08
3.7591.5
4.2591.5
4.090.82
15
18
21
NS
++
24
27
+++
+++
+++
+++
+++
+++
+++
30
33
35
+
+++
+
36
3.592.08
4.7590.96
3.590.58
37
Standard
+++
Zone of inhibition observed (+); no zone of inhibition observed (−). Zone of inhibition: +, 7–9 cm; ++, 10–13 cm; +++, 14
cm and above; NS, not screened.

V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
655
5.1.1. General procedure for the synthesis of diSchiff
5.1.1.8. Di-3,4-methylene dioxy benzylidene
ethylenediamine (25)
base from ethylenediamine and an appropriate aldehyde
A solution of an appropriate aromatic aldehyde (0.02
mol) and ethylenediamine (in slight excess of molar
ratio) in dry benzene (50 mL)with a small quantity of
1H-NMR (CDCl3), l ppm: 3.87(s, 4H, 2×CH2), 6.0
(s, 4H, 2×OCH2O), 6.8 (d, J=8 Hz, 2H, H-5,5%), 7.058
(dd, J=1.5, 9 Hz, 2H, H-6,6%), 7.58 (d, 2H, H-2,2%), 8.15
(s, 2H, aldimine protons).
,
molecular sieves (4 A) was refluxed azeotropically with
Dean–Stark apparatus. After complete removal of wa-
ter the reaction mixture was refluxed for further 7 h or
until TLC showed the reaction to be complete. On
completion of reaction, excess benzene was distilled off.
5.1.1.9. Di-2-hydroxy benzylidene ethylenediamine (28)
1H-NMR (CDCl3), l ppm: 3.87 (s, 4H, 2×CH2), 6.8
(dt, 2H, H-5,5%), 6.94 (dd, 2H, H-3,3%), 7.18 (dd, 2H,
H-6,6%), 7.27 (m, 2H, H-4,4%), 8.3 (s, 2H, aldimine
protons).
A
solid mass so obtained was crystallized from
methanol.
5.1.1.10. Di-4-diethylamino benzylidene ethylenediamine
(31)
5.1.1.1. Dibenzylidene ethylenediamine (1)
1H-NMR (CDCl3), l ppm: 3.95 (s, 4H, 2×CH2),
7.35(m, 6H, H aromatic), 7.67 (m, 4H, H aromatic),
8.25 (s, 2H, aldimine protons).
1H-NMR (CDCl3), l ppm: 1.13 (t, 12H, 4×CH2CH3),
3.34 (q, 8H, 4×CH2CH3), 3.85 (s, 4H, 2×CH2), 6.61 (d,
4H, A2/B2 pattern, H aromatic), 7.56 (d, J=9 Hz, 4H,
A2/B2 pattern, H aromatic), 7.56 (s, 2H, aldimine
protons).
5.1.1.2. Di-4-methoxy benzylidene ethylenediamine (7)
1H-NMR (CDCl3), l ppm: 3.77(s, 6H, 2×OCH3),
3.90 (s, 4H, 2×CH2), 6.87 (d, 4H, A2/B2 pattern, H
aromatic), 7.62 (d, 4H, A2/B2 pattern, H aromatic),
8.25( s, 2H, aldimine protons).
5.1.2. General procedure for synthesis of
tetrahydrodiSchiff’s base from diSchiff’s base
DiSchiff base (1.0 g) was dissolved in a mixture of
methanol (15 mL) and dichloromethane (10 mL). A
solution of sodium borohydride (0.5 g) in 2 N NaOH (1
mL) after dilution with distilled water (6 mL) was added
dropwise to the solution of diSchiff base with constant
magnetic stirring under ice-cold conditions to keep the
temperature of the reaction mixture below 18 °C. The
contents were stirred for 7 h or until TLC showed the
reaction to be complete. After completion of the reac-
tion, the solvent was distilled off and the residue diluted
with water and extracted with ether. The ethereal layer
was dried over sodium sulfate, filtered to remove inor-
ganic salt and ether was distilled off to give the expected
compound. The compounds obtained were semi-solid in
nature with the exception of tetrahydrodiSchiff base,
N,N%-di-2-hydroxy benzyl ethylenediamine (29).
5.1.1.3. Di-3,4,5-trimethoxy benzylidene ethylenediamine
(10)
1H-NMR (CDCl3), l ppm: 3.88 (s, 18H, 6×OCH3),
3.94 (s, 4H, 2×CH2), 6.95(s, 4H, H aromatic), 8.17(s,
2H, aldimine protons).
5.1.1.4. Di-2-chloro benzylidene ethylenediamine (13)
1H-NMR (CDCl3), l ppm: 4.03 (s, 4H, 2×CH2), 7.9
(m, 8H, H aromatic), 8.72(s, 2H, aldimine protons).
5.1.1.5. Di-4-chloro benzylidene ethylenediamine (16)
1H-NMR (CDCl3), l ppm: 3.95(s, 4H, 2×CH2),
7.34(d, 4H, H aromatic), 7.63 (d, J=9 Hz, 4H, H
aromatic), 8.22(s, 2H, aldimine protons).
5.1.1.6. Di-4-dimethylamino benzylidene ethylenediamine
(19)
5.1.2.1. N,N%-di-2-hydroxy benzyl ethylenediamine (29)
1H-NMR (CDCl3), l ppm: 2.80 (s, 4H, 2×CH2), 3.96
(s, 4H, 2×NCH2), 6.7 (dt, 2H, H-5,5%), 6.83 (dd, 2H,
H-3,3%), 6.97 (dd, 2H, H-6,6%), 7.16 (dt, 2H, H-4,4%).
1H-NMR (CDCl3), l ppm: 2.97(s, 12H, 4×CH3), 3.66
(s, 4H, 2×CH2), 6.64 (d, 4H, A2/B2 pattern, H aro-
matic), 7.56(d, 4H, J=9 Hz, A2/B2 pattern, H aro-
matic), 8.15 (s, 2H, aldimine protons).
5.1.3. General procedure for the synthesis of
tetrahydroimidazole from tetrahydrodiSchiff’s base
5.1.1.7. Di-2-thienylidene ethylenediamine (22)
1H-NMR (CDCl3), l ppm: 3.88 (s, 4H, 2×CH2), 6.9
(m, 2H, H-4,4%), 7.2(m, 2H, H-5,5%), 7.33(m, 2H, H-3,3%),
8.15 (s, 2H, aldimine protons).
5.1.3.1. Method 1
TetrahydrodiSchiff base (2 mmol) was dissolved in
ethanol (which had been purified by distilling over

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V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
NaOH) (15mL) in a test tube. To this solution was
added an appropriate aromatic aldehyde (2 mmol). The
test tube was shaken on a wrist action shaker till a solid
mass separated out which was filtered and washed with
ether. It was crystallized from ethanol.
2H, A2/B2 pattern, H aromatic), 6.77 (d, 4H, A2/B2
pattern, p-anisidine moiety), 7.18 (d, 4H, A2/B2 pattern,
p-anisidine moiety). Molecular formula C29H37N3O2
(M+) 459, m/z 338, 310, 189, 162 and 121.
5.1.3.6. N,N%-di-3,4,5-trimethoxy
5.1.3.2. Method 2
benzyl-2-(4-diethylamino phenyl) tetrahydroimidazole
(12)
TetrahydrodiSchiff base (2 mmol) and an appropriate
aldehyde (2 mmol) were taken in dry benzene (50 mL) in
a round-bottom flask. A Dean–Stark apparatus was
fitted on the flask along with an air condenser. The
reaction mixture was refluxed to remove water azeotrop-
ically. The Dean–Stark apparatus was dismantled after
complete removal of water and the reaction mixture was
refluxed for further 7 h for completion of the reaction.
Benzene was then distilled off and a solid mass so
obtained was crystallized to give the expected tetrahy-
droimidazole derivative.
1H-NMR (CDCl3), l ppm: 1.16 (t, 6H, 2×CH3CH2),
3.25 (q, 4H, 2×CH3CH2), 2.5, 3.2 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.14, 3.71 (d, 4H, 2×CH2 benzyl),
3.79 (s, 19H, 6×OCH3, CH tetrahydroimidazole), 6.48
(d, 4H, H-2,2%, 6,6%), 6.68, (d, 2H, A2/B2 pattern, H
aromatic), 7.42 (d, 2H, A2/B2 pattern, H aromatic).
Molecular formula C33H45N3O6 (M+) 579, m/z 550, 431,
400 and 398.
5.1.3.7. N,N%-di-2-chloro benzyl-2-(4-diethylamino
phenyl) tetrahydroimidazole (15)
5.1.3.3. N,N%-dibenzyl-2-(4-diethylamino phenyl)
tetrahydroimidazole (3)
1H-NMR (CDCl3), l ppm: 1.14 (t, 6H, 2×CH3CH2),
3.33 (q, 4H, 2×CH3CH2), 2.5, 3.2 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.45, 3.76 (d, 4H, 2×CH2 benzyl),
3.87 (s, 1H, CH tetrahydroimidazole), 6.68 (d, 2H,
A2/B2 pattern, H aromatic), 7.42 (d, 2H, A2/B2 pattern,
H aromatic), 7.17 (m, 6H, H-4,4%, H-5,5%, H-6,6%), 7.53
(dd, 2H, H-3,3%).
Molecular formula: C27H31N3Cl2, a cluster of peaks
were located at m/z 467, 469 and 471 due to the
presence of two chlorine atoms in the molecule. The
other peaks could be located at m/z 342, 323/321/319,
189 and 125/126.
1H-NMR (CDCl3), l ppm: 1.15 (t, 6H, 2×CH3CH2),
3.32 (q, 4H, 2×CH3CH2), 2.42 (m, 2H, CH2 tetrahy-
droimidazole), 3.10 (m, 2H, CH2 tetrahydroimidazole),
3.12 (d, 2H, CH2 benzyl), 3.84 (d, 2H, CH2 benzyl), 3.69
(s, H, CH tetrahydroimidazole), 6.67 (d, 2H, A2/B2
pattern, H aromatic), 7.44 (d, 2H, A2/B2 pattern, H
aromatic), 7.22 (m, H aromatic). Molecular formula
C27H33N3 (M+) 399, m/z 309, 252, 190, 163.
5.1.3.4. N,N%-di-2-methoxy benzyl-2-(4-diethylamino
phenyl) tetrahydroimidazole (6)
1H-NMR (CDCl3), l ppm: 1.109 (t, 6H, 2×CH3CH2),
3.30 (m, 4H, 2×CH3CH2), 2.45, 3.30(m, 4H, 2×CH2
tetrahydroimidazole), 3.4 (d, 2H, CH2 benzyl), 3.67 (d,
2H, CH2 benzyl), 3.7 (s, 6H, 2×OCH3), 3.8 (s, H, CH
tetrahydroimidazole), 6.62 (d, 2H, H-3,3%), 6.72 (d, 2H,
p-disubst. phenyl ring), 6.68 (m, 2H, H-5,5%), 7.11(m,
2H, 4,4%), 7.42 (m, 4H, H-6,6% and protons of p-disubst.
phenyl ring). Molecular formula C29H37N3O2 (M+) 459,
m/z 338, 310, 189, 162, 121.
5.1.3.8. N,N%-di-4-chloro benzyl-2-(4-diethylamino
phenyl) tetrahydroimidazole (18)
1H-NMR (CDCl3), l ppm: 1.13 (t, 6H, 2×CH3CH2),
3.33 (q, 4H, 2×CH3CH2), 2.38, 3.09 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.74 (m, 4H, 2×CH2 benzyl), 3.66
(s, 1H, CH of tetrahydroimidazole), 6.66, 7.39 (d, 4H,
J=9 Hz, A2/B2 pattern, H aromatic), 7.19 (s, 8H,
protons of p-chloro phenyl ring).
5.1.3.9. N,N%-di-4-dimethylamino benzyl-2-
5.1.3.5. N,N%-di-4-methoxy benzyl-2-(4-diethylamino
phenyl) tetrahydroimidazole (9)
(4-diethylamino phenyl) tetrahydroimidazole (21)
1H-NMR (CDCl3), l ppm: 1.17 (t, 6H, 2×CH3CH2),
3.36 (q, 4H, 2×CH3CH2), 2.89(s, 12H, 4×CH3), 2.4–3.7
(m, 9H, 2×CH2 benzyl, 2×CH2, CH of tetrahydroimi-
dazole), 6.65 (d, 8H, A2/B2 pattern, H aromatic), 6.69,
7.14 (d, 4H, A2/B2 pattern, H aromatic). Molecular
formula C31H43N5 (M+) 485, m/z 364, 351, 203, 189, 162
and 134.
1H-NMR (CDCl3), l ppm: 1.17 (t, 6H, 2×CH3CH2),
3.34 (q, 4H, 2×CH3CH2), 2.40 (m, 2H, CH2 tetrahy-
droimidazole,), 3.11 (m, 2H, CH2 tetrahydroimidazole),
3.08 (m, 2H, CH2 benzyl), 3.75 (m, 2H, CH2 benzyl), 3.8
(s, 6H, 2×OCH3), 3.64 (s, 1H, CH of tetrahydroimida-
zole), 6.68 (d, 2H, A2/B2 pattern, H aromatic), 7.42 (d,

V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
657
5.1.3.10. N,N%-di-2-thienylmethyl-2-(4-diethylamino
phenyl) tetrahydroimidazole (24)
8H, A2/B2 pattern, H aromatic), 7.30 (m, 3H, H-4¦,
H-5¦, H-6¦), 8.04(dd, 1H, H-3¦).
1H-NMR (CDCl3), l ppm: 1.13 (t, 6H, 2×CH3CH2),
3.30 (q, 4H, 2×CH3CH2), 2.54, 3.25 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.51, 3.87 (d, 4H, 2×CH2 benzyl),
3.77 (s, 1H, CH of tetrahydroimidazole), 6.67, 7.42 (d,
4H, A2/B2 pattern, H aromatic), 6.86 (m, 4H, H-3,3%,
H-4,4%), 7.14 (d, 2H, H-5,5%). Molecular formula
C23H29N3S2 (M+) 411, m/z 314, 263, 189, 162 and 97.
5.1.3.15. N,N%-di-4-diethylamino benzyl-2-(4-chloro
phenyl) tetrahydroimidazole (35)
1H-NMR (CDCl3), l ppm: 1.09 (t, 12H, 4×CH3CH2),
3.26 (q, 8H, 4×CH3CH2), 2.48, 3.17 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.15, 3.63 (d, 4H, 2×CH2 benzyl),
3.7 (s, 1H, CH), 8.5, 7.02 (d, 8H, A2/B2 pattern, H
aromatic), 7.31, 7.52 (d, 4H, A2/B2 pattern, H aromatic).
Molecular formula C31H41N4Cl (M+) 504, m/z 393, 355,
342, 189, 162, 147 and 118.
5.1.3.11. N,N%-di-3,4-methylene dioxy
benzyl-2-(4-diethylamino phenyl tetrahydroimidazole
(27)
1H-NMR (CDCl3), l ppm: 1.16 (t, 6H, 2×CH3CH2),
3.33 (q, 4H, 2×CH3CH2), 2.41, 3.13 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.05, 3.70 (d, 4H, 2×CH2 benzyl),
3.62 (s, 1H, CH of tetrahydroimidazole), 5.87 (s, 4H,
2×OCH2O), 6.65, 7.39 (d, 4H, A2/B2 pattern, H aro-
matic), 6.78 (d, 2H, H-2,2%), 6.67 (m, 4H, H-3,3%, 6,6%).
Molecular formula C29H33N3O4 (M+) 487, m/z 352, 339,
189, 162 and 77.
5.1.3.16. N,N%-di-4-diethylamino benzyl-2-
(3,4-methylene dioxy phenyl) tetrahydroimidazole (36)
1H-NMR (CDCl3), l ppm: 1.12 (t, 12H, 4×CH3CH2),
3.28 (q, 8H, 4×CH3CH2), 4.49, 3.12 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.05, 3.68 (m, 4H, 2×CH2 ben-
zyl), 3.67 (s, 1H, CH of tetrahydroimidazole), 5.95 (s,
2H, OCH2O), 6.56, 7.01 (d, 8H, A2/B2 pattern, H aro-
matic), 6.74(d, 1H, H-5¦), 6.94(dd, 1H, H-6¦), 7.26 (d,
1H, H-2¦). Molecular formula C32H42N4O2 (M+) 514,
m/z 393, 379, 366, 352, 295, 203, 162, 147 and 118.
5.1.3.12. N,N%-di-2-hydroxybenzyl-2-(4-diethylamino
phenyl) tetrahydroimidazole (30)
1H-NMR (CDCl3), l ppm: 1.13 (t, 6H, CH3CH2),
3.30 (q, 4H, CH3CH2), 2.58, 3.30 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.2, 4.07 (m, 4H, 2×CH2 benzyl),
6.66, 7.3(d, 4H, A2/B2 pattern, H aromatic), 6.93 (dd,
2H, H-3,3%), 7.12 (dt, 2H, H-4,4%), 6.7 (dt, 2H, H-5,5%),
6.8(dd, H-6,6%). Molecular formula C27H33N3O2 (M+)
431, m/z, 324, 283, 189, 162, 107 and 77.
5.1.3.17. N,N%-di-4-diethylamino benzyl-2-
(4-dimethylamino phenyl) tetrahydroimidazole (37)
1H-NMR (CDCl3), l ppm: 1.07 (t, 12H, 4×CH3CH2),
3.27 (q, 8H, 4×CH3CH2), 2.43, 3.13 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.06, 3.6 (d, 4H, 2×CH2 benzyl),
3.65 (s, 1H, CH of tetrahydroimidazole), 6.55, 7.06 (d,
8H, A2/B2 pattern, H aromatic), 6.75, 7.48 (d, 4H, H
aromatic). Molecular formula C33H47N5 (M+) 513, m/z
393, 379, 364, 351, 295 and 162.
5.1.3.13. N,N%-di-4-diethylamino benzyl-2-(2-methoxy
phenyl) tetrahydroimidazole (33)
1H-NMR (CDCl3), l ppm: 1.11 (t, 12H, 4×CH3CH2),
3.26 (q, 8H, 4×CH3CH2), 2.49, 3.26 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.13, 3.64(d, 4H, 2×CH2 benzyl),
3.61 (s, 1H, CH of tetrahydroimidazole), 3.80 (s, 3H,
OCH3), 6.54, 7.05 (d, 8H, A2/B2 pattern, H aromatic),
6.8 (dd, 1H, H-3¦), 7.02 (m, 1H, H-5¦), 7.24(dt, 1H,
H-4¦), 8.0 (dd, 1H, H-6¦). Molecular formula
C32H44N4O (M+) 500, m/z 394, 352, 296, 204, 190, 162
and 118.
5.2. Biology
5.2.1. Study of the anti-inflammatory activity
Study of the anti-inflammatory activity was carried
out according to Winter’s method [9].
The studies were carried out on healthy rats of either
sex, weighing between 120 and 200 g. All the test
compounds and drugs were suspended in 2% gum acacia
and were prepared on the day of experiment. The ani-
mals were weighed, numbered and divided into different
groups comprising six rats in each group. A mark was
made on the left hind paw to ensure constant paw
volume. The initial paw volume of each animal was
measured by the mercury displacement method. In one
group, normal saline was injected which acted as control
and to the other groups, the test compounds and stan-
5.1.3.14. N,N%-di-4-diethylamino benzyl-2-(2-chloro
phenyl) tetrahydroimidazole (34)
1H-NMR (CDCl3), l ppm: 1.11 (t, 12H, 4×CH3CH2),
3.28 (q, 8H, 4×CH3CH2), 2.53, 3.12 (m, 4H, 2×CH2 of
tetrahydroimidazole), 3.17, 3.67 (d, 4H, 2×CH2 benzyl),
4.54 (s, 1H, CH of tetrahydroimidazole), 6.57, 7.04 (d,

658
V. Sharma, M.S.Y. Khan / European Journal of Medicinal Chemistry 36 (2001) 651–658
dard drug indomethacin at the dose of 20 mg kg−1 were
administered intraperitoneally. After 30 min, 0.1 mL of
a 1% (w/v) carrageenan suspension in 0.9% saline solu-
tion was injected subcutaneously into the sub plantar
region of the left hind paw of all the animals. The paw
volume was determined plethysmographically at 60 and
180 min after carrageenan injection and the percent
anti-inflammatory activity calculated in comparison to
the standard drug at the same dose level. Results are
expressed as percentage inhibition of the edema.
45 °C and these seeded media were poured into plates
and allowed to solidify. A stainless steel cylinder of 8
mm diameter (pre-sterilized) was used to bore the cavi-
ties. All the synthesized compounds (100 mg mL−1
)
mentioned in table III were placed serially in the cavities
with the help of micropipettes and allowed to diffuse for
1 h. These plates were incubated at 37 °C for 24 h.
DMF was poured as a control. The plates were ob-
served after 24 h. The zone of inhibition observed is
indicated by (+) sign, (−) sign indicates no zone of
inhibition.
5.2.2. Study of the analgesic activity
The analgesic activity of the test compounds was
evaluated by the tail immersion method [10]. Albino
mice of either sex, weighing 25–30 g were selected for
testing by immersing the tail in hot water at a tempera-
ture 55 5 °C and the basal reaction time was noted.
The mice, which showed a positive response within a
2–5 s time duration for withdrawal of the tail clearly
out of water, were taken for further studies. The time
after which the mouse tried to remove the tail was taken
as the end point. Any animal not responding within 2–5
s was rejected from the study. Each group was adminis-
tered a different test compound and a standard drug,
aspirin, as 2% acacia suspension intaperitoneally. To
one group normal saline was injected which acted as a
control. Immediately after administration of the drug
and at intervals of 30, 60 and 120 min, the reaction time
was recorded. As the reaction time reached 12 s, it was
considered maximum analgesia and the tail was re-
moved from the hot water to avoid tissue damage.
Acknowledgements
One of the authors (V.S.) is thankful to C.S.I.R., New
Delhi, India, for the award of a senior research fellow-
ship.
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