Pharm. Pharmacol. Commun. 1999, 5: 273±275
Received December 15, 1998
Accepted January 13, 1999
# 1999 Pharm. Pharmacol. Commun.
Synthesis and Anti-in¯ammatory Activity of Some 1-Methyl-5-
(4-substituted benzoyl)imidazole-2-acetates
A. SHAFIEE, S. KAABINEJADIAN, A. FOROUMADI{ AND M. R. ZARRINDAST*
Department of Medicinal Chemistry, Faculty of Pharmacy, *Department of Pharmacology, Faculty of
Medicine, Tehran University of Medical Sciences, Tehran and {Department of Medicinal Chemistry,
Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
Abstract
1-Methyl-5-(4-X-benzoyl)imidazole-2-acetates were synthesized and tested for anti-
in¯ammatory activity. Tolmetin and aspirin were used as reference drugs.
The most active compound against carrageenan-induced oedema in rat hindpaw was a
4-chlorobenzoyl derivative, which was almost 1Á5-times more active than the reference
drug aspirin. In addition, it had half the activity of tolmetin.
Materials and Methods
Chemical procedures
Non-steroidal anti-in¯ammatory drugs (NSAIDs)
are widely used in the treatment of certain rheu-
matic disorders. These agents inhibit the biosynth-
esis of prostaglandins from arachidonic acid (Vane
1971). Some anti-in¯ammatory receptor models for
NSAIDs show the interaction of these agents with
the active site of the key enzyme in prostaglandin
biosynthesis namely prostaglandin synthetase
(Gund & Shen 1977; Salvetti et al 1981). These
receptor models indicate that most NSAIDs, pos-
sess the common structural features of an acidic
center, an aromatic or heteroaromatic ring, and an
additional center of lipophilicity in the form of
either an alkyl chain or an additional aromatic ring.
The proposed receptor to which indomethacin was
postulated to bind consisted of a cationic site to
which the carboxylate anion would bind, a ¯at area
to which the indole ring would bind to Van der
Waals' forces, and an out-of-plane trough to which
the benzene ring of the p-chlorobenzoyl group
binds through hydrophobic or charge±transfer
interactions.
The 1-methyl-5-(4-X-benzoyl)imidazole-2-acetates,
as sodium salts 5a±d, were synthesized as outlined
in Figure 1. 1,2-Dimethyl-imidazole-5-carboxalde-
hyde (1) was prepared according to the procedure
described by Godefroi et al (1972). Reaction of
compound 1 with the appropriate aryl magnesium
bromide in anhydrous tetrahydrofuran at 20ꢀC gave
compounds 2a±d. Oxidation of compounds 2a±d
with MnO2 in chloroform afforded compounds 3a±
d. Condensation of 3a±d with ethyl chloro-formate
in triethylamine±acetonitrile medium, at room
temperature (Macco et al 1975) gave the required
compounds 4a±d. These were converted by
hydrolysis with 2 M NaOH into the desired sodium
1-methyl-5-(4-X-benzolyl)imidazole-2-acetates
5a±d.
The physicochemical data of the intermediates
2a±d, 3a±d and 4a±d are given in Tables 1, 2 and
We designed and synthesized a series of 1-
methyl-5-(4-X-benzoyl)imidazole-2-acetates. In-
vivo anti-in¯ammatory activity was assessed by the
carrageenan-induced oedema test in rat hindpaw.
Table 1. Physicochemical properties of 1,2-dimethyl-5-(a-
hydroxy-4-X-benzyl)imidazoles.
Compound
X
Yield (%) Crystallization Mp (ꢀC)
solvent
2aa
2b
2c
H
Cl
CH3
OCH3
87
92
75
96
THF
THF
THF
THF
194±195
189±191
224±225
158±160
2d
Correspondence: A. Sha®ee, Faculty of Pharmacy, Tehran
University of Medical Sciences, PO Box 14155-6451, Tehran
14174, Iran.
aPreviously reported by Godefroi & Greenan (1975).
Shafiee
