Abstract
A variety of 4-(un)substituted phenylcarbamoyl methyl ester-containing compounds 3a-d, 5a-d and 7a-d were synthesized via reaction in N,N-dimethylformamide of (un)substituted chloroacetanilides 2a-d with the potassium salts of ibuprofen (1), naproxen (4) and N-acetylanthranilic acid (6). Moreover, other 4-(un)substituted phenylcarbamoylmethyl ester-containing compounds 10a-d were synthesized via the attack of (un)substituted chloroacetanilides 2a-d on one of the carboxylic acid groups of the potassium salt of 4-(2-carboxyethylcarboxamido)benzoic acid (8) in N,N-dimethylformamide, with subsequent cyclization of the other one giving finally a pyrrolidinone structure. Anti-inflammatory properties of the synthesized compounds were evaluated in vivo utilizing a standard acute carrageenan-induced paw oedema method in rats and the most promising prepared anti-inflammatory active agents were evaluated for ulcerogenic liability in rats using ibuprofen and naproxen as reference standards in both screenings. PGE2 inhibitory properties of the highly promising anti-inflammatory agents synthesized and low gastric ulcerogenic liabilities were tested with a PGE2 assay kit technique.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation
Most currently used NSAIDs suffer from limitations in their therapeutic uses, since they cause gastrointestinal and renal side effects, which are inseparable from their pharmacological activities
Several lines of evidence have suggested that modification of the carboxyl function of representative NSAIDs results in retained antiinflammatory activity and reduced ulcerogenic potential [7,8,9]
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. Most currently used NSAIDs suffer from limitations in their therapeutic uses, since they cause gastrointestinal and renal side effects, which are inseparable from their pharmacological activities. These compounds act via inhibition of the enzyme cyclooxygenase, preventing prostaglandin synthesis [1]. They have greater selectivity to inhibit COX-1 (constitutively expressed and providing cytoprotection in the gastrointestinal tract and necessary for normal platelet aggregation and renal function) than COX-2 (inducible by inflammatory stimuli) [2,3,4,5]. Several lines of evidence have suggested that modification of the carboxyl function of representative NSAIDs results in retained antiinflammatory activity and reduced ulcerogenic potential [7,8,9]
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