Synthesis and Preliminary Evaluation of Potential Highly Selective COX-2 Inhibitors of Some Non-Steroidal Anti-Inflammatory Derivatives

Abstract

The pocket in COX-1 or COX-2 isoenzyme which accommodates the Coxibs series is different and sterically specific and sensitive to the size and isomeric variation on the Coxibs group. This isomeric variation may play a role in directing the compound toward one of two isomers of COX enzymes (COX-2). The aim of the study is to synthesize novel NSAI compounds (aspirin, diflunisal and ketoprofen derivatives) as potential highly selective COX-2 inhibitors, and to evaluate their anti-inflammatory activity, safety and gastrointestinal side effects. The conversion of the carboxyl group of aspirin, diflunisal and ketoprofen to a carboxamide group through conjugating it with specifically selected moieties of heterocyclic rings may impart an effect toward selective COX-2 inhibition with lower side effects. Six compounds were synthesized: compounds 2 and 3 from aspirin, compounds 6 and 7 from diflunisal, and compounds 9 and 10 from ketoprofen. The synthesized derivatives were analyzed by IR and 1H-NMR spectroscopy to confirm their proposed chemical structures, and their purity was checked by melting point and Rf measurement. Pharmacological tests evaluated anti-inflammatory activity by the ovalbumin paw edema method and gastrointestinal effects by ulcer index screening. Most derivatives showed good anti-inflammatory activity ranging from 46.5% (compound 2) to 36.2% (compound 9), compared with 41% for the standard as percentage paw-edema inhibition. Compounds 2 and 6 showed ulcer indices analogous to celecoxib as a safe standard for gastric irritation. The preliminary evaluation showed that compound 2 had maximal therapeutic anti-inflammatory action with little gastric effect, while compound 6 showed good anti-inflammatory activity with the lowest ulcer index. The bulky structures of derivatives 2 and 6, which have a similar heterocyclic nucleus, may enhance their ability to occupy the side pocket of the COX-2 enzyme while maintaining anti-inflammatory activity.