Novel Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones Substituted with Ibuprofen as Potent and Safer Antiinflammatory/Analgesic Agents

EI Ozturk1, I Kazkayasi1, D Sarigol3, A Uzgoren3, G Okay3, M Ertan2, B Tozkoparan2, BC Tel1. 1Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Turkey, 2Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Turkey, 3Hacettepe University, Faculty of Science, Department of Chemistry, Division of Organic Chemistry, Turkey

Introduction: Inflammation is a spontaneous biological response to harmful stimuli. Prostaglandin synthesis inhibitors like non-steroidal antiinflammatory drugs (NSAIDs) are extensively used in the treatment of inflammation. NSAIDs suppress inflammation by inhibiting the cyclooxygenase (COX) enzymes. However, the gastrointestinal side effects of currently available NSAIDs pose a major problem in their clinical use. In this study, we develop new modified ibuprofen analogues with better analgesic, antiinflammatory activity and lower gastric risks. Our aim is to evaluate analgesic/anti-inflammatory activities as well as gastric risk of these new compounds.

Material: Compounds 1a-1g carrying ibuprofen residue were tested using Swiss albino mice of both sexes, weighing 20–35 g (Ethics Committee permission no: 2008/21-5). Animals were divided into groups (n=7), drugs were administered intragastrically (50 mg/kg) in 0.5% carboxymethyl cellulose (CMC) solution. Control group were received vehicle. Ibuprofen, opioid agonist oxycodone and indomethacin were used as reference drugs at 50 mg/kg dose. For the antiinflammatory activity carrageenan-induced hind paw oedema; for the analgesic activity tail flick and hot plate tests were used. The gastric safety on acute administration was conducted by microscopic examination of the stomachs. Acute toxicity test was also carried out.

Results: All new compounds were characterized by elementary and spectral analysis. In the carrageenan-induced hind paw oedema, all compounds were found active. All synthesized derivatives increased the latency of the tail-flick and hot-plate response compared to vehicle control. Ulcer scoring of the test compounds was lower than reference drugs (Table 1). In acute toxicity study, mortality was not observed. During the 14 day observation period animals showed no weight loss, no behavioural alteration or toxicity sign.

Conclusion: All test compounds showed similar or higher activity profile to ibuprofen in analgesic and antiinflammatory tests with lower ulcerogenic risk. The compounds 1a and 1f showing higher activity than ibuprofen, displayed a similar electrophilicity index value (generated by Gaussian 03) to selective COX-2 inhibitor celecoxib. Thus, their lower gastric side effect might be related to their preferential COX-2 inhibitory properties. The new ibuprofen derivatives might provide a safer alternative to ibuprofen for the treatment of inflammatory disease and pain.

Table 1: Antiinflammatory activity (AIA), analgesic activity (tail-flick (TF) and hot plate (HP) tests) and ulcer score results of the compounds.

p<0.05 vs vehicle control group; $ p<0.01 vs ibuprofen; # p<0.05 vs ibuprofen; data expressed as mean±SEM; one-way ANOVA followed by post hoc Dunnett’s test.

Supported by Hacettepe University Research Center (Grant no: 04A601005).