Abstract
A new series of N′-(substituted phenyl)-2-(1-(4-(methylsulfinyl) benzylidene)−5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide derivatives (1 – 25) were prepared in good yields in an efficient manner. All the compounds were fully characterised by the elemental analysis and spectral data. Synthesised compounds were evaluated for antioxidant activity by DPPH method. Compounds 7 (R = 3-methoxyphenyl), 3 (R = 4-dimethylaminophenyl) and 23 (R = 2,4,5-trimethoxy phenyl) substitutions were found to be having highly potent antioxidant activity. Compound 3, with para dimethylaminophenyl substitution was found to be having highest antioxidant activity. It was further evaluated in vivo for various analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibitory activity in different animal models. Lead compound 3 was found to be significant anti-inflammatory and analgesic agent. It was also evaluated for ulcerogenic activity and demonstrated significant ulcerogenic reduction activity in ethanol and indomethacin model. The LD50 of compound 3 was found to be 131 mg/kg. The animals treated with compound 3 prior to cisplatin treatment resulted in a significant reduction in COX-2 protein expression when compared to cisplatin-treated group. Sulindac derivative with para dimethylaminophenyl substitution was found to be the most potent antioxidant, anti-inflammatory and analgesic agent as well as with significant gastric sparing activity as compared to standard drug sulindac. Compound 3 significantly downregulated liver tissue COX‐2 gene expression.
Highlights
Cyclooxygenase (COX) enzyme catalyses the conversion of arachidonic acid to prostaglandin H2 (PGH2), which is converted to many prostanoids by specific isomerase enzymes because it is an unstable intermediate
Sulindac methyl ester (II) was synthesised from sulindac by refluxing in methanol with concentrated sulphuric acid according to the reported procedure
Compound 3 administration induced reticence of COX-2 protein expression in liver tissue We further examined the anti-inflammatory effect of compound 3 in liver tissues in cisplatin administrated rats by measuring protein expression of inflammatory mediators
Summary
Cyclooxygenase (COX) enzyme catalyses the conversion of arachidonic acid to prostaglandin H2 (PGH2), which is converted to many prostanoids by specific isomerase enzymes because it is an unstable intermediate. Non-beneficial effects of prostaglandins include pain and fever associated with inflammation; beneficial effects include gastro-intestinal protection and platelet function. The cyto-protection in the gastrointestinal (GI) tract is provided by COX-1 and COX-2 mediates inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation. Side effects include gastrointestinal toxicity such as gastro-duodenal perforations, ulcers and bleeding, ascribed to the inhibition of cyclooxygenase-1 (COX-1). Selective inhibitors of cyclooxygenase-2 (COX-2) were synthesised in an attempt to decrease these side effects. Physicians would prescribe gastro-protective agents with a conventional NSAID, prior to the introduction of the COX-2 selective inhibitors. Inhibition of COX-2 enzyme would result in the same anti-inflammatory benefits as that of non-selective NSAIDs provide but with less incidences of gastrointestinal side effects. Some COX-2 inhibitors have been found to have cardiovascular side effects
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