Abstract
The present investigation developed the ester prodrugs of Non-steroidal anti inflammatory drugs (NSAIDs), Mefenamic acid and Flurbiprofen by conjugating with the natural antioxidant, 4-methyl umbelliferone that resulted the formation of Mefenamic acid-umbelliferone ester prodrug and Flurbiprofen-umbelliferone ester prodrug .The principal objective this study is the synthesis of the ester prodrugs of NSAIDs with the enhanced therapeutic activity and minimized side effects. Prodrugs were synthesized by coupling method using N,N’- dicyclohexylcarbodiimide/4-dimethylaminopyrimidine, subjected to physical, chemical characterization, spectral characterization (IR, 1H NMR, 13C NMR and Mass spectra),hydrolysis-kinetic study and pharmacological evaluation such as anti-inflammatory, ulcerogenecity as well as the effect of the NSAIDs in the central nervous system against degenerative mechanisms. The current study revealed that the umbelliferone conjugates of NSAIDs which upon administration would release the parent drug as a result of enzymatic or non-enzymatic hydrolysis in the desired site with enhanced anti inflammatory activity and reduction in the gastro intestinal toxicity. Also the synthesized pordrugs showed enhanced brain targeting efficiency with protective action against the degenerative processes.
Highlights
NSAIDs, well accepted for the therapeutic activities such as Analgesic, Anti–inflammatory and Anti-pyretic activities based on the mechanism of cyclooxygenase(COX-1 and COX-2) enzyme inhibition and formation of prostaglandins (1) .The various pharmacological activities produced by the NSAIDs can be explained through different basic mechanisms such as nitric oxide system and transcriptional factors that showed direct relationship with cytokine expression which is having a significant role in the anti-inflammatory process (2)
The major side effect produced by the NSAIDs is the gastric-duodenal ulceration due to the free carboxylic acid functional group in the structure several mechanisms was put forward such as the inhibition of prostaglandin synthesis, irritant effect on the epithelial tissue, effect in the gastric-mucosal blood flow (4).The structure activity relationship of NSAIDs was proved that the free carboxylic acid functional group in the molecular structure of the NSAIDs is necessary for the binding with COX receptors to elicit the pharmacological action and the hydrolysis of the prodrugs produced the anti-inflammatory activity
The prodrugs based approaches such as carries linked and bioprecursor approaches have significant role in the drug research and development (7).The drug molecules after the development process may be failed in the required therapeutic activity because of the pharmacokinetic profile, transport profile and solubility etc and prodrug approach successfully overcome the above limitations (8).In the worldwide pharmaceutical market, about ten percentages of the drugs are considered as prodrugs that can effectively overcome the limitations of the NSAIDs
Summary
NSAIDs, well accepted for the therapeutic activities such as Analgesic, Anti–inflammatory and Anti-pyretic activities based on the mechanism of cyclooxygenase(COX-1 and COX-2) enzyme inhibition and formation of prostaglandins (1) .The various pharmacological activities produced by the NSAIDs can be explained through different basic mechanisms such as nitric oxide system and transcriptional factors that showed direct relationship with cytokine expression which is having a significant role in the anti-inflammatory process (2). The major side effect produced by the NSAIDs is the gastric-duodenal ulceration due to the free carboxylic acid functional group in the structure several mechanisms was put forward such as the inhibition of prostaglandin synthesis, irritant effect on the epithelial tissue, effect in the gastric-mucosal blood flow (4).The structure activity relationship of NSAIDs was proved that the free carboxylic acid functional group in the molecular structure of the NSAIDs is necessary for the binding with COX receptors to elicit the pharmacological action and the hydrolysis of the prodrugs produced the anti-inflammatory activity. This study expected to decrease the gastric ulceration by the synthesis of the prodrugs using the antioxidant conjugate (9)
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