Abstract
The present research aimed to synthesize ketoprofen prodrugs and to demonstrate their potentiality for oral treatment to treat chronic inflammation by reducing its hepatotoxicity and gastrointestinal irritation. Methyl 2-(3-benzoyl phenyl) propanoate, ethyl 2-(3-benzoyl phenyl) propanoate and propyl 2-(3-benzoyl phenyl) propanoate was synthesized by esterification and identified by nuclear magnetic resonance (1HNMR) and infrared (IR) spectrometric analysis. In silico SwissADME and ProTox-II analysis stated methyl derivative as ideal candidate for oral absorption, having a >30-fold LD50 value compared to ketoprofen with no hepatotoxicity. Moreover, in vivo hepatotoxicity study demonstrates that these ester prodrugs have significantly lower effects on liver toxicity compared to pure ketoprofen. Furthermore, ex vivo intestinal permeation enhancement ratio was statistically significant (* p < 0.05) compared to ketoprofen. Likewise, the prodrugs were found to exhibit not only remarkable in vitro anti-proteolytic and lysosomal membrane stabilization potentials, but also significant efficiency to alleviate pain induced by inflammation, as well as central and peripheral stimulus in mice model in vivo. These outcomes recommend that ketoprofen ester prodrugs, especially methyl derivative, can be a cost-effective candidate for prolonged treatment of chronic inflammatory diseases.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered as one of the most consumed drugs worldwide for management acute and chronic inflammation and pain associated illnesses such as osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, gout, systemic lupus erythematosus and so others [1,2,3]
Ketoprofen ester prodrugs were synthesized by esterification reaction (Scheme 1) using three alcohols involving reagent grade methanol, ethanol and propanol in order to obtain methyl 2-(3-benzoyl phenyl) propanoate, ethyl
As the findings showed clear evidence of no hepatotoxic activity of ester prodrug the findings showed clear evidence of no hepatotoxic activity of ester prodrug treatment, it treatment, it can bethat concluded that the ester synthesized ester prodrugs willtherapeutically be utilized theracan be concluded the synthesized prodrugs will be utilized by peutically oral route.by oral route
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered as one of the most consumed drugs worldwide for management acute and chronic inflammation and pain associated illnesses such as osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, gout, systemic lupus erythematosus and so others [1,2,3]. The NSAIDs group covers a large number of chemical families involving salicylates, aryl alkanoic acids, 2-arylpropionic acids or profens, fenamic acids, oxicams and sulfonamides. Rather than their variable structural and pharmacodynamics features, they exert therapeutic output by blocking cyclooxygenase enzymes (COX-I and COX-II) that regulate the prostaglandin (PG) synthesis pathway and pathogenesis of pyrexia, analgesia and inflammatory reactions mediated abnormalities [4]. A small dose of ketoprofen is capable of reducing mild to moderate analgesia to the same extent as a high dose of another profen
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