In Silico Analysis and Experimental Evaluation of Ester Prodrugs of Ketoprofen for Oral Delivery: With a View to Reduce Toxicity

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...

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Bibliographic Details
Published in:Processes 2021-12, Vol.9 (12), p.2221
Main Authors: Mazumder, Kishor, Hossain, Md. Emran, Aktar, Asma, Mohiuddin, Mohammad, Sarkar, Kishore Kumar, Biswas, Biswajit, Aziz, Md. Abdullah, Abid, Md. Ahsan, Fukase, Koichi
Format: Article
Language:English
Subjects:
Acids
Animals
Bioavailability
Biocompatibility
Chromatography
Drug dosages
Drugs
Enzymes
Esterification
Experiments
FDA approval
Hepatotoxicity
In vivo methods and tests
Inflammatory diseases
Infrared analysis
Irritation
Ketoprofen
Laboratories
Metabolism
NMR
Nuclear magnetic resonance
Osteoarthritis
Pain
Pathogenesis
Permeability
Pharmacokinetics
Prodrugs
Proteolysis
Rheumatoid arthritis
Spectrometry
Statistical analysis
Synthesis
Toxicity
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Summary: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.
ISSN:2227-9717
2227-9717
DOI:10.3390/pr9122221