Article
In Silico Analysis and Experimental Evaluation of Ester
Prodrugs of Ketoprofen for Oral Delivery: With a View to
Reduce Toxicity
Kishor Mazumder
1,2,3,
* , Md. Emran Hossain
1
, Asma Aktar
1
, Mohammad Mohiuddin
4
,
Kishore Kumar Sarkar
1
, Biswajit Biswas
1
, Md. Abdullah Aziz
2
, Md. Ahsan Abid
1
and Koichi Fukase
5
Citation: Mazumder, K.; Hossain,
M.E.; Aktar, A.; Mohiuddin, M.;
Sarkar, K.K.; Biswas, B.; Aziz, M.A.;
Abid, M.A.; Fukase, K. In Silico
Analysis and Experimental
Evaluation of Ester Prodrugs of
Ketoprofen for Oral Delivery: With a
View to Reduce Toxicity. Processes
2021, 9, 2221. https://doi.org/
10.3390/pr9122221
Academic Editors: Dimitrios
I. Gerogiorgis and Alina Pyka-Paj ˛ak
Received: 6 November 2021
Accepted: 26 November 2021
Published: 9 December 2021
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4.0/).
1
Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh;
emran.du2011@gmail.com (M.E.H.); asmaaktar121039@gmail.com (A.A.);
kishorekumar0811@gmail.com (K.K.S.); bb@just.edu.bd (B.B.); ahsanabid203517@gmail.com (M.A.A.)
2
School of Optometry and Vision Science, UNSW Medicine, University of New South Wales (UNSW),
Sydney, NSW 2052, Australia; md_abdullah.aziz@unsw.edu.au
3
School of Biomedical Sciences, Charles Sturt University, Booroma St, Wagga Wagga, NSW 2678, Australia
4
Department of Pharmacy, Faculty of Basic Medicine and Health Sciences, University of Science and
Technology Chittagong, Foy’s Lake, Chittagong 4202, Bangladesh; mohiuddin.bgc90@gmail.com
5
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka,
Osaka 560-0043, Japan; koichi@chem.sci.osaka-u.ac.jp
* Correspondence: kmazumder@just.edu.bd or k.mazumder@unsw.edu.au or kmazumder@csu.edu.bd
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 (
1
HNMR) 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.
Keywords: ketoprofen; prodrug; hepatotoxicity; gastric irritation; SwissADME; ProTox-II
1. Introduction
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
–
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
].
Ketoprofen, chemically known as 2-(3-benzoylphenyl)-propionic acid, is a substituted
2-phenylpropionic acid (aryl carboxylic acid) derivative, or simply profen. In 1967, it
Processes 2021, 9, 2221. https://doi.org/10.3390/pr9122221 https://www.mdpi.com/journal/processes
