Amino acid esters as prodrugs of an arylalkanoic acid COX inhibitor: Synthesis and biopharmaceutical and pharmacological evaluation

Nirmal, Nilesh Prakash, Rajput, Mithun Singh, Sarkar, Purnima Dey, Sinha, Sampada and Gupta, Amit (2015) Amino acid esters as prodrugs of an arylalkanoic acid COX inhibitor: Synthesis and biopharmaceutical and pharmacological evaluation. Journal of Taibah University for Science, 9 4: 455-464. doi:10.1016/j.jtusci.2014.11.005

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Author Nirmal, Nilesh Prakash
Rajput, Mithun Singh
Sarkar, Purnima Dey
Sinha, Sampada
Gupta, Amit
Title Amino acid esters as prodrugs of an arylalkanoic acid COX inhibitor: Synthesis and biopharmaceutical and pharmacological evaluation
Journal name Journal of Taibah University for Science   Check publisher's open access policy
ISSN 1658-3655
1658-3612
Publication date 2015-10-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.jtusci.2014.11.005
Open Access Status DOI
Volume 9
Issue 4
Start page 455
End page 464
Total pages 10
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Language eng
Formatted abstract
Sulindac is an analgesic and anti-inflammatory agent. It has the general side-effects of non-steroidal anti-inflammatory drugs, owing to presence of a free carboxylic acid group. The aim of the study was to retard the adverse gastrointestinal effects of the drug. Various conjugates of sulindac were synthesized by amidation with methyl esters of 10 amino acids. The synthesized conjugates were characterized by melting-point, thin-layer chromatography and Fourier transform infrared, nuclear magnetic resonance and mass spectroscopy. The synthesized conjugates were evaluated pharmacologically for analgesic, anti-inflammatory and ulcerogenic activity. Amide conjugation had a synergistic potentiating effect, with less disruption of mucosal surfaces. This conjugate approach can therefore be used successfully to minimize gastrointestinal toxicity with no loss of the desired anti-inflammatory and analgesic activities of the drug. Methyl 2-(2-((7Z)-1-(4-(methylsulfinyl)benzlidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamido)-3-phenylpropanoate and methyl 2-(2((6Z)-1-(4-(methylsulfinyl)benzlidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamido)-3-methylbutanoate showed excellent pharmacological responses and encouraging hydrolysis rates in simulated gastric fluid, simulated intestinal fluid and 80% human plasma. Conjugates with longer aliphatic side chains or aromatic substituents had higher partition coefficients but lower dissolution and hydrolysis rates. These conjugates could be considered for sustained release preparations.
Keyword Amino acid conjugate
Analgesic
Anti-inflammatory
Hydrolysis
Sulindac
Ulcerogenesis
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Centre for Nutrition and Food Sciences Publications
 
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