Acid Property of Carboxylic Acid Functionality of Diclofenac in Cyclooxygenase Inhibitory Activity

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Phurit Thanarangsarit,Padungpong Namwon, Pornchai Sudthanaphun and Ruengwit Kitbunnadaj

Abstract

Diclofenac [2-(2,6-dichloranilino) phenylacetic acid] is one of the most widely used traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Many studies indicated that the carboxylic acid group involve in serious side effect occurrences such as gastric damage and hepatotoxicity, thus removal of the acid group might alleviate the aforementioned side effects. X-ray crystal structures of diclofenac/COX (COX-1 and COX-2) complex, however, show that the carboxylic moiety plays a role by interacting with tyrosine-385 and serine-530 of COX via hydrogen bonds. Surprisingly, an ionic interaction is not observed through this acid functionality. The finding suggested that, in order to remain the key hydrogen-bond interactions, the carboxylic group can be replaced by non-acid functionalities. In this study, compounds such as esters, amides, nitriles, and alcohol derivatives were synthesized and evaluated pharmacologically for COX inhibitory activities. The results showed that diclofenac is the most potent COX-1 and COX-2 inhibitor with %inhibition of 65 and 77, respectively at 10 μM concentration. In general, replacement of the carboxylic group of diclofenac with non-acid functionality leads to the dramatic decrease in inhibitory activity against COX-2, but not COX-1. The ester (RKNU070), secondary and tertiary amide (RKNU076–082), nitrile (RKNU072), and alcohol (RKNU071) derivatives are inactive against COX-2 but with %inhibition ranging from 12 to 44 against COX-1, whereas the primary amide derivative (RKNU074) possessed %inhibition of 59 and 59 against COX-1 and COX-2, respectively. Taken all together, it can be concluded that the acid property of diclofenac is essential for binding interaction against COX-2 but less important against COX-1.


Keywords: Diclofenac, cyclooxygenase, nonsteroidal anti-inflammatory drugs, carboxylic acid


Keywords
Diclofenac, cyclooxygenase, nonsteroidal anti-inflammatory drugs, carboxylic acid
Section
Research Articles

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How to Cite
PORNCHAI SUDTHANAPHUN AND RUENGWIT KITBUNNADAJ, Phurit Thanarangsarit,Padungpong Namwon,. Acid Property of Carboxylic Acid Functionality of Diclofenac in Cyclooxygenase Inhibitory Activity. Naresuan University Journal: Science and Technology (NUJST), [S.l.], v. 23, n. 2, p. 1-7, aug. 2015. ISSN 2539-553X. Available at: <http://www.journal.nu.ac.th/NUJST/article/view/987>. Date accessed: 19 apr. 2019.