As a therapeutic group, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used, prescribed and over the counter (OTC) medications for the treatment of inflammatory diseases, but suffering from several undesired side effects, the most important being ulcerogenicity, mucosal hemorrhage and gastritis. Most of the NSAID moieties are chemically composed of carboxylic functional groups and this could be one of the reasons for the damage to the mucosal lining. The prodrug designing is one of the several strategies used to overcome this drawback. Hence, in the last decade, the design and the synthesis of prodrugs of NSAIDs have been explored and given much attention by medicinal chemists. The rationale behind the prodrug concept is to achieve temporary blockade of the free carboxylic group present in the NSAIDs till their systemic absorption. This review is aimed to highlight and provide important information on NSAID prodrugs that have been designed and reported to be safe and more effective. This review will also focus on NSAID prodrugs that have been designed for improving therapeutic i.e. anti-inflammatory action as well as improving drug delivery at the target site. The most common derivatives of carboxylic NSAIDs that are discussed here belong to the chemical classes of esters, amides, anhydrides, acetals and the other derivatives with completely masked carboxylic groups. The successful prodrugs were listed and their molecular structures were also demonstrated here. The present review covers the recent updates present in literature and will surely provide a greater insight into the designing of safer NSAIDs in the future.
Ketoprofen belongs to one of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione-type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining antiinflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen-antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic-OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants (IIa-h) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofenantioxidant through the glycolic acid spacer (-CH 2 COO; IIIa-h), have also been designed and synthesized. The synthesized codrugs were characterized by IR, 1 H NMR, 13 C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t 1/2 .The pharmacological evaluation results indicate that these ketoprofen-antioxidant mutual codrugs showed the retention of anti-inflammatory and analgesic activity with a significant reduction in the ulcer index.
Ketoprofen-antioxidant mutual prodrugs were synthesized to reduce the gastrointestinal effects associated with ketoprofen. For reducing the gastrointestinal toxicity, the free carboxylic group (-COOH) was temporarily masked by esterification with alcoholic/ phenolic -OH of natural antioxidants thymol, guaiacol, menthol and vanillin. In order to obtain the derivatives with improved in vivo lability, the double ester prodrugs i.e. ketoprofen-antioxidant through the glycolic acid spacer (-CH2COO-) have been synthesized. These mutual prodrugs were evaluated for their anti-inflammatory, analgesic and antiulcer properties. The results indicate that there is merit to extend the therapeutic utility of this potential NSAID by developing the ketoprofen-antioxidant mutual prodrugs as gastroprotective NSAIDs.
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