Mahdi M F et al. / Pharmacie Globale (IJCP) 2012, 1 (03) 1 Pharmacie Globale (IJCP), Vol. 03, Issue 01 Available online at www.pharmacie-globale.info PHARMACIE GLOBALE INTERNATIONAL JOURNAL OF COMPREHENSIVE PHARMACY DESIGN, SYNTHESIS, AND HYDROLYSIS STUDY OF MUTUAL PRODRUGS OF NSAIDS WITH DIFFERENT ANTIOXIDANTS VIA GLYCOLIC ACID SPACER Ali Basim Talib, Monther F Mahdi and Mohammed H Mohammed* Department of pharmaceutical chemistry, Collage of pharmacy, University of Baghdad, Baghdad, Iraq. Received: 25 November 2011; Revised: 23 December 2011; Accepted: 28 December 2011; Available online: 5 January 2012 INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in the world, owing to their analgesic, anti-inflammatory and antipyretic properties. 1,2 However, the use of “traditional” NSAIDs results in serious upper gastrointestinal (GI) adverse events e.g. (figure 1) Naproxen (I) and Indomethacin (II). 3 The pharmacological activity of NSAIDs is related to their ability to inhibit the activity of the enzyme cyclooxygenases (COXs) involved in the biosynthesis of prostaglandin H2 (PGH2). 4 It is now well known that COX exists in two isoforms, namely COX-I and COXII, which are regulated differently. 5 COX-I is constitutively expressed in stomach to provide cytoprotection in the GIT. 6 COX-II is inducible and plays a major role in prostaglandin biosynthesis in inflammatory cells. 7 Since most of the NSAIDs used clinically inhibit both isoforms, long term use of these agents results in gastric ulcer and there is enough evidence that inhibition of COX-I rather than that of COX-II underlies gastric ulcer formation. 8 But initial enthusiasm for selective COX-II inhibitors as safer NSAIDs has faded due to emergence of serious cardiovascular side effects on long term use and need for design and development of safer agents still remain. 9,10 It has been well known that local generation of various reactive oxygen species (ROS) plays a significant role in the formation of gastric ulceration associated with NSAID therapy. 11 These observations indicate that antioxidants may be used to prevent NSAIDs induced gastric ulcers. During the past few decades, a large number of naturally occurring compounds have been identified as *Corresponding Author: Monther F Mahdi Department of pharmaceutical chemistry, Collage of pharmacy, University of Baghdad, Baghdad, Iraq. E-mail: dmfalameri@yahoo.com antioxidants e.g. (figure 1) thymol (III), guaiacol (IV) and menthol (V), which are viewed as promising therapeutic agents for treating free radical mediated diseases including NSAID induced peptic ulcers. 12 Large number of herbs and spices are recognized as source of natural antioxidants and studies have confirmed their efficacy for the treatment of gastrointestinal ulcers. 13 Based on these observations, it has been suggested that coadminstration of antioxidants and NSAIDS in formulated dosage form may possibly decrease the risk of NSAIDs induced gastrointestinal side effects. 14 However, there are potential advantages in giving such coadministered drugs having complementary pharmacological activities in the form of a single chemical entity. Such agents are named as mutual prodrugs which are designed with improved physicochemical properties. 15,16 In the view of this background, the present study was conducted to design, synthesis, and preliminary kinetics study of mutual prodrugs of NSAIDs with different antioxidants to get NSAIDs with lesser ulcerogenic side effects while retaining the anti-inflammatory and analgesic activity. Figure 1. Chemical structures of NSAIDs and antioxidants ABSTRACT Non-steroidal anti-inflammatory drugs (NSAIDs); naproxen and indomethacin have been conjugated with different antioxidants (thymol, guaiacol, and menthol) having antiulcerogenic activity with the objective of obtaining NSAIDs- antioxidant prodrugs as gastrosparing NSAIDs devoid of ulcerogenic side effects. Six mutual prodrugs (1a-c and 2a-c) were synthesized using glycolic acid spacer and their structures were confirmed and characterized using elemental microanalysis (CHNO), IR, and some physiochemical properties. In-vitro chemical and enzymatic hydrolysis studies for naproxen derivatives (1a-c) revealed that these compounds were chemically stable in pH 1.2 and pH 7.4, with t 1/2 range from 6.22- 20.98 hr; while in 80% diluted plasma were found to be susceptible to enzymatic hydrolysis with more than 40% hydrolysis occur after 15 min the results indicate higher chemical stability of ester prodrugs in non enzymatic simulated gastro-intestinal fluid and rapid conversion to the parent drugs in 80% human plasma. Keywords: NSAIDs; mutual prodrug; antioxidant; ulcerogenicity. Research Article ISSN 0976-8157