Research: DESIGN AND SYNTHESIS OF POSSIBLE MUTUAL PRODRUGS BY COUPLING OF NSAIDS WITH SULFA DRUGS BY USING GLYCOLIC ACID AS SPACER

This study includes synthesis of mutual prodrugs of NSAIDs and different sulfa drugs using glycolic acid spacer (-OCH2COO-) to reduce the ulcerogenic side effects of NSAIDs, by esterfication the free carboxyl group of theNSAIDs that responsible for the local irritation. Two NSAIDs, ibuprofen and naproxen each one of them werelinked to two different sulfa drugs sulfathiazole and sulfadiazine through glycolic acid spacer (-OCH2COO- ) aspossible mutual prodrugs to reduce the ulcerogenic side effects of NSAIDs by esterfication of the free carboxylgroup of the NSAIDs that responsible for the local irritation. The structures of these compounds were confirmedand characterized using elemental microanalysis (CHNO), infrared spectroscopy (IR) and some physicochemicalproperties (melting point m.p. and thin layer chromatochraphy TLC). In-vitro preliminary kinetic study was donefor two target compounds at different pH (1.2 and 7.4) to identify the expected hydrolyses of these mutualprodrugs in the gastrointestinal tract. In-vitro preliminary kinetic study for target compounds (I) and (III) at pH(1.2 and 7.4) was revealed that these compounds were chemically stable in simulated gastrointestinal fluid,while 80% diluted plasma were found to be susceptible to enzymatic hydrolysis with more than 40% hydrolysisoccur after 15 min. The results indicate higher chemical stability of prodrugs in non enzymatic simulated gastrointestinalfluid and rapid conversion to the parent drugs in 80% human plasma.