International Journal of Chemical and Analytical Science ISSN: 0976-1206 Research Article www.ijcas.info Corresponding Author: Apurba Talukdar, Assistant Professor, Department of Pharmacy, Assam down town University, Gandhinagar, Panikhaiti, Guwahati-781026, Assam, India Received 12-11-2011; Accepted 22-01-2012 May, 2012 International Journal of Chemical and Analytical Science, 2012, 3(5), 1387-1390 1387 Syntheses of Some Novel Esters of NSAIDs as Prodrugs for Log P and In-Vitro Anti-Inflammatory Study Meghna P Patel 1 , Manoj Kakati 1 , Janardhan Saravanan 1 , Shamanna Mohan 1 , Satyendra Deka 2 , Apurba Talukdar 2* , Bapi Ray Sarkar 2 , Kamal Sharma 2 1 Department of Pharmaceutical Chemistry, PES College of Pharmacy, Bangalore-50, Karnataka, India 2 Department of Pharmacy, Assam down Town University, Guwahati-26, Assam, India INTRODUCTION Inflammation, which is basically a defensive phenomenon yet often leading to serious pathological conditions, is treated by various agents with good to moderate success because of either considerable toxicity and side-effects (e.g. glucocorticoids) and/or moderate therapeutic effectiveness (e.g. penicillamine, gold). Although non-steroidal anti- inflammatory drugs (1) are the most commonly prescribed drugs in the world, their use as anti-inflammatory (2,3), antipyretic, anti-thrombotic and analgesic agents continues to be principally limited by their undesired side effects, mainly on gastrointestinal (GI) tract. Other side effects, such as nephrotoxicity, hepatotoxicity and disturbance of the platelet functions/blood coagulation, are usually less frequent and serious compared to actions on the GI tract. Ibuprofen, Aspirin, Aceclofenac and Indomethacin are some of the aryl acetic acid derivatives with potent analgesic and anti- inflammatory activity. The gastric side effects of these drugs are attributed to the presence of free –COOH group and inhibition of endogenous prostaglandins. Therefore, blocking this group by synthesizing functional derivatives of carboxylic acids may reduce these side effects. Omeprazole is non-acidic benzimidazole drugs with good gastric acid pump inhibitor activity that regulates the final step in hydrogen ion production and blocks gastric acid secretion regardless of the stimulus. The present work is aimed at converting Omeprazole of their hydroxyl derivatives and coupling hydroxyl derivative of Omeprazole with different NSAIDs to get an ester prodrug. Ester prodrug (4-7) should exhibit decreased toxicity since they neither possess a free carboxylic acid group nor do they inhibit prostarglandin synthesis. The logP values of the ester prodrugs (OM I-IV), were measured by routine shake flask method and it’s also computed with a calculated logP (ClogP) contained in a PC-software package. The utility of using log P data in designing a prodrug is to optimize the chances for oral absorption and biological membrane penetration. MATERIALS AND METHODS Experimental Design: Step 1: Synthesis of Hydroxymethyl omeprazole: A suspension of omeprazole (10g, 0.028mol) and 15 ml formaldehyde solution (40%) in water (100 ml) was refluxed for three hours. The hot solution was left to cool, then dilute NaOH solution was added where solid product were formed. The separated product was filtered and recrystallized by dioxane. M.P.: 86 0 C, % Yield: 68.13 %, Rf = 0.84. Step 2: General method for the syntheses of ester prodrug of NSAIDs with omeprazole: To an ice-cold solution of the appropriate non-steroidal anti-inflammatory drug (3 mmol) in 30 ml dichloromehane, hydroxymethyl omeprazole (3 mmol), dimethylaminopyridine (DMAP, 20 mg) and dicyclohexylcarbodiimide (DCC, 3.3 mmol) were added. The reaction mixture was stirred at 4 0 C for one hour and kept overnight at room temperature. The precipitate formed was separated by filtration and the filtrate was washed with cold 0.05 N HCl followed by saturated solution of NaHCO3 and finally with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. The separated product was recrystallized by dioxane. ESTER PRODRUG S R ESTER PRODRUG S R OM-I C OCOCH3 ASPIRIN O OM-II H N Cl Cl O O ACECLOFENAC C O OM-III C CH3 H3C CH3 IBUPROFEN O OM-IV N CH3 C H3CO O Cl INDOMETHACIN O The discovery of the inducible isoform of cyclooxygenase enzyme (COX- 2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New Omeprazole ester (OM I-IV) prodrugs of some acidic NSAIDs (I–IV) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs were confirmed by melting point, IR, 1 H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. The logP values of omeprazole, hydroxymethyl omeprazole (OM ), and the target derivatives (OM I-IV) were measured by routine shake flask method and it is also computed with a calculated logP (ClogP) contained in a PC-software package. Hydrolysis study of synthesized prodrugs was also done by validated HPLC method to ensure that release of parent drugs. Ester prodrugs were evaluated for their in-vitro anti-inflammatory activity by inhibition of Bovine serum albumin denaturation. Synthesized prodrugs showed satisfactory anti-inlammatory activity. Key words: Syntheses, Prodrug, Cyclooxygenase enzyme, Anti-inflammatory activity