SYNTHESIS OF QUATERNARY AMMONIUM BASED NEW ANALGESIC, ANTI- INFLAMMATORY AND ANTIPYRETIC DRUGS

Abstract

The carboxylic acid group (-COOH) present in most commercial NSAIDs is thought to be partly responsible for the gastric toxicity associated with the long-term administration of these compounds. The goal of the present research was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti- inflammatory activity while exerting a lower degree of gastric toxicity compared to the corresponding parent NSAID. In this regard, we replaced the carboxylic acid group in aspirin, ibuprofen, flurbiprofen, and naproxen with a series of quaternary ammonium moieties, and the resulting water-soluble NSAID derivatives were tested for anti-inflammatory and ulcerogenic activity in vivo. Results of our investigation showed that replacement of quaternary ammonium moieties for the carboxylic acid group present in NSAIDs, yielded potent anti-inflammatory molecules without stomach ulceration when administered orally to rats. Among the new compounds, N- (2-hydroxyethyl)-2-(6-methoxynaphthalen-2-yl)propan-1-aminium chloride (a naproxen derivative) was the most potent anti-inflammatory agent (65.28% inhibition of inflammation at 6.4 mg/kg); however, unlike the reference compound naproxen (ulcer index = 108.7), N-(2-hydroxyethyl)-2-(6-methoxynaphthalen-2-yl)propan-1- aminium chloride did not produced gastric ulcers (Ulcer index = 0) when administered orally at equimolar doses (0.17mmol). These results suggest that the carboxylic acid group present in commercial 2-phenylpropionic acid NSAIDs is not an essential requirement for anti-inflammatory activity in vivo, and offers a new concept in drug design by using water-soluble ammonium moieties instead. Derivatives of salicylic acid were screened for analgesic, anti-inflammatory and antipyretic activities, and acute toxicity. The result of this study indicated that these compounds possess dose dependent statistically significant analgesic, anti- inflammatory and antipyretic properties, compared to aspirin, without causing gastric ulceration and acute toxicity.