Synthesis and evaluation of novel prodrugs of naproxen

A series of novel prodrugs of naproxen has been synthesized. Naproxen (1) was reacted with thionyl chloride to yield acid chloride (2) which was further reacted with glucose to form the glucosyl naproxen (3). Tetra-acetate of glucosyl naproxen was prepared and finally reacted with different amino acids to yield the title compounds. These compounds were evaluated for analgesic, anti-inflammatory activities, and for possible GI toxicity. Compound 5b depicted most potent analgesic activity with percentage inhibition of 98.15%. Compound 5a was found to be most potent anti-inflammatory agent with 76% inhibition. Compound 5n was second most active analgesic (92.26%) and anti-inflammatory (73%) agent. In vitro hydrolysis pattern of synthesized prodrugs was studied in phosphate buffer of pH 7.4 and acetate buffers of pH 3.0, 4.0, and 5.0, respectively. Selected compounds were evaluated for their ulcerogenic potential and all the tested derivatives were significantly less irritating to gastric mucosa than the parent drug.