Synthesis And Anti-Inflammatory And Analgesic Activities Of Pyrrolizinone Derivatives

The synthesis and structure-activity relationship(SAR) of the novel nonsteroidal anti-inflammatory agents, 1H-1, 2-dihydro-l-pyrrolizinone derivatives were reported in this paper.Nonsteroidal anti-inflammatory drugs(NSAIDs) are widely used in the treatment of arthritis and pain in clinic. However, most of the NSAIDs used in clinic now cause serious side effects on the gastrointestinal tract and kidney. Therefore, developing new anti-inflammatory agents with lower toxicity have been the interest of this research field. Since the study of mechanism of inflammation has made great achievements in the late last century, the research on NSAIDs has also made great progresses in recent years. Many new anti-inflammatory agents with new anti-inflammatory mechanism have been developed, such as selective inhibitors of cyclooxygenase-2(COX-2), dual inhibitors of cyclooxygenase and 5-lipoxygenase(COX/5-LOX) and nitric oxide-releasing NSAIDs(NO-NSAIDs), and so on. Some of them have been applied in clinic.It has been found that some pyrrolizinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR reported in our laboratory, and with computer-aided drug design, three types of pyrrolizinones were designed for further study of the SAR. Fifty-six new pyrrolizinone derivatives were synthesized with some new synthetic schemes, including twenty-five 5-arylpyrrolizinones, fifteen 5-aroyl-pyrrolizinones and sixteen 5-aralkylpyrrolizinones, and among them, fifty-one compounds have not been found in literature.With acetophenones as starting materials, a new synthetic scheme was developed for the synthesis of 5-arylpyrrolizinones, and it worked well. Also a facilescheme was designed for synthesis of 5-aralkylpyrrolizinones from pyrrole through acylation, reduction, Michael addition and Hoesch reaction.The anti-inflammatory activity was evaluated with xylene-induced ear swelling in mice, and the analgesic activity was evaluated with writhing induced by acetic acid in mice. Most of the prepared compounds showed remarkably anti-inflammatory and/or analgesic activities at a dose of 200 mg/kg. The activities of compounds ZY-302, ZY-309, ZY-319, ZY-337, ZY-340 and ZY-351 are comparable to ibuprofen, the positive control. Therefore, they are regarded as valuable compounds for further study to develop new anti-inflammatory drugs.Some SAR could be found from the results of pharmacological tests above. For 5-arylpyrrolizinones, the alkyl and sulfur-containing groups at 4 position of the benzene ring make great contribution to the anti-inflammatory and analgesic activities; while amino, hydroxy, alkoxy and amido might decrease the activities. Most of 5-aralkylpyrrolizinones have remarkable analgesic activity. The 3D-QSAR of the compounds has been studied with the computer-aided drug design CoMFA. The results show that the nature of a variety of substituents on the phenyl moiety play an important role for the anti-inflammatory and analgesic activities. These would be very helpful for new designs of the compounds of the kind.In conclusion, most of the synthesized compounds have definite anti-inflammatory and analgesic activities and they are promising for developing new potent anti-inflammatory and analgesic agents.