Design,Synthesis And Anti-inflammatory Effect Of Novel Naproxen Derivatives Containing Cinnamic Acids

Excessive inflammation brings pain to the patients,which may even lead to death.As a non-steroidal anti-inflammatory drug,naproxen can effectively alleviate excessive inflammation.However,long-term use of naproxen will lead to numbers of adverse effect.In order to obtain new anti-inflammatory drug,with excellent anti-inflammatory activity and low toxicity,S-（+）-naproxen,used as the basic skeleton,would be modified with cinnamic acid and its analogues due to the diversity of biological activity and low toxicity.The biological assays in vitro and mechanistic studies of the novel derivatives would be determined to obtain new anti-inflammatory drugs with high efficiency and low toxicity.Firstly,the basic skeleton S-（+）-naproxen was modified with cinnamic acid and its analogues by Steglich esterification reactions,and the 88 novel derivatives synthetized were classified into three series,and characterized for their physical properties and chemical structures in order to confirm their purity and geometries.Secondly,LPS-induced RAW 264.7cell model was uesd to test the NO release inhibition of novel derivatives at 50μM and their IC₅₀.Meanwhile,the cytotoxicity tests of the derivatives were carried out by MTT experiments.Thirdly,the anti-inflammatory mechanism of the derivatives which respectively has the highest NO release inhibition and low cytotoxicity from three series were tested by Western Blotting experiment.Finally,the interactions between the selected derivatives and the inflammatory cytokines were simulated by a docking software called Sybyl-X 2.0.The chemical structures of the 88 novel derivatives have confirmed and they show the high purity.Through the anti-inflammatory experiments and the cytotoxicity tests in vitro,ten derivatives with excellent anti-inflammatory activity and low toxicity have been screened in present study（Compound 10,23,26,28,53,58,68,73,86 and 87）.The anti-inflammatory mechanistic studies reveal that Compound 23,53 and 68 which has the strongest inhibition on NO release from three series,can block up the NF-κB signal pathway and inhibit the over-expression of NLRP3 inflammasome and the three cytokines（i NOS,COX-2 and IL-1β）.The docking results indicate that as the three compounds are embedded in the active pockets,the certain interactions between the three compounds and the cytokines above emerge.In the thesis,Compound 23,53 and 68 with advantages of high efficiency and low toxicity,effectively block up NF-κB signal pathway effectively and inhibit the over-expression of NLRP3 inflammasome and the three inflammatory cytokines（i NOS,COX-2 and IL-1β）,thus inhibiting NO release.Therefore,the synthetic strategy of anti-inflammatory drugs modified with natural molecules with biological activity is expected to provide new thoughts for the further researches of new anti-inflammatory drugs.