Discovery Of Polypharmacological Anti-inflammatory Agents And The Pharmacological Mechanism Study

Until now,the therapy market still has a great need for well-tolerated and effective drugs that will aid chronic inflammatory patients.Currently,a majority of anti-inflammatory drugs in the clinic work by inhibiting a single target,their therapeutic strategies to treat inflammation either directly interferes with the biological function of the pro-inflammatory mediators by interacting with them or their targets or hinders the production of pro-inflammatory mediators.However,the generation and regression of inflammation involves many targets and signaling pathways.It is doubtful whether a magic bullet can be developed based on a single target.Clinically,the drug combination is often used to treat chronic inflammatory diseases through the synergy of multiple inflammatory signaling pathways.Given that the drug–drug interactions and off-target effects of drug combination,polypharmacological agents may be the most effective treatment for chronic inflammatory diseases.In this work,the novel compound from an accidental synthetic reaction was used as the hit compound.After database search and comparison,molecular docking and biological activity tests,we confirmed that the novel compound had anti-inflammatory activity.In further structural optimization,we obtained 19 new compounds,and all of which were confirmed by ¹H-NMR,¹³C-NMR and ESI-MS.The anti-inflammatory activity of compounds was evaluated by mouse model of allergic contact dermatitis and enzymatic assay in vitro,and western bloting was used to investigate their anti-inflammatory mechanisms.The result of this in vivo trial revealed that most compounds exhibited some anti-inflammatory activity.Among them,compound 3f,3j,3n and 6 significantly inhibited ear swelling in mice.Further enzymatic assay identified 3n as a potent inhibitor against both p38αMAPK（IC50=1.95μM）and COX-2（IC50=0.036μM）.As illustrated by the western blot analysis,3n downregulated both the NF-κB signalling and p38 MAPK phosphorylation.By virtue of the concomitant inhibition of p38αMAPK,its upstream effector,and COX-2,along with its capability to downregulate NF-κB and MAPK-signalling pathways,3n,a polypharmacological anti-inflammatory agent,deserves further development as a novel anti-inflammatory drug.