Design,Synthesis And Biological Evaluation Of Indole-2-amides As COX-2/5-LOX Dual Inhibitors

The inflammatory mediators produced by the arachidonic acid cascade pathway are the main cause of many human diseases.Cyclooxygenase and lipoxygenase,as the main rate-limiting enzymes regulating the cascade reaction,have always been important drug targets.Traditional non-steroidal anti-inflammatory drugs(t NSAIDs)work by non-selective inhibition of cyclooxygenase pathway,but cause severe gastrointestinal side effects.Subsequent,selective COX-2 inhibitors have a potential cardiovascular risk.A large number of clinical results have demonstrated that inhibition of any one of the cascade reaction pathways may lead to the transfer of excessive metabolism to another,and leading to the emergence of adverse reactions.Therefore,dual mechanism anti-inflammatory drugs that can simultaneously inhibit the release of prostaglandins and leukotrienes are urgently needed.Although some drugs have been synthesized and their biological activity has been verified,they cannot be used in clinical practice due to toxicity and other reasons.This study that based on the previous research results,indole as a privileged scaffold,was first designed and synthesized 11 indole-2-amide compounds,and the target compounds were tested in vivo as a model of inflammation,Inhibition of COXs/5-LOX enzyme activity and molecular docking experiment.in order to studying the effect of dual inhibitors on tumor proliferation,new 12 compounds were to further optimize and synthesized,and were tested in vitro antiproliferative and cell apoptosis experiment.All the compounds were confirmed by the structure of the spectraExperiment results show that compared with positive control dexamethasone,compound 7f,7g and 7i have showed good anti-inflammatory activity in vivo.Among them,7f manifested similar to positive control of anti-inflammatory activity.And the enzyme inhibition experiment,the compound 6 and 7f showed quite COX-2/5-LOX inhibitory activities compared with positive control celecoxib and zileuton,and had the good COX-2 selective.In docking experiment of compound 7f,we found that the combination of its and COX-2 way similar to celecoxib with it.Further anti-tumor activity test,compounds 7f and 8b shows good antiproliferative activity,among them,the anti-proliferation activity of 8b against HCT-116 and A549 cell lines was significantly better than that of the positive control,and also showed excellent antiapoptotic activity in apoptosis experiment.The research work of this study showed certain value for the development of COX-2/5-LOX dual inhibitor drugs.