Design,Synthesis,and Bioactivity Evaluation Of DJ-1 Inhibitors,and The Nickel-Catalyzed C3-Acylation Of 2H-indazoles With Aldehydes

DJ-1 protein is widely expressed under physiological conditions,and its active form is usually dimer.Recently,many studies have shown that DJ-1 is a kind of deglycosylation enzyme,and as a result,its main function is composed of deglycosylation.Therefore,measuring the activity of its deglycosylase can well reflect the protein activity of DJ-1,which can be used to build a biological model for biological evaluation of the compounds that inhibit DJ-1 protein.In this paper,19 hydrazide compounds and 18 isatoic compounds have been designed and synthesized based on the previous studies in the laboratory and the newly reported eutectic structures of DJ-1 and active ligands,respectively.The biological activity test was carried out via deglycosylase method.The results showed that hydrazide compounds have shown no obvious inhibition on DJ-1 protein,while some of the isatin compounds not only showed the inhibition of DJ-1 protein,of which is even better than the controls.Among them,B12 compound showed the best inhibitory effect on DJ-1,and the inhibition rate was as high as 80%.This provides a direction for the further optimization of DJ-1 protein inhibitors.In addition,the direct acylation at C3 site of 2H-indazole initiated by free radicals was also studied.Through the screens of experimental conditions and the discussions of the adaptability of many substrates,we have obtained a new method to directly synthesize 3-acyl-2H-indazole by coupling the C3 position of 2H-indazole with acyl group.In the presence of free radical initiator TBHP and additive PivOH,the direct acylation of 2Hindazole with aldehydes was carried out by free radical route with nickel chloride as catalyst.This method provides a better way for the direct C3 acylation of 2H-indazole,and the highest yield is 91%.At the same time,the method has good tolerance to all kinds of substituted 2H-indazole.Comparing with the previously reported 2H-indazole C3 acylation method,this reaction is a more simple and economic method,which opens a new chapter for improving the diversity of indazole derivatives.