Design,Synthesis And Screening Of Biological Activity Of Fluorinated Sertraline Analogs

Depression is the fourth largest disease in the world.According to the mechanism of action,drugs for treating depression are divided into five categories,one of which is selective serotonin reuptake inhibitor antidepressants(SSRIs).SSRIs are safer,more efficient,less dosed,less toxic,and have fewer side effects.Sertraline is the mainstream drug for the treatment of depression.Fluorine has special properties such as small size and strong electric absorption.How to efficiently introduce fluorine-containing groups into compounds to obtain the expected fluorine-containing compounds,and to study the potential biological activities of these fluorine-containing compounds,and develop more for humans.Fluorine-containing drugs that bring well-being are the eternal theme of medicinal fluorine chemistry.The first part introduces the study of copper-mediated reaction of naphthyl iododifluoromethyl ketone and block to obtain perylene difluoro substituted tetrahydronaphthone.After screening the conditions to obtain the optimal conditions,the substrate adaptability test is performed.19 compounds were obtained with moderate yield.In order to prove that the reaction has a wide range of applications,the substrate was further transformed to obtain different fluorine-containing molecular structures including-CF2CF2-,-CH(OH)CF2-,etc.,and proved the adaptability of the reaction.Finally,through free radical inhibition reaction and control experiments,it is proved that the reaction is a radical cyclization mechanism involving difluoro radical intermediates.A universal density function(DFT)calculation is also performed to further prove the regioselectivity of the reaction.In the second part,we first designed thirty structural analogues of flusertraline,carried out computer-assisted drug research,screened some compounds with higher activity,and then used copper to mediate the reaction of naphthyl iododifluoromethyl ketone and olefins.The method is to synthesize a tetralinone structure,and then further methylated to obtain two sertraline analogs.This method provides a simple way to develop new sertraline fluorinated analogs for biological activity screening,and it is planned to test them for biological activity in the future.The third part introduces the work of Na BH4 to selectively reduce ?,?,?-iododifluoroacetophenones to prepare ?,?,?-difluoroiodo-1-phenylethanol compounds.This method has a mild reaction,high reduction selectivity,and high stepwise.It is simpler than other methods,the reaction time is greatly shortened,and the efficiency is higher.It is also theoretically suitable for the base and halogen groups in the presence of fluorene difluoro groups.The selective reduction of the group makes this method highly selective and reductive for a large number of ?,?,?-iododifluoroethanone substrates,without any effect on the halogen atom at the ? position,resulting in ?,?,?-difluoro Iodine-1-phenylethanol block.