Design,Synthesis And Activity Evaluation Of Indoleamine 2,3-Dioxygenase 1 Inhibitor

Kynurenine pathway of tryptophan(Trp)metabolism play a central role in immune escape,which leads to the depletion of more than 95%of dietary tryptophan(Trp)metabolism.This process will generate a number of bioactive metabolites,which are responsible for local immunosuppression.Indoleamine 2,3-dioxygenase 1(IDO1)catalyzes the initial and rate limiting step of the kynurenine pathway,high IDO1 expression is associated with poor prognosis in avariety of cancer types.Both in vitro and in vivo studies demonstrate that co-administration of an IDO1 inhibitor would improve the efficacy of therapeutic vaccination,chemotherapy,or radiationtherapy.Apart from cancer,inhibition of IDO1 helps to improve therapeutic outcome in neurological disorders,such as schizophrenia,Alzheimer's diseasesa and Huntington's.Therefore,IDO1 inhibition is suggested to posess therapeutic potentical for the treatment of diseases such as cancer which involves pathological immune escape.In this thesis,4-phenyl imidazole(4-PI)was employed as a reference compound as well as a fragment as further IDO1 inhibitor design.Thiazole and triazole were used as bioisosteric substituents of the imidazole group.A total number of 29 4-PI derivatives(A Series)were designed and synthesized.Next,triazole and triazole thiadiazolo derivatives were employed isosteric groups of imidazole,and a total number of 36 triazolederivatives(B Series)and 20 triazole thiadiazolo derivatives(C Series)were synthesized and evaluated as inhibitors of EDO1 using reported enzymatic assay method.Structure activity relationship was discussed and summarized.Overall,The A Series of compounds exhibited higher inhibitory activity for IDO1,including the thiadiazole and 1,2,4-triazole heterocyclic moiety.the B series displayed the highest inhibitory activity for IDO1.Among these compounds,Bll B19 B21 B24 displayed higher than 50%IDO1 inhibitory activity at 20?M.By comparision,the C series of compounds demonstrated low inhibitory activity against IDO1.