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

Indoleamine 2,3-dioxygenasel(IDO1)is a heme-containing monomeric enzyme.Itis the rate-limiting enzyme of the tryptophan catabolism pathway.Oxidation of the pyrrole ring of L-Trp by IDO1 produced the N-formylkynurenine(NFK)kynurenine,quinolinic acid and other cytotoxic metabolites.Recently,It has been shown that IDO1 is emerging as a potential target for the treatment of avariety of major human diseases,such as cancer,cataracts,neurological diseases et al.The IDO1 protein consists of two major domains,one is large and theother is small.The active site is located in the large domain.Wherein this domain contains two catalytic pockets(The crystal structures of human IDO1 show one binding pocket in the distal heme site connected to a second pocket toward the entrance of the active site.)The substrate Trp interacts with IDO1 in the catalytic pocket through hydrogen bonds,salt bridges,and hydrophobic effects.Many IDO1 inhibitors have been reported to bind to the A,B pockets.Although many IDO1 inhibitors have been reported,only nine of them have entered clinical studies.In this thesis,4-phenyl imidazole(4-PI)was used as a reference compound.Based on the basic principles of drug design,A series of 2-phenyl-1,3,4-thiadiazole derivatives were designed and synthesized.Totally,54 4-PI derivatives(A-D Series)and 13 other types of compounds(E-G Series)were obtained.Their IDO1 inhibitory activity was evaluated,and the inhibition rate at single concentration was obtained,and the structure-activity relationship was analyzed.Aseries of compounds exhibited higher inhibitory activity for IDO1,which containedthiadiazole heterocyclic moiety.Among all these compounds,compound A40displayed the most potent inhibitory effect,with inhibitory rate against IDO1 36%at 20 ?M.Overall,these compounds demonstrated low to moderate inhibitory activity against IDO1.Further exploration is needed to discover more active compounds.