Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de-novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the and synthesis apoxidoles, a novel pseudo-NP class, whereby indole- tetrahydropyridine linked in monopodal connectivity found nature. Apoxidoles efficiently accessible an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define new potent type IV inhibitor chemotype indoleamine 2,3-dioxygenase 1 (IDO1), heme-containing enzyme considered treatment neurodegeneration, autoimmunity cancer. apo-IDO1, prevent heme binding induce unique amino acid positioning as crystal structure analysis. Novel apo-IDO1 inhibitors high demand, may opportunities biology medicinal chemistry research.