A privileged dual action Alzheimer's disease therapeutic platform targeting immunopathic and proteopathic mechanisms: (E)-3-styrylindoles as inhibitors of indoleamine 2,3-dioxygenase-mediated tryptophan metabolism and β-amyloid aggregation

Abstract

The design of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors targeting immunopathic neuroinflammation has emerged as an area of interest for the treatment of Alzheimer's disease (AD); additionally, recent findings on the clinical benefits of antibodies preventing β-amyloid (Aβ) aggregation have renewed efforts to discover small molecule anti-aggregants targeting proteopathic protein misfolding. Exploiting an endogenous tryptophan-like scaffold, we describe the design and synthesis of small-molecule inhibitors of both immunopathic and proteopathic processes, thus presenting the possibility of single therapeutics acting simultaneously on multiple AD pathogeneses. Specifically, investigations on compounds that inhibit both IDO1 (in human recombinant enzyme, transfected HEK293 cells, and interferon-γ stimulated human microglia assays) and Aβ aggregation (in thioflavin-T and biotinylated-Aβ oligomeric assays) are presented. Five compounds have been identified with high potency against both targets, identifying ( E)-3-styryl indoles as useful tool compounds for developing Alzheimer's therapeutics. Brain penetration of these compounds via passive diffusion or active transport was predicted using Blood-Brain Barrier Score and Brain Exposure Efficiency Score calculations, respectively; the effects of efflux (pgp, BCRP), and influx (OCT1, OCT2) transporters were similarly predicted. Structure–activity relationships were rationalised with molecular docking and molecular dynamics simulations, which also provide insights for future lead compound optimisation.