Discovery of imidazoleisoindole derivatives as potent IDO1 inhibitors: Design, synthesis, biological evaluation and computational studies

摘要

Abstract Indoleamine-2,3-dioxygenase-1 (IDO1) is an attractive target for cancer immunotherapy. Herein, a series of novel imidazoleisoindole derivatives were prepared and evaluated for their ability to inhibit IDO1. Among these, derivative 11r was the most active compound with nanomolar potency in the Hela cell-based assay, while showed negligible cellular toxicity. UV-visible spectra study demonstrated that compounds 11p and 11r bound to IDO1 and coordinated with the heme iron. Furthermore, they could significantly promote T cell proliferation, increase IFN- γ production, and reduce the numbers of Foxp3 + regulatory T cells. Finally, induced fit docking (IFD) and quantum mechanics/molecular mechanics (QM/MM) calculation were performed to understand the interactions of these compounds to IDO1 protein, which provided a comprehensive guide for further structural modification and optimization. Graphical abstract Display Omitted Highlights ? The extensive structural modification of GDC-0919 analogue was explored. ? T-lymphocytes assays were performed to evaluate the capacity of the compounds in the reversal of IDO1-mediated immunosuppression. ? UV spectra provided a direct evidence of our compounds binding to the active site of IDO1. ? Molecular simulations were performed to predict the binding mode of our compounds.