Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold

Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer’s disease and arthritis. Herein, we report the structure-based design of two related series of molecules: <i>N</i>1-substituted 5-indoleimidazoles and <i>N</i>1-substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure–activity relationship studies