Identification of Substituted 1H-Indazoles as Potent Inhibitors for Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase 1

Overexpression of the immunosuppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1) is associated with poor prognosis of patients for a wide range of malignancies. IDO1 is a validated target for the treatment of diseases that are associated with immune suppression, including cancer. In this report, we described the synthesis of a series of C3-substituted 1H-indazoles. Activity studies of IDO1 enzyme assisted to the identification of 3-carbohydrazide derivatives of 1H-indazoles, 5a and 5d (IC50=720 and 770 nM, respectively) as potent inhibitors with negligible cytotoxicity. Moderate selectivity of these potent compounds for IDO1 enzyme over tryptophan 2,3-dioxygenase enzyme (17-25 fold) also suggest that these heterocyclic compounds are attractive molecules for immunotherapeutic applications.