Evaluation of mode of indoleamine 2,3-dioxygenase 1 inhibition by 4,7-dichloroquinolines

Herein, we report the development of synthetically simpler analogs of 4,7-dichloroquinoline (DCQ) as apo-indoleamine 2,3-dioxygenase 1(IDO1) protein targeting ligand to inhibit the activity of IDO1 enzyme. Derivatization of the DCQ moiety improved the IDO1 inhibitory activity both against purified enzyme and the cellular environment without any significant cytotoxicity, leading to the identification of piperazine containing DCQ derivative DCQ4 as a potent IDO1 inhibitor. A series of biophysical studies, including UV–Vis spectroscopy of the Soret band, docking, as well as protoporphyrin IX binding studies, suggested that the IDO1 inhibitory activity of potent compound could be due to its direct binding to apo-IDO1 protein and formation of DCQ4-heme complex. This simple strategy of developing apo-IDO1 targeting molecules having DCQ, piperazine, and amino acid moieties as potent IDO1 inhibitors could be useful in fighting against immune-related diseases.