Design, synthesis and biological evaluation of novel 1,2,3-triazoles chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors

A series of chromone-oxime derivatives containing 1,2,3-triazole moieties were designed, synthesized and evaluated for their IDO1 inhibitory activities. These compounds displayed moderate to good inhibitory activity against IDO1 with IC ₅₀ values in low micromolar range. Among them, compound D20 displayed the most potent IDO1 inhibitory activities (hIDO1 IC ₅₀  = 0.084 µM, HeLa IDO1 IC ₅₀  = 0.059 µM) and was selected for further investigation. Surface plasmon resonance analysis confirmed that compound D20 directly interacted with IDO1 protein with a K _D value of 0.57 µM. Molecular docking study revealed the oxygen atom in chromone-oxime moiety of compound D20 coordinated to the heme iron, and the 1,2,3-triazole group formed a hydrogen bond with the key residue ARG231. The UV spectra showed that D20 induced a Soret peak shift from 404 to 415 nm. Furthermore, compound D20 exhibited no cytotoxicity at its effective concentration in MTT assay. In summary, our study suggested that chromone-oxime derivatives containing 1,2,3-triazole moieties might serve as a potential agent for the further development of IDO1 inhibitors.