Structure-activity relationship studies of 5-(Pyridin-3-yl)-1H-indole-4,7-diones as indoleamine 2,3-dioxygenase 1 inhibitors

Indoleamine 2,3-dioxygenase 1 (IDO1) is the key enzyme that catalyzes the conversion of L-tryptophan (Trp) to N-formyl-kynurenine in the tryptophan-kynurenine (Trp-Kyn) pathway. Overexpression of IDO1 contributes to the depletion of Trp and the accumulation of Kyn, which can result in tumor immune escape. Inhibition of IDO1 can restore the host immune response to eradicate cancer cells. 5-(Pyridin-3-yl)-1H-indole-4,7-dione was developed as the scaffold for a type of IDO1 inhibitors from simplification of the structure of exiguamine A in our previous work. In the present study, we designed and synthesized a series of compounds with different side-chain substituents, and linkers of varying lengths, at the 3-position, to design compounds with an aryl motif that can occupy pocket B of the IDO1 protein. Most compounds exhibited potent IDO1 inhibitory activity with IC50 values at the micromolar level, and 3-(2-((4-fluorobenzyl)amino)ethyl)-5-(3-pyridyl)-1H-indole-4,7-dione (1d) displayed the most potent inhibition with a half-maximal inhibitory concentration (IC50) value of 0.125 mu M in an enzymatic assay and a half-maximal effective concentration (EC50) value of 0.821 mu M in a cellular assay. Compound 1d showed higher selectivity for IDO1 over indoleamine 2,3-dioxygenase 2 and tryptophan 2,3-dioxygenase at the effective concentration. Molecular docking studies and molecular dynamic simulations suggested that the phenyl ring of these inhibitors can enter into pocket B of IDO1 and interact with the residue Phe 226 through hydrophobic interactions.