Design, synthesis and biological evaluation of exiguamine A analogues as IDO1 inhibitors

A series of exiguamine A analogues were designed and synthesized via 15 steps. Their inhibitory activities against IDO1 were tested and the structure-activity relationships were studied. Most compounds exhibited potent IDO1 inhibitory activities with IC50 values at the level of 10(-7)-10(-8) M. Compound 21f was the most potent IDO1 inhibitor with an IC50 value of 65.3 nM, which was comparable with the positive control drug epacadostat (IC50 = 46 nM). Moreover, compound 21f showed higher selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO) and no cytotoxicity at its effective concentration, rending it justifiable for further optimization and evaluation. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Newly synthesized exiguamine A analogues demonstrated potent inhibitory activities against IDO1, with compound 21f showing high selectivity for IDO1 and no cytotoxicity. Further optimization and evaluation of compound 21f is warranted.