Nanomolar potency of imidazo[2,1-b]thiazole analogs as indoleamine 2,3-dioxygenase inhibitors

Novel series of imidazo[2,1-b]thiazole analogs were designed, synthesized, and biologically evaluated as indoleamine 2,3-dioxygenase (IDO1) inhibitors. Imidazo[2,1-b]thiazoles 6, 7, and 8 showed inhibitory profiles against IDO1 at IC50 values of 68.48, 82.39, and 48.48 nM, respectively, compared with IDO5L at IC50 67.40 nM. Benzo[d]imidazo[2,1-b]thiazoles 17, 20, and 22 showed promising IDO1 inhibition at IC50 values of 53.58, 53.16, and 57.95 nM, respectively. Compound 7 showed a growth-inhibitory profile at GI of 39.33% against the MCF7 breast cancer cell line, while 8 proved lethal to ACHN renal cancer cells. Cells treated with compounds 17 and 22 showed a typical apoptosis pattern of DNA fragments that reflected the G0/G1, S, and G2/M phases of the cell cycle, together with a pre-G1 phase corresponding to apoptotic cells, which indicates that cell growth arrest occurred at the S phase. Molecular modeling simulations validated the potential of benzo[d]imidazo[2,1-b]thiazole analogs to chelate iron(III) within the IDO1 binding pocket and, hence, to have a better binding affinity via hydrophobic-hydrophobic interactions.

Automated summary

A series of imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole analogs were synthesized and evaluated for their inhibitory effects on IDO1, with several compounds showing promising activity. Molecular modeling simulations suggested that these analogs can chelate iron(III) within the IDO1 binding pocket and have better binding affinity through hydrophobic interactions.