Discovery of Novel 1,2,3-triazole Derivatives as IDO1 Inhibitors

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) has received much attention as an immunomodulatory enzyme in the field of cancer immunotherapy. While several IDO1 inhibitors have entered clinical trials, there are currently no IDO1 inhibitor drugs on the market. To explore potential IDO1 inhibitors, we designed a series of compounds with urea and 1,2,3-triazole structures. Organic synthesis and IDO1 enzymatic activity experiments verified the molecular-level activities of the designed compounds, and the IC₅₀ value of compound 3a was 0.75 μM. Molecular docking and quantum mechanical studies further explained the binding mode and reaction potential of compound 3a with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases.

Keywords: 1,2,3-triazole; indoleamine 2,3-dioxygenase 1; molecular docking; quantum mechanical studies.

Figure 1

Chemical structures of four IDO1 inhibitors.

Figure 2

Pocket surface map of the crystal structure of IDO1 complexed with Amg-1 (PDB code: 4PK5). Purple represents amino acids contained in pocket A; green represents amino acids contained in pocket B.

Figure 3

The reaction routes to compounds 3a–3i, 5a–5f, and 7a–7f.

Figure 4

The binding modes of compounds 3a (A), 5e (B) and 7f (C).

Figure 5

Frontier molecular orbitals of compounds 3a (A), 5e (B) and 7f (C).

Figure 6

MEP surfaces of compound 3a.