A multicomponent approach in the discovery of indoleamine 2,3-dioxygenase 1 inhibitors: Synthesis, biological investigation and docking studies.
Bioorg Med Chem Lett
; 28(4): 651-657, 2018 02 15.
Article
en En
| MEDLINE
| ID: mdl-29398544
ABSTRACT
Indoleamine 2,3-dioxygenase plays a crucial role in immune tolerance and has emerged as an attractive target for cancer immunotherapy. In this study, the Passerini and Ugi multicomponent reactions have been employed to assemble a small library of imidazothiazoles that target IDO1. While the p-bromophenyl and the imidazothiazole moieties have been kept fixed, a full SAR study has been performed on the side-chain, leading to the discovery of nine compounds with sub-micromolar IC50 values in the enzyme-based assay. Compound 7d, displaying a α-acyloxyamide substructure, is the most potent compound, with an IC50 value of 0.20⯵M, but a low activity in a cell-based assay. Compound 6o, containing a α-acylaminoamide moiety, shows an IC50 value of 0.81⯵M in the IDO1-based assay, a full biocompatibility at 10⯵M, together with a modest inhibitory activity in A375 cells. Molecular docking studies show that both 7d and 6o display a unique binding mode in the IDO1 active site, with the side-chain protruding in an additional pocket C, where a crucial hydrogen bond is formed with Lys238. Overall, this work describes an isocyanide based-multicomponent approach as a straightforward and versatile tool to rapidly access IDO1 inhibitors, providing a new direction for their future design and development.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tiazoles
/
Inhibidores Enzimáticos
/
Indolamina-Pirrol 2,3,-Dioxigenasa
/
Imidazoles
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia