Discovery of novel sulfonamide chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors

• Published in: European journal of medicinal chemistry 2023-06, Vol.254, p.115349-115349, Article 115349
• Main Authors: Wang, Ke, Song, Long-Hao, Liang, Qiao-Ling, Zhang, Ye, Ma, Xian-Li, Wang, Qi, Zhang, Hui-Yong, Jiang, Cai-Na, Wei, Jian-Hua, Huang, Ri-Zhen
• Format: Article
• Language: English
• Subjects: Animals; Anticancer agents; Chromone-oxime; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heme; Indoleamine 2,3-dioxygenase 1; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inhibitors; Mice; Molecular Docking Simulation; Oximes - pharmacology; Structure-Activity Relationship; Sulfonamide; Sulfonamides - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115349

A series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed, synthesized and evaluated for their inhibitory activities against IDO1. These compounds displayed moderate to good inhibitory activity against IDO1 with IC50 values in low micromolar range. Among them, compound 10m bound effectively to IDO1 with good inhibitory activities (hIDO1 IC50 = 0.64 μM, HeLa IDO1 IC50 = 1.04 μM) and were selected for further investigation. Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein. Molecular docking study of the most active compound 10m revealed key interactions between 10m and IDO1 in which the chromone-oxime moiety coordinated to the heme iron and formed several hydrogen bonds with the porphyrin ring of heme and ALA264, consistent with the observation by UV–visible spectra that 10m induced a Soret peak shift from 403 to 421 nm. Moreover, compound 10m exhibited no cytotoxicity at its effective concentration in MTT assay. Consistently, in vivo assays results demonstrated that 10m displayed potent antitumor activity with low toxicity in CT26 tumor–bearing Balb/c mice, in comparison with 1-methyl-l-tryptophan (1-MT) and 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L). In brief, the results suggested that chromone-oxime derivatives containing sulfonamide moieties might serve as IDO1 inhibitors for the development of new antitumor agents. [Display omitted] •A novel series of chromone-oxime derivatives containing piperazine sulfonamide moieties were designed and synthesized.•Compound 10m exhibited potent IDO1 inhibitory activity.•Surface plasmon resonance analysis confirmed the direct interaction between compound 10m and IDO1 protein.•Molecular modeling suggested that 10m coordinated to the heme iron in the active site of IDO1.•Compound 10m displayed potent antitumor activity with low toxicity in a CT26 tumor–bearing BALB/c mice.