Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) are rate-limiting enzymes in the kynurenine pathway (KP) of L-tryptophan (L-Trp) metabolism and are becoming key drug targets in the combination therapy of checkpoint inhibitors in immunoncology. To discover a selective and potent IDO1 inhibitor, a structure-activity relationship (SAR) study of N-hydroxybenzofuran-5-carboximidamide as a novel scaffold was investigated in a systematic manner. Among the synthesized compounds, the N-3-bromophenyl derivative 19 showed the most potent inhibition, with an IC₅₀ value of 0.44 μM for the enzyme and 1.1 μM in HeLa cells. The molecular modeling of 19 with the X-ray crystal structure of IDO1 indicated that dipole-ionic interactions with heme iron, halogen bonding with Cys129 and the two hydrophobic interactions were important for the high potency of 19.

人吲哚胺 2,3-双加氧酶 1 ( h IDO1) 和色氨酸双加氧酶 ( h TDO) 是L-色氨酸 ( L- Trp) 代谢犬尿氨酸途径 (KP) 的限速酶，正在成为组合中的关键药物靶点免疫肿瘤学中检查点抑制剂的治疗。为了发现一种选择性和有效的 IDO1 抑制剂，以系统的方式研究了N-羟基苯并呋喃-5-羧酰亚胺酰胺作为一种新型支架的构效关系 (SAR) 研究。在合成的化合物中，N -3-溴苯基衍生物 19 显示出最有效的抑制作用，IC ₅₀该酶的值为 0.44 μM，HeLa 细胞中的值为 1.1 μM。具有 IDO1 的 X 射线晶体结构的 19 的分子模型表明，与血红素铁的偶极离子相互作用、与 Cys129 的卤素键合以及两种疏水相互作用对于 19 的高效能很重要。