Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.

中文翻译：

---

多巴胺衍生物的合成和SARs作为流感病毒PAN核酸内切酶的潜在抑制剂。

当前，流感PAN核酸内切酶已成为开发用于治疗流感感染的新药物的有吸引力的靶标。在本文中，我们报道了从螯合剂多巴胺部分衍生的新PAN核酸内切酶抑制剂的发现。精心制作了一系列多巴胺酰胺衍生物及其受构象限制的1,2,3,4-四氢异喹啉-6,7-二醇基类似物，并针对流感病毒A / WSN / 33（H1N1）进行了分析。大多数化合物表现出中度到出色的抗病毒活性，产生初步的SAR。其中，与参考的Peramivir相比，化合物14和19显示出更强的抗IAV活性。此外，基于FRET测定和SPR测定，14和19证明了浓度依赖性抑制PAN核酸内切酶。还进行了对接研究，以阐明14和19与PAN蛋白的结合模式，并鉴定参与其作用机理的氨基酸，这与生物学数据非常一致。这一发现为合理开发更有效的PAN核酸内切酶抑制剂奠定了基础。