Department of Chemistry and Biochemistry, ‡Department of Pediatrics, and §Department of Molecular and Medical Pharmacology, University of California , Los Angeles, California 90095, United States.
J Med Chem. 2018 Feb 22;61(4):1688-1703. doi: 10.1021/acs.jmedchem.7b01863. Epub 2018 Jan 31.
A series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the structure-activity relationship was obtained by utilizing the variation of four positions, namely, N1, C6, C4, and linker unit. From the screened analogues, the inhibitors with the highest selectivity indices at 50% inhibition of viral replication (SI) were those with isopropyl at the N1 position and thiophenyl-2-yl unit at C6 position. Furthermore, the C4 position offered the greatest potential for improvement because many different N-aryl groups had better antiviral activities and compatibilities than the lead compound JX001. For example, JX040 with a 2-pyridyl group was the analogue with the most potent activity against non-polio enteroviruses, and JX025, possessing a 3-sulfamoylphenyl moiety, had the best activity against polioviruses. In addition, analogue JX037, possessing a novel pyrazolopyridine heterocycle, was also shown to have good antienteroviral activity, which further enlarges the compound space for antienteroviral drug design.
我们设计并合成了一系列新型吡唑并吡啶类化合物，采用一般的合成路线。评估了它们对脊髓灰质炎病毒-1、EV-A71 和 CV-B3 肠道病毒复制的活性。通过改变四个位置（即 N1、C6、C4 和连接单元），全面了解了结构-活性关系。在所筛选的类似物中，在抑制病毒复制 50%时具有最高选择性指数（SI）的抑制剂是 N1 位具有异丙基和 C6 位具有噻吩-2-基单元的抑制剂。此外，C4 位具有最大的改进潜力，因为许多不同的 N-芳基比先导化合物 JX001 具有更好的抗病毒活性和相容性。例如，具有 2-吡啶基的 JX040 是针对非脊髓灰质炎肠道病毒最有效的类似物，而具有 3-磺酰胺基苯基部分的 JX025 对脊髓灰质炎病毒具有最佳活性。此外，具有新型吡唑并吡啶杂环的类似物 JX037 也表现出良好的抗肠道病毒活性，这进一步扩大了抗肠道病毒药物设计的化合物空间。
