环丙烷螺环乙內酰脲衍生物的合成及其作为流感病毒神经氨酸酶抑制剂的作用研究

For the purpose of inhibiting influenza virus neuraminidase activity, the study of cyclopropanespirohydantoin derivatives as novel neuraminidase inhibitors will be carried out. Based on the molecular design, synthesis and biological testing, we hope to discover a new type of influenza virus neuraminidase inhibitors with our own intellectual property rights and expected to be used as a non-conventional drug or prodrug for the influenza treatment. According to some reserch results in earlier works, this project comprising of synthesis of seven groups of cyclopropanespirohydantoin derivatives, high-throughput screening to study their inhibitory effect of neuraminidase and the structural optimization of these compounds based on their structure-activity relationships. Moreover, with the aid of computer simulation and protein crystal structure analysis, the possible mechanism of action of these compounds with neuraminidase will also be investigated. The results of this project will likely discover new structure hits with lower toxicity and open a new avenue for influenza treatment, and may avoid the Source and secondary resistance problems faced by the general clinical treatment.

以抑制流感病毒神经氨酸酶的活性为目的，开展新型环丙烷螺环乙內酰脲衍生物抑制剂的研究。从分子设计、合成及生物测试等多方面着手，希望能够发现一类新型的具有我国自主知识产权的流感病毒神经氨酸酶抑制剂，可望用作流感治疗的非传统药物或前体药物。在前期工作中，发现了环丙烷螺环乙内酰胺某些化合物具有较好的神经氨酸酶抑制活性。本课题拟合成七组环丙烷螺环乙內酰脲衍生物，并通过高通量筛选研究其对神经氨酸酶的抑制效果，进而利用构效关系有针对性地进行结构优化，利用计算机模拟和蛋白质晶体结构分析对其与神经氨酸酶的相互作用机理进行研究，探索这些新型化合物作为有效神经氨酸酶抑制剂的可行性。本项目将可能发现新结构和低毒性的抗流感病毒候选药物，为流感治疗开辟一条新的途径，又可能避免目前一般的临床治疗面临的原、继发耐药等主要问题。

以抑制流感病毒神经氨酸酶的活性为目的，开展新型抑制剂的研究。从分子设计、合成及生物测试等多方面着手，设计和成了四大类（螺环乙内酰脲、奥司他韦衍生物、苯甲酸衍生物、嘧啶酮酸酯）共200余个化合物。并通过高通量筛选研究其对神经氨酸酶的抑制效果，进而利用构效关系有针对性地进行结构优化，利用计算机模拟和蛋白质晶体结构分析对其与神经氨酸酶的相互作用机理进行研究，探索这些新型化合物作为有效神经氨酸酶抑制剂的可行性。本项目将可能发现新结构和低毒性的抗流感病毒候选药物，为流感治疗开辟一条新的途径，又可能避免目前一般的临床治疗面临的原、继发耐药等主要问题。