作用于人IMPDH的新型苯基噁唑类抗病毒药物的设计、优化及活性研究

Guanine, which can not be synthesized by virus, is indispensable for the virus replication. The virus can replicate only by utilizing the guanine nucleotides from host cell. Therefore, inosine 5-monophosphate dehydrogenase (IMPDH) which controls the gateway to guanine nucleotides can serve as target for the discovery of broad-spectrum antiviral agents. In our previous study, based on the X-ray crystal structure of NAD active site and chemical structures of the ligand, target structure-based drug design and structural optimization have been conducted. Some computer-assistant designed compounds have been synthesized and their antiviral activities were also evaluated. Phenyl oxazole derivatives such as 0520-2 showed potent inhibitory activities both against IMPDH and also virus, and both their antiviral activity and selectivity were superb to that of RBV. In this project, taking compounds with good antiviral activity as the lead compounds, we continue to investigate the design, structural optimization (using computer-assistant drug design) and structure-activity-relationships of phenyl oxazole derivatives. Compounds with inhibitory activity against IMPDH are evaluated for their activity against sensitive strains such as HCV, Cox, and EV71 etc and drug resistant strains such as HIV-1, HBV, flu etc, in order to discover novel agents with broad-spectrum antiviral activities, activity against drug resistant strains and low toxicity, and lay a solid foundation for the research and development of novel antiviral drugs.

病毒不能合成鸟嘌呤，必须依靠宿主细胞的鸟嘌呤核苷酸作为基础物质才能完成自身复制，对宿主细胞次黄嘌呤核苷酸脱氢酶(IMPDH)进行抑制可产生广谱抗病毒作用。前期研究中，依据人IMPDH2催化中心NAD结合位点空间结构及结合于该位点已知化合物的母核骨架，课题组进行了基于靶点结构的药物设计与结构优化，并对虚拟优化得到的分子结构进行合成与活性验证，筛选得到了体外对IMPDH和实验病毒均显示强抑制活性的苯基噁唑化合物0520-2等，抗病毒活性与选择性均优于对照药RBV。本课题将以前期得到的活性化合物为先导结构，借助计算机辅助药物设计，继续进行苯基噁唑类的分子设计、优化和构效关系研究，对具有IMPDH抑制活性的化合物，进行抗HCV、Cox、EV71等病毒敏感株和抗HIV-1、HBV、流感等病毒耐药株的活性，以寻找抗病毒谱广、对耐药株有效及毒性降低的新结构类型化合物，为新型抗病毒药物研究发现打下基础。

次黄嘌呤核苷酸脱氢酶(IMPDH)是鸟嘌呤核苷酸（GMP）生物合成关键酶,抑制IMPDH将导致GMP缺乏,核酸合成受阻。人IMPDH有两种亚型，其中，2型显示为诱导性表达，在增殖细胞或病毒侵袭细胞内的表达水平会不断提高。病毒不能合成鸟嘌呤，必须依靠宿主细胞的GMP作为基础物质才能完成自身复制，对宿主细胞IMPDH进行抑制可产生抗病毒作用。依据人IMPDH2催化中心NAD结合位点的空间结构及结合于该位点已知活性化合物的母核骨架，进行基于靶点结构的药物设计与结构优化，并对虚拟优化结构进行合成及活性验证，课题研究得到了体外对IMPDH、HBV和Cox病毒均显示强抑制活性的苯基噻唑化合物0520-2等，抗病毒活性强于先导物MPA及对照药RBV，选择性指数也较MPA有明显改善。本课题在前期研究基础上，继续进行苯基噻唑类的分子设计与优化研究，以期发现新型抗病毒药物。.课题研究完成了项目任务书规定的研究计划，实现预期目标。项目任务书中计划的研究策略，完成了噁唑苯基脲类、酰胺或双酰胺类、胺类和亚胺类、N-取代胺类化合物、硫脲类和胍类和苯并杂环胺类等不同化合物的合成方法研究；共合成目的物253个，其中未见文献报道的新化合物249个；对所有目标化合物进行了结构确证(1H NMR, 13C NMR, HR-MS)，并确证了4个化合物的晶体结构；进行了抗病毒生物活性研究。研究得到具有强抗HCV、抗CVB3和CVB6的胺类化合物8个，对其中的3个进行了制备工艺、理化性质与质量控制方法、晶体结构、初步急性毒性、早期代谢评价等药物候选物研究；筛选得到硫脲类强IMPDH抑制活性化合物7个、并杂环氨衍生物中得到抗流感病毒、抗CVB3的活性化合物7个；总结了各类化合物的构效关系。除抗病毒活性和IMPDH活性外，还检测了部分化合物对人肝癌细胞HepG2和人肺腺癌细胞A549的抑制作用、抗结核杆菌活性及对脾细胞增殖抑制活性等，也得到较好结果。.总结发表SCI文章2篇，综述1篇，授权中国专利2项，申请PCT专利和美国专利各1项。培养毕业硕士生1名、博士生2名。