N-苯磺酰苦参酸衍生物抗柯萨奇病毒B3的构效关系以及活性小分子探针的化学构建

Up to now, no specific anti-enterovirus drug has been approved. Our patented compound (E)-12-N-(m-cyanobenzenesulfonyl)sophocarpinic acid (IMB84) bearing a novel structure skeleton, showed a reasonable inhibition towards coxsackie virus B3 (CVB3) as well as other enteroviruses. Besides, it exhibited a good druggable characteristics demonstrated by a low toxicity and good pharmacokinetic parameters..Based on theses original work, taking IMB84 as the lead, an anti-CVB3 activity-oriented systematic structural modifications and optimization focusing on its structural fragments will be carried out in the titled project, at least 200 sophocarpine acid derivatives with novel structures will be synthesized to illustrate their anti-CVB3 structure-activity relationships (SAR). By a comprehensive evaluation study on their activities against other enteroviruses, for example, CVB6, CVA16, EV71, toxicity, pharmacokinetics as well as pharmacodynamics properties in vivo, several novel anti-CVB3 and / or broad-spectrum anti-enterovirus candidates characterized by a high drugabbility will be selected out, so as to provide candidates for the treatment of viral myocarditis, and provide a strategic reserve for emergency and prevention of acute enterovirus infections. On the other hand, active biotin-tagged and Rhodamine B-tagged probe molecules will be constructed in the study, which will certainly serve as important chemical tools to explore the anti-CVB3 mechanism of sophocarpine acid analogues and provide key scientific data and material basis for their development into a class of innovative anti- enterovirus drugs.

迄今尚未有专门用于抗肠道病毒药物批准上市。我们自主创新、全新结构N-间乙腈苯磺酰苦参烯酸(IMB84)对柯萨奇病毒B3(CVB3)显示较强活性，对多种肠道病毒有效，还拥有毒性低、药代参数良好等成药性特征。.本项目拟在一系列原创性工作基础上，以IMB84为先导物，抗CVB3活性为导向，对分子中多个结构片断开展系统结构修饰与优化，累计合成不少于200 个新衍生物，阐明构效关系。通过对CVB6、CVA16、EV71等测定, 以及初步毒性、药代及体内药效等综合性评价，优选成药性高、抗CVB3强和广谱抗肠道病毒候选物，为病毒性心肌炎的治疗提供候选物；为突发肠道病毒性疾病爆发的应急与防控提供战略储备。另外，构建生物素亲和标记和罗丹明荧光标记的两类活性目标探针，为探索其全新抗CVB3作用机制提供重要的化学工具。为将此类化合物发展成一类抗肠道病毒创新药物提供关键的科学数据与物质基础。

迄今尚未有专门用于抗肠道病毒药物批准上市。我们自主创新、全新结构N-间氰基苯磺酰苦参烯酸(IMB84)对柯萨奇病毒B3(CVB3)显示较强活性，对多种肠道病毒有效，还拥有毒性低、药代参数良好等成药性特征。.本课题以IMB-84为先导化合物，以抗CVB3为活性导向，开展了系统的结构修饰与优化，通过合成200余个目标化合物，成功构建一个具有自主知识产权的N-取代苦参烯酸类似物库。基本阐明此类化合物抗CVB3的构效关系：12N上引入苯甲/磺酰有利于活性的提高，5S手性构型为活性必需，11-侧链的双键为活性非必需基团，苦参丁烷类化合物普遍具有广谱抗柯萨奇病毒活性。获得了一个具有自主知识产权12-N-苯磺酰苦参酰胺化合物IMB-21j，体外显示出良好的抗CVB3活性，可以作为抗CVB3候选物进一步研究；获得了12-N-苯磺酰苦参丁烷化合物DB-11，其在体外对多种柯萨奇病毒均显示出良好的抑制活性，且具有药代稳定、安全性高等成药性特征，可以作为广谱抗CVBs活性的化合物推荐进入临床前研究。成功构建了活性生物素亲和标记探针分子可以作为有效的化学工具开展机制研究。获奖2项(包括中国药学会科学技术二等奖一项），发表SCI论文4篇，中文核心期刊一篇，申请发明专利2项，顺利完成了研究任务。