新型抗幽门螺杆菌药物的骨架构建及其生物活性研究

Treatment with anti-Helicobacter pylori drugs is one of the important means in the field of gastrointestinal diseases, but the drug resistance and side effects caused by non-selective effect restrict the clinical application. Based on the previous studies on natural leading compound furancoumarin against Helicobacter pylori, which were first discovered and reported by our group, this project is focused on the design and evaluation of novel selective anti-Helicobacter pylori drugs via scaffold hopping to broaden the design range and druggability. Under the guidance of computer-aided Helicobacter pylori urease docking, two classes of molecular system are designed by scaffold hopping, including structure-simplified unsaturated lactone derivatives and new lactone scaffold. Combined with antibacterial and urease inhibitory activity, the characteristics of structure-activity relationship will be disclosed. This project can provide a novel class of selective anti-Helicobacter pylori drug against drug-resistant and lay the theoretical and experimental foundation for the effective, safe treatment of Helicobacter pylori infection.

抗幽门螺杆菌（Hp）药物是胃肠病治疗领域中里程碑式的突破，但耐药问题和非选择性抗菌治疗导致的毒副作用严重制约了其临床应用。申请者曾发现报道了天然呋喃香豆素骨架的选择性抗Hp活性及抗耐药特性，但与现有药物相比优效性有待提高。新近的骨架考察及靶点对接研究揭示了抗耐药、选择性抗菌作用基本药效团结构及选择性作用机制。本课题在前期基础上，采用保留苯并不饱和内酯基本药效团和全新Hp脲酶对接模式两种方式进行骨架迁越，拓宽设计空间和边链操作范围，增加优化和成药性可能，在计算机对接辅助设计指导下，构建两类全新结构类型的骨架体系，结合抗菌和脲酶抑制活性，阐明其骨架迁越可行性及构效关系规律，为进一步创制高效、抗耐药和副作用小的选择性抗Hp感染治疗药物奠定理论与实验基础。

抗幽门螺杆菌（Hp）药物是慢性炎性胃肠疾病和相关肿瘤治疗领域中里程碑式的突破，但幽门螺杆菌耐药问题和非选择性抗菌治疗导致的毒副作用严重制约了其临床应用。本课题在前期发现报道的具有选择性抗Hp活性及抗耐药特性的天然呋喃香豆素骨架基础上，对天然骨架进行了进一步结构改造研究，构建并合成了两类结构类型的骨架体系，通过核磁共振氢谱、质谱、红外光谱及元素分析等波谱技术确证了其化学结构，并对其抗幽门螺杆菌活性进行了测定。研究结果表明，采用保留苯并不饱和内酯基本药效团和Hp脲酶对接模式进行骨架迁越具有可行性，可拓宽设计空间和边链操作范围，增加优化和成药性可能，而且意外发现分子骨架中定位引入硝基可增加该类化合物的生物活性。上述研究结果进一步揭示了抗耐药、选择性抗菌作用基本药效团结构及选择性作用机制，为进一步创制高效、抗耐药和副作用小的选择性抗Hp感染治疗药物奠定了理论与实验基础。