基于骨架迁越策略的新型喹唑啉类化合物抗血吸虫活性研究

Schistosomiasis is one of the major endemic infectious diseases that significantly endanger the public health, ecological security and sustainable development of China. Elimination of schistosoma is important for schistosomiasis control. Salicylate amides (such as niclosamide) have favorable antischistosomal activities, however, there are some shortcoming including toxicities and resistances. This project aims at the design and synthesis of quinazoline derivatives based on the scaffold-hopping of salicylate amide structure, and the screening of new quinazoline lead compounds with high-effective antischistosomal activities via biological activity test. The major contents of the project are as follows: (1) design and synthesis of quinazoline derivatives; (2) antischistosomal activities and toxicities study of as-sythesized quinazoline derivatives; (3) observing the tissue structure changes in schistosoma after applying the drugs, studying the interactions between the drugs and the key enzymes in schistosoma, and exploring the mechanisms and possible targets at the same time; (4) study of the 3D structure-activity relationships of quinazoline compounds. These results will lay a solid foundation for the development of quinazoline compounds with novel antischistosomal activities.

血吸虫病是严重危害人类身体健康、影响生态安全和社会经济可持续发展的重大地方性传染病之一。消灭血吸虫是控制血吸虫病流行的重要措施。氯硝柳胺等水杨酰胺类药物具有较好的抗血吸虫活性，但是毒性大，且存在耐药性风险。本项目对水杨酰胺进行骨架迁越，环化成喹唑啉类化合物，通过生物活性测试，筛选出新一轮具有抗血吸虫活性的喹唑啉类先导化合物。主要研究内容：（1）基于水杨酰胺的骨架迁越，设计并合成多种喹唑啉类目标化合物；（2）研究喹唑啉类化合物的抗血吸虫活性和药物毒性；（3）观察药物作用后血吸虫体内组织结构的变化、研究药物与血吸虫体内重要酶的相互作用，探索喹唑啉类化合物对血吸虫的作用机理和可能的作用靶标；（4）研究喹唑啉类化合物的结构-活性关系。该研究将为发现具有抗血吸虫活性的新型喹唑啉类先导化合物打下坚实基础。

血吸虫病是重大地方性传染病，消灭血吸虫是控制血吸虫病流行的重要措施。针对血吸虫成虫，我们设计与合成了一系列喹唑啉类，喹唑啉酮类以及嘧啶类、吲哚羧酸酯类、噻唑类、2-亚氨基噻唑烷酮类等其他含氮杂环有机化合物，表征了这些化合物的结构，探索了化合物制备的最优条件，总结了合成规律和制备机理。研究了上述有代表性化合物体内、外抗血吸虫的活性，初步探讨了化合物结构和活性的关系。观察了药物对血吸虫虫体作用的形貌变化，研究了筛选出的药物对SOD、AKP、ACP、AChE、SDH、CCO及和NOS等作用。初步研究了药物对KB细胞的毒性。发表SCI收录学术论文15篇，申请专利8项，授权8项。