新型广谱高效抗真菌苗头化合物TJ33的结构优化和作用机制研究

鉴于现有抗真菌药物种类少、抗菌谱窄、耐药性严重等问题，临床上迫切需要发现新结构和新机制的抗真菌药物。课题组前期对化合物库进行筛选发现广谱高效抗真菌化合物31C，经初步的结构修饰，获得具有杀真菌作用的噻唑酰肼类化合物TJ33，该类化合物为课题组首次报道并已申请专利。TJ33对8种常见病原真菌的体外活性显著优于氟康唑、伏立康唑等8种对照药物，MIC值范围为0.0156-1 μg/ml。TJ33对10株氟康唑耐药菌具有高抑制活性，并且对“超级真菌”耳念珠菌的MIC值达到0.0625 μg/ml。初步作用机制研究表明TJ33与现有药物不同。本项目拟以TJ33为苗头化合物，开展系统的结构优化和作用机制研究，以期发现新型高效广谱安全的抗真菌先导化合物，为开发具有我国自主知识产权的新型抗真菌药物奠定基础。

Given the limited array of antifungal drug classes, narrow antifungal spectrum and the dramatically increasing incidence of resistance to current agents, the discovery of new chemotypes that act in ways that are mechanistically distinct from the available armamentarium is desperately needed. In previous study, our group discovered a broad-spectrum antifungal compound 31C by screening the compound library. After preliminary structural modification, we obtained a fungicidal thiazolylhydrazide compound TJ33, which was firstly reported by our group and completed the patent application. Compound TJ33 exhibited superior in vitro activities against eight common pathogenic fungi with MIC values in the range of 0.0156-1 μg/ml than eight control drugs such as fluconazole and voriconazole. TJ33 showed potent antifungal activities against 10 fluconazole-resistant clinical isolates and was significantly more active than control drugs against Candida auris with MIC value of 0.0625 μg/ml. The preliminary mechanism of action study showed that TJ33 is different from available drugs. Therefore, this project intends to carry out systematic structural optimization and mechanism of action studies based on the hit compound TJ33, with the aim of discovering novel antifungal leads with high potency, broad-spectrum and less toxicity and laying the foundation for the development of novel antifungal drugs with independent intellectual property rights.