抗艰难梭菌rakicidin B1新衍生物的设计、合成及生物学活性评价

目的 以rakicidin B1为起始原料，经2步反应合成得到4个全新结构的rakicidin B1衍生物，并对其进行生物学活性研究，以期获得低细胞毒、高效抗艰难梭菌活性的化合物。方法 课题组前期首次发现rakicidin B1具有较强的抗艰难梭菌活性，在其结构基础上进行修饰和优化，通过氨基甲酸酯连接基团引入含氮杂环，设计合成得到4个全新目标化合物。所有化合物结构经高分辩质谱和核磁确证，并经抗艰难梭菌活性测试和细胞毒性活性测试。结果 在合成的4个化合物中，有3个化合物具有与先导化合物更强或相当的抗艰难梭菌活性；同时，MTT测试结果表明，3个化合物的细胞毒性降低，以3b的细胞毒性降低最多。结论 通过对rakicidin B1母核结构进行修饰和优化，获得全新结构的rakicidin B1衍生物并对其进行抗菌和细胞毒活性筛选。其中，化合物3b保留潜在抗艰难梭菌活性且细胞毒性降低最多，作为全新结构类型的抗艰难梭菌活性化合物，有潜在的开发价值。

Design,synthesis and biological evaluation of novel rakicidin B1 analogues as Clostridium difficile targeted anti-bacterial agents

Objective Taking rakicidin B1 as starting material, 4 novel rakicidin B1 analogues (3a~3d) were designed and synthesized with hybrid strategy via two steps. Meanwhile, all of them were screened with the aim of getting more potential compounds with decreased cytotoxicity as compared with rakicidin B1. Methods Rakicidin B1 was isolated and found to possess anti-Clostridium difficile (CD) activity firstly by our research group. Based on the structure of rakicidin B1, four novel rakicidin analogues were obtained through structural modification on the 3-OH group by introduction of N-heterocycle with carbamate linkage. The structure of all of the targets was confirmed by HRMS and NMR, and all targets were evaluated for their anti-CD activity and cytotoxicity. Results Among them, three derivatives (3b~3d) appeared to have stronger or equipotent activity than that of rakicidin B1. Meanwhile, the cytotoxicity of 3b~3d was evaluated against A549, HT29 and Caco-2 cell lines, the results demonstrated that 3b was decreased mostly with poorest cytotoxicity in all of targets. Conclusions A series of rakicidin B1 analogues were prepared and evaluated for their anti-CD activities and cytotoxicity. Finally, 3b was identified as the most promising compound for its potent anti-CD activity and poorest cytotoxicity, which empower it with increased safety space andhigh possibility to be developed as new anti-CD drugs with limited