LaMarche Matthew J, Leeds Jennifer A, Brewer Jason, Dean Karl, Ding Jian, Dzink-Fox Joanne, Gamber Gabe, Jain Akash, Kerrigan Ryan, Krastel Philipp, Lee Kwangho, Lombardo Franco, McKenney David, Neckermann Georg, Osborne Colin, Palestrant Deborah, Patane Michael A, Rann Elin M, Robinson Zachary, Schmitt Esther, Stams Travis, Tiamfook Stacey, Yu Donghui, Whitehead Lewis
Infectious Disease Area, Novartis Institutes for Biomedical Research , Emeryville, California 94608, United States.
Natural Products Unit, Novartis Institutes for Biomedical Research , Basel, Switzerland.
J Med Chem. 2016 Jul 28;59(14):6920-8. doi: 10.1021/acs.jmedchem.6b00726. Epub 2016 Jul 12.
Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) provided access to analogues in the Northern region (C2-C10). Selective hydrolysis of the C10 amide of lead compound 2 and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., 3) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster C. difficile models of disease. Optimal efficacy in the hamster model of C. difficile was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility.
抗菌次级代谢产物硫代muracin A（1）的合成研究为获取其北部区域（C2 - C10）的类似物提供了途径。先导化合物2的C10酰胺的选择性水解及随后的衍生化产生了新型的碳连接和氮连接类似物（如3），这些类似物提高了对一系列革兰氏阳性菌的抗菌效力。此外，还鉴定出了具有改善的物理化学性质的同系物，它们在小鼠败血症和仓鼠艰难梭菌疾病模型中被证明有效。在艰难梭菌仓鼠模型中，具有强效抗菌活性和高水溶性的化合物实现了最佳疗效。
