Tian Jing-Chao, Han Xu, Lv Wei, Li Ya-Xin, Wang Hui, Fan Bing-Zhi, Cushman Mark, Liang Jian-Hua
School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 47907, USA.
Bioorg Med Chem Lett. 2017 Apr 1;27(7):1513-1524. doi: 10.1016/j.bmcl.2017.02.041. Epub 2017 Feb 20.
Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar=3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar=6-quinolyl), 13b (Ar=3-quinolyl) and 24a (Ar=4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar=3-aminopyridyl) and 24b (Ar=3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.
红霉素长期以来被视为一种抑菌剂。红霉素衍生物9-肟基酮内酯具有种属特异性杀菌谱。其中，9-肟基酮内酯1的3'-烯丙基衍生物（Ar = 3-喹啉基；17a）对肺炎链球菌和化脓性链球菌具有杀菌作用。相比之下，1的2-氟类似物，13a（Ar = 6-喹啉基）、13b（Ar = 3-喹啉基）和24a（Ar = 4-异喹啉基），对肺炎链球菌、金黄色葡萄球菌和卡他莫拉菌具有杀菌活性，而2-氟类似物13c（Ar = 3-氨基吡啶基）和24b（Ar = 3-氨甲酰基吡啶基）仅对肺炎链球菌和流感嗜血杆菌具有杀菌作用。酮内酯的还原产生了新型表酰化物，即酰化物的3-O-差向异构体。连接子长度的改变（30b对30a）、2-氟化（33对30a）以及在9-肟基或6-OH处引入额外的间隔基团（35、40对30a）并未使表酰化物恢复到与酰化物31一样的活性。分子对接表明，3位的差向异构化重塑了3-O-侧链的方向，并导致与细菌核糖体的结合显著减弱。
