Actelion Pharmaceuticals Limited , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
J Med Chem. 2017 May 11;60(9):3776-3794. doi: 10.1021/acs.jmedchem.6b01831. Epub 2017 Apr 24.
There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens. Physicochemical properties (polarity and basicity) were considered to guide the design process. Dibasic tetrahydropyran-based compounds such as 6 and 21 are potent inhibitors of both DNA gyrase and topoisomerase IV, displaying antibacterial activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Compounds 6 and 21 are efficacious in clinically relevant murine infection models.
临床上急需新型抗生素来有效应对多种细菌，尤其是多种耐药菌。基于四氢吡喃的 II 型拓扑异构酶（DNA 回旋酶和拓扑异构酶 IV）抑制剂对革兰氏阳性病原体具有很强的活性，并且与氟喹诺酮类药物没有靶标介导的交叉耐药性。我们报告了我们旨在将这类分子的抗菌谱扩展到难以治疗的革兰氏阴性病原体的研究工作。物理化学性质（极性和碱性）被认为是指导设计过程的因素。双碱性四氢吡喃类化合物，如 6 和 21，是 DNA 回旋酶和拓扑异构酶 IV 的强效抑制剂，对革兰氏阳性和革兰氏阴性病原体（金黄色葡萄球菌、肠杆菌科、铜绿假单胞菌和鲍曼不动杆菌）均具有抗菌活性。化合物 6 和 21 在临床相关的小鼠感染模型中有效。
