Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens
Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens
复制标题
抗革兰氏阴性多重耐药病原体的新型嘧啶并[4,5-b]吲哚衍生物的设计、合成和生物学评价
DOI：
10.1021/acs.jmedchem.1c00621
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发表时间：
2021-06-03
影响因子：
7.3
通讯作者：
Yang, Yushe
中科院分区：
文献类型：
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作者：
Kong, Qidi;Pan, Wei;Yang, Yushe
由于革兰氏阴性菌膜的渗透性差和麻烦的细菌外排机制，只有少数GyrB/帕雷抑制剂具有针对革兰氏阴性病原体的有效活性。其中，以GP-1为代表的嘧啶并[4，5-B]吲哚衍生物对革兰氏阳性菌和革兰氏阴性菌均表现出优异的广谱抗菌活性，但受到hERG抑制和不良药代动力学特征的限制。为了改善它们的类药物性质，我们设计了一系列基于GP-1的三环骨架和acoraflastine的C-7部分的新型嘧啶并[4，5-B]吲哚衍生物。这些努力最终发现了一种有前途的化合物18 r，其具有降低的hERG倾向和改善的PK特征。与GP-1相比，化合物18 r表现出上级的广谱体外抗菌活性，包括多种临床多药G（-）病原体，尤其是鲍曼不动杆菌，并且在感染多药耐药A.鲍曼不动杆菌。
Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G(-) pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.