Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens

doi:10.1021/acs.jmedchem.1c00621

	Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens
	Kong, Qidi 1,2; Pan, Wei 1; Xu, Heng 3; Xue, Yaru 1; Guo, Bin 1; Meng, Xin 1; Luo, Cheng 1,3; Wang, Ting 4; Zhang, Shuhua 4; Yang, Yushe 1,2
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-06-24
卷号	64 期号:12 页码:8644-8665
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.1c00621
通讯作者	Yang, Yushe(ysyang@mail.shcnc.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81872726]
WOS关键词	DNA GYRASE ; ANTIBIOTIC-RESISTANCE ; INHIBITORS ; DISCOVERY ; DRUG ; PREDICTION ; BACTERIA
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000668340800043
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296855]
专题	中国科学院上海药物研究所
通讯作者	Yang, Yushe
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China 4.Sichuan Primed Biotech Grp Co Ltd, Dept Microbiol, Chengdu 610041, Sichuan, Peoples R China
推荐引用方式 GB/T 7714	Kong, Qidi,Pan, Wei,Xu, Heng,et al. Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(12):8644-8665.
APA	Kong, Qidi.,Pan, Wei.,Xu, Heng.,Xue, Yaru.,Guo, Bin.,...&Yang, Yushe.(2021).Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens.JOURNAL OF MEDICINAL CHEMISTRY,64(12),8644-8665.
MLA	Kong, Qidi,et al."Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives Against Gram-Negative Multidrug-Resistant Pathogens".JOURNAL OF MEDICINAL CHEMISTRY 64.12(2021):8644-8665.