Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity

doi:10.1016/j.bioorg.2020.104176

	Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity
	Song, Runzhe 4; Wang, Yue 4; Wang, Minghui 5; Gao, Ruixuan 5; Yang, Teng 1,3; Yang, Song 1; Yang, Cai-Guang 3; Jin, Yongsheng 2; Zou, Siyuan 4; Cai, Jianfeng 5
刊名	BIOORGANIC CHEMISTRY
	2020-10-01
卷号	103 页码:10
关键词	Desfluoroquinolone Aminopyrimidine Hybrids Anti-MRSA hERG activity
ISSN号	0045-2068
DOI	10.1016/j.bioorg.2020.104176
通讯作者	Cai, Jianfeng(jianfengcai@usf.edu) ; Fan, Renhua(rhfan@fudan.edu.cn) ; He, Qiuqin(qqhe@fudan.edu.cn)
英文摘要	Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 mu g/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with topoisomerase IV. These results indicate a promising strategy for developing new antibiotic quinolones to combat multidrug resistance and cardiotoxicity.
资助项目	National Natural Science Foundation of China[21971043] ; National Natural Science Foundation of China[81861138046] ; Science and Technology Commission of Shanghai Municipality[17XD1404400] ; Science and Technology Commission of Shanghai Municipality[18XD1400800] ; Science and Technology Commission of Shanghai Municipality[19ZR1403400]
WOS关键词	RESISTANT STAPHYLOCOCCUS-AUREUS ; IN-VITRO ; HYBRIDIZATION ; DERIVATIVES ; QUINOLONES ; INFECTIONS ; VIRULENCE ; EVOLUTION ; DISEASE ; SKIN
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000578958200008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291418]
专题	中国科学院上海药物研究所
通讯作者	Cai, Jianfeng; Fan, Renhua; He, Qiuqin
作者单位	1.Guizhou Univ, Ctr R&D Fine Chem, State Key Lab Breeding Base Green Pesticide & Agr, Key Lab Green Pesticide & Agr Bioengn,Minist Educ, Guiyang 550025, Peoples R China 2.Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Fudan Univ, Dept Chem, 2005 Songhu Rd, Shanghai 200438, Peoples R China 5.Univ S Florida, Dept Chem, Tampa, FL 33620 USA
推荐引用方式 GB/T 7714	Song, Runzhe,Wang, Yue,Wang, Minghui,et al. Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity[J]. BIOORGANIC CHEMISTRY,2020,103:10.
APA	Song, Runzhe.,Wang, Yue.,Wang, Minghui.,Gao, Ruixuan.,Yang, Teng.,...&He, Qiuqin.(2020).Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity.BIOORGANIC CHEMISTRY,103,10.
MLA	Song, Runzhe,et al."Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity".BIOORGANIC CHEMISTRY 103(2020):10.