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

文献类型：期刊论文

作者Song, Runzhe1; Wang, Yue1; Wang, Minghui2; Gao, Ruixuan2; Yang, Teng3,4; Yang, Song3; Yang, Cai-Guang4; Jin, Yongsheng5; Zou, Siyuan1; Cai, Jianfeng2
刊名BIOORGANIC CHEMISTRY
出版日期2020-10-01
卷号103页码:10
关键词Desfluoroquinolone Aminopyrimidine Hybrids Anti-MRSA hERG activity
ISSN号0045-2068
DOI10.1016/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.
WOS关键词RESISTANT STAPHYLOCOCCUS-AUREUS ; IN-VITRO ; HYBRIDIZATION ; DERIVATIVES ; QUINOLONES ; INFECTIONS ; VIRULENCE ; EVOLUTION ; DISEASE ; SKIN
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研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000578958200008
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/291418]  
专题新药研究国家重点实验室
通讯作者Cai, Jianfeng; Fan, Renhua; He, Qiuqin
作者单位1.Fudan Univ, Dept Chem, 2005 Songhu Rd, Shanghai 200438, Peoples R China
2.Univ S Florida, Dept Chem, Tampa, FL 33620 USA
3.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
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China
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.

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来源：上海药物研究所

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