中文版 | English
Title

Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents

Author
Corresponding AuthorXia, Jie; Wu, Song
Publication Years
2022-12-31
DOI
Source Title
ISSN
1475-6366
EISSN
1475-6374
Volume37Issue:1
Abstract
Emerging drug resistance is generating an urgent need for novel and effective antibiotics. A promising target that has not yet been addressed by approved antibiotics is the bacterial DNA gyrase subunit B (GyrB), and GyrB inhibitors could be effective against drug-resistant bacteria, such as methicillin-resistant S. aureus (MRSA). Here, we used the 4-hydroxy-2-quinolone fragment to search the Specs database of purchasable compounds for potential inhibitors of GyrB and identified AG-690/11765367, or f1, as a novel and potent inhibitor of the target protein (IC50: 1.21 mu M). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 mu M) and f14 (IC50: 0.28 mu M). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4-8 mu g/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 mu M), and metabolically stable (t(1/2): > 372.8 min for plasma; 24.5 min for liver microsomes). In summary, this study showed that the discovered N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides are novel GyrB-targeted antibacterial agents; compound f1 is promising for further development.
Keywords
URL[Source Record]
Indexed By
Language
English
SUSTech Authorship
Others
Funding Project
CAMS Innovation Fund for Medical Sciences[2021-I2M-1-069] ; Fundamental Research Program of Shanxi Province[20210302124300] ; Shanxi Bethune Hospital Scientific Research Fund for Talent Recruitment[2021RC008] ; "Universities and Colleges Key Programs for Foreign Talent" of State Administration of Foreign Experts Affairs P.R. China[T2018042]
WOS Research Area
Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
WOS Subject
Biochemistry & Molecular Biology ; Chemistry, Medicinal
WOS Accession No
WOS:000807329500001
Publisher
Data Source
Web of Science
Citation statistics
Cited Times [WOS]:0
Document TypeJournal Article
Identifierhttps://kc.sustech.edu.cn/handle/2SGJ60CL/336171
DepartmentDepartment of Biology
Affiliation
1.Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Dept New Drug Res & Dev, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China
2.Shanxi Med Univ, Shanxi Bethune Hosp, Tongji Shanxi Hosp, Shanxi Acad Med Sci,Dept Pharm,Hosp 3, Taiyuan, Shanxi, Peoples R China
3.Jiangsu Ocean Univ, Sch Pharm, Lianyungang, Peoples R China
4.Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, Beijing, Peoples R China
5.Univ Vienna, Dept Pharmaceut Sci, Div Pharmaceut Chem, Vienna, Austria
6.Southern Univ Sci & Technol, Dept Biol, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen Key Lab Cell Microenvironm, Shenzhen, Peoples R China
7.Southern Univ Sci & Technol, SUSTech HKU Joint Labs Matrix Biol, Shenzhen, Peoples R China
Recommended Citation
GB/T 7714
Xue, Wenjie,Wang, Yaling,Lian, Xu,et al. Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents[J]. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,2022,37(1).
APA
Xue, Wenjie.,Wang, Yaling.,Lian, Xu.,Li, Xueyao.,Pang, Jing.,...&Wu, Song.(2022).Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents.JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY,37(1).
MLA
Xue, Wenjie,et al."Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents".JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 37.1(2022).
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