Titel
Discovery of N-quinazolinone-4-hydroxy-2-quinolone-3-carboxamides as DNA gyrase B-targeted antibacterial agents
Autor*in
Wenjie Xue
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
Yaling Wang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
Xu Lian
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
... show all
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 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC50: 0.31 µM) and f14 (IC50: 0.28 µM). Additional experiments indicated that compound f1 is more potent than the others in terms of antibacterial activity against MRSA (MICs: 4–8 µg/mL), non-toxic to HUVEC and HepG2 (CC50: approximately 50 µM), and metabolically stable (t1/2: > 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.
Stichwort
Antibiotic resistanceMRSAantibacterial agentDNA
Gyrase inhibitorscomputeraided
drug design
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Journal of Enzyme Inhibition and Medicinal Chemistry
Band
37
Ausgabe
1
ISSN
1475-6366
Erscheinungsdatum
2022
Seitenanfang
1620
Seitenende
1631
Publication
Informa UK Limited
Erscheinungsdatum
2022
Zugänglichkeit
Rechte
Rechteangabe
© 2022 The Author(s)
Universität Wien | Universitätsring 1 | 1010 Wien | T
+43-1-4277-0