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

• Published in: Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.1620-1631
• Main Authors: Xue, Wenjie, Wang, Yaling, Lian, Xu, Li, Xueyao, Pang, Jing, Kirchmair, Johannes, Wu, Kebin, Han, Zunsheng, You, Xuefu, Zhang, Hongmin, Xia, Jie, Wu, Song
• Format: Article
• Language: English
• Subjects: Antibacterial activity; antibacterial agent; Antibacterial agents; Antibiotic resistance; Antibiotics; computer-aided drug design; DNA Gyrase inhibitors; DNA topoisomerase; Drug resistance; Methicillin; Microsomes; MRSA; Quinazolinone; Research Paper; Staphylococcus aureus
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2022.2084088

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 (IC 50 : 1.21 µM). Structural modification was used to further identify two more potent GyrB inhibitors: f4 (IC 50 : 0.31 µM) and f14 (IC 50 : 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 (CC 50 : approximately 50 µM), 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.