Exploration of the Structural Space in 4(3H)-Quinazolinone Antibacterials

被引:36
作者
Qian, Yuanyuan [1 ]
Allegretta, Giuseppe [1 ]
Janardhanan, Jeshina [1 ]
Peng, Zhihong [1 ]
Mahasenan, Kiran, V [1 ]
Lastochkin, Elena [1 ]
Gozun, Melissa Malia N. [1 ]
Tejera, Sara [1 ]
Schroeder, Valerie A. [1 ]
Wolter, William R. [2 ]
Feltzer, Rhona [1 ]
Mobashery, Shahriar [1 ]
Chang, Mayland [1 ]
机构
[1] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
[2] Univ Notre Dame, Freimann Life Sci Ctr, Notre Dame, IN 46556 USA
基金
美国国家卫生研究院;
关键词
BINDING PROTEIN 2A; RESISTANT STAPHYLOCOCCUS-AUREUS; METHICILLIN RESISTANCE; ANALYSIS COMSIA; CELL-WALL;
D O I
10.1021/acs.jmedchem.0c00153
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We report herein the syntheses of 79 derivatives of the 4(3H)-quinazolinones and their structure-activity relationship (SAR) against methicillin-resistant Staphylococcus aureus (MRSA). Twenty one analogs were further evaluated in in vitro assays. Subsequent investigation of the pharmacokinetic properties singled out compound 73 ((E)-3-(5-carboxy-2-fluoropheny1)-2-(4-cyanostyryl)quinazolin-4(3H)-one) for further study. The compound synergized with piperacillin-tazobactam (TZP) both in vitro and in vivo in a clinically relevant mouse model of MRSA infection. The TZP combination lacks activity against MRSA, yet it synergized with compound 73 to kill MRSA in a bactericidal manner. The synergy is rationalized by the ability of the quinazolinones to bind to the allosteric site of penicillin-binding protein (PBP)2a, resulting in opening of the active site, whereby the beta-lactam antibiotic now is enabled to bind to the active site in its mechanism of action. The combination effectively treats MRSA infection, for which many antibiotics (including TZP) have faced clinical obsolescence.
引用
收藏
页码:5287 / 5296
页数:10
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