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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 10期

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

页码：5287 / 5296

页数：10

共 40 条

[1] The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles' Heel of Methicillin-Resistant Staphylococcus aureus [J].

Acebron, Ivan ;

Chang, Mayland ;

Mobashery, Shahriar ;

Hermoso, Juan A. .

CURRENT MEDICINAL CHEMISTRY, 2015, 22 (14) :1678-1686

[2]

[Anonymous], 2018, SCHROD REL FIELD BAS

[3] New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays [J].

Baell, Jonathan B. ;

Holloway, Georgina A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) :2719-2740

[4]

Bouley R., 2015, J AM CHEM SOC

[5] Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials [J].

Bouley, Renee ;

Ding, Derong ;

Peng, Zhihong ;

Bastian, Maria ;

Lastochkin, Elena ;

Song, Wei ;

Suckow, Mark A. ;

Schroeder, Valerie A. ;

Wolter, William R. ;

Mobashery, Shahriar ;

Chang, Mayland .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (10) :5011-5021

[6]

Braaten D, 2007, NAT MED, V13, P522, DOI 10.1038/nm0507-522

[7]

Bush K., 2018, Antibacterials, VI, P69, DOI [DOI 10.1007/7355201723, 10.1007/7355_2017_23]

[8]

CDC, 2019, ANTIBIOTIC RESISTANC

[9] COMPARATIVE MOLECULAR-FIELD ANALYSIS (COMFA) .1. EFFECT OF SHAPE ON BINDING OF STEROIDS TO CARRIER PROTEINS [J].

CRAMER, RD ;

PATTERSON, DE ;

BUNCE, JD .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (18) :5959-5967

[10] The Tipper-Strominger Hypothesis and Triggering of Allostery in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus (MRSA) [J].

Fishovitz, Jennifer ;

Taghizadeh, Negin ;

Fisher, Jed F. ;

Chang, Mayland ;

Mobashery, Shahriar .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137 (20) :6500-6505

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