恶二唑类抗菌药物的构效关系
Structure-Activity Relationship for the Oxadiazole Class of Antibacterials.
作者信息
Boudreau Marc A, Ding Derong, Meisel Jayda E, Janardhanan Jeshina, Spink Edward, Peng Zhihong, Qian Yuanyuan, Yamaguchi Takao, Testero Sebastian A, O'Daniel Peter I, Leemans Erika, Lastochkin Elena, Song Wei, Schroeder Valerie A, Wolter William R, Suckow Mark A, Mobashery Shahriar, Chang Mayland
机构信息
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States.
出版信息
ACS Med Chem Lett. 2019 Oct 3;11(3):322-326. doi: 10.1021/acsmedchemlett.9b00379. eCollection 2020 Mar 12.
A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant (MRSA) infection. Oxadiazole shows potent antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.
通过合成72种类似物并测定对ESKAPE细菌组的最低抑菌浓度（MIC），评估了恶二唑类抗菌剂的构效关系（SAR）。对选定的化合物进一步评估其毒性、血浆蛋白结合率、药代动力学（PK）以及耐甲氧西林金黄色葡萄球菌（MRSA）感染的小鼠模型。恶二唑显示出强效抗菌活性，清除率低，分布容积高，口服生物利用度为41%，并在MRSA感染的小鼠模型中显示出疗效。
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