Identification of Better Pharmacokinetic Benzothiazinone Derivatives as New Antitubercular Agents

被引：56

作者：

Lv, Kai ^{[1
,2
]}

You, Xuefu ^{[1
,2
]}

Wang, Bin ^{[3
]}

Wei, Zengquan ^{[4
]}

Chai, Yun ^{[1
,2
]}

Wang, Bo ^{[1
,2
]}

Wang, Apeng ^{[1
,2
]}

Huang, Guocheng ^{[1
,2
]}

Liu, Mingliang ^{[1
,2
]}

Lu, Yu ^{[3
]}

机构：

[1] Chinese Acad Med Sci, Inst Med Biotechnol, Beijing 100050, Peoples R China

[2] Peking Union Med Coll, Beijing 100050, Peoples R China

[3] Capital Med Univ, Dept Pharmacol, Beijing TB & Thorac Tumor Res Inst, Beijing Key Lab Drug Resistance TB Res,Beijing Ch, Beijing 101149, Peoples R China

[4] Tianjin Chase Sun Pharmaceut Co Ltd, Tianjin 301700, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 06期

关键词：

Antitubercular agents; benzothiazinones; spiro-heterocycles; structure-activity relationships; pharmacokinetics; RESISTANT MYCOBACTERIUM-TUBERCULOSIS; POTENT ANTIMYCOBACTERIAL ACTIVITY; D-RIBOSE 2'-EPIMERASE; DRUG TARGET; IN-VIVO; DPRE1; INHIBITORS; DESIGN; DISCOVERY; APPROVAL;

D O I：

10.1021/acsmedchemlett.7b00106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of new 8-nitro-6-(trifluoromethyl)-1,3benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen Spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent in vitro activity (MIC < 0.15 mu M) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically. isolated multidrug-resistant strains. Compounds 11l and 11m display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.

引用

页码：636 / 641

页数：6

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