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1. 发明授权

US09333193B2 Compositions and methods for treating tuberculosis 有权
标题翻译：治疗结核病的组合物和方法
公开(公告)号：US09333193B2
公开(公告)日：2016-05-10
申请号：US13885414
申请日：2011-09-20
申请人： Paul S. Hoffman , Timothy L. MacDonald , Eric R. Houpt , Thomas E. Ballard, Jr.
发明人： Paul S. Hoffman , Timothy L. MacDonald , Eric R. Houpt , Thomas E. Ballard, Jr.
IPC分类号： A61K31/381 , A61P31/04 , A61P31/06 , A61K31/426 , A61K31/427
CPC分类号： A61K31/381 , A61K31/426 , A61K31/427 , A61K2300/00
摘要： The invention provides for the use of antimicrobial chemical entities based on a nitrothiazolide backbone that exhibit anti-mycobacteria activity, including the mycobacterium causing tuberculosis. Multiple compounds were synthesized and screened for anti-tuberculosis activity. Disclosed herein are a series of compounds with anti-tuberculosis activity, including six leads that completely inhibited bacterial growth at 5 micrograms per ml or less. Three of these compounds were tested to determine MIC and these ranged between 1 and 4 micrograms per ml against both drug susceptible Mycobacterium tuberculosis strains and strains that are multi-drug resistant (MDR) including XDR strains. The compounds developed are derived from parent compound nitazoxanide, which had no inhibitory activity in the stringent testing format used herein. The derivatives were synthesized using a di-nitro-thiophene or 4-Chloro-5-Nitro-thiazole scaffold and R groups connected via a peptide bond (NHCO) to cyclic compounds such as benzene, thiophene or furans. Many of these compounds have broad spectrum activity against Gram positive bacteria including Staphylococcus aureus (MRSA) and Staphylococcus epidermidis. Several of these lead compounds were not toxic for mice at 200 mg/Kg doses administered over a period of three days.
摘要翻译：本发明提供了使用显示抗分枝杆菌活性的基于硝基噻唑化物主链的抗微生物化学实体，包括引起结核分枝杆菌的分枝杆菌。合成多种化合物并筛选抗结核活性。本文公开了一系列具有抗结核活性的化合物，其包括以5微克/毫升或更少完全抑制细菌生长的六种引物。测试这些化合物中的三种以测定MIC，并且对于药物敏感的结核分枝杆菌菌株和包含XDR菌株的多重耐药菌株（MDR），这些化合物中的三种测定MIC，其范围为1至4微克/ ml。开发的化合物衍生自母体化合物硝唑尼特，其在本文使用的严格测试形式中没有抑制活性。使用二硝基噻吩或4-氯-5-硝基噻唑支架和通过肽键（NHCO）连接的环状化合物如苯，噻吩或呋喃来合成衍生物。许多这些化合物对革兰氏阳性细菌（包括金黄色葡萄球菌（MRSA））和表皮葡萄球菌（Staphylococcus epidermidis）具有广谱活性。这些铅化合物中的几种对于在三天内施用的200mg / Kg剂量的小鼠无毒性。

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