多价药物设计. 多价药物设计. 合成和体外分析一系列的万科米辛二元体的组合
John H Griffin1, Martin S Linsell, Matthew B Nodwell
1Contribution from Theravance, Inc., 901 Gateway Boulevard, South San Francisco, California 94080, USA. jgriffin@pharmix.com
Journal of the American Chemical Society
|June 6, 2003
概括
研究人员合成并测试了四十种万科米辛二次体,以了解左边体的方向和长度如何影响抗菌活性对抗包括耐药菌株在内的阳性病原体.
科学领域:
- 药用化学 医学化学
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
背景情况:
- 范科米辛是治疗格拉姆阳性细菌感染的关键抗生素.
- 耐万科米细菌的出现需要开发新的治疗策略.
- 了解万科米辛衍生物的结构-活性关系是提高疗效的关键.
研究的目的:
- 合成和评估一系列具有连接部位和连接器长度系统变化的万科米辛二元体.
- 调查这些结构修改对抗敏和抗性格拉姆阳性病原体的抗菌功效的影响.
- 为了确定最佳的二聚体配置,以增强抗微生物活性.
主要方法:
- 设计和合成四十个共价连接的万科米辛二聚体.
- 通过四个不同的万科胺位置 (C端,N端,万科胺,复素环) 的结合.
- 使用四种不同长度的两性,基于的链接器.
- 在体外微生物学分析针对各种格拉姆阳性细菌菌株,包括抗万素的菌 (Enterococcus faecalis (VRE)) 和黄金菌 (Staphylococcus aureus (MRSA,GISA)).
主要成果:
- 连接方向和连接器长度都显著影响了体外抗菌功效.
- 在V-V二聚体系列显示了对敏感生物和VanB VRE.最大的功效.
- C-C,C-V和V-R系列显示出有前途的宽频活动,包括对抗VanA VRE.
- 较短的链路一直被优先选择为与VRE相对的活动.
- 效力因结合部位,结合体长度和测试的特定细菌菌株而异;没有一个单一的二元对所有菌株都表现优于所有其他菌株.
结论:
- 通过二元化系统地修改万科米辛,为开发新抗生素提供了可行的策略.
- 链接方向和链接器长度是抗菌活性和光谱的关键决定因素.
- V-V,C-C,C-V和V-R二聚体系列,特别是较短的链接器,代表了对抗耐药性格拉姆阳性感染的有希望的线索.
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