重新评估强效抗结核2-alkylsulfonyl) acetamides的假定分子标的研究结果
Dylan C Farr1, Thomas Haselhorst1, Lendl Tan2
1Institute for Glycomics, Griffith University, Gold Coast, QLD, 4222, Australia.
European journal of medicinal chemistry
|December 4, 2023
概括
新的硫乙衍生物通过抑制脂肪乙-AMP酶,一种与脂肪酸合成酶不同的新型药物标,对Mycobacterium tuberculosis表现出强烈的活性. 这项研究推动了抗结核药物开发.
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:
- 简单的基-硫乙胺通过降低菌根细菌中的酸水平来表现出抗结核活性.
- 之前的假设将脂肪酸合成酶确定为目标,但证据表明情况不同.
- 菌根细菌中的脂肪酸-AMP酶 (FAAL) 对于酸生物合成和脂肪酸代谢至关重要.
研究的目的:
- 合成新的硫乙胺衍生物,以验证FAALs作为分子标.
- 为了探索结构性异为增强的抗结核药物设计.
- 为了改善硫乙胺对Mycobacterium结核病的活性.
主要方法:
- 一个扩展的库的合成硫乙胺衍生物.
- 结构与活动关系 (SAR) 分析.
- 分子建模以验证作用机制.
- 针对Mycobacterium tuberculosis (H37Rv) 的抗结核活性测试.
主要成果:
- 基于假定的FAAL目标,合成和修改了新的硫乙衍生物.
- 几种衍生品表现出针对Mycobacterium结核病的改善活性.
- 化合物19,22b,22c和46的显著MIC90值分别为1.4,16.0,13.0和5.9μg/mL.
结论:
- 脂肪乙-AMP连接酶 (FAALs) 是Mycobacterium tuberculosis中硫乙胺的可能分子标.
- 合成的衍生品代表了开发新的抗结核剂的有希望的线索.
- 硫乙胺对FAALs的竞争性抑制提供了针对结核病的新治疗策略.
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