作为有前途的三酸剂的新型脂性胺酸:设计,合成,SAR和合规行为研究
George Fytas1, Grigoris Zoidis1, Antonios Drakopoulos2
1Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece.
ACS medicinal chemistry letters
|July 17, 2024
概括
针对Trypanosoma brucei的新型胺酸衍生物显示出强大的生长抑制作用. 化合物22和23表现出中纳米分子活性和高选择性,为治疗寄生虫感染提供了有希望的线索.
科学领域:
- 药用化学 医学化学
- 寄生虫学的寄生虫学
- 有机合成 有机合成
背景情况:
- trypanosoma brucei 引起非洲睡眠病,这是一个被忽视的热带疾病.
- 开发针对寄生虫感染的新疗法仍然是一个关键的全球卫生挑战.
- 胺酸是一种已知的类化合物,具有潜在的抗寄生虫活性.
研究的目的:
- 设计和合成新的酸衍生物.
- 为了评估这些化合物对血流形式Trypanosoma brucei的增长抑制活性.
- 研究这些新型化合物的结构-活性关系.
主要方法:
- 构造上受约束的螺旋碳循环 2,6-二基托皮佩拉зин支架的合成.
- 加入一个乙胺酸部分.
- 使用体外试验测试对抗寄生虫活性的评估.
- 结构-活动关系研究涉及各种替代.
- 核磁共振光谱学和构造分析的理论计算.
主要成果:
- 大多数合成的类似物在中纳米到低微分子范围内对T. brucei.表现出活性.
- 化合物22和23,具有特定的异布/和甲基替代物,是最强的 (IC50 = 34和53nM).
- 化合物22和23在哺乳动物细胞上表现出显著的选择性 (SI = 940和470).
- 研究了关键胺酸衍生物的E/Z形态行为.
结论:
- 基于2,6-二基托皮佩拉зин支架的新型酸衍生物对Trypanosoma brucei.有效.
- 特定的结构修改,包括异布/和甲基替代,增强功效和选择性.
- 这些化合物代表了开发新抗试体药物的有希望的领先候选人.
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