在体外的三酸性活性和普洛素类型的结构-活性关系
Helena D Janse van Rensburg1, Keisuke Suganuma2, David D N'Da1
1Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
Molecular diversity
|July 22, 2023
概括
新的诺基诺-三混合物显示出对抗热带疾病如非洲试索米亚症的希望. 化合物22显示出显著的三酸性活性,这表明针对被忽视的热带疾病进行优化药物开发的潜力.
科学领域:
- 药用化学 医学化学
- 寄生虫学的寄生虫学
- 药物发现 药物发现 药物发现
背景情况:
- 热带疾病,包括非洲三虫病,迫切需要开发新药.
- 现有的治疗方法在有效性和安全性方面面临挑战,需要新的抗松体药物.
- 诺基诺,传统上是抗菌药物,在体外表现出三酸性活性.
研究的目的:
- 为了合成和评估诺基诺和1,2,3-三醇杂交物对抗松体活性.
- 识别具有提高针对各种Trypanosoma物种的疗效和选择性的新型化合物.
- 探索结构-活性关系,以优化类药物候选药物.
主要方法:
- 合成西普罗夫洛克萨辛 (CPX) 类似物和CPX-1,2,3-triazole杂交物.
- 在体外对T. brucei brucei,T. b. gambiense,T. b. rhodesiense,T. evansi,T. equiperdum和T. congolense. 的血液形式进行检测.
- 使用Madin-Darby牛细胞进行细胞毒性评估以确定选择性.
主要成果:
- 齐普罗夫洛克萨 (1) 对T.congolense (IC50 7.79 μM,SI 39.6) 显示有选择性的活性.
- CPX-triazole混合物 (11-24) 根据C-3功能和电子效应表现出不同的选择性和活性.
- 鉴定到的打击化合物包括CPX (1),对T. congolense的胺衍生物22 (IC50 5.42 μM,SI 25.2) 和对T. brucei rhodesiense的酸衍生物13 (IC50 4.51 μM,SI 10.2).
结论:
- 诺基诺-三混合物代表了开发新抗类药物的有希望的支架.
- 化合物22是优化的一个潜在的头,专注于其4 - 甲基皮佩拉辛胺基组和三醇部分.
- 进一步的修改,包括取出电子的替代剂,可能会增强药物动力学特性和tripanocidal的疗效.
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