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西亚津的昆类型:合成,抗结核性结构-活性关系和ADME分析
Phelelisiwe S Dube1, Lesetja J Legoabe1, Audrey Jordaan2
1Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa.
European journal of medicinal chemistry
|June 15, 2023
概括
研究人员开发了基于类素的新型化合物,其向DprE1,DprE1是Mycobacterium tuberculosis (Mtb) 细胞壁合成的必要酶. 六种化合物显示出对Mtb的亚微分子活性,其中一种化合物对耐药菌株和特定的DprE1突变有效.
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:
- 结核菌 (Mycobacterium tuberculosis,Mtb) 具有强大的细胞壁,使其对许多抗生素具有抗性.
- DprE1 是一个验证的药物标,对Mtb细胞壁生物合成至关重要.
- 像PBTZ169这样的现有DprE1抑制剂正在临床开发中,这突显了对新药候选物的需求.
研究的目的:
- 探索使用脚手架跳跃方法的新型DprE1抑制剂.
- 合成和评估新的基于诺的化合物,以对抗Mtb.
主要方法:
- 通过将PBTZ169的类环替换为类核来实现脚手架跳跃策略.
- 合成了22种新型化合物.
- 对Mtb进行抗微生物敏感性测试,包括野生型,诺基诺耐药和DprE1突变菌株.
主要成果:
- 六种合成的化合物显示了微小分子下最小抑制度 (MIC90) 值 (<0.244μM) 与Mtb.相比.
- 化合物25表现出强大的亚微分子活性,对野生类型和耐诺类型的Mtb.
- 化合物25保留了对DprE1 P116S突变的活性,但对DprE1 C387S突变的有效性降低了.
结论:
- 这种基于诺的新型化合物代表了新的抗结核药物开发的有希望的线索.
- 化合物25显示出作为治疗剂的潜力,其活性概况表明与DprE1.1的特定相互作用.
- 需要进一步研究化合物25的作用机制和耐药性概况.
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