全细胞化物梅森海默复合生物转化指导优化抗菌细菌的本佐酸
Melanie Joch1, K Philip Wojtas1, Héctor Torres-Gómez1
1Transfer Group Anti-infectives, Leibniz Institute for Natural Products Research and Infection Biology, Leibniz-HKI, Beutenbergstr. 11a., 07745, Jena, Germany.
European journal of medicinal chemistry
|December 10, 2023
概括
尼索提亚 (BTZs) 在治疗结核病方面表现有前途. 研究人员开发了一种新的测定方法来优化BTZs,从而改善了药物候选物,在小鼠中具有更好的新陈代谢和有效性.
科学领域:
- 药理学和药物化学 药理学和药物化学
- 微生物学与传染病的研究
背景情况:
- 酸酸 (BTZs) 是一种强大的抗结核药物,在临床试验中有两种候选药物.
- 在哺乳动物中,BTZs是第一个被证明能形成暂时化物Meisenheimer复合体 (HMC) 的化合物.
研究的目的:
- 通过评估它们对化物迈森海默复合物 (HMC) 形成的倾向来优化二二 (BTZ) 化合物.
- 开发和实施一种基于细胞的新型试验,用于评估HMC形成和指导药物设计.
主要方法:
- 准备一个由5和7替代BTZ组成的库.
- 使用新开发的基于细胞的测定方法对HMC形成倾向的系统评估.
- 多参数评估,包括体外微小体稳定性和体内疗效研究.
主要成果:
- 5甲基化BTZ被确定为具有减少HMC形成的首选支架.
- 优化的BTZ表现出强大的抗菌菌活性和良好的体外微小体稳定性.
- 在体内研究表明,在小鼠结核病模型中,有利的全身暴露和有效性.
结论:
- 开发了一种合格的体外HMC测定方法,使得下一代BTZ的选择成为可能.
- 优化的BTZ具有更好的药理动力学特性,并减少了HMC的形成.
- 该试验有助于预测体内代谢,以改善结核病药物开发.
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