多功能有机金属化合物 活跃于对抗感染性三子体:Ru(II) 铁烯基衍生物与两种不同的生物活性联体
Feriannys Rivas1, Carolina Del Mármol1, Gonzalo Scalese1,2
1Área Química Inorgánica, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay.
Inorganic chemistry
|June 11, 2024
概括
新的 (Ru) 铁烯基化合物在体外对人类非洲试和查加斯病寄生虫表现出强烈的活性. 虽然在体外有效,但有一种化合物没有表现出急性毒性,但在体内未能控制寄生虫的增殖.
科学领域:
- 药用化学 医学化学
- 寄生虫学的寄生虫学
- 无机化学 无机化学 有机化学
背景情况:
- 人类非洲三虫病 (HAT) 和查加斯病是被忽视的热带疾病,是由Trypanosoma寄生虫引起的.
- 目前对这些疾病的治疗方法有限,几乎没有药物可用,通常表现为不良的安全性和有效性.
- 迫切需要针对这些原生动物感染的新型治疗剂.
研究的目的:
- 设计和合成新型的多功能鲁 (II) 铁烯基化合物作为潜在的抗寄生虫剂.
- 评估这些化合物的体外疗效和对Trypanosoma brucei和Trypanosoma cruzi的选择性.
- 研究最有前途的候选药物的作用机制和初步的体内治疗潜力.
主要方法:
- 合理设计和合成含dppf和生物活性连接物 (mpo,NN) 的Ru (II) 铁化合物.
- 使用光谱和分析技术对合成化合物的表征.
- 在体外对血流Trypanosoma brucei和Trypanosoma cruzi trypomastigotes进行抗寄生虫活性测定.
- 作用机制研究包括DNA相互作用,ROS生成,酶抑制 (酸缩酶) 和硫醇氧化试验.
- 在非洲试索米病的小鼠模型中的体内疗效评估.
主要成果:
- 合成的Ru(II) 化合物在体外对T. brucei (EC50 = 31-160 nM) 和T. cruzi (EC50 = 190-410 nM) 具有强大的活性.
- 相比以前开发的金属基药物,这些化合物在体外对T. brucei表现出更高的活性,并且具有良好的选择性.
- 作用机制研究排除了DNA相互作用和ROS生成,这意味着抑制T. cruzi依赖NADH的烟酸减少酶.
- 一种代表性化合物[Ru(mpo) ((dppf) ((bipy) ]Cl在体内没有表现出急性毒性,但未能控制寄生虫的增殖,这可能是由于药理学限制.
结论:
- 新型Ru (II) 铁烯化合物代表了一类具有显著的抗寄生虫活性的有前途的药物,用于抗HAT和查加斯病.
- 这些化合物向特定的寄生虫途径,如T. cruzi fumarate reductase,与传统药物机制不同.
- 需要进一步的药理动力学研究和优化,以将这些化合物的体外疗效转化为可行的体内治疗策略.
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Isomers are different chemical species that have the same chemical formula. Structural isomerism of coordination compounds can be divided into two subcategories, the linkage isomers and coordination-sphere isomers.
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