Universidad de Navarra, Department of Pharmaceutical Technology and Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain.
Department of Parasitology, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios De Granada/University of Granada, Granada 18071, Spain.
Bioorg Med Chem. 2019 Sep 1;27(17):3902-3917. doi: 10.1016/j.bmc.2019.07.029. Epub 2019 Jul 19.
The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model. Both compounds caused a substantial decrease in parasitemia in the chronic phase, which was an even better result than that of the reference drug benznidazole. In addition, compound 9 also showed better antichagasic activity during the acute phase. Moreover, metabolite excretion, effect on mitochondrial membrane potential and the inhibition of superoxide dismutase (SOD) studies were also performed to identify their possible mechanism of action. Finally, docking studies proposed a binding mode of the Fe-SOD enzyme similar to our previous series, which validated our design strategy. Therefore, the results suggest that these compounds should be considered for further preclinical evaluation as antichagasic agents.
目前针对恰加斯病的化疗方法并不完善。我们合成了一系列十种曼尼希碱型衍生物，以评估它们的体外抗恰加斯病活性。经过初步筛选，化合物 7 和 9 进行了体内实验，在小鼠模型中进行了检测。这两种化合物在慢性期都导致寄生虫血症显著下降，这一结果甚至优于对照药物苯并咪唑。此外，化合物 9 在急性期也表现出更好的抗恰加斯病活性。此外，还进行了代谢产物排泄、对线粒体膜电位的影响以及超氧化物歧化酶（SOD）抑制研究，以确定其可能的作用机制。最后，对接研究提出了一种与我们之前的系列类似的 Fe-SOD 酶的结合模式，验证了我们的设计策略。因此，这些结果表明，这些化合物应被考虑作为进一步的临床前抗恰加斯病药物进行评估。
