Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185, Rome, Italy.
Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland.
Eur J Med Chem. 2018 Aug 5;156:53-60. doi: 10.1016/j.ejmech.2018.06.063. Epub 2018 Jun 28.
We discovered a series of azole antifungal compounds as effective antiprotozoal agents. They displayed promising inhibitory activities within the micromolar-submicromolar range against P. falciparum, L. donovani, and T. b. rhodesiense. Moreover, most of such compounds showed excellent nanomolar IC against T. cruzi, showing also very low cytotoxicity. Discussion of structure-activity relationships and biological data for these compounds are provided against the different parasites. To assess the mechanism of action against T. cruzi we proved that the most potent compounds (3b, 3j-l) inhibited the T. cruzi CYP51. Moreover, the most active derivative 3j dramatically reduced parasitemia in T. cruzi mouse model without acute toxicity.
我们发现了一系列唑类抗真菌化合物，它们作为有效的抗原生动物药物具有显著的活性。这些化合物在微摩尔到亚微摩尔范围内对疟原虫、利什曼原虫和非洲锥虫表现出了良好的抑制活性。此外，大多数此类化合物对克氏锥虫的纳米摩尔 IC 也表现出优异的抑制活性，同时显示出非常低的细胞毒性。我们针对不同的寄生虫提供了这些化合物的结构-活性关系和生物学数据的讨论。为了评估这些化合物对克氏锥虫的作用机制，我们证明了最有效的化合物（3b、3j-l）抑制了克氏锥虫 CYP51。此外，最有效的衍生物 3j 在没有急性毒性的情况下显著降低了克氏锥虫感染的小鼠模型中的寄生虫血症。
