Laboratório de Síntese e Química Medicinal (LASQUIM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79051-470, Brazil.
Laboratório de Síntese e Química Medicinal (LASQUIM), Faculdade de Ciências Farmacêuticas, Alimentos e Nutrição, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79051-470, Brazil; Laboratório de Parasitologia Humana, Instituto de Biociências, Universidade Federal de Mato Grossso do Sul- UFMS, Campo Grande, Mato Grosso do Sul, CEP 79070-900, Brazil.
Eur J Med Chem. 2023 Nov 15;260:115451. doi: 10.1016/j.ejmech.2023.115451. Epub 2023 May 5.
Chagas disease and leishmaniasis are neglected diseases of high priority as a public health problem. Pharmacotherapy is based on the administration of a few drugs, which exhibit hazardous adverse effects and toxicity to the patients. Thus, the search for new antitrypanosomatid drugs is imperative to overcome the limitations of the treatments. In this work, 46 2-nitroimidazole 3,5-disubstituted isoxazole compounds were synthesized in good yields by [3 + 2] cycloaddition reaction between terminal acetylene (propargyl-2-nitroimidazole) and chloro-oximes. The compounds were non-toxic to LLC-MK2 cells. Compounds 30, 35, and 44 showed in vitro antichagasic activity, 15-fold, 12-fold, and 10-fold, respectively, more active than benznidazole (BZN). Compounds 30, 35, 44, 45, 53, and 61 acted as substrates for the TcNTR enzyme, indicating that this might be one of the mechanisms of action involved in their antiparasitic activity. Piperazine series and 4-monosubstituted compounds were potent against T. cruzi parasites. Besides the in vitro activity observed in compound 45, the in vivo assay showed that the compound only reduced the parasitemia levels by the seventh-day post-infection (77%, p > 0.001) compared to the control group. However, 45 significantly reduced the parasite load in cardiac tissue (p < 0.01) 11 days post-infection. Compounds 49, 52, and 54 showed antileishmanial activity against intracellular amastigotes of Leishmania (L.) amazonensis at the same range as amphotericin B. These findings highlight the antitrypanosomatid properties of 2-nitroimidazole 3,5-disubstituted isoxazole compounds and the possibility in using them as antitrypanosomatid agents in further studies.
恰加斯病和利什曼病是作为公共卫生问题的高度优先被忽视的疾病。药物治疗基于少数几种药物的管理，这些药物对患者表现出危险的不良反应和毒性。因此，寻找新的抗锥虫病药物对于克服治疗的局限性是必要的。在这项工作中，通过末端炔烃（丙炔基-2-硝基咪唑）和氯肟之间的[3+2]环加成反应，以良好的产率合成了 46 个 2-硝基咪唑 3,5-二取代异恶唑化合物。这些化合物对 LLC-MK2 细胞无毒。化合物 30、35 和 44 的体外抗恰加斯病活性分别比苯并硝唑（BZN）高 15 倍、12 倍和 10 倍。化合物 30、35、44、45、53 和 61 作为 TcNTR 酶的底物，表明这可能是其抗寄生虫活性涉及的作用机制之一。哌嗪系列和 4-单取代化合物对 T. cruzi 寄生虫具有强大的作用。除了在化合物 45 中观察到的体外活性外，体内试验表明，与对照组相比，该化合物仅在感染后第 7 天（77%，p > 0.001）降低了寄生虫血症水平。然而，45 在感染后第 11 天显著降低了心脏组织中的寄生虫负荷（p < 0.01）。化合物 49、52 和 54 对利什曼原虫（L.）亚马逊利什曼原虫的细胞内无鞭毛体表现出抗利什曼病活性，与两性霉素 B 相同。这些发现突出了 2-硝基咪唑 3,5-二取代异恶唑化合物的抗锥虫病特性，并有可能在进一步的研究中将它们用作抗锥虫病药物。
