Department of Molecular Pharmacology and Clinical, Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
Laboratorio de Química-Médica, Facultad de Ciencia y Tecnología, Universidad del Azuay, Av. 24 de Mayo 777, Cuenca 010204, Ecuador.
Int J Mol Sci. 2024 Oct 16;25(20):11107. doi: 10.3390/ijms252011107.
Chagas disease is a prevalent health problem in Latin America which has received insufficient attention worldwide. Current treatments for this disease, benznidazole and nifurtimox, have limited efficacy and may cause side effects. A recent study proposed investigating a wide range of nitroindazole and indazolone derivatives as feasible treatments. Therefore, it is proposed that adding a nitro group at the 5-position of the indazole and indazolone structure could enhance trypanocidal activity by inducing oxidative stress through activation of the nitro group by NTRs (nitroreductases). The study results indicate that the nitro group advances free radical production, as confirmed by several analyses. Compound (5-nitro-2-picolyl-indazolin-3-one) shows the most favorable trypanocidal activity (1.1 ± 0.3 µM in epimastigotes and 5.4 ± 1.0 µM in trypomastigotes), with a selectivity index superior to nifurtimox. Analysis of the mechanism of action indicated that the nitro group at the 5-position of the indazole ring induces the generation of reactive oxygen species (ROS), which causes apoptosis in the parasites. Computational docking studies reveal how the compounds interact with critical residues of the NTR and FMNH (flavin mononucleotide reduced) in the binding site, which is also present in active ligands. The lipophilicity of the studied series was shown to influence their activity, and the nitro group was found to play a crucial role in generating free radicals. Further investigations are needed of derivatives with comparable lipophilic characteristics and the location of the nitro group in different positions of the base structure.
恰加斯病是拉丁美洲流行的健康问题，在全球范围内受到的关注不足。目前治疗该病的药物苯硝唑和硝呋替莫疗效有限，且可能引起副作用。最近的一项研究提出了研究一系列硝基吲唑和吲唑啉衍生物作为可行的治疗方法。因此，有人提出在吲唑和吲唑啉结构的 5 位加上硝基，可能通过 NTR（硝基还原酶）激活硝基来诱导氧化应激，从而增强杀锥虫活性。研究结果表明，硝基会促进自由基的产生，这一点得到了多项分析的证实。化合物（5-硝基-2-吡啶基-吲唑啉-3-酮）表现出最有利的杀锥虫活性（在epimastigotes 中为 1.1 ± 0.3 µM，在 trypomastigotes 中为 5.4 ± 1.0 µM），其选择性指数优于硝呋替莫。作用机制分析表明，吲唑环 5 位的硝基诱导活性氧（ROS）的产生，导致寄生虫凋亡。计算对接研究揭示了化合物如何与 NTR 和 FMNH（还原黄素单核苷酸）的关键残基在结合位点相互作用，该结合位点也存在于活性配体中。研究系列的脂溶性被证明会影响它们的活性，而硝基在产生自由基方面起着关键作用。需要进一步研究具有类似脂溶性特征的衍生物，以及硝基在碱基结构不同位置的位置。
