Department of Parasitology, Instituto de Investigación Biosanitaria (ibs. Granada), Hospitales Universitarios de Granada/University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
Department of Parasitology, Instituto de Investigación Biosanitaria (ibs. Granada), Hospitales Universitarios de Granada/University of Granada, Severo Ochoa s/n, E-18071 Granada, Spain.
Bioorg Med Chem. 2019 Mar 1;27(5):865-879. doi: 10.1016/j.bmc.2019.01.033. Epub 2019 Jan 29.
Chagas Disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi and affects more than 10 million people. It is a paradigmatic example of a chronic disease without an effective treatment in Latin America where the current therapies, based on Benznidazole and Nifurtimox, are characterised by limited efficacy, toxic side-effects and frequent failures in the treatment. We present a series of new long-chain squaramides, identified based on their H and C NMR spectra, and their trypanocidal activity and cytotoxicity were tested in vitro through the determination of IC values. Compounds 4 and 7 were more active and less toxic than the reference drug Benznidazole, and these results were the basis of promoting in vivo assays, where parasitaemia levels, assignment of cure, reactivation of parasitaemia and others parameters were determined in mice treated in both the acute and chronic phases. Finally, the mechanisms of action were elucidated at metabolic and mitochondrial levels and superoxide dismutase inhibition. The experiments allowed us to select compound 7 as a promising candidate for treating Chagas Disease, where the activity, stability and low cost make long-chain squaramides appropriate molecules for the development of an affordable anti-chagasic agent versus current treatments.
恰加斯病由经昆虫传播的原生动物克氏锥虫感染引起，影响超过 1000 万人。它是一种没有有效治疗方法的慢性疾病的典型范例，在拉丁美洲，目前基于苯并咪唑和硝呋替莫的治疗方法具有疗效有限、毒性副作用和治疗频繁失败等特点。我们根据其氢和碳 NMR 光谱鉴定了一系列新的长链 squaramides，并通过测定 IC 值测试了它们的杀锥虫活性和细胞毒性。化合物 4 和 7 的活性比参考药物苯并咪唑更高，毒性更低，这些结果是促进体内试验的基础，在急性和慢性阶段治疗的小鼠中，确定了寄生虫血症水平、治愈分配、寄生虫血症再激活和其他参数。最后，在代谢和线粒体水平以及超氧化物歧化酶抑制方面阐明了作用机制。这些实验使我们能够选择化合物 7 作为治疗恰加斯病的有前途的候选药物，其活性、稳定性和低成本使长链 squaramides 成为开发具有成本效益的抗恰加斯病药物的合适分子，与当前的治疗方法相比。
