Balfour Michael N, Franco Caio H, Moraes Carolina B, Freitas-Junior Lucio H, Stefani Hélio A
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil.
Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, SP, Brazil.
Eur J Med Chem. 2017 Mar 10;128:202-212. doi: 10.1016/j.ejmech.2017.01.040. Epub 2017 Feb 3.
A library of 16 4-substituted 2-(1H-pyrrolo[3,2-c]pyridin-2-yl)propan-2-ols 17-32 has been synthesized for use in biological testing against Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. The 4-substituted 2-(1H-pyrrolo[3,2-c]pyridin-2-yl)propan-2-ols 17-32 were subjected to biological testing to evaluate their efficacy against intracellular Trypanosoma cruzi (Y strain) amastigotes infecting U2OS human cells, with benznidazole as a reference compound. The assay was performed in duplicate (two independent experiments) and submitted to High Content Analysis (HCA) for determination of trypanocidal activity. Three of the tested compounds presented relatively high trypanocidal activity (19, 22 and 29), however severe host cell toxicity was observed concomitantly. Chemical optimization of the highly active compounds and the synthesis of more compounds for biological testing against Trypanosoma cruzi will be required to improve selectivity and so that a structure-activity relationship can be generated to provide a more insightful analysis of both chemical and biological aspects.
已合成了一个包含16种4-取代的2-(1H-吡咯并[3,2-c]吡啶-2-基)丙-2-醇（17 - 32）的文库，用于针对克氏锥虫进行生物学测试，克氏锥虫是引起恰加斯病的原生动物寄生虫。以苯并硝唑作为参考化合物，对4-取代的2-(1H-吡咯并[3,2-c]吡啶-2-基)丙-2-醇（17 - 32）进行生物学测试，以评估它们对感染U2OS人细胞的细胞内克氏锥虫（Y株）无鞭毛体的疗效。该试验重复进行两次（两个独立实验），并提交给高内涵分析（HCA）以测定杀锥虫活性。三种测试化合物表现出相对较高的杀锥虫活性（19、22和29），然而同时观察到严重的宿主细胞毒性。需要对高活性化合物进行化学优化，并合成更多用于针对克氏锥虫进行生物学测试的化合物，以提高选择性，从而能够建立构效关系，以便对化学和生物学方面进行更深入的分析。
