Universidade Federal Fluminense, Faculdade de Farmácia, Laboratório de Química Medicinal, RJ, Brazil.
Universidade de São Paulo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, SP, Brazil.
Bioorg Med Chem. 2021 Jan 1;29:115855. doi: 10.1016/j.bmc.2020.115855. Epub 2020 Nov 6.
Despite the serious public health problems caused by Chagas disease in several countries, the available therapy remains with only two drugs that are poorly active during the chronic phase of the disease in addition to having severe side effects. In search of new trypanocidal agents, herein we describe the synthesis and biological evaluation of eleven new 1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine compounds containing the carbohydrazide or the 2,3-dihydro-1,3,4-oxadiazole moieties. Two of them showed promising in vitro activity against amastigote forms of T. cruzi and were evaluated in vivo in male BALB/c mice infected with T. cruzi Y strain. Our results suggest that the substitution at the C-2 position of the phenyl group connected to the carbohydrazide or to the 2,3-dihydro-1,3,4-oxadiazole moieties plays an important role in the trypanocidal activity of this class of compounds. Moreover, the compound containing the 2,3-dihydro-1,3,4-oxadiazole moiety has demonstrated more favorable structural requirements for in vivo activity than its carbohydrazide analog.
尽管在一些国家，恰加斯病引发了严重的公共卫生问题，但现有的治疗方法仍然只有两种药物，而且这两种药物在疾病的慢性阶段活性不佳，此外还具有严重的副作用。为了寻找新的杀锥虫药物，我们在此描述了 11 种新的 1,6-二苯基-1H-吡唑并[3,4-b]吡啶化合物的合成和生物学评价，这些化合物含有 carbohydrazide 或 2,3-二氢-1,3,4-噁二唑部分。其中两种化合物对 T. cruzi 的无鞭毛体形式表现出有希望的体外活性，并在感染 T. cruzi Y 株的雄性 BALB/c 小鼠中进行了体内评估。我们的结果表明，与 carbohydrazide 或 2,3-二氢-1,3,4-噁二唑部分连接的苯基在 C-2 位置的取代对这类化合物的杀锥虫活性起着重要作用。此外，含有 2,3-二氢-1,3,4-噁二唑部分的化合物在体内活性方面具有更有利的结构要求，优于其 carbohydrazide 类似物。
