Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, 21941902, Rio de Janeiro, RJ, Brazil.
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, 21040-360, Rio de Janeiro, RJ, Brazil.
Biomed Pharmacother. 2020 Jul;127:110162. doi: 10.1016/j.biopha.2020.110162. Epub 2020 May 11.
Herein, we present the design, synthesis and trypanocidal evaluation of sixteen new 1,3,4-thiadiazole derivatives from N-aminobenzyl or N-arylhydrazone series. All derivatives were assayed against the trypomastigote form of Trypanosoma cruzi, showing IC values ranging from 3 to 226 μM, and a better trypanocidal profile was demonstrated for the 1,3,4-thiadiazole-N-arylhydrazones (3a-g). In this series, the 2-pyridinyl fragment bound to the imine subunit of the hydrazine moiety presented pharmacophoric behavior for trypanocidal activity. Compounds 2a, 11a and 3e presented remarkable activity and excellent selectivity indexes. Compound 2a was also active against the intracellular amastigote form of T. cruzi. Moreover, its corresponding hydrochloride, compound 11a, showed the most promising profile, producing phenotypic changes similar to those caused by posaconazole, a well-known inhibitor of sterol biosynthesis. Thus, 1,3,4-thiadiazole derivative 11a could be considered a good prototype for the development of new drug candidates for Chagas disease therapy.
本文介绍了十六个新的 1,3,4-噻二唑衍生物的设计、合成和杀锥虫活性评价，这些衍生物来自 N-氨甲基苄基或 N-芳基腙系列。所有衍生物均针对锥虫的无鞭毛体形式进行了测试，IC 值范围为 3 到 226μM，1,3,4-噻二唑-N-芳基腙（3a-g）表现出更好的杀锥虫活性。在该系列中，与腙部分的亚胺单元结合的吡啶片段表现出对杀锥虫活性的药效团行为。化合物 2a、11a 和 3e 表现出显著的活性和优异的选择指数。化合物 2a 对 T. cruzi 的细胞内无鞭毛体形式也具有活性。此外，其相应的盐酸盐化合物 11a 表现出最有前途的特性，产生与泊沙康唑（一种著名的固醇生物合成抑制剂）相似的表型变化。因此，1,3,4-噻二唑衍生物 11a 可以被认为是开发用于治疗恰加斯病的新型药物候选物的良好原型。
