Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv, 79010, Ukraine.
Enamine Ltd., Chervonotkatska 78, Kyiv, 02094, Ukraine.
Eur J Med Chem. 2019 Jul 15;174:292-308. doi: 10.1016/j.ejmech.2019.04.052. Epub 2019 Apr 24.
Different compounds have been investigated as potent drugs for trypanosomiasis treatment, but no new drug has been marketed in the past 3 decades. 4-Thiazolidinone/thiazole as privileged structures and thiosemicarbazides cyclic analogs are well known scaffolds in novel antitrypanosomal agent design. We present here the design and synthesis of new hybrid molecules bearing thiazolidinone/thiazole cores linked by the hydrazone group with various molecular fragments. Structure optimization led to compounds with phenyl-indole or phenyl-imidazo[2,1-b][1,3,4]thiadiazole moieties showing excellent antitrypanosomal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Biological study allowed identifying compounds with the submicromolar levels of IC, good selectivity indexes and relatively low cytotoxicity upon human primary fibroblasts as well as low acute toxicity.
不同的化合物已被研究作为治疗锥虫病的有效药物，但在过去的 30 年里没有新的药物上市。4-噻唑烷酮/噻唑作为特权结构和硫代氨基脲环类似物是新型抗锥虫药物设计中众所周知的支架。我们在这里介绍了具有噻唑烷酮/噻唑核心的新型杂合分子的设计和合成，这些分子通过腙基团与各种分子片段连接。结构优化导致了具有苯基-吲哚或苯基-咪唑并[2,1-b][1,3,4]噻二唑部分的化合物，对布氏锥虫和冈比亚锥虫表现出优异的抗锥虫活性。生物学研究确定了具有亚微摩尔水平的 IC 的化合物，对人原代成纤维细胞具有良好的选择性指数和相对低的细胞毒性，以及低的急性毒性。
