Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC₅₀ = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC₅₀ value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained.

中文翻译：

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利用 2-氨基-1,3,4-噻二唑支架抑制布氏锥虫蝶啶还原酶以支持早期药物发现

蝶啶还原酶-1 (PTR1) 是治疗锥虫病的有希望的药物靶点。我们研究了先前确定的一类主要利什曼原虫PTR1噻二唑抑制剂对布氏锥虫( Tb ) 的活性的潜力。我们解决了几种Tb PTR1 抑制剂复合物的晶体结构，以指导新的噻二唑衍生物的基于结构的设计。随后的合成以及基于酶和细胞的分析证实了新的中等微摩尔Tb PTR1抑制剂具有低毒性。特别是化合物4m，一种 IC ₅₀的联苯-噻二唑-2,5-二胺= 16 μM，能够增强二氢叶酸还原酶抑制剂甲氨蝶呤 (MTX) 的抗锥虫活性，EC ₅₀值降低 4.1 倍。此外，4m和 MTX组合的抗寄生虫活性被添加叶酸逆转。通过采用高效的命中发现平台，我们展示了如何使用 2-氨基-1,3,4-噻二唑支架，获得开发抗布氏锥虫药物的有前途的工具。