Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125, Modena, Italy.
Department of Pharmaceutical Sciences, University of Milan, Via Mangiagalli 25, 20133, Milan, Italy.
Eur J Med Chem. 2020 Mar 1;189:112047. doi: 10.1016/j.ejmech.2020.112047. Epub 2020 Jan 10.
The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.
LIBRA 化合物库是由意大利各学术实验室提供的 522 种非商业性化合物的集合。这些化合物是在不同的药物化学项目中设计和合成的，并由意大利技术研究所托管。我们报告了对利什曼原虫和布氏锥虫喋呤还原酶 1（TbPTR1 和 LmPTR1）进行 LIBRA 化合物库的筛选。有 9 种化合物对寄生性 PTR1 具有活性，并被选为基于细胞的寄生虫筛选，作为单一药物和与甲氨蝶呤（MTX）联合使用。鉴定出的最有趣的 TbPTR1 抑制剂是 4-(苄氧基)嘧啶-2,6-二胺（LIB_66）。随后，合成了六个新的 LIB_66 衍生物，以探索其结构-活性关系（SAR）和吸收、分布、代谢、排泄和毒性（ADMET）特性。结果表明，PTR1 优先与类似于其生物蝶呤/叶酸底物的抑制剂结合，如 2,4-二氨基嘧啶衍生物。
