The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure–activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.

中文翻译：

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利什曼原虫N-肉豆蔻酰基转移酶的新型硫代嘧啶抑制剂在细胞内变形虫中具有靶向活性。

由利什曼原虫种的原生动物寄生虫引起的利什曼病是被忽视的热带病，全世界有数百万例。当前的治疗方法受到毒性，耐药性和成本的限制。N-肉豆蔻酰基转移酶（NMT）是一种在所有真核生物中普遍存在且必不可少的酶，已通过遗传和药理学方法验证为有希望的抗利什曼原虫靶标。在这里，我们描述了以前在针对利什曼原虫的高通量筛选中鉴定的硫代嘧啶系列的全面结构-活性关系（SAR）研究NMT，以基于酶和细胞的测定形式涵盖68种化合物。使用化学标签的目标参与生物标志物分析，我们确定了在利什曼原虫中具有目标NMT活性的该系列中的第一种抑制剂。此外，对与利什曼原虫主要NMT配合的12种衍生物的晶体结构分析揭示了关键因素，这些因素对于未来的结构导向优化具有重要意义，可提供IMP-105（43），该化合物对利什曼原虫donovani胞内变形虫具有适度的活性，并且具有出色的选择性（> 660倍） ）用于利什曼原虫NMT而非人类NMT。