Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
Molecules. 2018 Nov 26;23(12):3085. doi: 10.3390/molecules23123085.
Nucleoside antibiotics are uridine-derived natural products that inhibit the bacterial membrane protein MraY. MraY is a key enzyme in the membrane-associated intracellular stages of peptidoglycan biosynthesis and therefore considered to be a promising, yet unexploited target for novel antibacterial agents. Muraymycins are one subclass of such naturally occurring MraY inhibitors. As part of structure-activity relationship (SAR) studies on muraymycins and their analogues, we now report on novel derivatives with different attachment of one characteristic structural motif, i.e., the aminoribose moiety normally linked to the muraymycin glycyluridine core unit. Based on considerations derived from an X-ray co-crystal structure, we designed and synthesised muraymycin analogues having the aminoribose attached (via a linker) to either the glycyluridine amino group or to the uracil nucleobase. Reference compounds bearing the non-aminoribosylated linker units were also prepared. It was found that the novel aminoribosylated analogues were inactive as MraY inhibitors in vitro, but that the glycyluridine-modified reference compound retained most of the inhibitory potency relative to the unmodified parent muraymycin analogue. These results point to 6'alkylated muraymycin analogues as a potential novel variation of the muraymycin scaffold for future SAR optimisation.
核苷抗生素是一类来源于尿嘧啶的天然产物，能够抑制细菌膜蛋白 MraY。MraY 是肽聚糖生物合成过程中与细胞膜相关的细胞内阶段的关键酶，因此被认为是一种有前途但尚未开发的新型抗菌药物靶标。Muraymycins 是此类天然存在的 MraY 抑制剂的一个子类。作为 Muraymycins 及其类似物结构活性关系 (SAR) 研究的一部分，我们现在报告了具有不同连接方式的新型衍生物，即通常与 Muraymycin 甘氨酰尿嘧啶核心单元相连的氨基核糖部分。基于来自 X 射线共晶结构的考虑，我们设计并合成了将氨基核糖（通过连接子）连接到 Muraymycin 的氨基或尿嘧啶核苷碱基上的 Muraymycin 类似物。还制备了带有非氨基核糖连接子单元的参考化合物。结果发现，新型氨基核糖化类似物在体外作为 MraY 抑制剂没有活性，但甘氨酰尿嘧啶修饰的参考化合物相对于未修饰的母 Muraymycin 类似物保留了大部分抑制活性。这些结果表明 6'烷基化 Muraymycin 类似物是未来 SAR 优化的 Muraymycin 支架的一种潜在新型变体。
