Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1′ position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1′ chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)-enantiomers. Two ANPs, with K_i values of 0.39 μM and 0.57 μM, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites.

一些病原体，包括引起人类和动物非洲锥虫病的锥虫属寄生虫，不能从头合成嘌呤，它们完全依赖嘌呤补救途径 (PSP) 来产生核苷酸。因此，它们的 PSP 酶被认为是有前途的药物靶点，迄今为止很少有人探索。最近，已发现无环核苷膦酸酯 (ANPs) 作为 PSP 的关键酶，即 6-氧代嘌呤磷酸核糖基转移酶 (PRTs) 的抑制剂的重要作用。在此，我们设计并合成了在 C1' 位置分支的两个系列新的 ANP，作为单磷酸腺苷的模拟物。新型 ANP 有效抑制布氏锥虫腺嘌呤 PRT ( Tbr APRT1) 活性体外实验表明，C1' 手性中心的构型强烈影响了它们的活性：与( S )-对映异构体相比，( R )-对映异构体被证明更有效。两种K _i值分别为 0.39 μM 和 0.57 μM 的 ANP 代表了迄今为止报道的最有效的Tbr APRT1抑制剂，它们是进一步研究各种寄生虫中嘌呤代谢的重要工具。