Sulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation
Sulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation
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DOI：
10.1016/j.ejmech.2019.111667
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发表时间：
2019-12-01
影响因子：
6.7
通讯作者：
Hockova, Dana
中科院分区：
文献类型：
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作者：
Klejch, Tomas;Keough, Dianne T.;Hockova, Dana
次黄嘌呤-鸟嘌呤-黄嘌呤磷酸核糖基转移酶（HGXPRT）是公认的抗疟疾化疗靶点。它合成了疟原虫恶性疟原虫（Pf）所需的所有6-氧嘌呤核苷单磷酸、IMP、GMP和XMP。PfHGXPRT还间接负责单磷酸腺苷（AMP）的合成。无环核苷膦酸盐（ANPs）是一类PfHGXPRT抑制剂。这些化合物的前药能够抑制细胞培养中Pf的生长。为了寻找新的PfHGXPRT抑制剂，设计并合成了一系列含硫ANPs （thia-ANPs）。这些化合物基于2-（磷乙氧基）乙基鸟嘌呤（PEEG）和PEEHx的结构，其中嘌呤碱（即鸟嘌呤或次黄嘌呤）由五个原子（即四个碳和一个氧）连接到膦酸基团。在这里，PEEG和PEEHx是通过用硫化物、亚砜或砜桥取代连接体中的氧原子来修饰的。研究了这些取代对人类HGPRT和PfHGXPRT的K-i值的影响，结果表明大多数thia-ANPs明显有利于PfHGXPRT。例如，PEEHx的植物类似物PfHGXPRT的K-i值为0.2 μ M，比人类同类物低25倍。这些化合物的前药在基于细胞的抗疟试验中具有4-6 μ M范围内的IC50值，这使它们成为抗疟药物进一步开发的有吸引力的先导化合物。(C) 2019 Elsevier Masson SAS。版权所有。
Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the K-i values for human HGPRT and PfHGXPRT was investigated and showed that most of the thia-ANPs distinctively favour PfHGXPRT. For example, the thia-analogue of PEEHx has a K-i value of 0.2 mu M for PfHGXPRT, a value 25-fold lower than for the human counterpart. Prodrugs of these compounds have IC50 values in the 4-6 mu M range in antimalarial cell-based assays, making them attractive compounds for further development as antimalarial drug leads. (C) 2019 Elsevier Masson SAS. All rights reserved.