Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
ChemMedChem. 2011 Feb 7;6(2):309-20. doi: 10.1002/cmdc.201000445. Epub 2011 Jan 18.
2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action.
2'-脱氧尿苷三磷酸核苷水解酶（dUTPase）是治疗疟疾的潜在药物靶点。我们之前报道了脱氧尿苷 5'-三苯甲基类似物的发现，它们是这种恶性疟原虫酶的选择性抑制剂。在此，我们报告了进一步的结构活性研究；特别是 5'-三苯甲基基团的变化、脱氧尿苷 3'-位引入各种取代基以及碱基的修饰。对化合物进行了酶和寄生虫的双重测试。5'-三苯甲基基团和 3'-取代基的变化都得到了很好的容忍，并产生了活性化合物。然而，对于活性，尿嘧啶碱基是明确必需的，因为尿嘧啶环的修饰会导致酶抑制作用丧失和抗疟活性显著降低。
