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无环尿苷酰胺和 5'-酰胺核苷类似物作为疟原虫 dUTP 酶潜在抑制剂的研究。

Investigation of acyclic uridine amide and 5'-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase.

机构信息

Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Sir James Black Centre, UK.

出版信息

Bioorg Med Chem. 2013 Sep 15;21(18):5876-85. doi: 10.1016/j.bmc.2013.07.004. Epub 2013 Jul 12.

DOI:10.1016/j.bmc.2013.07.004
PMID:23916149
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3776224/
Abstract

Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays.

摘要

先前我们已经表明，三苯甲基和二苯去氧尿苷衍生物及其非环类似物可以抑制恶性疟原虫 dUTP 酶（PfdUTPase）。我们报告了构象受限酰胺衍生物作为 PfdUTPase 抑制剂的合成，包括无环和环状实例。活性取决于酰胺约束基团的取向和位置。在无环系列的情况下，我们能够获得酰胺约束类似物，其显示出与非约束类似物相似或更高的效力。不幸的是，这些化合物在细胞测定中显示出较低的选择性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/9fe6fe9a9eb0/fx3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/485063571f2d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/442553781ac5/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/a3de88c827b6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/908396144824/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/1d013967e163/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/daf3ed38a6ac/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/a6e593b66811/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/c98ebabd498d/fx2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/9fe6fe9a9eb0/fx3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/485063571f2d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/442553781ac5/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/a3de88c827b6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/908396144824/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/1d013967e163/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/daf3ed38a6ac/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/a6e593b66811/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/c98ebabd498d/fx2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f4/3776224/9fe6fe9a9eb0/fx3.jpg

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本文引用的文献

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2
Kinetics of DNA refolding from longitudinal exchange NMR spectroscopy.基于纵向交换核磁共振光谱法的DNA重折叠动力学
Chembiochem. 2011 Sep 5;12(13):2007-10. doi: 10.1002/cbic.201100318. Epub 2011 Jul 7.
3
β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.
β-支链无环核苷类似物作为恶性疟原虫 dUTP 酶的抑制剂。
Bioorg Med Chem. 2011 Apr 1;19(7):2378-91. doi: 10.1016/j.bmc.2011.02.012. Epub 2011 Feb 17.
4
New medicines to improve control and contribute to the eradication of malaria.用于改善疟疾控制并助力消除疟疾的新型药物。
Nat Rev Drug Discov. 2009 Nov;8(11):879-91. doi: 10.1038/nrd2972. Epub 2009 Oct 16.
5
Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase.新型尿嘧啶乙酰胺衍生物作为恶性疟原虫dUTP核苷酸水解酶潜在抑制剂的设计、合成与评价
Eur J Med Chem. 2009 Feb;44(2):678-88. doi: 10.1016/j.ejmech.2008.05.018. Epub 2008 Jul 10.
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Malaria. Did they really say ... eradication?疟疾。他们真的是在说……根除吗？
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