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下一代杂环亲电试剂作为小分子共价MurA抑制剂

Next-Generation Heterocyclic Electrophiles as Small-Molecule Covalent MurA Inhibitors.

作者信息

Ábrányi-Balogh Péter, Keeley Aaron, Ferenczy György G, Petri László, Imre Tímea, Grabrijan Katarina, Hrast Martina, Knez Damijan, Ilaš Janez, Gobec Stanislav, Keserű György M

机构信息

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.

MS Metabolomics Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.

出版信息

Pharmaceuticals (Basel). 2022 Nov 29;15(12):1484. doi: 10.3390/ph15121484.

DOI:10.3390/ph15121484
PMID:36558935
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9781958/
Abstract

Heterocyclic electrophiles as small covalent fragments showed promising inhibitory activity on the antibacterial target MurA (UDP-N-acetylglucosamine 1-carboxyvinyltransferase, EC:2.5.1.7). Here, we report the second generation of heterocyclic electrophiles: the quaternized analogue of the heterocyclic covalent fragment library with improved reactivity and MurA inhibitory potency. Quantum chemical reaction barrier calculations, GSH (-glutathione) reactivity assay, and thrombin counter screen were also used to demonstrate and explain the improved reactivity and selectivity of the -methylated heterocycles and to compare the two generations of heterocyclic electrophiles.

摘要

作为小的共价片段的杂环亲电试剂对抗菌靶点MurA（UDP-N-乙酰葡糖胺1-羧乙烯基转移酶，EC：2.5.1.7）显示出有前景的抑制活性。在此，我们报道了第二代杂环亲电试剂：具有改善的反应活性和MurA抑制效力的杂环共价片段文库的季铵化类似物。量子化学反应势垒计算、谷胱甘肽（GSH）反应性测定和凝血酶反筛选也被用于证明和解释甲基化杂环的改善的反应活性和选择性，并比较两代杂环亲电试剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/290ac1a66fb1/pharmaceuticals-15-01484-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/23ffc79e4d1c/pharmaceuticals-15-01484-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/ca52c601a4b0/pharmaceuticals-15-01484-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/290ac1a66fb1/pharmaceuticals-15-01484-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/23ffc79e4d1c/pharmaceuticals-15-01484-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/ca52c601a4b0/pharmaceuticals-15-01484-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3273/9781958/290ac1a66fb1/pharmaceuticals-15-01484-sch002.jpg

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