期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 208, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112773
关键词
Anti-tuberculosis; DprE1; 1,3-Benzothiazin-4-one scaffold; Covalent inhibitors
资金
- National Natural Science Foundation of China [8187169]
- Italian Ministry of Education, University and Research (MIUR) (Dipartimenti di Eccellenza, Program 2018-2022)
- Slovak Research and Development Agency [APVV-15-0515]
Decaprenylphosphoryl-beta-D-ribose 2'-oxidoreductase (DprE1) is a promising drug target for the development of novel anti-tubercular agents, and inhibitors of DprE1 are being investigated extensively. Among them, the 1,3-benzothiazinone compounds such as BTZ043, and its closer congener, PBTZ169, are undergoing clinical studies. It has been shown that both BTZ compounds are prodrugs, the nitro group is reduced to nitroso first, to which an adjacent Cys387 in the DprE1 binding pocket is covalently bound and results in suicide enzyme inhibition. We figured that replacement of the nitro with an electrophilic warhead would still achieve covalent interaction with nucleophilic Cys387, while the required reductive activation could be circumvented. To test this hypothesis, a number of covalent inhibitors of DprE1 were designed and prepared. The compounds inhibitory potency against DprE1 and anti-tubercular activity were investigated, their chemical reactivity, formation of covalent adduct between the warhead and the enzyme was demonstrated by mass spectrometry. (c) 2020 Elsevier Masson SAS. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据