Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents
Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents
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DprE1 共价抑制剂作为抗结核药物的设计、合成和评估。
DOI：
10.1016/j.ejmech.2020.112773
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发表时间：
2020-12-15
影响因子：
6.7
通讯作者：
Qiao, Chunhua
中科院分区：
文献类型：
--
作者：
Liu, Lingfeng;Kong, Chengcheng;Qiao, Chunhua
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.
