Discovery of 3-methacylic acid substituted benzoxaboroles as dual metallo- and serine-β-lactamase inhibitors

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-05-08 DOI:10.1016/j.ejmech.2025.117723

Guo-Qing Liang, Ying-Ying Jiang, Cheng-Long Han, Yao Wang, Si-Yao Wang, Yi-Ting Chen, Gen Li, Guo-Bo Li, You-Cai Xiao

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Abstract

Carbapenem resistance is an ongoing clinical problem, largely driven by production of evolved serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs). We here report a series of new 3-methacrylic acid-substituted benzoxaboroles as dual MBL/SBL inhibitors. Structure-activity relationship studies showed that the new compounds manifested nanomolar inhibition to the SBLs KPC-2 and OXA-48, and single-digit micromolar inhibition to the MBLs VIM-2, NDM-1, and NDM-5. Co-crystallographic analyses revealed their binding modes with VIM-2 and OXA-48, which are similar as those of taniborbactam and xeruborbactam. Bacterial assays demonstrated that compound 10 can potentiate meropenem against multidrug-resistant Gram-negative strains. This work provides new lead compounds and structural basis for developing new drug candidates against MBL/SBL-mediated carbapenem resistance.

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发现3-甲基乙酸取代苯并恶波罗作为双金属和丝氨酸-β-内酰胺酶抑制剂

碳青霉烯耐药是一个持续存在的临床问题，主要是由丝氨酸β-内酰胺酶（SBLs）和金属β-内酰胺酶（MBLs）的产生所驱动的。我们在此报道了一系列新的3-甲基丙烯酸取代苯并恶波罗作为双MBL/SBL抑制剂。构效关系研究表明，新化合物对SBLs KPC-2和OXA-48具有纳米摩尔的抑制作用，对MBLs VIM-2、NDM-1和NDM-5具有个位数的微摩尔抑制作用。共晶分析表明，它们与VIM-2和OXA-48的结合模式与三波巴坦和异波巴坦相似。细菌试验表明，化合物10可以增强美罗培南对多重耐药革兰氏阴性菌株的作用。本研究为开发抗MBL/ sbl介导的碳青霉烯类耐药新药提供了新的先导化合物和结构基础。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.