Structure–Activity Relationship of Anti-Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2022-02-28 DOI:10.1021/acsmedchemlett.1c00549

Andreas Beuchel, Dina Robaa, Dereje A. Negatu, Abdeldjalil Madani, Nadine Alvarez, Matthew D. Zimmerman, Adrian Richter, Lea Mann, Sophie Hoenke, René Csuk, Thomas Dick, Peter Imming*

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引用次数: 2

Abstract

Mycobacterium abscessus causes difficult-to-cure pulmonary infections. The bacterium is resistant to most anti-infective agents, including first line antituberculosis (anti-TB) drugs. MMV688844 (844) is a piperidine-4-carboxamide (P4C) with bactericidal properties against M. abscessus. We recently identified DNA gyrase as the molecular target of 844. Here, we present in silico docking and genetic evidence suggesting that P4Cs display a similar binding mode to DNA gyrase as gepotidacin. Gepotidacin is a member of the Novel Bacterial Topoisomerase Inhibitors (NBTIs), a new class of nonfluoroquinolone DNA gyrase poisons. Thus, our work suggests that P4Cs present a novel structural subclass of NBTI. We describe structure–activity relationship studies of 844 leading to analogues showing increased antibacterial activity. Selected derivatives were tested for their inhibitory activity against recombinant M. abscessus DNA gyrase. Further optimization of the lead structures led to improved stability in mouse plasma and increased oral bioavailability.

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新型NBTI DNA螺旋酶抑制剂抗脓肿分枝杆菌哌啶-4-羧酰胺的构效关系

脓肿分枝杆菌引起难以治愈的肺部感染。这种细菌对大多数抗感染药物都有耐药性，包括一线抗结核药物。MMV688844(844)是一种对脓疡分枝杆菌具有杀菌作用的哌啶-4-羧酸酰胺(P4C)。我们最近确定DNA回转酶是844的分子靶点。在这里，我们提出了硅对接和遗传证据，表明P4Cs与DNA旋切酶的结合模式与gepotidacin相似。Gepotidacin是新型细菌拓扑异构酶抑制剂(NBTIs)的成员，NBTIs是一类新的非氟喹诺酮类DNA回转酶毒药。因此，我们的研究表明P4Cs是一种新的NBTI结构亚类。我们描述了844的结构-活性关系研究，导致类似物显示出增加的抗菌活性。所选衍生物对重组脓肿分枝杆菌DNA旋切酶的抑制活性进行了测试。进一步优化导联结构可改善其在小鼠血浆中的稳定性和提高口服生物利用度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.