Facile Synthesis of FimH Antagonist and Its Analogues: Simple Entry to Complex C-Mannoside Inhibitors of E. coli Adhesion

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-09-09 DOI:10.1021/acsmedchemlett.4c00308

Zhaobo Zhou, Renpeng Tang, Ya Fang, Tinghong Lv, Jian Liu, Xiaolei Wang

引用次数: 0

Abstract

Synthesizing FimH antagonists is challenging because of their densely functionalized and stereochemically complex C-mannoside structures, resulting in low yields and lengthy processes. We present an efficient method for synthesizing C-mannoside FimH antagonists by nickel-catalyzed reductive coupling and stereocontrolled reduction, thereby significantly simplifying the process and enabling the synthesis of FimH antagonists in just four steps with an overall yield of 34–50%. This efficient synthesis holds significant potential for the rapid development of analogues targeting the treatment of urinary tract infections or Crohn’s disease caused by Escherichia coli (E. coli).

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FimH 拮抗剂及其类似物的简易合成：大肠杆菌粘附的复杂 C-甘露糖苷抑制剂的简单入口

由于 FimH 拮抗剂的 C-甘露糖苷结构具有密集的官能度和复杂的立体化学结构，因此合成 FimH 拮抗剂具有挑战性，导致产量低、过程长。我们提出了一种通过镍催化还原偶联和立体控制还原合成 C-甘露糖苷 FimH 拮抗剂的高效方法，从而大大简化了合成过程，只需四个步骤就能合成 FimH 拮抗剂，总产率高达 34-50%。这种高效的合成方法为快速开发治疗由大肠杆菌（E. coli）引起的尿路感染或克罗恩病的类似物提供了巨大的潜力。

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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.