Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin adjuvants

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-29 DOI:10.1016/j.bmcl.2024.130008

Susan L. Harris, Somnath Dutta, Nianzi Liu, Tilmann Wollenberg, Xiang Wang

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Abstract

Antimicrobial resistance (AMR) is a formidable global health challenge. Multidrug-resistant (MDR) Gram-negative bacterial infections are of primary concern due to diminishing treatment options and high morbidity and mortality. Colistin, a polymyxin family antibiotic, is a last-resort treatment for MDR Gram-negative infections, but its wider use has resulted in escalating resistance. In 2022, using a screening approach, we discovered that a [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP)-containing compound selectively re-sensitized various MDR Gram-negative bacteria to colistin. Initial structure–activity relationship (SAR) studies confirmed that bisanilino ODP compounds are colistin adjuvants with low mammalian toxicity. Herein, we report our extended SAR studies on a wide range of ODP analogs bearing alkyl- or arylalkylamines. Specifically, we discovered two new compounds, 5q and 8g, with potent colistin-potentiating activity and low mammalian toxicity in a wide range of clinically relevant pathogens.

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含[1,2,5]噁二唑并[3,4-b]吡嗪的可乐定佐剂的扩展结构-活性关系研究。

抗菌药耐药性（AMR）是全球健康面临的严峻挑战。耐多药（MDR）革兰氏阴性细菌感染是首要关注的问题，因为其治疗选择越来越少，发病率和死亡率也越来越高。多粘菌素系列抗生素中的秋水仙素是治疗耐多药革兰氏阴性菌感染的最后手段，但它的广泛使用导致耐药性不断升级。2022 年，我们利用筛选方法发现，一种含[1,2,5]噁二唑并[3,4-b]吡嗪（ODP）的化合物可选择性地使多种 MDR 革兰氏阴性菌对可乐定重新敏感。初步的结构-活性关系（SAR）研究证实，双苯胺基 ODP 化合物是具有低哺乳动物毒性的可乐定佐剂。在此，我们报告了对含有烷基或芳基烷基胺的多种 ODP 类似物进行的扩展 SAR 研究。具体来说，我们发现了 5q 和 8g 这两种新化合物，它们对多种临床相关病原体具有强效的可乐定促进活性和较低的哺乳动物毒性。

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

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.