含[1,2,5]噁二唑并[3,4-b]吡嗪的多黏菌素选择性耐药修饰剂的构效关系研究。
Structure-activity relationship studies of [1,2,5]oxadiazolo[3,4-b]pyrazine-containing polymyxin-selective resistance-modifying agents.
机构信息
Department of Chemistry, University of Colorado, Boulder, CO 80309, USA.
Department of Chemistry, University of Colorado, Boulder, CO 80309, USA.
出版信息
Bioorg Med Chem Lett. 2022 Sep 15;72:128878. doi: 10.1016/j.bmcl.2022.128878. Epub 2022 Jul 3.
Abstract
Multidrug-resistant (MDR) Gram-negative bacteria are an urgent and rapidly spreading threat to human health with limited treatment options. Previously, we discovered a novel [1,2,5]oxadiazolo[3,4-b]pyrazine-containing compound (1) that selectively re-sensitized a variety of MDR Gram-negative bacteria to colistin, one of the last-resort antibiotic. Herein, we report the structure-activity relationship studies of compound 1 that led to the discovery of several more potent and/or less toxic resistance-modifying agents (RMAs). Further evaluation of these RMAs showed that they were effective in a wide range of MDR bacteria. These results demonstrated these compounds as a novel class of RMAs and may be further developed as therapeutic agents.
摘要
多药耐药（MDR）革兰氏阴性菌对人类健康构成了紧迫且迅速蔓延的威胁，而可用的治疗选择却十分有限。此前，我们发现了一种新型[1,2,5]恶二唑并[3,4-b]吡嗪类化合物（1），它可选择性地使多种多药耐药革兰氏阴性菌重新对粘菌素（一种最后手段的抗生素）敏感。在此，我们报告了化合物 1 的构效关系研究，这些研究导致发现了几种更有效和/或毒性更低的耐药调节剂（RMA）。对这些 RMA 的进一步评估表明，它们在多种多药耐药菌中均有效。这些结果表明这些化合物为一类新型 RMA，并且可能被进一步开发为治疗剂。
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