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从喹啉到基于喹唑啉的金黄色葡萄球菌 NorA 外排泵抑制剂：通过偶联聚焦的骨架跳跃方法和药效团搜索。

From Quinoline to Quinazoline-Based S. aureus NorA Efflux Pump Inhibitors by Coupling a Focused Scaffold Hopping Approach and a Pharmacophore Search.

机构信息

Department of Life and Environmental Sciences, Università Politecnica delle Marche, via Brecce Bianche, 60131, Ancona, Italy.

Current address: Department of Pharmacy, University of Napoli "Federico II", via D. Montesano 49, 80131, Napoli, Italy.

出版信息

ChemMedChem. 2021 Oct 6;16(19):3044-3059. doi: 10.1002/cmdc.202100282. Epub 2021 Jun 26.

DOI:10.1002/cmdc.202100282
PMID:34032014
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8518402/
Abstract

Antibiotic resistance breakers, such as efflux pump inhibitors (EPIs), represent a powerful alternative to the development of new antimicrobials. Recently, by using previously described EPIs, we developed pharmacophore models able to identify inhibitors of NorA, the most studied efflux pump of Staphylococcus aureus. Herein we report the pharmacophore-based virtual screening of a library of new potential NorA EPIs generated by an in-silico scaffold hopping approach of the quinoline core. After chemical synthesis and biological evaluation of the best virtual hits, we found the quinazoline core as the best performing scaffold. Accordingly, we designed and synthesized a series of functionalized 2-arylquinazolines, which were further evaluated as NorA EPIs. Four of them exhibited a strong synergism with ciprofloxacin and a good inhibition of ethidium bromide efflux on resistant S. aureus strains coupled with low cytotoxicity against human cell lines, thus highlighting a promising safety profile.

摘要

抗生素耐药性破解剂，如外排泵抑制剂 (EPIs)，是开发新抗菌药物的有力替代品。最近，我们使用先前描述的 EPIs，开发了能够识别 NorA 抑制剂的药效团模型，NorA 是金黄色葡萄球菌研究最多的外排泵。在此，我们报告了基于药效团的虚拟筛选，筛选了通过喹啉核心的计算机骨架跳跃方法生成的新潜在 NorA EPIs 文库。经过对最佳虚拟命中的化学合成和生物学评估，我们发现喹唑啉核心是表现最佳的支架。因此，我们设计并合成了一系列功能化的 2-芳基喹唑啉，进一步评估为 NorA EPIs。其中有 4 个与环丙沙星表现出强烈的协同作用，并能有效抑制耐多药金黄色葡萄球菌菌株的溴化乙锭外排，同时对人细胞系的细胞毒性低，因此具有有希望的安全性特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/41bfa5333a63/CMDC-16-3044-g037.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/d1e84c198dac/CMDC-16-3044-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/6e30fbedcd5c/CMDC-16-3044-g027.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/41bfa5333a63/CMDC-16-3044-g037.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/4d2bd39c5eae/CMDC-16-3044-g021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/6f649c36505a/CMDC-16-3044-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/1d2ee944a8ce/CMDC-16-3044-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/d1e84c198dac/CMDC-16-3044-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/6e30fbedcd5c/CMDC-16-3044-g027.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/896f/8518402/41bfa5333a63/CMDC-16-3044-g037.jpg

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