基于配体的新型n -芳基吡咯衍生物作为具有抗生物膜和抗毒活性的广谱抗菌药物的发现。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Basma M Qandeel, Samar Mowafy, Mohamed F El-Badawy, Nahla A Farag, Galal Yahya, Khaled Abouzid
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引用次数: 0

摘要

抗菌素耐药性的威胁不断升级,需要新的治疗药物。本研究采用基于配体的设计方法开发了三个系列的n -芳基吡咯衍生物(Va-e、VIa-e和VIa-e),并通过分子建模进行了细化。合成的化合物对ESKAPE病原菌、MRSA和静脉分枝杆菌进行了抗性评价。Va-e系列最有希望,化合物Vb、Vc和Ve的抗MRSA效果优于左氧氟沙星(MIC = 4 μg/mL vs. 8 μg/mL)。Vc对大肠杆菌、肺炎克雷伯菌和鲍曼不动杆菌也有明显的抑制作用(MIC = 8 μg/mL)。评估了化合物的抗生素膜和抗毒性,针对与感染持续和传播相关的耐药机制。大多数具有广谱生物膜抑制和抗毒活性。细胞毒性研究显示对细菌细胞有选择性。ADMET研究支持类似药物的特性。对接研究提示UPPP抑制可能是其潜在机制。进行了SAR分析,以支持未来的优化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ligand-based discovery of novel N-arylpyrrole derivatives as broad-spectrum antimicrobial agents with antibiofilm and anti-virulence activity.

The escalating threat of antimicrobial resistance calls for novel therapeutic agents. This study employed a ligand-based design approach to develop three series of N-arylpyrrole derivatives (Va-e, VIa-e, and VIIa-e), refined through molecular modeling. Synthesized compounds were evaluated against ESKAPE pathogens, MRSA, and Mycobacterium phlei. Series Va-e showed the most promise, with compounds Vb, Vc, and Ve outperforming levofloxacin against MRSA (MIC = 4 μg/mL vs. 8 μg/mL). Vc also exhibited activity against E. coli, K. pneumoniae, and A. baumannii, and showed significant inhibition against M. phlei (MIC = 8 μg/mL). Compounds were evaluated for antibiofilm and antivirulence properties, targeting resistance mechanisms linked to infection persistence and dissemination. Most exhibited broad-spectrum biofilm inhibition and antivirulence activity. Cytotoxicity studies revealed selectivity for bacterial cells. ADMET studies supported drug-like properties. Docking studies suggested UPPP inhibition as the potential mechanism. SAR analysis was conducted to support future optimizations.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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