Basma M Qandeel, Samar Mowafy, Mohamed F El-Badawy, Nahla A Farag, Galal Yahya, Khaled Abouzid
{"title":"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。","authors":"Basma M Qandeel, Samar Mowafy, Mohamed F El-Badawy, Nahla A Farag, Galal Yahya, Khaled Abouzid","doi":"10.1080/14756366.2025.2523970","DOIUrl":null,"url":null,"abstract":"<p><p>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 (<b>Va-e</b>, <b>VIa-e</b>, and <b>VIIa-e</b>), refined through molecular modeling. Synthesized compounds were evaluated against ESKAPE pathogens, MRSA, and <i>Mycobacterium phlei</i>. Series <b>Va-e</b> showed the most promise, with compounds <b>Vb</b>, <b>Vc</b>, and <b>Ve</b> outperforming levofloxacin against MRSA (MIC = 4 μg/mL vs. 8 μg/mL). <b>Vc</b> also exhibited activity against <i>E. coli, K. pneumoniae</i>, and <i>A. baumannii</i>, and showed significant inhibition against <i>M. phlei</i> (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.</p>","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"40 1","pages":"2523970"},"PeriodicalIF":5.4000,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239241/pdf/","citationCount":"0","resultStr":"{\"title\":\"Ligand-based discovery of novel N-arylpyrrole derivatives as broad-spectrum antimicrobial agents with antibiofilm and anti-virulence activity.\",\"authors\":\"Basma M Qandeel, Samar Mowafy, Mohamed F El-Badawy, Nahla A Farag, Galal Yahya, Khaled Abouzid\",\"doi\":\"10.1080/14756366.2025.2523970\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 (<b>Va-e</b>, <b>VIa-e</b>, and <b>VIIa-e</b>), refined through molecular modeling. Synthesized compounds were evaluated against ESKAPE pathogens, MRSA, and <i>Mycobacterium phlei</i>. Series <b>Va-e</b> showed the most promise, with compounds <b>Vb</b>, <b>Vc</b>, and <b>Ve</b> outperforming levofloxacin against MRSA (MIC = 4 μg/mL vs. 8 μg/mL). <b>Vc</b> also exhibited activity against <i>E. coli, K. pneumoniae</i>, and <i>A. baumannii</i>, and showed significant inhibition against <i>M. phlei</i> (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.</p>\",\"PeriodicalId\":15769,\"journal\":{\"name\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"volume\":\"40 1\",\"pages\":\"2523970\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239241/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Enzyme Inhibition and Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/14756366.2025.2523970\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Enzyme Inhibition and Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14756366.2025.2523970","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/8 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.