{"title":"Sustainable synthesis of antibacterial 3-aryl-2<i>H</i>-benzo[b,1,4]oxazin-2-ones via S<sub>N</sub>Ar Csp<sup>2</sup>-Csp<sup>2</sup> coupling.","authors":"Fatemeh Salehzadeh, Maryam Esmkhani, Milad Noori, Shahrzad Javanshir, Aida Iraji, Mohammad Mahdavi","doi":"10.3389/fchem.2024.1472342","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The increasing prevalence of antibiotic-resistant pathogens necessitates the urgent development of new antibacterial agents. Concurrently, synthetic chemistry is moving towards more sustainable practices that minimize environmental impact. This study aims to synthesize 3-aryl-2<i>H</i>-benzo[b][1,4]oxazin-2-one derivatives, including the natural product cephalandole A, using a sustainable approach that avoids metal catalysts.</p><p><strong>Methods: </strong>We employed nucleophilic aromatic substitution (SNAr) under microwave-assisted conditions to facilitate the synthesis of the targeted compounds. This metal-free carbon-carbon coupling reaction was optimized for efficiency, yielding good results with reduced reaction times. The synthesized derivatives were then subjected to an <i>in silico</i> molecular docking study to predict their antibacterial potential against key bacterial targets, focusing on the binding affinity and interaction profiles.</p><p><strong>Results: </strong>The microwave-assisted SNAr method provided good yields of 55% to 82% and significantly reduced reaction times ranging from 7 to 12 minutes, simplifying the overall workup process. Among the synthesized compounds, 3-(<i>1H</i>-indol-3-yl)-6-methyl-2H-benzo[b][1,4]oxazin-2-one (<b>6b</b>) emerged as a promising candidate, demonstrating favorable binding interactions in the molecular docking studies.</p><p><strong>Discussion: </strong>The integration of sustainable synthetic methodologies with in silico screening offers a novel and effective strategy for drug discovery. Our findings highlight the potential of the synthesized compounds as antibacterial agents and emphasize the importance of adopting eco-friendly approaches in pharmaceutical chemistry. This research contributes to the global effort to combat antibiotic resistance by providing new compounds for further biological evaluation.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"12 ","pages":"1472342"},"PeriodicalIF":3.8000,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625556/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.3389/fchem.2024.1472342","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction: The increasing prevalence of antibiotic-resistant pathogens necessitates the urgent development of new antibacterial agents. Concurrently, synthetic chemistry is moving towards more sustainable practices that minimize environmental impact. This study aims to synthesize 3-aryl-2H-benzo[b][1,4]oxazin-2-one derivatives, including the natural product cephalandole A, using a sustainable approach that avoids metal catalysts.
Methods: We employed nucleophilic aromatic substitution (SNAr) under microwave-assisted conditions to facilitate the synthesis of the targeted compounds. This metal-free carbon-carbon coupling reaction was optimized for efficiency, yielding good results with reduced reaction times. The synthesized derivatives were then subjected to an in silico molecular docking study to predict their antibacterial potential against key bacterial targets, focusing on the binding affinity and interaction profiles.
Results: The microwave-assisted SNAr method provided good yields of 55% to 82% and significantly reduced reaction times ranging from 7 to 12 minutes, simplifying the overall workup process. Among the synthesized compounds, 3-(1H-indol-3-yl)-6-methyl-2H-benzo[b][1,4]oxazin-2-one (6b) emerged as a promising candidate, demonstrating favorable binding interactions in the molecular docking studies.
Discussion: The integration of sustainable synthetic methodologies with in silico screening offers a novel and effective strategy for drug discovery. Our findings highlight the potential of the synthesized compounds as antibacterial agents and emphasize the importance of adopting eco-friendly approaches in pharmaceutical chemistry. This research contributes to the global effort to combat antibiotic resistance by providing new compounds for further biological evaluation.
期刊介绍：
Frontiers in Chemistry is a high visiblity and quality journal, publishing rigorously peer-reviewed research across the chemical sciences. Field Chief Editor Steve Suib at the University of Connecticut is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to academics, industry leaders and the public worldwide.
Chemistry is a branch of science that is linked to all other main fields of research. The omnipresence of Chemistry is apparent in our everyday lives from the electronic devices that we all use to communicate, to foods we eat, to our health and well-being, to the different forms of energy that we use. While there are many subtopics and specialties of Chemistry, the fundamental link in all these areas is how atoms, ions, and molecules come together and come apart in what some have come to call the “dance of life”.
All specialty sections of Frontiers in Chemistry are open-access with the goal of publishing outstanding research publications, review articles, commentaries, and ideas about various aspects of Chemistry. The past forms of publication often have specific subdisciplines, most commonly of analytical, inorganic, organic and physical chemistries, but these days those lines and boxes are quite blurry and the silos of those disciplines appear to be eroding. Chemistry is important to both fundamental and applied areas of research and manufacturing, and indeed the outlines of academic versus industrial research are also often artificial. Collaborative research across all specialty areas of Chemistry is highly encouraged and supported as we move forward. These are exciting times and the field of Chemistry is an important and significant contributor to our collective knowledge.
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