دورية أكاديمية
Structure-Activity Relationships of Pyrazolo[1,5- a ]pyrimidin-7(4 H )-ones as Antitubercular Agents.
| العنوان: | Structure-Activity Relationships of Pyrazolo[1,5- a ]pyrimidin-7(4 H )-ones as Antitubercular Agents. |
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| المؤلفون: | Oh S; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Libardo MDJ; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Azeeza S; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Pauly GT; Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States., Roma JSO; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Sajid A; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Tateishi Y; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Duncombe C; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Goodwin M; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Ioerger TR; Department of Computer Science and Engineering, Texas A&M University, College Station, Texas 77843, United States., Wyatt PG; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., Ray PC; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., Gray DW; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom., Boshoff HIM; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Barry CE 3rd; Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.; Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7935, South Africa. |
| المصدر: | ACS infectious diseases [ACS Infect Dis] 2021 Feb 12; Vol. 7 (2), pp. 479-492. Date of Electronic Publication: 2021 Jan 06. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : ACS Publications, [2015]- |
| مواضيع طبية MeSH: | Antitubercular Agents*/pharmacology , Mycobacterium tuberculosis*/genetics, High-Throughput Screening Assays ; Structure-Activity Relationship |
| مستخلص: | Pyrazolo[1,5- a ]pyrimidin-7(4 H )-one was identified through high-throughput whole-cell screening as a potential antituberculosis lead. The core of this scaffold has been identified several times previously and has been associated with various modes of action against Mycobacterium tuberculosis ( Mtb ). We explored this scaffold through the synthesis of a focused library of analogues and identified key features of the pharmacophore while achieving substantial improvements in antitubercular activity. Our best hits had low cytotoxicity and showed promising activity against Mtb within macrophages. The mechanism of action of these compounds was not related to cell-wall biosynthesis, isoprene biosynthesis, or iron uptake as has been found for other compounds sharing this core structure. Resistance to these compounds was conferred by mutation of a flavin adenine dinucleotide (FAD)-dependent hydroxylase (Rv1751) that promoted compound catabolism by hydroxylation from molecular oxygen. Our results highlight the risks of chemical clustering without establishing mechanistic similarity of chemically related growth inhibitors. |
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| معلومات مُعتمدة: | 203134/Z/16/Z United Kingdom WT_ Wellcome Trust; Z01 AI000693 United States ImNIH Intramural NIH HHS |
| فهرسة مساهمة: | Keywords: antitubercular activity; pyrazolo[1,5-a]pyrimidin-7(4H)-one; structure−activity relationship; tuberculosis |
| المشرفين على المادة: | 0 (Antitubercular Agents) |
| تواريخ الأحداث: | Date Created: 20210106 Date Completed: 20210623 Latest Revision: 20220318 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC7887755 |
| DOI: | 10.1021/acsinfecdis.0c00851 |
| PMID: | 33405882 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 2373-8227 |
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| DOI: | 10.1021/acsinfecdis.0c00851 |