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Tytuł:
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Identification of Unique Quinazolone Thiazoles as Novel Structural Scaffolds for Potential Gram-Negative Bacterial Conquerors.
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Autorzy:
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Wang J; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China.
Ansari MF; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China.
Zhou CH; Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, P. R. China.
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Źródło:
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Journal of medicinal chemistry [J Med Chem] 2021 Jun 10; Vol. 64 (11), pp. 7630-7645. Date of Electronic Publication: 2021 May 19.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
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MeSH Terms:
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Anti-Bacterial Agents/*pharmacology
Azoles/*chemistry
Gram-Negative Bacteria/*drug effects
Thiazoles/*chemistry
Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/metabolism ; Bacterial Outer Membrane/drug effects ; Bacterial Outer Membrane/metabolism ; Binding Sites ; Binding, Competitive ; Biofilms/drug effects ; Crystallography, X-Ray ; Drug Design ; Drug Resistance, Bacterial/drug effects ; Escherichia coli/physiology ; Gram-Positive Bacteria/drug effects ; L-Lactate Dehydrogenase/antagonists & inhibitors ; L-Lactate Dehydrogenase/metabolism ; Microbial Sensitivity Tests ; Molecular Conformation ; Molecular Docking Simulation ; Pseudomonas aeruginosa/physiology ; Reactive Oxygen Species/metabolism ; Thiazoles/metabolism ; Thiazoles/pharmacology
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Substance Nomenclature:
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0 (Anti-Bacterial Agents)
0 (Azoles)
0 (Reactive Oxygen Species)
0 (Thiazoles)
EC 1.1.1.27 (L-Lactate Dehydrogenase)
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Entry Date(s):
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Date Created: 20210519 Date Completed: 20210617 Latest Revision: 20210617
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Update Code:
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20240104
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DOI:
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10.1021/acs.jmedchem.1c00334
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PMID:
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34009979
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A class of quinazolone thiazoles was identified as new structural scaffolds for potential antibacterial conquerors to tackle dreadful resistance. Some prepared compounds exhibited favorable bacteriostatic efficiencies on tested bacteria, and the most representative 5j featuring the 4-trifluoromethylphenyl group possessed superior performances against Escherichia coli and Pseudomonas aeruginosa to norfloxacin. Further studies revealed that 5j with inappreciable hemolysis could hinder the formation of bacterial biofilms and trigger reactive oxygen species generation, which could take responsibility for emerging low resistance. Subsequent paralleled exploration discovered that 5j not only disintegrated outer and inner membranes to induce leakage of cytoplasmic contents but also broke the metabolism by suppressing dehydrogenase. Meanwhile, derivative 5j could intercalate into DNA to exert powerful antibacterial properties. Moreover, compound 5j gave synergistic effects against some Gram-negative bacteria in combination with norfloxacin. These findings indicated that this novel structural type of quinazolone thiazoles showed therapeutic foreground in struggling with Gram-negative bacterial infections.