Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-Positive Staphylococcus aureus
| Autor: | Josh Powell, Justin T Seffernick, Jonathan L. Papa, Daniel J. Wozniak, Jack C. Yalowich, Sheri Nolan, Mark J. Mitton-Fry, Yanran Lu, Nicholas Shkolnikov, Steffen Lindert, Anthony English |
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| Rok vydání: | 2020 |
| Předmět: |
biology
010405 organic chemistry medicine.drug_class Topoisomerase IV Organic Chemistry Antibiotics medicine.disease_cause 01 natural sciences Biochemistry DNA gyrase 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry Staphylococcus aureus Amide Drug Discovery medicine biology.protein Moiety Antibacterial activity Topoisomerase inhibitor |
| Zdroj: | ACS Medicinal Chemistry Letters. 11:2446-2454 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00428 |
| Popis: | In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compound 3 inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Optimization of this series of analogues led to the discovery of a subseries of compounds (22-25) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of S. aureus DNA gyrase. |
| Databáze: | OpenAIRE |
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