Structurally Optimized Potent Dual-Targeting NBTI Antibacterials with an Enhanced Bifurcated Halogen-Bonding Propensity
| Autor: | Irena Zdovc, Nikola Minovski, Martina Hrast, Matjaž Weiss, Maja Kokot, Marko Anderluh |
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| Rok vydání: | 2021 |
| Předmět: |
Letter
Topoisomerase IV medicine.drug_class Stereochemistry Farmacevtska kemija medicine.disease_cause Dual targeting Biochemistry DNA gyrase topoisomerase IV Drug Discovery medicine NBTIs Encimska aktivnost udc:615.4 Escherichia coli chemistry.chemical_classification biology Chemistry Bifurcated halogen bonds dual targeting Organic Chemistry Enzyme Staphylococcus aureus bifurcated halogen bonds Lipophilicity biology.protein Efflux NBTIs DNA gyrase topoisomerase IV bifurcated halogen bonds dual targeting Topoisomerase inhibitor Patogeni udc:615.4:54:579 |
| Zdroj: | ACS Medicinal Chemistry Letters ACS medicinal chemistry letters, vol. 12, no. 9, pp. 1478-1485, 2021. ACS Medicinal Chemistry Letters, str. 1478-1485 : Ilustr., Vol. 12, iss. 9, 2021 COBISS-ID: 2959217 |
| ISSN: | 1948-5875 |
| Popis: | We designed and synthesized an optimized library of novel bacterial topoisomerase inhibitors with p-halogenated phenyl right-hand side fragments and significantly enhanced and balanced dual-targeted DNA gyrase and topoisomerase IV activities of Staphylococcus aureus and Escherichia coli. By increasing the electron-withdrawing properties of the p-halogenated phenyl right-hand side fragment and maintaining a similar lipophilicity and size, an increased potency was achieved, indicating that the antibacterial activities of this series of novel bacterial topoisomerase inhibitors against all target enzymes are determined by halogen-bonding rather than van der Waals interactions. They show nanomolar enzyme inhibitory and whole-cell antibacterial activities against S. aureus and methicillin-resistant S. aureus (MRSA) strains. However, due to the relatively high substrate specificity for the bacterial efflux pumps, they tend to be less potent against E. coli and other Gram-negative pathogens. Abstract. Bibliografija: str. 1484-1485. ARRS ARRS Young Researcher’s Program |
| Databáze: | OpenAIRE |
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