1. Antimicrobial and KPC/AmpC inhibitory activity of functionalized benzosiloxaboroles.
- Author
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Durka K, Laudy AE, Charzewski Ł, Urban M, Stępień K, Tyski S, Krzyśko KA, and Luliński S
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Antifungal Agents chemical synthesis, Antifungal Agents chemistry, Boron Compounds chemical synthesis, Boron Compounds chemistry, Cell Line, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Structure-Activity Relationship, beta-Lactamase Inhibitors chemical synthesis, beta-Lactamase Inhibitors chemistry, beta-Lactamases metabolism, Anti-Bacterial Agents pharmacology, Antifungal Agents pharmacology, Bacteria drug effects, Boron Compounds pharmacology, Fungi drug effects, beta-Lactamase Inhibitors pharmacology
- Abstract
A series of 22 benzosiloxaboroles, silicon analogues of strong antimicrobial agents - benzoxaboroles, have been synthesized and tested against β-lactamases KPC- and pAmpC-producing strains of Gram-negative rods. Comprehensive structural-property relationship studies supported by molecular modelling as well as biological studies reveal that 6-B(OH)
2 -substituted derivative 27 strongly inhibits the activity of cephalosporinases (chromosomally encoded AmpC and plasmid encoded CMY-2) and KPC carbapenemases. It also shows strong ability to inhibit growth of the strains producing KPC-3 when combined with meropenem. In addition, halogen-substituted (mono-, di- or tetra-) benzosiloxaboroles demonstrate high antifungal activity (MIC 1.56-6.25 mg/L) against C. tropicalis, C. guilliermondii and S. cerevisiae. The highest activity against pathogenic yeasts (C. albicans, C. krusei and C. parapsilosis - MICs 12.5 mg/L) and against Gram-positive cocci (S. aureus and E. faecalis - 6.25 mg/L and 25 mg/L respectively) was displayed by 6,7-dichloro-substituted benzosiloxaborole. The studied systems exhibit low cytotoxity toward human lung fibroblasts., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
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