| Autor: |
Nowicki, Krzysztof, Krajewska, Joanna, Stpniewski, Tomasz M., Wielechowska, Monika, Wiska, Patrycja, Kaczmarczyk, Anna, Korpowska, Julia, Selent, Jana, Marek-Urban, Paulina H., Durka, Krzysztof, Woniak, Krzysztof, Laudy, Agnieszka E., Luliski, Sergiusz |
| Zdroj: |
MedChemComm; 2024, Vol. 15 Issue: 5 p1751-1772, 22p |
| Abstrakt: |
Benzosiloxaboroles are an emerging class of medicinal agents possessing promising antimicrobial activity. Herein, the expedient synthesis of two novel thiol-functionalized benzosiloxaboroles 1eand 2eis reported. The presence of the SH group allowed for diverse structural modifications involving the thiol-Michael addition, oxidation, as well as nucleophilic substitution giving rise to a series of 27 new benzosiloxaboroles containing various polar functional groups, e.g., carbonyl, ester, amide, imide, nitrile, sulfonyl and sulfonamide, and pendant heterocyclic rings. The activity of the obtained compounds against selected bacterial and yeast strains, including multidrug-resistant clinical strains, was investigated. Compounds 6, 12, 20and 22–24show high activity against Staphylococcus aureus, including both methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) strains, with MIC values in the range of 1.56–12.5 μg mL−1, while their cytotoxicity is relatively low. The in vitroassay performed with 2-(phenylsulfonyl)ethylthio derivative 20revealed that, in contrast to the majority of known antibacterial oxaboroles, the plausible mechanism of antibacterial action, involving inhibition of the leucyl-tRNA synthetase enzyme, is not responsible for the antibacterial activity. Structural bioinformatic analysis involving molecular dynamics simulations provided a possible explanation for this finding. |
| Databáze: |
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