Issue 5, 2024

Exploiting thiol-functionalized benzosiloxaboroles for achieving diverse substitution patterns – synthesis, characterization and biological evaluation of promising antibacterial agents

Abstract

Benzosiloxaboroles are an emerging class of medicinal agents possessing promising antimicrobial activity. Herein, the expedient synthesis of two novel thiol-functionalized benzosiloxaboroles 1e and 2e is 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, 20 and 22–24 show 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 vitro assay performed with 2-(phenylsulfonyl)ethylthio derivative 20 revealed 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.

Graphical abstract: Exploiting thiol-functionalized benzosiloxaboroles for achieving diverse substitution patterns – synthesis, characterization and biological evaluation of promising antibacterial agents

Supplementary files

Article information

Article type
Research Article
Submitted
23 Jan 2024
Accepted
18 Mar 2024
First published
20 Mar 2024
This article is Open Access
Creative Commons BY license

RSC Med. Chem., 2024,15, 1751-1772

Exploiting thiol-functionalized benzosiloxaboroles for achieving diverse substitution patterns – synthesis, characterization and biological evaluation of promising antibacterial agents

K. Nowicki, J. Krajewska, T. M. Stępniewski, M. Wielechowska, P. Wińska, A. Kaczmarczyk, J. Korpowska, J. Selent, P. H. Marek-Urban, K. Durka, K. Woźniak, A. E. Laudy and S. Luliński, RSC Med. Chem., 2024, 15, 1751 DOI: 10.1039/D4MD00061G

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