Abstract
The synthesis of potassium 6-hydroxy-7-chloro-1,1-dimethyl-3,3-difluorobenzo-1,2,3-siloxaborolate 5b from readily available 4-bromo-2-chlorophenol was developed. This compound proved useful in various derivatizations resulting in a wide range of O-functionalized benzosiloxaboroles. Reactions of 5b with selected substituted benzoyl chlorides gave rise to a series of respective derivatives with 6-benzoate side groups attached to the benzosiloxaborole core. Furthermore, treatment of 5b with substituted benzenesufonyl chlorides afforded several benzosiloxaboroles bearing functionalized benzenesulfonate moieties at the 6 position. The synthesis of related chloropyridine-2-yloxy substituted benzosiloxaboroles was accomplished by a standard approach involving silylation/boronation of appropriate heterodiaryl ethers. Investigation of biological activity of obtained compounds revealed that some benzoate and most benzenesulfonate derivatives exhibit high activity against Gram-positive cocci such as methicillin-sensitive Staphylococcus aureus ATCC 6538P as well as methicillin-resistant S. aureus ATCC 43300 with the MIC values in the range of 0.39–3.12 mg L−1. Some benzenesulfonate derivatives showed also potent activity against Enterococcus faecalis ATCC 29212 and E. faecium ATCC 6057 with MIC = 6.25 mg L−1. Importantly, for the most promising cocci-active benzenesulfonate derivatives the obtained MIC values were far below the cytotoxicity limit determined with respect to human normal lung fibroblasts (MRC-5). For those derivatives, the obtained IC50 values were higher than 12.3 mg L−1. The results of antimicrobial activity and cytotoxicity indicate that the tested compounds can be considered as potential antibacterial agents.
Highlights
Organoboron compounds have attracted increased attention as a subject of studies in the area of medicinal chemistry.[1,2,3] Numerous compounds were found to exhibit biological activity, mostly as anti-cancer, anti-in ammatory and anti-microbial agents
In this study we have investigated antimicrobial activity of the following groups of the newly synthesized benzosiloxaboroles: Group I (TBDMSO derivatives 4a–4b), Group II, Group III and Group IV
As in our previous publications, we have investigated the contribution of efflux pumps to the resistance of Gram-negative bacilli to the new synthesized compounds.[23,26]
Summary
From the point of view of biological activity it is important to note that Lewis acidity of the boron atom is increased when comparing benzosiloxaboroles to benzoxaboroles which may be attributed to increased p-acceptor ability of silicon vs saturated carbon atom.[25] In addition, one can expect that lipophilicity will be increased when the methylene group is replaced with the larger SiMe2 fragment. We decided to check whether introduction of larger substituents adjacent to chlorine will further enhance antibacterial potency It is necessary to search for new groups of compounds active against these bacteria, preferably with a new mechanism of action
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