The influence of fluorine position on the properties of fluorobenzoxaboroles

doi:10.1016/j.bioorg.2015.05.004

Bioorganic Chemistry

Volume 60, June 2015, Pages 130-135

https://doi.org/10.1016/j.bioorg.2015.05.004 Get rights and content

Highlights

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Four isomers of fluoro-substituted benzoxaboroles: synthesis, multinuclear NMR, pK_a.
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Activity against several fungi.
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6-Fluorobenzoxaborole: molecular and crystal structure compared with AN2690.

Abstract

5-Fluoro-2,1-benzoxaborol-1(3H)-ol, a potent antifungal drug also known as Tavaborole or AN2690, has been compared with its three isomers in terms of its activity against several fungi as well as pK_a and multinuclear NMR characterization. The molecular and crystal structure of 6-fluoro-2,1-benzoxaborol-1(3H)-ol was determined and compared with that of AN2690.

Graphical abstract

Introduction

Benzoxaboroles are important organoboron compounds due to their specific properties and wide applications. The benzoxaborole structural motif has been applied for medicinal purposes [1] such as HIV entry inhibitors [2], [3], [4], antiprotozoal drugs [5], antibacterial or antifungal agents [6], [7] as well as a potential drug delivery scaffold [8]. Their applications in biotechnology and therapeutic treatments was recently reviewed [9].

5-Fluoro-substituted benzoxaborole (1, Chart 1), is a FDA-approved drug KERYDIN™ (Tavaborole), the first oxaborole antifungal dedicated for the topical treatment of onychomycosis of the toenails [10]. The mechanism of its antifungal activity is based on the interaction with the active site of enzyme, which results in inhibition of LeuRS and blocking the protein synthesis [11], [12]. The history of these investigations and mechanism of action have been recently described [9].

Our recent research on the structures and properties of organoboron compounds was focused on the characterization of fluoro-substituted phenylboronic compounds. Generally, introduction of fluorine atoms increases the acidic character of the boronic center. It was found that cyclic boronic esters with fluorine atom at the ortho position display higher acidity in comparison with other monosubstituted isomers. Increasing the number of fluorine substituents does not simply result in rise of the acceptor number for these compounds [13], and the overall Lewis acidity of equally fluorinated diol phenylboronates is significantly affected by the structure of the diol [14]. The number and position of the fluorine substituents has also a substantial influence on the crystal structure of phenylboronates [15]. In case of fluorinated acids, introduction of ortho-fluorine atom weakens the intermolecular hydrogen bond [16], [17]. Moreover, results of the systematic NMR studies of fluorinated phenylboronic acids revealed a close correlation between their structure and spectroscopic properties [18].

Tomsho et al. [19] showed that the substituents in benzene ring of benzoxaboroles follow a Hammett relationship with the pK_a values. Moreover, these substituents’ effects are also related to the polyols binding properties of these compounds under physiologically relevant conditions. The presence of fluorine substituent as well as its position are crucial from the point of view of the antifungal activity [20], [21].

The compounds under investigation are four isomeric benzoxaboroles with fluorine substituent in benzene ring at various positions. The aim of this work is to compare their properties: structural and spectral parameters, acidity as well as antifungal activity.

Section snippets

Results and discussion

The compounds investigated in the present paper with numbering of carbon atoms are shown in Chart 1.

Conclusions

Molecular and crystal structure of isomers 1 and 2 are very similar. There are also no essential differences in spectral characteristics of all the investigated compounds. The position of fluorine substituent influences the acidity as well as biological activity of the studied benzoxaboroles. The surprisingly low acidity of 4 (pK_a value higher than that of the unsubstituted benzoxaborole) can be explained by the rigidity of the molecule caused by the formation of intramolecular hydrogen bond

Synthesis

Compounds 1 was synthesized as described previously [22]. Compounds 2, 3 and 4 were obtained from the corresponding fluoro-substituted 2-formylphenylboronic acids according to the procedure for 2 described below.

Acknowledgment

L. Popenda acknowledges the support of the National Centre for Research and Development under research Grant number 178479, contract number PBS1/A9/13/2012.

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The influence of fluorine position on the properties of fluorobenzoxaboroles

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

Synthesis

Acknowledgment

Polymer

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Inorg. Chem. Commun.

Chem. Rev.

Mol. Pharm.

Mol. Pharm.

Curr. Opin. Infect. Dis.

Appl. Organometal. Chem.

Appl. Organometal. Chem.

J. Am. Chem. Soc.

Science

J. Phys. Org. Chem.

Cryst. Growth Des.

Cryst. Growth Des.

J. Phys. Org. Chem.

Magn. Reson. Chem.

A.C.S. Med. Chem. Lett.

J. Med. Chem.