Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine

doi:10.1016/j.bmc.2013.04.051

Bioorganic & Medicinal Chemistry

Volume 21, Issue 14, 15 July 2013, Pages 4388-4395

https://doi.org/10.1016/j.bmc.2013.04.051 Get rights and content

Abstract

A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5 μg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA.

Graphical abstract

Introduction

Organophosphorus compounds have been extensively utilized in organic synthesis. Among them quaternary phosphonium salts are of special interest due to their use in material sciences1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and medicinal chemistry.11, 12, 13, 14, 15, 16, 17 In particular, these compounds have been applied as intracellular antioxidants,11, 12, 13 anticholinesterase inhibitors,¹⁴ tumor imaging agents15, 16 and chemotherapeutic agents.¹⁷

Antimicrobial properties of some quaternary phosphonium salts have been reported. Phosphonium salts grafted on styrene–divinylbenzene copolymers were shown to exhibit antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.¹⁸ Triphenylphosphonium-modified PPO (polyphenylene oxide) polymer also found to have antimicrobial activity on Staphylococcus epidermidis and Escherichia coli.¹⁹ Taladriz et al., recently demonstrated antitrypanosomal activity of benzyltriphenylphosphonium salts against Trypanosoma brucei.²⁰ Benzophenone-derived bisphosphonium salts exhibited lethal activity towards human protozoan parasite Leishmania.²¹ Kanazawa et al.,²² synthesized di- and trimethyl-substituted phosphonium salts with long alkyl chaines (C₁₀–C₁₈) with bacteriostatic action against 11 widespread pathogens including methicillin-resistant S. aureus (MRSA). Organ-clay minerals intercalated by tetradecyl tributyl phosphonium bromide (TDTB)²³ as well as tetradecyl triphenyl phosphonium bromide (TTP) functionalized few-layered graphite (FG)²⁴ exerted long-term antimicrobial activity against E. coli and S. aureus.

Chemical modification of biologically active compounds of natural origin is one of the most efficient approaches in drug development. Among them, vitamin B₆ (pyridoxine) is of particular interest as a starting compound as it participates in over a hundred enzymatic reactions involved in biosynthesis, metabolism, and regulatory functions in living organisms.25, 26, 27, 28, 29

In our study, we describe the synthesis of novel derivatives of quaternary phosphonium salts on the basis of pyridoxine and its 6-hydroxymethyl derivatives. We reveal the effect of quantity and location of phosphonium fragments in pyridoxine molecule on the antibacterial activity of synthesized substances as well as the probable mechanism of action.

Section snippets

Chemistry

The synthesis of the target compounds was based on the nucleophilic substitution of chlorine derivatives of pyridoxine with triphenylphosphine resulting in the corresponding phosphonium salts (Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6, Scheme 7).

Various known synthetic approaches were used for the synthesis of different chlorine derivatives of pyridoxine, such as: introduction of ketal or acetate protection to the hydroxyl groups for selective functionalization of pyridoxine

Conclusion

We have synthesized a series of novel phosphonium salts on the basis of pyridoxine and 6-hydroxymethyl pyridoxine. 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) demonstrated high activity against S. aureus and S. epidermidis with minimal inhibitory concentration of 5 μg/ml. Structure–activity relationships of phosphonium salt derivatives revealed in our study are of interest in the development of new antimicrobials.

General information

¹H, ¹³C, ³¹P NMR spectra were recorded on a ‘Bruker AVANCE 400’ at operating frequency 400, 101.56, and 161.92 MHz respectively. Chemical shifts were measured with reference to the residual protons of the solvents (DMSO-d₆, ¹H, 2.50 ppm, ¹³C, 39.52 ppm; CDCl₃, ¹H, 7.26 ppm, ¹³C, 77.16 ppm). Phosphoric acid was used as an external standard for the ³¹P NMR. Coupling constants (J) are given in Hertz (Hz). The following abbreviations are used to describe coupling: s = singlet; d = doublet; t = triplet; m =

Acknowledgments

The work was supported from Russian Federal Target Programme (Projects 14.A18.21.0113 and 14.A18.21.1236).

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Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

General information

Acknowledgments

Tetrahedron

Sep. Purif. Technol.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Mutat. Res.

React. Funct. Polym.

React. Funct. Polym.

Colloids Surf., B

Mater. Sci. Eng., B

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Nutr. Res.

Tetrahedron Lett.

Angew. Chem., Int. Ed.

Chem. Rev.

Synthesis

J. Org. Chem.

Angew. Chem., Int. Ed.

Chem. Rev.