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Antibacterial properties and mode of action of new triaryl butene citrate compounds

Significance Statement

 

While 1,1-Bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene (5) was shown previously to inhibit Pseudomonas aeruginosa (MIC<21.02 µM), its conversion to 1,1-Bis-[4-(3-dimethylamoniumpropoxy)phenyl]-2-ferrocenyl-but-1-ene citrate (1)caused a dramatic decrease in its antibacterial activity (MIC > 5000 µM). The transformation of compounds to citrate salts was accompanied by a significant regression of antibacterial activity against Pseudomonas aeruginosa, for both organic and ferrocenic molecules.

The loss of activity of the salts against Pseudomonas aeruginosa prompted us to look for other salts forms of compounds. Thus, 1,1-Bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene (5) was converted into hydrochloric salt (6).

1,1-Bis-[4-(3-dimethylamoniumpropoxy)phenyl]-2-ferrocenyl-but-1-ene dichloride (6) preserved both solubility in water and 1,1-Bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene (5) activity observed against Staphylococcus aureus, Enterococcus hirae and Escherichia coli. Interestingly, the loss of activity observed against Pseudomonas aeruginosa following the conversion of 1,1-Bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene (5), into 1,1-Bis-[4-(3-Dimethylamoniumpropoxy)phenyl]-phenyl]-2-ferrocenyl-but-1-ene citrate (1) was recovered by the 1,1-Bis-[4-(3-dimethylamoniumpropoxy)phenyl]-2-ferrocenyl-but-1-ene dichloride (6).

 

1,1-Bis-[4-(3-dimethylamoniumpropoxy)phenyl]-2-ferrocenyl-but-1-ene dichloride (6)was prepared by adding 2 equivalents of hydrochloric acid to 1,1-Bis[4-(3-dimethylaminopropoxy)phenyl]-2-ferrocenyl-but-1-ene (5) dissolved in diethyl ether and was obtained in the yield of 59%.

 

Antibacterial properties and mode of a

Journal Reference

El Arbi M1, Théolier J2, Pigeon P3, Jellali K4, Trigui F4, Top S3, Aifa S4, Fliss I2, Jaouen G3, Hammami R5.

Eur J Med Chem. 2014 Apr 9;76:408-13.

 

1Centre de Biotechnologie de Sfax, Université de Sfax, Route de Sidi Mansour Km 6, BP 1177, 3018 Sfax, Tunisia; Chimie ParisTech, Ecole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France. Electronic address: [email protected] and

2STELA Dairy Research Centre, Institute of Nutrition and Functional Foods, Université Laval, G1V 0A6 Québec, QC, Canada and

3Chimie ParisTech, Ecole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France and

4Centre de Biotechnologie de Sfax, Université de Sfax, Route de Sidi Mansour Km 6, BP 1177, 3018 Sfax, Tunisia and

5STELA Dairy Research Centre, Institute of Nutrition and Functional Foods, Université Laval, G1V 0A6 Québec, QC, Canada. Electronic address: [email protected]

 

Abstract

 

The aim of this study was to evaluate the antibacterial activity of newly synthesized triaryl butene analogues of tamoxifen. Several compounds were synthesized and converted to citrate salts to ensure greater solubility. Four compounds showed significant antibacterial activity at micromolar concentrations against Gram-positive and Gram-negative foodborne pathogens including , Listeria ivanovii, Enterococcus faecalis, Staphylococcus aureus and Escherichia coli. Two compounds at 50 uM, caused only 7.8 and 11% hemolysis. One of these as well as the remaining two caused high K(+) and Na(+) efflux from bacterial cells. Ultrastructural alterations were also visible using transmission electron microscopy, which revealed severe damage of the inner or outer membrane of E. coli. L. ivanovii showed swelling, corrugations and similar damage indicating a loss of cell-wall integrity. Organometallic compounds may offer interesting opportunities for the design of novel classes of antimicrobial compounds.

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