Effect of the amino chain length and the transformation
into citric acid salts of aryl-diphenyl-butenes and
ferrocenyl-diphenyl-butenes bearing two
dimethylaminoalkyl chains on their antimicrobial
activities

Karim Jellali, Pascal Pigeon, Fatma Trigui, Siden Top, Sami Aifa, Gérard

Jaouen, Mehdi El Arbi

► To cite this version:

Karim Jellali, Pascal Pigeon, Fatma Trigui, Siden Top, Sami Aifa, et al.. Effect of the amino chain length and the transformation into citric acid salts of aryl-diphenyl-butenes and ferrocenyl-diphenyl-butenes bearing two dimethylaminoalkyl chains on their antimicrobial activities. SpringerPlus, 2013, 2 (1), pp.508. 10.1186/2193-1801-2-508. http://hal-01230378

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RESEARCH

Open Access

# Effect of the amino chain length and the transformation into citric acid salts of aryl-diphenyl-butenes and ferrocenyl-diphenyl-butenes bearing two dimethylaminoalkyl chains on their antimicrobial activities

Karim Jellali<fnref n="1" />†, Pascal Pigeon<fnref n="2" />, Fatma Trigui<fnref n="1" />, Siden Top<fnref n="2" />, Sami Aifa<fnref n="1" />, Gérard Jaouen<fnref n="2" /> and Mehdi El Arbi<fnref n="1" />,<fnref n="2" />*†

## Abstract

In a previous work we have demonstrated the antimicrobial activity of ferrocenyl or phenyl derivatives of diphenyl butene series. This finding has opened a new area of applications of organometallic compounds.

In order to improve these activities, we have synthesized new organic and organometallic diaryl butene compounds with different lengths of their amino chains. These new compounds, and also their ammonium salts, were tested against man pathogenic microorganisms *Escherichia coli* (ATCC 10536), *Pseudomonas aeruginosa* (ATCC 15442), *Staphylococcus aureus* (ATCC 6538) and *Enterococcus hirae* (ATCC 10541).

It emerged from the tests that the Gram+ bacteria are more sensitive to the compounds than Gram-, and the compounds with 3 carbon amino chains have a better antimicrobial activity than the one having a chain of 2 or 4 carbons.

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. This resistance problem has been solved using hydrochlorides salts rather than citrates one.

**Keywords:** Diaryl butene; Antimicrobial activity; Citrate formulation; Citrate salts resistance; Hydrochlorides formulation

## Introduction

According to global risk report published in 2013, antibiotic-resistant infections kill every year 100,000 Americans, 80,000 Chinese and 25,000 Europeans (Spellberg et al. 2011; Howell 2013). In fact, infections cost 21 to 34 Bn US$/year in USA and 1,5 Bn Euro/year in Europe.

The frequency of antibiotic resistance is profoundly different from one European country to another. Europe was subject of an antibiotherapy study (ICAAC), made

by the team of Prof Voss, presented in 1992 to the U.S. Congress and published few years later (Voss et al. 1994). This study showed considerable differences in resistance rates of *Staphylococcus aureus* to meticillin (MRSA) between European countries, with rates ranging from 0% in some northern countries (Finland, Denmark, Sweden) to 35% and 40% in some countries that are more "Latin" (Italy, France). In some countries, MRSA studies, (Voss et al. 1994; Goldstein and Acar 1995) show that almost all strains were resistant to other antibiotics, especially quinolones and rifampicin. Resistance of *Staphylococcus aureus* to meticillin increased also in the most medically-advanced countries, even in United States of America (Gaynes et al. 1993). Every year MRSA kills 19,000 USA patients (more than emphysema, HIV/AIDS, Parkinson's disease, and homicide combined).

<footnote>* Correspondence: mehdi_arbi@yahoo.fr</footnote>

<footnote>†Equal contributors</footnote>

<footnote n="1">¹Centre de Biotechnologie de Sfax (Université de Sfax), Route de Sidi Mansour Km 6, BP 1177, 3018 Sfax, Tunisia</footnote>

<footnote n="2">²Chimie 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</footnote>
Recently a report titled « Global Risks 2013 », pub-
lished by World economic forum, demonstrates a de-
crease on the rate of MRSA infections from 2008 to
2011 in the UK, Germany, Belgium, France and Spain to
reach a rate included between 10% and 25%, this rate in-
creased in Hungary and Slovakia (25% to < 50%). In
Portugal and Romania MRSA infections statistics are the
highest with a rate up to 50%. In addition, the increase
of resistance rates for Gram negative bacilli such as
*Klebsiella pneumoniae* in all Europe has been reported.
This germ shows resistance to three classes of antibiotics
combination (3rd generation cephalo-sporins, fluoroqui-
nolones and aminoglycosides) with rates included be-
tween 1% and up to 50%. A resistance that can be
explained by production of β-lactamase with extended
spectrum (Sirot et al. 1993; Burwin et al. 1994). Some
countries are also faced with epidemic phenomena asso-
ciated with the two species of gram-negative willingly
multiresistant bacilli *Acinetobacter baumannii* and *Ste-
notrophomonas maltophilia* (Lortholary et al. 1995).

In Spain and France, an increase of pneumococcal re-
sistance to penicillin has been reported (Pallares et al.
1995). This increase is due to the appearance of resistant
gram positive cocci like *Pneumococci* (Pallares et al.
1995) and *Enterococci* (Spellberg et al. 2011; Howell
2013).

Clinical resistance is a complex phenomenon and its
manifestation is dependent on many factors, but hospi-
tals are not the only places where bacterial resistance
can be developed. The use of biocides in agriculture and
antibiotics in animal husbandry are two causes that ac-
centuate the problem.

Allergy is one of the unpredictable problems as-
sociated with antibiotics use. This hypersensitivity is a
drug reaction that is usually related to either the dose or
the pharmacological action of the drug (Solensky 2006;
Volcheck 2004). It accounts for approximately 6-10% of
all adverse drug reactions and the classes of antibiotics
that are most commonly associated with allergic reac-
tions are penicillins, cephalosporins, sulfonamides and
macrolides (Gruchalla 2003).

To overcome drug resistance and to find new types of
drugs, researchers have been exploring the possibility of
using transition metal complexes as drugs against di-
verse diseases (Jaouen 2006; Hillard and Jaouen 2011;
Patra et al. 2012; Gasser and Metzler-Nolte 2012; Chavin
and Biot 2010; Hartinguer et al. 2009; Omelas 2011).

Ferrocenyl or phenyl derivatives of diphenyl butene
series, tamoxifen analogues, known for their antitumor
activity (Jaouen et al. 2000), showed also an excellent
antimicrobial activity against *Escherichia coli*, *Pseudomo-
nas aeruginosa*, *Staphylococcus aureus* and *Enterococcus
hirae* (El Arbi et al. 2011). This finding, supported by
published results of an American team regarding the

efficacy of tamoxifen against *Candida albicans* (Dolan
et al. 2009), opens a new area of applications to this type
of compounds.

Bacterial resistance problems, the inefficiency of anti-
biotics discovered many years ago, the dual role of anti-
biotics in combating infectious and cancer diseases and
the problem of allergy are good reasons to expend more
efforts on the discovery of new active molecules.

On the same vision, this work has as objectives the
synthesis of various diphenyl butene compounds with
two amino chains, the exploration of the most effective
structure microbiologically and the best appropriate for-
mulation to make it water-soluble.

**Materials and methods**

Synthesis and characterization of compounds

The synthesis of all compounds was performed under an
argon atmosphere, using standard Schlenk techniques.
Anhydrous THF (tetrahydrofurane) was obtained by dis-
tillation from sodium/benzophenone. Thin layer chro-
matography was performed on silica gel 60 GF254.
Infrared spectra were obtained on FT/IR-4100 JASCO
spectrometers (http://www.jascofrance.fr). ¹H and ¹³C
NMR spectra were recorded on a 300 MHz Bruker spec-
trometer (http://www.bruker.com). Mass spectrometry
was performed with a Nermag R 10-10C spectrometer.
Elemental analyses were performed by the microanalysis
service of CNRS at Gif - sur - Yvette (https://www.
imagif.cnrs.fr). The preparative HPLC (high performance
liquid chromatography) separations were performed on
a Shimadzu apparatus (http://www.shimadzu.fr) with a
Nucleodur C18 column (length of 25 cm, diameter of
2.5 cm, and particle size of 10 µm).

1-[Bis(4-hydroxyphenyl)methylidene]indan 10

Titanium chloride (15.177 g, 8.79 mL, 80 mmoles) was
added dropwise to a suspension of zinc powder (7.844 g,
120 mmoles) in dry THF (200 mL) at 0-20°C. The
mixture was heated at reflux for 2 hours. A second so-
lution was prepared by dissolving 1-indanone (2.643 g,
20 mmoles) and 4,4'-dihydroxybenzophenone (4.284 g,
20 mmoles) in dry THF (50 mL). This latter solution
was added dropwise and the reflux was continued over-
night. After cooling, the mixture was poured in water
and dichloromethane was added. The mixture was aci-
dified with diluted hydrochloric acid until dark color
disappeared and was decanted. The aqueous layer was
extracted with dichloromethane and the combination of
organic layers was dried over magnesium sulphate. After
concentration under reduced pressure, the crude prod-
uct was chromatographed on silica gel column with a
mixture of cyclohexane and ethyle acetate 50/50 as the
eluent to give **10** as a white solid with a 79% yield. The
characteristics of the product were identical to that of the literature (Kim and Katzenellenbogen 2000).

## 1-[Bis(4-{3-dimethylaminopropoxy)phenyl)methylidene] indan 4

Compound 10 (1.886 g, 6mmol), potassium carbonate (8.29 g, 60 mmol) and cesium carbonate (3.91 g, 12 mmol) were stirred in 120 mL of acetone, then 3-dimethylamino-1-propyl chloride hydrochloride (5.69 g, 36 mmol) was added. The mixture was refluxed overnight, cooled and concentrated under reduced pressure. The residue was extracted with a mixture of dichloromethane and water, then was decanted. The organic layer was washed twice with a diluted aqueous solution of sodium hydroxide followed with water, dried over magnesium sulphate then was concentrated under reduced pressure. The mixture was purified by HPLC using a 10% triethylamine solution in methanol to give 4 as oil with a 67% yield.

¹H NMR (CDCl₃): δ 1.87-2.06 (m, 4 H, CH₂), 2.27 (s, 6 H, NMe₂), 2.28 (s, 6 H, NMe₂), 2.41-2.55 (m, 4 H, CH₂N), 2.93 (s, 4 H, H₃₆₄), 3.95-4.09 (m, 4 H, CH₂O), 6.50 (d, J = 7.7 Hz, 1 H, H₃₆₄), 6.78-6.92 (m, 5 H, H₃₆₄), 7.01-7.25 (m, 6 H, H₃₆₄). ¹³C NMR (CDCl₃): δ 27.9 (2 CH₂), 31.6 (CH₂ₗₗ₄), 34.8 (CH₂ₗₗ₄), 45.8 (2 NMe₂), 56.7 (CH₂N), 56.8 (CH₂N), 66.5 (2 CH₂O), 114.1 (2 CH C₆H₄), 114.9 (2 CH C₆H₄), 125.2 (CH₃₆₄), 125.3 (CH₃₆₄), 125.9 (CH₃₆₄), 127.3 (CH₃₆₄), 130.7 (2 CH C₆H₄), 131.4 (2 CH C₆H₄), 134.6 (C), 135.6 (C), 136.7 (C), 139.6 (C), 142.0 (C), 147.9 (C), 157.9 (C), 158.4 (C). IR (KBr, v cm⁻¹): 3063, 3033, 2940, 2854, 2813, 2763 (CH₂, CH₃). MS (EI, 70 eV) m/z: 484 [M]⁺, 439, 86 [CH₂CH₂CH₂NMe₂]⁺, 58 [CH₂NMe₂]⁺.

## (1,1-bis-[4-(3-Dimethylamoniumpropoxy)phenyl]-2-ferrocenyl-but-1-ene dichloride 9)

Diamino compound 5 (2.2 g, 3.7 mmol) was dissolved into 200 mL of diethyl ether. A 2 M solution of hydrochloric acid in diethyl ether (3.7 mL, 7.4 mmol) was added dropwise into the solution. An orange precipitate was immediately formed. After stirring for 20 min, the mixture was filtered under argon and the obtained orange solid was washed with 3 x 5 mL of diethyl ether and was dried under vacuum giving compound 9 in 59% yield. Crystals contain traces of diethyl ether.

¹H NMR (DMSO-d₆): δ 1.02 (t, J = 7.4 Hz, 3 H, CH₃), 2.04-2.27 (m, 4 H, 2 CH₂), 2.44-2.63 (m, 2 H, CH₂), 2.79 (s, 12 H, NMe₂H⁺), 3.10-3.30 (m, 4 H, CH₂N), 3.85 (s, 2 H, C₅H₄), 3.97-4.25 (m, 11 H, C₅H₄ + C₅H₅ + CH₂O), 6.86 (d, J = 8.0 Hz, 2 H, C₆H₄), 6.90-7.01 (m, 4 H, C₆H₄), 7.14 (d, J = 8.0 Hz, 2 H, C₆H₄). ¹³C NMR (DMSO-d₆): δ 16.3 (CH₃), 24.8 (2 CH₂), 28.1 (CH₂), 42.9 (2 NMe₂H⁺), 54.9 (2 CH₂N), 65.6 (CH₂O), 65.8 (CH₂O), 68.8 (2 CH C₅H₄), 69.6 (2 CH C₅H₄), 69.9

(5 CH C₅H₅), 86.8 (C C₅H₄), 115.1 (2 x 2 CH C₆H₄), 130.8 (2 CH C₆H₄), 131.3 (2 CH C₆H₄), 137.1 (C), 137.4 (C), 137.9 (C), 138.2 (C), 157.5 (2 C) IR (KBr, v cm⁻¹): 3425 (NH), 3029, 2960, 2685, 2510, 2470 (CH₂, CH₃).

## Microbial strains

Known and newly synthesized compounds were tested against *Escherichia coli* (ATCC 10536), *Pseudomonas aeruginosa* (ATCC 15442), *Staphylococcus aureus* (ATCC 6538) and *Enterococcus hirae* (ATCC 10541).

All strains were cultured in liquid LB (1% Bactotryptone, 0.5% Yeast extract, 0.5% NaCl).

## Estimation of the antimicrobial effect

The estimation of the antimicrobial effect against microbial strains was performed by the method of microdilution in ELISA plates. A 2.54 10⁻³ M stock solutions of the tested products were prepared in DMSO or water, depending on their solubility. In Elisa plates and for each product a series of eight wells containing 100 µl of culture medium with decreasing concentration of the product were prepared by the successive ½ dilution.

A 100 µl of overnight shaking microbial culture, incubated at adequate temperature, depending on bacterial strains, were used to inoculate the plate wells containing different concentrations of compounds. The final concentration of each product, for a series of eight wells was 2.54 10⁻⁴ M, 1.27 10⁻⁴ M, 6.35 10⁻⁵ M, 3.18 10⁻⁵ M, 1.59 10⁻⁵ M, 7.94 10⁻⁶ M, 3.97 10⁻⁶ M and 1.98 10⁻⁶ M. The plates were incubated with shaking overnight at the same temperature, depending on bacterial strains, and their OD was measured at 620 nm.

A negative control (uninoculated wells), a positive control (seeded and without antimicrobial compound wells) were prepared under the same experimental conditions.

The inhibitory activity of the tested compounds was calculated according to the formula:

$$IA(\%) = 100 - 100(OD_{620(x)} / OD_{620(i)})$$

where (x) is the microbial culture containing the inhibitor and (i) is the microbial culture without inhibitor.

## Results

All compounds studied in the present work are shown in Figure 1.

## Synthesis

The synthesis of compounds 1 (Shiina et al. 2008), 2 (Pigeon et al. 2011), 5 (Pigeon et al. 2011), and 8 (El Arbi et al. 2011), has already been published. Compounds 3, 6 and 7 are newly-synthesised products and their synthesis will be published in the future.
<figure><img src="image_2.png" /><figcaption>Figure 1 Chemicals tested.</figcaption></figure>

Figure 2 shows the synthetic pathways of **4**. **10** was first prepared by reacting 1-indanone with 4,4'-dihydroxybenzophenone in the McMurry coupling conditions. This compound was converted into the diamine compound **4** by heating at reflux 3-dimethylamino-1-propyl chloride hydrochloride with **10** in acetone in the

presence of potassium carbonate and cesium carbonate as bases. **4** was obtained in the yield of 67%.

Hydrochloride **9** was prepared by adding 2 equivalents of hydrochloric acid to diamine compound **5** dissolved in diethyl ether (Figure 3). **9** was obtained in the yield of 59%.
<figure><img src="image_3.png" /><figcaption>**Figure 2** Synthesis of compounds 4 and 10.</figcaption></figure>

## Effect of amino chain length on antimicrobial activity

To evaluate the impact of the amino chain length on the antibacterial activity, organic compounds 1, 2 and 3, having an amino chain of 2, 3 and 4 carbons, respectively, were selected for the test with four bacteria. At a concentration of 2.54 10⁻⁴M, as shown on Figure 4, all tested strains were sensitive to the three compounds. This result confirms again the activity of compound 3 (El Arbi et al. 2011). The tested compounds are effective against Gram+ and Gram- strains, but not with the same efficiency. Gram+ bacteria, *Staphylococcus aureus* and *Enterococcus hirae*, seem to be more sensitive than Gram- strains, *Escherichia coli* and *Pseudomonas aeruginosa*. Therefore, there is a potential use against Gram+ bacterial infections for these compounds. Within these compounds, the ones with 3 and 4 carbons are more potent comparing to the one of 2 carbons. It is interesting to note that these molecules increase the proliferation of micro-organisms when used at low doses.

## Effect of organic or organometallic compound on the antimicrobial activity

It has been shown that ferrocenyl compounds are more active than their organic analogues against cancer cells (Top et al. 2003). It is interesting to see if this behavior is also verified for the antibacterial activity. Therefore, we compare now the activity of two organic compounds, the compounds 2 and 4, to that of ferrocenic compound 5. As shown in Figure 5, all compounds are more active against Gram+ than Gram- bacteria. The difference in

activity between organic and ferrocenic compounds is clearly observed in the case of *Staphylococcus aureus*. The inhibition percentage (IP) of 2 and 4 is about 94.32% at a dose of 3.59 10⁻⁵M while that of 5 is 7.94 10⁻⁶M. In the case of *Enterococcus hirae*, the IP value of 59.21% is obtained using 7.94 10⁻⁶M for both organic compounds and 1,98 10⁻⁶M for organometallic compound. Therefore, the organometallic compound 5 is more potent, against Gram+ strains, than the organic compounds (4.5 times for *Staphylococcus aureus* and 4 times for *Enterococcus hirae*).

## Effect of the formulation of salts of citric acid on the antimicrobial activity

Compounds 2, 4, 5 are not soluble in water. Their use as antimicrobial agents may be more convenient if they could be transformed into aqueous soluble forms. This transformation was achieved by their conversion into salts of citric acid. Thus, compounds 2, 4, and 5 were converted into compounds 6, 7, and 8, respectively. Figure 6 shows that the transformation of the compounds into salts did not alter their activity except for *Pseudomonas aeruginosa*. The activities against *Staphylococcus aureus* and *Enterococcus hirae* were maintained. We even observed an improvement of the antimicrobial activity effect against *Escherichia coli*, compound 6 expressed an IP of 96.2% at a dose of 6.35 10⁻⁵M while 2 reaches this level of inhibition at a dose of 2.54 10⁻⁴M. By contrast, the loss of effectiveness against *Pseudomonas aeruginosa* was observed for all salts. Indeed, at the

<figure><img src="image_4.png" /><figcaption>**Figure 3** Synthesis of compound 9.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Figure 4 Antimicrobial activity of compounds 1, 2 and 3.</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Figure 5 Antimicrobial activity of compounds 2, 4 and 5.</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>Figure 6 Antimicrobial activity of compounds 6, 7 and 8.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>Figure 7 Antimicrobial activity of compounds 5, 8, 9 and Doxycycline.</figcaption></figure>
highest dose tested (2.54 10⁻⁴M), the inhibitory activity decreased from 89%, 89.46% and 63.38% for 2, 4 and 5, to 32.7%, 5.6% and -2.7% for 6, 7, and 8, respectively.

## Effect of the transformation to hydrochloride on the antimicrobial activity

The loss of activity of the salts against *Pseudomonas aeruginosa* prompted us to look for other salts forms of compounds. Thus, compound 5 was converted into hydrochloric salt 9. Figure 7 shows that 9 preserved both solubility in water and the compound 5 activity observed against *Staphylococcus aureus*, *Enterococcus hirae* and *Escherichia coli*. Interestingly, the loss of activity observed against *Pseudomonas aeruginosa* following the conversion of compound 5 into 8 was recovered by the compound 9.

Comparing to Doxycycline, an antibiotic of reference, 9 shows a similar activity and has an excellent antibacterial activity, especially against Gram+ (Figure 7).

## Discussion

The present study confirms the importance of using tamoxifen and tamoxifen analogues in microbial inhibition. We found that tamoxifen and ferrocifen derivatives bearing two amino chains are active against bacteria. The activity of compounds can be improved by varying the length of the amino chain, the replacement of one of the arene rings of tamoxifen by a ferrocenyl unit, and by transforming the compounds into aqueous soluble forms. Thus, compounds with 3 carbon amino chain are more active than compounds with 2 and 4 carbon chains. Ferrocene derivatives, the ferrocifen series, have better activity than pure organic compounds (the tamoxifen series). Moreover, transforming the compounds into ammonium salts make the compounds soluble in water and improve the activity of compounds. For this last purpose, hydrochloric salts should be used rather than the citrate ones because of the resistance of *Pseudomonas aeruginosa* of this last salt form.

In addition to its antitumor efficacy, tamoxifen possession of antimicrobial properties has been recently reported (Dolan et al. 2009); meanwhile, knowing that tamoxifen is marketed as tamoxifen citrate, we want to warn following the results the possible ineffectiveness against *Pseudomonas aeruginosa* and the risk of aggravation of nosocomial infections, caused among others, by *Pseudomonas aeruginosa*.

We conclude that it is imperative to avoid the citrate salt formulation for antimicrobial products, because of the loss of compound activity against *Pseudomonas aeruginosa*. We also recommend trying other types of formulation for anti-tumor compounds, especially in the case of chemotherapy treatment, where citrate is used in low doses, which can offer an advantage of proliferative effect for microorganisms and biofilm formation (Robert et al. 2006).

## Competing interests

We declare that we have no competing financial interests.

## Authors' contributions

The French team, PP, ST and GJ, is responsible for the synthesis of compounds and the Tunisian team, KJ, FT, SA and ME is responsible for microbiological testing. In the same context, all authors contributed to the drafting and revision of the article and all have read and approved the final version.

## Acknowledgements

This work was supported by the Ministry of Higher Education and Scientific Research of Tunisia and the "Agence Nationale de la Recherche" (France).

Received: 3 August 2013 Accepted: 27 September 2013
Published: 4 October 2013

## References

Burwin D, Banerjee S, Gaynes R (1994) Ceftazidime resistance among selected nosocomial gram negative bacilli in United States. J Infect Dis 170:1622-1625

Chavain N, Biot C (2010) Organometallic complexes: new tools for chemotherapy. Curr Med Chem 17(25):2729-45

Dolan K, Montgomery S, Buchheit B, DiDone L, Wellington M, Krysan DJ (2009) Antifungal activity of tamoxifen: in vitro and in vivo activities and mechanistic characterization. Antimicrob Agents Chemother 53:3337-3346

El Arbi M, Pigeon P, Top S, Rhouma A, Aifa S, Rebai A, Vessières A, Plamont MA, Jaouen G (2011) Evaluation of bactericidal and fungicidal activity of ferrocenyl or phenyl derivatives in the diphenyl butene series. J Organomet Chem 696:1038-1048

Gasser G, Metzler-Nolte N (2012) The potential of organometallic complexes in medicinal chemistry. Curr Opin Chem Biol 16:84-91

Gaynes R, Culver D, Horan T et al (1993) Trends in meticillin-resistant Staphylococcus aureus in United States hospitals. Infect Dis Clin Practice 2:452-455

Goldstein F, Acar J (1995) Epidemiology of quinolone resistance: Europe and North and South America. Drugs 49(2):36-42

Gruchalla RS (2003) Drug allergy. J Allergy Clin Immunol 111(suppl 2):S548-S59

Hartinger CG, Dyson PJ (2009) Bioorganometallic chemistry: from teaching paradigms to medicinal applications. Chem Soc Rev 38:391-401

Hillard EA, Jaouen G (2011) Bioorganometallics: future trends in drug discovery, analytical chemistry and catalysis. Organometallics 30:20-27

Howell L (2013) Global risks: «The dangers of hubris on human health». World Economic Forum 8:28-35

Jaouen G (ed) (2006) Bioorganometallics: Biomolecules, Labeling, Medicine. Wiley-VCH Verlag GmbH & Co, Weinheim, Germany

Jaouen G, Top S, Vessières A, Leclercq G, Quivy J, Jin L, Croisy A (2000) The first organometallic antioestrogens and their antiproliferative effects. Comptes Rendus de l'Académie des Sciences - Series IIC – Chemistry 3:89-93

Kim S, Katzenellenbogen JA (2000) Triarylethylene bisphenols with a novel cycle are ligands for the estrogen receptor. Bioorg Med Chem 8:785-793

Lortholary O, Fagon JY, Buu Hoi A, Slama MA et al (1995) Nosocomial acquisition of multiresistant Acinetobacter baumanii: risk factors and prognosis. Clin Infect Dis 20:790-796

Omelas C (2011) Application of ferrocene and its derivatives in cancer research. New J Chem 35:1973-1985

Pallares R, Linares J, Vadillo M (1995) Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona. Spain N Engl J Med 333:474-480

Patra M, Gasser G, Metzler-Nolte N (2012) Small organometallic compounds as antibacterial agents. Dalton Trans 41:6350-6358

Pigeon P, Top S, Vessières A, Huché M, Gormen M, El Arbi M, Plamont MA, McGlinchey MJ, Jaouen G (2011) A new series of ferrocifen derivatives, bearing two aminoalkyl chains, with strong antiproliferative effects on breast cancer cells. New J Chem 35(10):2212-2218

Robert MQ, Shanks JL, Sargent RMM, Martha LG, George AOT (2006) Catheter lock solutions influence staphylococcal biofilm formation on abiotic surfaces. Nephrol Dial Transplant 21:2247-2255

Shiina I, Sano Y, Nakata K, Kikuchi T, Sasaki A, Ikekita M, Nagahara Y, Hasome Y, Yamori T, Yamazaki K (2008) Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents. Biochem Pharmacol 75:1014-1026
Sirot D, Goldstein F, Soussy C (1993) Resistance to cefotaxime and seven other lactams in members of the family enterobacteriaceae: a three years survey in France. Antimicrob Agents Chemother 36:1667–1681

Solensky R (2006) Drug hypersensitivity. Med Clin N Am 90:233–60

Spellberg B, Blaser M, Guidos RJ et al (2011) Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 52:S397–428

Top S, Vessières A, Leclercq G, Quivy J, Tang J, Vaissermann J, Huché M, Jaouen G (2003) Synthesis, Biochemical Properties and Molecular Modelling Studies of Organometallic Specific Estrogen Receptor Modulators (SERMs), the Ferrocifens and Hydroxyferrocifens: Evidence for an Antiproliferative Effect of Hydroxyferrocifens on both Hormone-Dependent and Hormone-Independent Breast Cancer Cell Lines. Chem Eur J 9:5223–5236

Volcheck G (2004) Clinical evaluation and management of drug hypersensitivity. Immunol Allergy Clin N Am 24:357–71

Voss A, Milatovic D, Wallrauch-Schwartz C, Rosdahl V, Braveny I (1994) Meticillin-
resistant Staphylococcus aureus in Europe. Eur J Clin Microbiol Infect Dis
13:50–55

doi:10.1186/2193-1801-2-508

**Cite this article as:** Jellali *et al.*: Effect of the amino chain length and the transformation into citric acid salts of aryl-diphenyl-butenes and ferrocenyl-diphenyl-butenes bearing two dimethylaminoalkyl chains on their antimicrobial activities. *SpringerPlus* 2013 2:508.

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