4-Thiazolidinones in heterocyclic synthesis: Synthesis of novel enaminones, azolopyrimidines and 2-arylimino-5-arylidene-4-thiazolidinones

Article abstract of DOI:10.3390/molecules17066386

The 4-thiazolidinones 3a-d were used as a key intermediates for the synthesis of 2-arylimino-5-arylidene-4-thiazolidinones derivatives 7a-p via nucleophilic addition reactions with the arylidene malononitrile. Moreover the 4-thiazolidinones 3a and 3c condensed with the DMF-DMA to form the corresponding enamines 8 and 9 depending on the reaction conditions. Otherwise the 4-thiazolidinone 3b reacts regioselectively with DMF-DMA to afford the enaminones 10 and 11, respectively. The latter reacts with many heterocyclic amines affording polyfunctionally substituted fused pyrimidine derivatives 13-18. The enamine 8b was also reacted with the 3-amino-1,2,4-triazole to afford the acyclic product 19, which could not be further cyclized to the corresponding tricyclic system 20. Moreover the 4-thiazolidinone 3c reacted with the benzenediazonium chloride to afford the arylhydrazones 12. The X-ray single crystal technique was employed in this study for structure elucidation and Z/E potential isomerism configuration determination. The X-ray crystallographic analyses of eight products could be obtained, thus establishing with certainty the structures proposed in this work.

Full text of DOI:10.3390/molecules17066386

Molecules 2012, 17, 6386-6394; doi:10.3390/molecules17066386
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Preparation of Quinolinium Salts Differing in the Length of the
Alkyl Side Chain
Jan Marek 1,2, Vladimir Buchta 3, Ondrej Soukup 4,5, Petr Stodulka 6, Jiri Cabal 1,
Kallol K. Ghosh 7, Kamil Musilek 8 and Kamil Kuca 5,6,
*
1
Department of Toxicology, Faculty of Military Health Sciences, University of Defence,
Hradec Kralove, 50001, Czech Republic
2
Department of Epidemiology, Faculty of Military Health Sciences, University of Defence,
Hradec Kralove, 50001, Czech Republic
3
4
Department of Clinical Microbiology, University Hospital, Hradec Kralove, 50005, Czech Republic
Department of Public Health, Faculty of Military Health Sciences, University of Defence,
Hradec Kralove, 50001, Czech Republic
5
6
Centre for Biomedical Research, University Hospital, Hradec Kralove, 50005, Czech Republic
Centre of Advanced Study, Faculty of Military Health Sciences, University of Defence,
Hradec Kralove, 50001, Czech Republic
7
8
School of Studies in Chemistry, Pt. Ravishankar Shukla University Raipur, Raipur, 492010, India
Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62,
Hradec Kralove, 50003, Czech Republic
* Author to whom correspondence should be addressed; E-Mail: kucakam@pmfhk.cz.
Received: 11 May 2012, in revised form: 16 May 2012 / Accepted: 17 May 2012 /
Published: 25 May 2012
Abstract: Quaternary quinolinium salts differing in alkyl chain length are members of a
widespread group of cationic surfactants. These compounds have numerous applications in
various branches of industry and research. In this work, the preparation of quinoline-derived
cationic surface active agents differing in the length of the side alkyl chains (from C8 to
C20) is described. An HPLC method was successfully developed for distinction of all
members of the series of prepared long-chain quinolinium derivatives. In conclusion, some
possibilities of intended tests or usage have been summarized. In vitro testing using a
microdilution broth method showed good activity of a substance with a C12 chain length
against Gram-positive cocci and Candida species.

Molecules 2012, 17
6387
Keywords: quinolinium salts; synthesis; HPLC; surfactants; detergents; disinfectants;
in vitro antimicrobial activity
1. Introduction
Cationic surfactants usually consist of a hydrophilic part represented by quaternary nitrogen moiety
and a hydrophobic part represented by a long alkyl chain. They can be used in various branches of
industry and in analytical or physical chemistry. However the use of these agents is very widespread
and much more practical applications have been discovered. The most useful analogues are
benzalkonium and pyridinium salts [1]. Some of the pyridinium salts have already been used as
disinfectants in various technological applications (e.g., components of eye drops, disinfectant
solutions, disinfectant foams) and their surfactant characteristics (e.g., critical micellar concentration,
surface tension) have already been determined and published [2]. Some of the pyridinium salts (C12
and C16) were used to solubilize water-insoluble compounds in analytical chemistry applications,
where these can also serve as a qualitative and quantitative tool [3]. There are other interesting
applications of cationic surfactants such as their addition to chewing gums as an antiplaque agent or
other uses in dentistry [4,5]. Pyridinium quaternary compounds are known as competitive inhibitors of
acetylcholinesterase [6], analogues with C10 and longer chains are also known as nicotinic receptor
antagonists [7] and their influence on adsorption of oligonucleotides to a phospholipid membrane was
observed [8]. Many non-pyridinium compounds are utilized in the industrial applications such as
road construction and repair, enhanced oil recovery and as pigment or corrosion inhibitors [9]. It has
been known that these compounds are able to form micelles, which play an important role in the
decontamination process [10–12]. These formations are created in a water solution, when the critical
micellar concentration (CMC) is exceeded. Therefore, many cationic surfactants work as micellar
catalysts, i.e., they can accelerate chemical (decomposition) reactions [13,14].
However, this study is focused on an antimicrobial activity of cationic surfactants that were
described earlier by several authors [15,16]. Picking one practical application, description of a method
using a C16 pyridinium as a spray for protecting poultry against bacterial contamination has been
reported [17]. Furthermore, a rather potent antimicrobial activity of quinoline analogues (quinolinium
stilbene benzenesulfonates) was already described, especially against Gram positive bacteria [18].
The aim of our project was to synthesize quinolinium salts series with different alkyl chains and to
test their antimicrobial profile. The compound containing a C12 alkyl chain was selected for testing as a
representative of the whole series, since benzalkonium compounds with C12 side alkyl chain length
(together with C14 and C16) are usually the main components of commercially used disinfectant
mixtures. This length of alkyl chain probably allows incorporation of the compound into biological
membranes and leads to the lysis of the microbial cell.

Molecules 2012, 17
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2. Results and Discussion
2.1. Synthesis and HPLC Analysis
Preparation of several quinolinium derivatives has been described before [19]. However, there has
been no description for a synthesis of the whole series of such salts differing in alkyl chain length
(C8 to C20). Formerly, a similar method for preparation of benzalkonium and pyridinium salts was
reported [20,21]. Therefore, a universal method for preparation of monoquaternary quinolinium salts
with chain substituents was developed. Subsequently, a universal HPLC method for analysing
quaternary surfactants was developed too.
The results achieved with the prepared compounds are shown in Table 1 (yields, melting points and
HPLC retention times). Apparently, the preparation of quinolinium salts with C8-C18 side chains is
relatively trivial, but the yields are rather low compared to the yields of the quaternized N,N-dimethyl-
N-benzylamine or pyridine (previously prepared compounds [20,21]). The larger nucleophilic moiety
(quinoline) decreases the probability of a nucleophilic attack. In general, we have obtained a small
amount of white crystals of the desired compound from the reaction mistures. Reaction products were
detected using the TLC method. Satisfactory purity was reached after one recrystallization from ether.
On the other hand, the compound with the C20 alkyl group length had to be recrystallized several times
to achieve sufficient purity, however the yield decreased rapidly in this case. It was observed that
yields decreased with the increased alkyl length.
Table 1. Yields, melting points and retention times of prepared quinolinium salts.
Compound Side alkylating chain (R) Yield (%)
m.p. (°C)
66–68
48–50
73–75
98–100
90–92
92–94
98–99
HPLC Rt (min)
5.15
3
4
5
6
7
8
9
C8
40.64
34.32
33.71
34.99
22.32
22.16
7,35
C10
C12
C14
C16
C18
C20
5.94
6.84
7.87
9.07
10.48
12,09
Additionally, a HPLC method was developed for product evaluation. It was able to distinguish
among all prepared quaternary quinolinium salts (Figure 1). The shortest retention time was found for
the C8 quinolinium salt. This novel HPLC method could be easily used for characterization of mixtures
of such quinolinium compounds.
2.2. In-Vitro Antimicrobial Activity Assessment
The antimicrobial efficacy of the synthesized compounds with 12 carbons in the alkyl chain
(compound 5) was chosen and tested using the microdilution broth method. The MICs, MBCs and
MFCs were determined for eight fungal and eight bacterial strains. The antibacterial activity is
summarized in Table 2. Compound 5 was more effective against Gram-positive bacteria than against
Gram-negative bacteria. The effect does not vary substantially in time and a relatively fast effect onset
of activity is supposed. MIC values after 48 h were usually equivalent to MBC values.

Molecules 2012, 17
Figure 1. HPLC chromatogram of a quinolinium compound mixture.
6389
1,50
1,25
1,00
0,75
0,50
0,25
0,00
0,0
2,5
5,0
7,5
10,0
12,5
Time [min.]
Table 2. In vitro antibacterial activity of compound 5.
MIC (M/L)
MBC (M/L)
48 hours
15.62
Bacterial strains
24 hours 48 hours
Staphylococcus aureus ATCC6538
Staphylococcus aureus MRSA HK5996/08
Staphylococcus epidermidis HK6966/08
Enterococcus sp. HK14365/08
Escherichia coli ATCC8739
Klebsiella pneumoniae HK11750/08
15.62
15.62
7.81
31.25
125.00
125.00
15.62
15.62
15.62
15.62
15.62
62.50
125.00
125.00
125.00
250.00
62.50
125.00
125.00
125.00
250.00
Klebsiella pneumoniae ESBL HK14368/08 125.00
Pseudomonas aeruginosa ATCC9027 250.00
The antifungal activity is summarized in Table 3. Compound 5 was more effective against Candida
strains compared to filamentous fungi. The strain Lichthemia corymbifera 272 was susceptible only to
the highest dose tested (500 M·L−1). The values of MICs for bacterial as well as fungal strains were
identical with the MBCs and MFCs suggesting a microbicidal potential of these compounds. This
property is desirable for the type of substances such as disinfectants.
Table 3. In vitro antifungal activity of compound 5.
Fungal strains
MIC (M/L)
24 hours 48 hours
MFC (M/L)
48 hours
15.62
Candida albicans ATCC 44859
Candida krusei E28
Candida tropicalis 156
15.62
15.62
15.62
7.81
15.62
62.50
500.00
31.25
15.62
15.62
15.62
15.62
62.50
125.00
500.00
31.25
15.62
15.62
15.62
62.50
250.00
500.00
62.50
Candida glabrata 20/I
Trichosporon beigelii 1188
Aspergillus fumigatus 231
Aspergillus corymbifera 272
Trichophyton mentagrophytes 445

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3. Experimental
3.1. General
3.1.1. Synthesis
A universal method for preparation (Figure 2) of monoquaternary quinolinium salts 3–9 was
developed as follows: pure quinoline (1; 1 eq.) in dry ethanol was mixed with the appropriate
1-bromoalkane 2 (14 eq.). The mixture was refluxed for 40 hours. The solution was evaporated under
reduced pressure and the crude oily product was recrystallized from ether, filtered, washed with ether
and allowed to dry at r.t. The reaction process was followed by TLC (Kieselgel Merck; mobile phase
chloroform/methanol 100/1; detection UV 254, Dragendorff reagent).
Figure 2. Preparation of quinolinium salts. R = C8–C20 (Table 1).
1
Yields (%), melting points (Boetius, m.p. were uncorrected) are summarized in Table 1. H-NMR
spectra (Varian Gemini 300, 300 MHz) characterizing each compounds are summarized below:
1
N-Octylquinolinium bromide (3). H-NMR (300 MHz, DMSO) ppm 9.37 (d, J = 5.25, 1.37 Hz, 1H),
9.22 (d, J = 8.20 Hz, 1H), 8.51 (d, J = 7.56 Hz, 1H), 8.30 (d, 1H), 7.95 (d, J = 7.62 Hz, 1H), 8.11–8.07
(m, 1H), 8.16 (d, J = 8.50 Hz, 1H), 5.09 (t, J = 7.55 Hz, 2H), 1.94 (t, J = 7.33 Hz, 2H), 1.45–1.08 (m,
10H), 0.80 (t, J = 6.59 Hz, 3H).
1
N-Decylquinolinium bromide (4). H-NMR (300 MHz, DMSO) ppm 9.38 (d, J = 5.26 Hz, 1H), 9.23
(d, J = 8.34 Hz, 1H), 8.51 (d, J = 8.18 Hz, 1H), 8.32 (d, J = 8.61 Hz, 1H), 8.19 (d, 1H), 8.12–8.07 (m,
1H), 7.95 (d, J = 7.62 Hz, 1H), 5.09 (t, J = 7.51 Hz, 2H), 1.94 (t, J = 7.19 Hz, 2H), 1.44–1.10 (m,
14H), 0.80 (t, J = 6.59 Hz, 3H).
N-Dodecylquinolinium bromide (5). 1H-NMR (300 MHz, DMSO) ppm 9.37 (d, J = 5.25 Hz, 1H), 9.22
(d, J = 8.32 Hz, 1H), 8.51 (d, J = 8.21 Hz, 1H), 8.16 (d, J = 7.31 Hz, 1H), 7.95 (t, J = 7.63 Hz, 1H),
8.12–8.07 (m, 1H), 8.30 (d, 1H), 5.08 (t, J = 7.50 Hz, 2H), 1.92 (t, 2H), 1.45–1.09 (m, 18H), 0.81
(t, J = 6.48 Hz, 3H).
1
N-Tetradecylquinolinium bromide (6). H-NMR (300 MHz, DMSO) ppm 9.38 (d, J = 5.26 Hz, 1H),
9.19 (d, J = 8.35 Hz, 1H), 8.51 (d, J = 8.16 Hz, 1H), 8.30 (d, J = 8.52 Hz, 1H), 8.01 (d, 1H), 8.15–8.09
(m, 1H), 7.94 (d, J = 7.61 Hz, 1H), 5.08 (t, J = 7.52 Hz, 2H), 1.94 (t, J = 7.16 Hz, 2H), 1.47–1.14 (m,
22H), 0.82 (t, J = 6.61 Hz, 3H).
N-Hexadecylquinolinium bromide (7). 1H-NMR (300 MHz, DMSO) ppm 9.32 (d, J = 5.26 Hz, 1H), 9.18
(d, J = 8.38 Hz, 1H), 8.51 (d, J = 8.25 Hz, 1H), 8.28 (d, J = 3.80 Hz, 1H), 8.05 (d, 1H), 8.12–8.08 (m,
1H), 7.89 (d, 1H), 5.08 (t, J = 7.23 Hz, 2H), 1.85 (t, 2H), 1.46–1.11 (m, 26H), 0.82 (t, J = 5.94 Hz, 3H).

Molecules 2012, 17
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1
N-Octadecylquinolinium bromide (8). H-NMR (300 MHz, DMSO) ppm 9.33 (d, J = 3.96 Hz, 1H),
9.15 (d, J = 8.31 Hz, 1H), 8.50 (d, J = 8.18 Hz, 1H), 8.20 (d, 1H), 8.09 (d, J = 2.70 Hz, 1H), 7.95–8.13
(m, 1H), 8.27 (d, 1H), 5.07 (t, J = 7.50 Hz, 2H), 1.93 (t, J = 7.05 Hz, 2H), 1.47–1.12 (m, 30H), 0.82
(t, J = 6.51 Hz, 3H).
N-Eicosylquinolinium bromide (9). 1H-NMR (300 MHz, DMSO) ppm 9.12 (d, J = 3.96 Hz, 1H), 9.31
(d, J = 8.38 Hz, 1H), 8.54 (d, 1H), 8.35 (d, J = 7.88 Hz, 1H), 8.25 (d, 1H), 8.06–8.14 (m, J = 3.03 Hz,
1H), 7.92 (d, J = 7.30 Hz, 1H), 5.10 (t, 2H), 2.02 (t, 2H), 1.46–1.21 (m, 34H), 0.83 (t, J = 5.94 Hz, 3H).
3.1.2. HPLC Analysis
After preparation of the quinolinium salts, an appropriate HPLC method for their distinction in the
mixture was developed. The HPLC system consisted of a P200 gradient pump (Spectra-Physics
Analytical, Fremont, CA, USA), a 7125 injection valve – 10 µL loop (Rheodyne, Cotati, WA, USA), a
UV1000 detector (Spectra-Physics Analytical), and a CSW Chromatography Station 1.5 software
(DataApex, Praha, Czech Republic). A 250 × 4 mm I.D. Waters Spherisorb Cyano (5 μm) column was
used (Supelco Inc., Bellefonte, PA, USA) for analysis. The mobile phase consisted of 45% acetonitrile
and 55% water. This mixture was prepared as a 0.1 M sodium acetate solution. Finally, the pH was
adjusted with acetic acid to 5.0. The samples were delivered isocratically at a flow-rate of 1 mL/min.
The absorbance was measured at 257 nm.
3.2. In-Vitro Antimicrobial Testing
3.2.1. Antifungal Activity
An in vitro antifungal activity of the prepared compounds was evaluated on a panel of eight clinical
isolates of fungi, four yeasts (C. albicans ATCC 44859, C. krusei E28, C. tropicalis 156, C. glabrata
20/I), and four filamentous fungi (Trichosporon asahii 1188, Aspergillus fumigatus 231, Lichthemia
corymbifera 272, Trichophyton mentagrophytes 445). All strains were part of the collection of fungal
strains and were deposited at the Department of Biological and Medical Sciences, Faculty of
Pharmacy, Charles University, Hradec Kralove, Czech Republic. The ATCC strains C. albicans ATCC
90028, C. parapsilosis ATCC 22019, and C. krusei ATCC 6258 served as the quality control strains.
All isolates were maintained on Sabouraud dextrose agar prior to being tested. A minimum
inhibitory concentration (MIC) was determined by a modified microdilution format of the CLSI
M27-A3 and M38-A2 for yeasts and filamentous fungi, respectively [22,23]. Dimethylsulfoxide
(Sigma, Prague, Czech Republic) served as a diluent for all compounds and its final concentration
did not exceed 2%. RPMI 1640 (KlinLab, Prague, Czech Republic) medium supplemented with
L-glutamine and buffered with 0.165 M morpholinepropanesulfonic acid (Sigma-Aldrich, Prague,
Czech Republic) to pH 7.0 by 10 M NaOH was used as a test medium. The wells of the microdilution
tray contained 200 µL of the RPMI 1640 medium with two fold serial dilutions of the prepared
compounds (500–0.49 µmol/L) and were inoculated with 10 µL of suspension. Fungal inoculum in
RPMI 1640 was prepared to give a final concentration of 5 × 103 ± 0.2 cfu/mL and 5 × 104 ± 0.5 cfu/mL
for yeasts and moulds, respectively. The trays were incubated at 36 ± 1 °C and MIC was read visually

Molecules 2012, 17
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and spectrophotometrically (OD 450nm) for filamentous fungi and yeasts respectively after 24 and
48 hours. The MIC values for the dermatophytic strain (T. mentagrophytes) were determined after
72 hours and 120 hours. The MICs were defined as 80% inhibition (IC80) of the growth of control. A
minimum fungicidal concentration (MFC) was established for all compounds tested as a concentration
which provided a decrease of a number of colonies by ≥99.9% after subculturing of a 100 µL aliquot
of each well with a maximum growth of 20% of control.
3.2.2. Antibacterial Activity
An in vitro antibacterial activity of the prepared compounds was tested on a panel of eight bacterial
strains (Staphylococcus aureus ATCC6538, S. aureus MRSA HK5996/08, S. epidermidis HK6966/08,
Enterococcus sp. HK14365/08, Escherichia coli ATCC8739, Klebsiella pneumoniae HK11750/08,
K. pneumoniae ESBL HK14368/08, and Pseudomonas aeruginosa ATCC9027). The ATCC strains
also served as quality control strains, the rest of them were clinical isolates from patients and were
deposited at the Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles
University, Hradec Kralove, Czech Republic. Before the testing the strains were passaged on
Mueller-Hinton Agar (HiMedia, Cadersky-Envitek, Hradec Kralove, Czech Republic).
A minimum inhibitory concentration (MIC) of the prepared compounds was determined by the
microdilution broth method modified according to standard M07-A07 [24]. Mueller-Hinton Broth
(MH, HiMedia) adjusted to pH 7.4 (±0.2) was used as the test medium. DMSO served as a diluent for
all compounds and its final concentration did not exceed 2% in the test medium. The wells of the
microdilution tray contained 200 µL of the MH broth with twofold serial dilutions of the compounds
(500–0.49 µmol/L) and were inoculated with 10 µL of bacterial suspension. Bacterial inoculum in
sterile water was prepared to match 0.5 McFarland scale (1.5 × 108 CFU/mL). The MIC values were
read visually after 24 h and 48 h incubation at 36 ± 1 °C. The MIC was defined as a complete
inhibition of the growth. A minimum bactericidal concentration (MBC) was established for all
compounds tested as a concentration that provided a decrease of a colonies number by ≥99.9% after
subculturing of a 100 µL aliquot of each well without a visible growth.
4. Conclusions
In conclusion, the developed synthetic protocol seems to be useful for a fast preparation of
quinolinium salts. The simplicity of the synthesis becomes even more important with respect to the
broad-spectrum and high efficiency antimicrobial activity of the C12 representative in our tests. Similar
antimicrobial properties are expected for the analogues where the antimicrobial efficacy is supposed
(C14 and C16 analogues). Furthermore, this synthetic procedure seems to be a reliable route of synthesis
in semi-industrial laboratories, too. By using such a simple synthetic route, a large number of highly
biologically active compounds could be prepared within a short period. Therefore, it could be of a high
interest of companies focused on the development on novel detergents. As a larger consequence, a
practical HPLC protocol was developed for estimation of quaternary detergent purity.

Molecules 2012, 17
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Acknowledgements
This work was supported by project of Ministry of Defense project OVUOFVZ200803.
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Sample Availability: Samples of the compounds are available from the authors.
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