Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 5 pp. 1155ñ1161, 2016
ISSN 0001-6837
Polish Pharmaceutical Society
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF 5-SUBSTITUED
4-THIAZOLIDINONES WITH SULFANILAMIDE PHARMACOPHORE
AUGUSTA ZEVZIKOVIENE1*, ANDREJUS ZEVZIKOVAS1, AUDRONIS LUKOSIUS2
and EDUARDAS TARASEVICIUS3
Department of Analytical and Toxicological Chemistry, Lithuanian University of Health Sciences,
Kaunas, Lithuania
2
Department of Pharmacognosy, Lithuanian University of Health Sciences, Kaunas, Lithuania
3
Department of Pathology, Forensic Medicine and Pharmacology, Medical Faculty, Vilnius University
1
Abstract: After incorporation pharmacophores of allylamine and sulfanilamide into 4-thiazolidinoneís ring ñ
no antimicrobial activity was determined. This outcome stimulated synthesis of new group - 5-substituted 4-thiazolidinones. In the literature it is noted that the fragment of aldehyde in 5 position of 4-thiazolidinoneís ring
should give or increase biological activity. So, it was decided to incorporate fragment of aldehyde into 4-thiazolidinoneís ring together with sulfanilamide pharmacophore, investigate antimicrobial activity and compare it
with initial compounds ñ sulfanilamides. It was established that new compounds suppressed growth of S.
aureus, E. coli, B. subtilis, P. mirabilis, C. albicans. Sulfanilamide, sulfapyridine and/or 2-chlorobenzaldehyde
were incorporated into the structure of the most active compounds. It was concluded that synthesis of 4-thiazolidinones substituted by aldehyde in 5 position and sulfanilamide in 2 position are not potential antimicrobial
agents.
Keywords: antimicrobial activity, 4-thiazolidinones, sulfanilamide.
Currently, more than 200 antimicrobial agents
are used in clinical practice for the treatment of
infectious diseases. However, infectious diseases are
still one of the most common causes of death (1, 2).
Due to growing resistance of microorganisms, it is
necessary to continue the search for new active substances, because the infections caused by resistant
bacteria in the future may become the cause of epidemic which would be dangerous for many people
(3, 4).
The analysis of the structure of compounds
synthesized previously showed that 4-thiazolidinone
derivatives with sulfonamide pharmacophore are
more active against bacteria than sulfanilamides
themselves, also they are characterized by antifungal activity (5, 6). Recently, the various synthetic
reactions using sulfonamides fragments are
described with expectation of products with antifungal activity and decreased toxicity (7-9).
Previous synthesis of similar compounds
(incorporation pharmacophores of allylamine and
sulfanilamide into 4-thiazolidinoneís ring) without
antimicrobial activity, induced synthesis of new
group - 5-substituted 4-thiazolidinones (10). In 5position of 4-thiazolidones the methylene group is
enough active, so most new compounds are synthesized by modification of this position. (11, 12).
Knoevenagel condensation of the C-5 active methylene of 4-thiazolidones with oxo compounds under
basic catalysis yielding of 5-arylidene derivatives
constitutes an efficient way to new biologically
active substances. 5-Arylidene-4-thiazolidones display a wide spectrum of pharmacological properties.
(12-15). Also, the aldehyde fragment into 5 position
of 4-thiazolidinoneís ring should give or increase
biological activity. (15, 16).
EXPERIMENTAL
Materials and Metods
New compounds were synthesized at
Department of Pharmaceutical Chemistry in
Lithuanian University of Health Sciences. All reactions were monitored by TLC (Merck Kieselgel 60
* Corresponding author:e-mail: [email protected]
1155
1156
AUGUSTA ZEVZIKOVIENE et al.
F254). Melting points were determined with Koflerës
melting point apparatus and are uncorrected.
Elemental analyses were performed by analyzator
Gerhardt Vapodest 20 (nitrogen) and by Schonigerís
method (sulfur). Infrared (IR) spectra were recorded
on spectrometer Spectrum 100 FT-IR (ìPerkinElmerî). The NMR spectra were taken on a Varian
Unity Inova spectrometer (300 MHz for H). Purity
was checked at Department of Analytical and
Toxicological Chemistry in Lithuanian University
of Health Sciences by HPLC method (chromatograph Waters 2695 with photodiode detector Waters
996 PDA, analytes were separated using C18
1
Hypersil ÑThermo Scientificì analytical column (5
µm, 250 ◊ 4.6 mm) with precolumn).
CHEMISTRY
Synthesis of 5-substituted-2-methylmercaptothiazolidin-4-ones (intermediates)
2-Methylrhodanine (0.04 mol) dissolved in
glacial acetic acid (30 mL) and the appropriate
aldehyde (0.05 mol) was added (Fig. 1).
Ammonium acetate (0.005 mol) was used as catalyst. The reaction mixture was stirred for 5-20 min
at 60OC. Then, the solid separated was filtered,
Table 1. Characterization data of new compounds.
Compound
no.
Molecular formula
and molecular weight
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Calculated, %
found, %
Yield
(%)
Melting point, OC
(solvent)
N
S
C21H17FN4O4S2
472.52
80
318ñ320
(CH3COOH)
11.86
11.6
13.57
13.3
C21H15FN4O3S2
454.51
88
326ñ328
(CH3COOH)
12.33
12.6
14.11
14.5
C21H16FN5O4S2
485.52
91
313ñ314
(CH3COOH)
14.42
14.8
13.21
13.5
C22H18FN5O3S2
483.55
89.6
300ñ302
(CH3COOH)
14.48
14.9
13.26
13.6
C21H14Cl2N4O3S2
505.40
90.1
218ñ220
(CH3COOH)
11.09
10.9
12.69
12.5
C21H18N4O5S2
470.53
77
348ñ350
(CH3COOH)
11.91
11.6
13.63
13.3
C12H17ClN4O4S2
488.98
82
319ñ320
(CH3COOH)
11.46
11.3
13.11
13.0
C21H16ClN5O4S2
501.97
98
310ñ312
(CH3COOH)
13.95
14.1
12.78
12.9
C22H20N6O6S2
528.56
73.2
322ñ324
(dioxane)
15.09
15.8
12.13
12.6
C21H17BrN4O4S2
533.43
93.8
325ñ327
(CH3COOH)
10.50
10.9
12.02
12.1
C22H18BrN5O3S2
544.45
55.2
318ñ320
(CH3COOH)
12.86
13.1
11.78
12.0
C21H15BrN4O3S2
515.41
90.3
345ñ348
(CH3COOH)
10.87
10.7
12.44
12.3
C21H17FN4O4S2
472.51
84.5
324-326
(CH3COOH)
11.86
11.52
13.57
13.01
C22H18FN5O3S2
483.54
89.6
306-308
(CH3COOH)
14.48
15.02
13.26
13.40
C21H16FN5O4S2
485.52
95.9
317ñ319
(CH3COOH)
14.42
14.2
13.21
13.0
C21H15FN4O3S2
454.51
88.2
323ñ325
(CH3COOH)
12.33
12.21
14.11
14.0
C19H15N5O7S2
489.49
81.6
348ñ350
(CH3COOH)
14.31
14.5
13.10
13.2
Synthesis and antimicrobial activity of 5-substituted 4-thiazolidones with...
washed with water, ethanol, ether and recrystallized
from acetone.
Synthesis of 5-substituted-2-sulfanilamide-thiazolidin-4-ones
Intermediate (5-substituted-2-methylmercaptothiazolidin-4-one) (0.003 mol) dissolved in glacial
acetic acid (10-40 mL) or dioxane (9, 30 mL) and
the appropriate sulfanilamide (0.004-0.005 mol)
was added. The reaction mixture was heated at 90OC
for 3 h (4, 6, 7, 8, 9) or 4 h (5, 10, 11, 12, 13, 14, 15,
16, 17) or 6 h (1, 2) or 24 h (3). Then, the solid separated was filtered, washed with water, ethanol,
ether and recrystallized from glacial acetic acid or
dioxane (9).
1157
Cockeysville, USA). Antimicrobial activity of new
compounds was tested in standard bacteria cultures:
Staphylococcus aureus ATCC 25923, Enterococcus
faecalis ATCC 29212, Escherichia coli ATCC
25922, Pseudomonas aeruginosa ATCC 27853,
Klebsiella pneumoniae ATCC 33499, Proteus
mirabilis ATCC 12459, Bacillus subtilis ATCC 6633
and standard fungal culture: Candida albicans ATCC
60193. These bacterial and fungal strains were selected for research because of different structure and
functions. Also they are used as standard microorganisms for determination of antimicrobial activity.
Determination of antimicrobial activity
Antimicrobial activity was tested at Department of Microbiology in Lithuanian University of
Health Sciences.
Preparation of standard microorganism cultures
Standard bacteria and fungal cultures were cultivated 20ñ24 h on Mueller-Hinton agar at 35ñ37OC
temperature. Bacterial and fungal suspensions were
prepared from cultivated cultures in physiological
solution according to turbidity standard 0.5
McFarland.
Antimicrobial susceptibility tests
Antimicrobial activity was tested in vitro in
Mueller-Hinton agar (Mueller-Hinton II Agar, BBL,
Preparation of test compounds solutions
Test compounds were dissolved in dimethyl
sulfoxide (20 mg/mL) and then diluted to obtain
Figure 1. Synthesis of final compounds
1158
AUGUSTA ZEVZIKOVIENE et al.
final concentration ranging from 1 to 1000 µg/mL.
Diluted solutions were mixed with 10 mL of
Mueller-Hinton agar. Petri plates were incubated for
20ñ24 h at 35ñ37OC. The minimal concentration of
antimicrobial (antifungal) compound that prevents
any growth of tested bacteria (fungi) was indicated
Table 2. Spectral data of new compounds.
Compd.
no.
IR
(cm-1)
1
1725 (C=O).
710 (-CH=)
2.23 (3H, s, CH3-), 2.29 (3H, s, CH3-), 7.17 (1H, m, ArH),
7.41 (1H, m, ArH), 7.61 (1H, s, -CH=), 7.63 (1H, m, ArH), 7.79 (1H, m, ArH),
8.23 ñ 7.97 (4H, m, ArH)
2
1710 (C=O).
711 (-CH=)
7.16 (1H, m, ArH), 7.22 (1H, m, ArH), 7.31 (1H, m, ArH), 7.61 (1H, s, -CH=),
7.69 (1H, m, ArH), 7.74 (1H, m, ArH), 7.79 (1H, m, ArH), 7.97 (1H, m, ArH),
7.97 (1H, m, ArH), 8.05 (1H, m, ArH), 8.23 (1H, m, ArH), 8.23 (1H, m, ArH),
8.48 (1H, m, ArH)
3
1732 (C=O).
715 (-CH=)
3.83 (3H, s CH3-), 7.17 (1H, m, ArH), 7.24 (1H, d, ArH), 7.30 (1H, m, ArH),
7.35 (1H, d, ArH), 7.61 (1H, s, -CH=), 7.63 ñ 7.79 (2H, m, ArH), 8.23 ñ 7.97
(4H, m, ArH)
4
1710 (C=O).
689 (-CH=)
2.58 (3H, s, CH3-), 2.59 (3H, s, CH3-), 6.576 (1H, s, -CH=), 7.61 (1H, s, -CH=),
7.79 ñ 7.32 (4H, m, ArH), 8.23 ñ 7.97 (4H, m, ArH)
5
1720 (C=O).
742 (-CH=).
658 (C-Cl)
7.35 (1H, dd, ArH), 7.38 (1H, dd, ArH), 7.45 (1H, m, ArH), 7.57
(1H, dd, ArH), 7.74 (1H, m, ArH), 7.79 (1H, s, -CH=), 7.96 (1H, m, ArH),
7.97 (2H, m, ArH), 8.23 (2H, m, ArH), 8.61 (1H, m, ArH)
6
3256 (OH)
1734 (C=O).
730 (-CH=).
2.23 (3H, s, CH3-), 2.29 (3H, s, CH3-), 7.49 ñ 6.95 (4H, m, ArH),
7.66 (1H, s, -CH=), 8.24 ñ 7.97 (4H, m, ArH)
7
1740 (C=O).
710 (-CH=)
658 (C-Cl)
2.23 (3H, s, CH3-), 2.29 (3H, s, CH3-), 7.57 ñ 7.50 (4H, m, ArH),
7.71 (1H, s, -CH=), 8.24 ñ 7.97 (4H, m, ArH)
8
1742 (C=O)
705 (-CH=)
662 (C-Cl)
3.84 (3H, s, CH3-), 7.10 (1H, d, ArH), 7.51 (1H, m, ArH), 7.56 (2H, m, ArH),
7.60 (1H, d, ArH), 7.71 (1H, s, -CH=), 7.74 (1H, m, ArH), 8.26 ñ 7.99
(4H, m, ArH)
9
1715 (C=O)
709 (-CH=)
1562 (NO2)
3.83 (3H, s, CH3-), 7.35 ñ 7.24 (2H, d, -CH=), 7.80 (1H, s, -CH=), 7.86 ñ 7.85
(2H, m, ArH), 7.95 (2H, m, ArH), 8.14 ñ 8.12 (2H, m, ArH), 8.30 (2H, m, ArH)
10
1714(C=O)
713 (-CH=)
536 (C-Br)
2.23 (3H, s, CH3-), 2.29 (3H, s, CH3-), 7.68 (1H, s, -CH=), 7.73 ñ 7.30
(4H, m, ArH), 8.24 ñ 7.97 (4H, m, ArH)
11
1723 (C=O)
721 (-CH=)
545 (C-Br)
2.58 (3H, s, CH3-), 2.59 (3H, s, CH3-), 6.58 (1H, s, ArH), 7.68 (1H, s,
-CH=), 7.73 ñ 7.30 (4H, m, ArH), 8.25 ñ 7.97 (4H, m, ArH)
12
1734 (C=O)
695 (-CH=)
539 (C-Br)
7.46 (2H, m, ArH), 7.47 (1H, m, ArH), 7.49 (1H, m, ArH), 7.68 (1H, s, -CH=),
7.73 (1H, m, ArH), 7.91 (1H, m, ArH), 7.96 (1H, m, ArH), 7.98 (2H, m, ArH), 8.23
(2H, m, ArH), 8.62 (1H, m, ArH)
13
1712 (C=O)
700 (-CH=)
2.23 (3H, s, CH3-), 2.27 (3H, s, CH3-), 7.23 (2H, m, ArH), 7.70 (1H, s, -CH=),
7.82 (2H, m, ArH), 8.24ñ7.97 (4H, m, ArH)
1741 (C=O)
699 (-CH=)
2.58 (s, 3H, CH3-), 2.59 (s, 3H, CH3-), 6.58 (s, 1H, ArH), 7.22 (2H, m, ArH),
50 (s, 1H, =CH-), 7.7-7.8 (2H, m, ArH), 7.96 (2H, m, ArH), 8.16-8.19 (2H, m,
ArH)
1738 (C=O)
724 (-CH=)
3.83 (3H, s, CH3-), 7.24 (1H, d, ArH), 7.33 (2H, m, ArH), 7.35 (1H, d, ArH),
7.70 (1H, s, -CH=), 7.82 (2H, m, ArH), 8.24 ñ 7.97 (4H, m, ArH)
1720(C=O)
715 (-CH=)
7.04 (1H, m, ArH), 7.26 (2H, m, ArH), 7.29 (1H, m, ArH), 7.70 (1H, s, -CH=),
7.81 (1H, m, ArH), 7.87 (1H, m, ArH), 7.97 (2H, m, ArH), 7.98 (1H, m, ArH),
8.23 (2H, m, ArH), 8.60 (1H, m, ArH)
1718 (C=O)
716 (-CH=)
1550 (NO2)
2.23 (3H, s, CH3-), 2.29 (3H, s, CH3-), 7.14 (1H, d, -CH=), 7.51 (1H, d, -CH=),
7.71 (1H, s, -CH=), 7.95 ñ 8.16 (4H, m, ArH)
14
15
16
17
1
H NMR
(300 MHz, DMSO-d6, δ, ppm)
1159
Synthesis and antimicrobial activity of 5-substituted 4-thiazolidones with...
Table 3. Antimicrobial data of new compounds.
Microorganism
Compound
Minimal inhibitory concentration, µg/mL
S. aureus
E. faecalis
E. coli
B. subtilis
P. mirabilis
C. albicans
1
250 ± 25
-
150 ± 25
250 ± 25
250 ± 25
300 ± 50
2
-
300 ± 50
150 ± 25
250 ± 25
250 ± 25
-
3
250 ± 25
-
150 ± 25
500 ± 50
250 ± 25
300 ± 50
4
250 ± 25
150 ± 25
150 ± 25
250 ± 25
250 ± 25
500 ± 50
5
25 ± 5
25 ± 5
25 ± 5
20 ±5
250 ± 25
25 ± 5
6
100 ± 10
-
1 ± 0.1
300 ± 50
250 ± 25
300 ± 50
7
250 ± 25
-
150 ± 25
500 ± 50
250 ± 25
300 ± 50
8
250 ± 25
-
150 ± 25
-
250 ± 25
300 ± 50
16
250 ± 25
-
50 ± 10
100 ± 10
-
50 ± 10
17
400 ± 50
-
400 ± 50
500 ± 50
-
-
Sulfamethoxypyridazine
300 ± 50
100 ± 10
100 ± 10
50 ± 10
100 ± 10
500 ± 50
Sulfamoxole
-
-
500 ± 50
100 ± 10
300 ± 50
500 ± 50
Sulfapyridine
-
-
500 ± 50
100 ± 10
-
-
Sulfisomidine
-
-
300 ± 50
100 ± 10
500 ± 50
-
Sulfafurazole
-
-
300 ± 50
100 ± 10
100 ± 10
-
as minimal inhibitory concentration (MIC).
Sulfanylamides (sulfamethoxypyridazine, sulfamoxole, sulfapyridine, sulfisomidine, sulfafurazole) were used as standard drugs.
RESULTS
All new compounds were synthesized successfully. Obtained compounds are yellow, orange or
brown crystals, insoluble in water, slightly soluble
in alcohol, glacial acetic acid, soluble in DMSO and
DMF. It was determined that purity of new compounds is 98-99%. The structures of new compounds were confirmed by elemental analysis (we
have determined quantity of nitrogen (N) and sulfur
(S) in each compound) and spectral analysis (IR and
1
H NMR). All characterization data (molecular formula and molecular weight, yield, melting point,
quantity of nitrogen (N) and sulfur (S)) are shown in
Table 1, spectral data are shown in Table 2.
The results of antimicrobial activity showed that
new compounds can be characterized as antimicrobial
and antifungal agents. Antimicrobial activity of new
compounds was compared with initial compounds ñ
sulfanilamides, which antimicrobial activity was tested at the same conditions as new compounds. It was
concluded that 7 new compounds (9, 10, 11, 12, 13,
14, 15) were inactive at all. No one of the tested com-
pounds showed activity against Pseudomonas aeruginosa (MIC > 1 mg/mL) and Proteus mirabilis (MIC
> 1 mg/mL). The inhibitory concentrations for S.
aureus, E. coli, B. subtilis, P. mirabilis, C. albicans
were the lowest. Data of antibacterial and antifungal
activity are shown in Table 3.
DISCUSSION
Derivatives of 2-thioxo-4-thiazolidinone exist
in tautomeric forms: 2-thioxo-4-thiazolidinone, 4hydroxy-2(5H)-thiazolethione, 2-mercapto-4(5H)thiazolone, 4-hydroxy-2(3H)-thiazolethione and 2mercapto-4-thiazolol (17). 2-Alkylthio-4-thiazolidinone can be obtained by alkylation from 2-mercapto-4(5H)-thiazolone. Amination of 2-alkylthio-4thiazolidinone goes faster than with rhodanine.
Also, higher yield and purer compounds are
obtained. 2-Alkylrhodanine can be obtained by reaction of rhodanine and halogen alkane in the presence
of base (NaOH, KOH, NaH, EtN3) (12). In our
experiments, 2-methylrhodanine was synthesized
according to the methodology suggested by
Tarasevicius. This method allows to obtain a higher
yield of 2-methylrhodanine (82ñ91%) (15). During
the condensation of 2-methylrhodanine with various
aldehydes, the reaction proceeded by heating initial
substances in glacial acetic acid at 60OC. It was
1160
AUGUSTA ZEVZIKOVIENE et al.
found that increasing the temperature makes the
reaction time shorter, but the yield is lower (15).
Ammonium acetate or sodium acetate was used as
catalyst. Catalyst for the reaction was chosen considering the results, obtained from the results
described in previous works (10, 15), and our experiments.
2-Alkylthio-4-thiazolidinone can react with
aromatic amines to form derivatives of 2-imino-4thiazolidinone (15, 18). 5-Substituted 4-thiazolidinone derivatives, having sulfanilamide pharmacophore were synthesized according to Knoevenagelís condensation, which is based on addition
of an active hydrogen compound to carbonyl group
followed by dehydration reaction (12, 19). The
process of reaction between 5-substituted rhodanine
and sulfanilamide was observed using the lead
acetate indicator. It was determined that the time of
reaction depends on reagents proportion and structure of sulfanilamide. Also it was found that the
excess of one of the initial reaction substrates,
increases the speed of reaction.
Antimicrobial activity of compounds was compared with initial compounds ñ sulfanilamides. Five
different sulfanilamides: sulfamethoxypyridazine,
sulfamoxole, sulfafurazole, sulfisomidine and sulfapyridine were used in synthesis. Sulfamethoxypyridazine showed the highest antibacterial activity
(MIC = 50ñ300 µg/mL), but all sulfanilamides had
not shown antifungal activity (MIC = 500 µg/mL).
Sulfapyridine itself was active only against B. subtilis (MIC = 100 µg/mL) and showed insignificant
activity against E. coli (MIC = 500 µg/mL).
However, after incorporation into 4-thiazolidone
ring, its antimicrobial activity was increased. The
most active compounds (2, 5, 16) had fragment of
sulfapyridine (MIC = 25ñ300 µg/mL).
Influence of an aldehydes was studied from a
viewpoint of a functional group, situated in benzaldehyde ring. The compounds having halogen
formed the largest group, their MIC = 25ñ500
µg/mL. Because various halogens have been introduced into the structure of compounds, their various
quantity and position in the molecule and the influence of this differences on activity have been compared too. It has been established that compounds
activity depends on halogen nature (7 ñ chlorine, 10
ñ bromine, 13 ñ fluorine). The best activity showed
compounds with chlorine (7), as compounds having
bromine and fluorine (10, 13) were inactive. Also,
the compound having two chlorine atomes in its
structure (5), was more active (MIC = 25ñ250
µg/mL) than compounds, in which structure only one
chlorine atom was present (7, 8). However, in this
case it is not possible to suggest that incorporation of
the second chlorine atom increases antibacterial
activity, because there are fragments of different sulfanilamides in these structures. Because we had compounds with 4 different sulfanilamides and 2- or 4fluorobenzaldehyde substitutents, we could compare
the influence of halogen position in benzaldehyde
ring. It was found that change of halogens position
(from 2 for 4) had influence on antibacterial activity.
This activity was decreased (2, 16) or disappeared (1,
3, 4, 13, 14, 15). Sulfapyridine derivatives (after
change of halogen position from 2 for 4) assumed an
activity against S. aureus or C. albicans. The influence on antifungal activity was similar.
Comparing antimicrobial activity of 3 compounds (3, 8, 9), it was determined that nitro group
2ñ3 times decreased the antibacterial activity, either
1.5 time antifungal activity. Compound having
nitrofurane substitutent (17) suppressed the growing
of investigated bacteria only in high concentrations
(S. aureus and E. coli ñ MIC = 400 µg/mL, B. subtilis ñ MIC = 500 µg/mL) or absolutely did not
affect them (MIC > 500 µg/mL). Either this compound hadnët antifungal activity.
In general, the incorporation of the aldehyde
into the structure of new compounds increased the
antimicrobial activity (p < 0.05). This confirmed the
literature data of previous studies (15, 16, 20), but in
most cases activity was not greater than 100 µg/mL
(with the exception of compound 5, which MIC
varies within 25-250 µg/mL). After evaluation of
impact of tested aldehydes, it can be concluded that
the best way is to introduce 2-chloroaldehydes, if
antimicrobial activity is expected.
CONCLUSION
We concluded that synthesis of 4-thiazolidinones substituted by aldehyde in 5 position and sulfanilamide in 2 position are not potential antimicrobial agents.
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Received: 24. 08. 2015