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Studies on the syntheses of 4-oxo-thiazolidine, thiazolidine and thiazoline derivatives
from 3-aryl-4-formylsydnone thiosemicarbazones
Mei-Hsiu Shih*, Fang-Ying Ke and Ching-Ying Kuo
Department of Chemical Engineering, Southern Taiwan University of Technology,Tainan, Taiwan 710, R.O.C.
A series of novel thiazolidine and thiazoline derivatives 5a-7h, containing the sydnonyl moiety, were synthesized by the reactions of 3-aryl-4-formylsydnone thiosemicarbazones (3a-3e) with cyclic reagents such as ethyl chloroacetate (4a), ethyl 2-chloroacetoacetate (4b) and
2-bromoacetophenone (4c). The synthesized compounds 5a-7h were evaluated for the antioxidant and antimicrobial activities. Among these compounds, 4-methyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydrothiazole-5-carboxylicacidethylester (6e-6h) and
4-phenyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydrothiazoles (7e-7h) possess the potent DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity comparable with that of vitamin E. The results indicated that the 2,3-dihydrothiazole moiety of
compounds 6e-6h and 7e-7h played the important role in the scavenging radical activity.
S
Results and discussion
H2N
Several sydnone derivatives have associated with a broad range of physiological activities,
N
N
H
H
exhibiting antimicrobial, anti-inflammatory, analgesic and antipyretic properties. Hence,
2a
chemists have been enthusiastically pursuing the syntheses of these derivatives.
N
with
4'-phenylthiosemicarbazide
(2a)
and
H2N
N
NH2
N
1a, 3a, 3e: Ar = C6H5;
1b, 3b, 3f: Ar = p-CH3C6H4;
N
N H
H
H
yield: 71-80 %
O
O
3e-3h
derivatives that contain the sydnonyl moiety, with the aim of obtaining new biologically
yield: 80-90 %
S
N
exhibit various biological activities. This study seeks to synthesize a series of novel thiazole
Scheme 1.
H
N
2b
active compounds. An efficient and useful method is reported herein to synthesize some new
N
H
H
Ar
H
thiosemicarbazide (2b), respectively (Scheme 1). Besides, thiazoles and their derivatives
N
O
O
3a-3d
S
O
O
1a-1d
thio- semicarbazones (3e-3h) were synthesized in good yields by the reactions of
(1a-1d)
H
N
3-aryl-4-formylsydnone 4'-phenylthiosemicarbazones (3a-3d) and 3-aryl-4-formylsydnone
3-aryl-4-formylsydnones
N
Ar
precursors for the syntheses of thiazolidine and thiazoline derivatives. Therefore,
N
N
O
Thiosemicarbazones have been reported to exhibit antituberculosis activity and are good
S
H
Ar
1c, 3c, 3g: Ar = p-CH3OC6H4;
1d, 3d, 3h: Ar = p-C2H5OC6H4
sydnonyl-substituted thiazolidinones (5a-5h) and thiazolines (6a-6h, 7a-7h) by the reaction
O
of 3-aryl-4-formylsydnone 4'-phenylthiosemicarbazones (3a-3d) or 3-aryl-4-formylsydnone
H
Cl
thiosemicarbazones (3e-3h) with cyclic reagents such as ethyl chloroacetate (4a), ethyl
4a
2-chloroacetoacetate (4b) and 2-bromoacetophenone (4c) (Scheme 2). The sydnone ring is
OC2H5
N
80 o C , 27-45 h
sensitive to acids such as hydrochloric acid, and sydnone compounds are sometimes
N
Ar
N
N
O
O
5a-5h
decomposed during reaction and/or work up, so the reaction was carried out in acetic acid/
S
N
sodium acetate buffer system to maintain the pH value of the reaction solution at 4.6-4.7 and
O
avoided the decomposition of sydnones. Sodium acetate was used to scavenge the released
O
O
H
hydrogen halide that could cause the decomposition of sydnones. Acetic acid was used to
catalyze the cyclization. Increasing the amount of acetic acid accelerated the reaction. All
N
Ar
these products were spectro-scopically characterized. Among the new products 5a-7h, the
N
crystals 5c, 6b and 7c were analytically pure and suitable for X-ray structure analyses. Figures
N
O
3a-3h
1, 2 and 3 show the molecular structures of compounds 5c, 6b and 7c. On the basis of the
reaction time, the reaction temperature and the corresponding yields of compounds 3a-3h
CH3
S
H
O
N
H
N
OC2H5
Cl
4b
R
N
OC2H5
S
N
N
O
O
CH3
R
6a-6h
with reagents 4a-4c imply that compounds 3e-3h are more reactive than compounds 3a-3d,
H
Br
N
Ar
because the steric effect of the phenyl group reduces the ability of compounds 3a-3d to
N
O
undergo nucleophilic cyclization, and the greater electron density on the NH2 in compounds
50 o C , 7-12 h, for 7a-7d
0 o C , 8-19 h, for 7e-7h
4a-4c, 2-bromoacetophenone
S
N
N
N
4c
3e-3h than on the NH in compounds 3a-3d increases the ability of compounds 3e-3h to
undergo nucleophilic cyclization. Among the cyclic reagents
N
Ar
N
80 o C , 20-25 h
H
O
R
O
O
R
7a-7h
(4c) is the most reactive reagent with thiosemicarbazones 3. The reactions of 4c with 3e-3h
Scheme 2.
must be performed in an ice-cooled system to prevent the decomposition of sydnones during
3a, 3e: Ar = C6H5;
3b, 3f: Ar = p-CH3C6H4;
3a-3d, 5a-5d, 6a-6d, 7a-7d: R = C6H5;
the reaction. The reaction time and reaction temperature of these cyclic reagents 4a-4c with
3c, 3g: Ar = p-CH3OC6H4;
3d, 3h: Ar = p-C2H5OC6H4;
3e-3h, 5e-5h, 6e-6h, 7e-7h: R = H
compounds 3 imply that the order of their reactivities is 4c > 4b > 4a.
Biological assay
Scavenging effect on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical
The scavenging effect of the synthesized compounds 5-7 on DPPH radical was estimated
according Shimada, K. (1992). The various concentration of test compound in 1.5 mL
methanol was added to a 1.5 mL (0.2 mM) solution of DPPH radical in methanol (final
concentration of DPPH was 0.1 mM). Absorbance at 517 nm was determined (Hitachi
U-2001 Spectrophotometer) after 30 min, and percentage of activity was calculated. Vitamin
E was used as reference compound. The result indicated that 4-methyl-2-[(3-arylsydnon
-4-yl-methylene)hydrazono]-2,3-dihydrothiazole-5-carboxylic acid ethyl ester (6e-6h) and
4-phenyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydrothiazoles (7e-7h) possess
the potent DPPH radical scavenging activity comparable with that of vitamin E (Figures 4
and 5). The biological assay showed that the 2,3-dihydrothiazole moiety of compounds 6e-6h
Figure 1. Crystal structure of compound 5c.
Figure 2. Crystal structure of compound 6b.
Figure 3. Crystal structure of compound 7c.
and 7e-7h played the important role in the scavenging radical activity. Compounds 7e-7h
showed the strongest action.
Scavenging activity (%)＝{[(Ab+As)-Am]/Ab}× 100%
100
100
100
100
Ab: absorbance of 0.1 mM DPPH methanol solution at 517 nm
As: absorbance of various concentration of test compound solution at 517 nm
Am: absorbance of mixture solution at 517 nm
viz, Staph. aureus, Esch. coli, Proteus vulgaris and Pseudomonas aeruginosa and two fungal
cultures viz, Aspergillus niger and Penicillium citrinum. The reference drugs used were
60
60
6e6e
6f
6f
6g
6g
6h
6h
Vit E
Vit E
40
40
Norfloxacin and Griseofulvin, respectively. The tests were carried out with the title
compounds and the reference drugs, under identical conditions by paper-disc method with 15
DPPH reduction %
%
All these compounds 5a-7h were screened their antimicrobial activity against four bacterias
DPPH
DPPHreduction
reduction %
%
Antimicrobial activity
80
80
80
80
20
20
60
60
40
40
7e7e
7f7f
7g7g
7h7h
Vit.
EE
Vit.
20
20
μg of the substance in 50 μL of DMF. The total area of inhibition was calculated by the zone
of inhibition, in comparision with the reference drug, as follows:
Relative % inhibition = 100(X-Y)/(Z-Y)
X = total area of inhibition in the test compound
0
0 0.0
0.0
0.2
0.2
0.4
0.4
0.6
0.6
0.8
0.8
Concentration mM
Concentration mM
00
0.00
0.00
0.05
0.05
0.10
0.10
0.15
0.15
0.20
0.20
0.25
0.25
0.30
0.30
Concentration
ConcentrationmM
mM
Y = total area of inhibition in DMF
Z = total area of inhibition in reference drug.
In general these compounds are found to possess more antifungal than antibacterial activity.
Compounds 5a-5d have the obvious activity against Penicillium citrinum.
Figure 4. Scavening activity of compounds 6e-6h on DPPH radical
Figure 5. Scavening activity of compounds 7e-7h on DPPH radical