Synthesis and Antimicrobial Activity of New Thiazolidine-Based Heterocycles as Rhodanine Analogues

Article abstract of DOI:10.1002/jhet.3087

A new series of compounds containing thiazole nucleus as Rhodanine analogues have been synthesized. The new compounds were prepared from the reactions of the thiosemicarbazones (3a,b) with a series of α-halo carbonyl compounds to give the corresponding Rh

Full text of DOI:10.1002/jhet.3087

Month 2018
Synthesis and Antimicrobial Activity of New Thiazolidine-Based
Heterocycles as Rhodanine Analogues
a
Naglaa A. Abdel Hafez,
Mohamed A. Elsayed,a Manal M. El-Shahawi,b Ghada E. A. Awad,c and Korany A. Alia,d
*
aApplied Organic Chemistry Department, National Research Centre, Dokki, Giza 12622, Egypt
bChemistry Department, Faculty of Science, Ain Shams University, Abbasia, Cairo 11566, Egypt
cChemistry of Natural and Microbial Products Department, National Research Centre, Dokki, Giza 12622, Egypt
dCenter of Excellence, Advanced Materials and Nanotechnology Group, National Research Centre, Dokki,
Giza 12622, Egypt
*
E-mail: naglaa1810@gmail.com
Received September 5, 2017
DOI 10.1002/jhet.3087
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new series of compounds containing thiazole nucleus as Rhodanine analogues have been synthesized.
The new compounds were prepared from the reactions of the thiosemicarbazones (3a,b) with a series of
α-halo carbonyl compounds to give the corresponding Rhodanine analogues. The thiosemicarbazones deriv-
atives (3a,b) were reacted also with hydrazonoyl chlorides to afford the corresponding tri-substituted and
tetra-substituted thiazoles. The structures of the newly synthesized compounds were confirmed by elemental
analysis and spectral data. The biological activities of the new synthesized Rhodanine analogues’ were eval-
uated for their antimicrobial activities. The results showed that some of these compounds showed excellent
activity against two fungal strains, including Aspergillus niger and Aspergillus flavus, in addition to three
yeast strains, including Saccharomyces cervesi, Candida albicans NRRL Y-477, and Candida Pathological
specimen compared with the ketoconazol, as the reference drug.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
psychedlis drug under a class of drugs known as
amphetamines [12].
Thiosemicarbazones are a class of organic compounds
that used for many decades in medicinal chemistry as they
developed as antimicrobial, anticonvulsant, antihelminthic,
and anticancer activities [1–5]. On the other hand,
thiosemicarbazones consider as a good precursors for the
preparation of new class of thiazoles. Moreover, thiazoles
as Rhodanine analogues (Fig. 1), in many publications,
exhibited a wide range of biological activities such as
anti-inflammatory [6], antimicrobial [7,8], anti-apoptotic
[9], antioxidant [10], and anticancer [11] properties.
As part of our targets to synthesize biologically active
heterocycles [13,14] and our ongoing interests in the
chemistry of hydrazonoyl halides and α-halo carbonyl
compounds, we have prepared new series of Rhodanine
analogues containing the dimethoxy phenyl scaffold
and investigated their biological activities as antifungal
agents.
RESULTS AND DISCUSSION
On the other hand, dimethoxy phenyl is an important
scaffold in pharmaceutical chemistry with
range of registered drugs due to their biological activity.
For example, 2,5-dimethoxy-4-chloroamphetamine is a
a
wide
The starting materials for this study, 3,4-dimethoxy
acetophenone thiosemicarbazones (3a,b), were prepared
from the reaction of 3,4-dimethoxyacetophenone with the
© 2018 Wiley Periodicals, Inc.

N. A. Abdel Hafez, M. A. Elsayed, M. M. El-Shahawi, G. E. A. Awad, and K. A. Ali
Vol 000
S
In a similar manner, the thiosemicarbazones (3a,b) were
treated with chloroacetone and phenacyl chloride to afford
the corresponding substituted thiazole derivatives 6a,b and
7, respectively (Scheme 3).
S
N
O
H
1
Rhodanine
The H NMR of compound 7, as example, showed five
singlets signals at 2.09, 3.81, 3.91, 6.84, and 7.81 ppm
characteristic for CH3, 2 OCH3, CH-thiazole, and NH
protons, respectively. The mass spectra of compounds 6a,b
and 7 revealed peaks at m/z: 291, 319, and 353
corresponding to their molecular ion peaks, respectively.
Hydrazonoyl halides are highly versatile active reagents
that used for the preparation of different series of
substituted pyrazoles and thiazoles [15–18]. Thus herein,
we reported the reaction of the thiosemicarbazones (3a,b)
with two series of hydrazonoyl chlorides to prepare tri-
substituted and tetra-substituted thiazoles. Treatment of
the thiosemicarbazide derivatives (3a,b) with C-acetyl-N-
arylhydrazonoyl chlorides (8a–c) in ethanol, and in the
presence of catalytic amount of triethylamine, yielded the
azo-thiazole derivatives 9a–e rather than the tautomeric
Figure 1. Rhodanine.
thiosemicarbazides (2a,b), in the presence of sodium
acetate, in refluxing ethanol (Scheme 1).
Thiosemicarbazones have a special interest for the
preparation of biologically active ingredients and consider
as good precursors for the preparation of novel series
of fused thiazole systems. Thus, the thiosemicarbazones
(3a,b) were treated with the α-halo esters, namely,
ethyl bromoacetate and ethyl-2-bromoprpionate, in
ethanol and in the presence of equivalent amount of
sodium acetate, to afford the corresponding substituted
thiazole derivatives 4 and 5a,b, respectively, (Scheme 2)
according to elemental analysis and spectral data. For
example, the 1H NMR spectrum of compound 4
showed three singlets signals at δ 2.34, 3.80, and
3.84 ppm because of CH3, CH2-thiazole, and 2OCH3
groups, respectively. The aromatic and NH protons
appeared at 6.98–7.5 and 11.85 ppm, respectively. The
1
structure 10 (Scheme 4). The H NMR and IR spectral
data of the products revealed the absence of hydrazinyl
NH bands, in addition to the red color of the obtained
products because of presence of azo group (-N=N-)
proves that the azo-tautomeric structures 9a–e are the
correct and more stable structures.
structure of compound
4 was confirmed by an
independent synthesis via the reaction of the
thiosemicarbazones (3a) with bromoacetic acid in
ethanolic solution of sodium acetate.
On the contrary, treatment of the thiosemicarbazide
derivatives (3a,b) with C-ethoxycarbonyl-N-arylhydrazonoyl
Scheme 1. Synthetic pathway for the formation of compounds 3a,b.
Scheme 2. Synthetic pathway for the formation of compounds 4 and 5a,b.
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Scheme 3. Synthetic pathway for the formation of compounds 6a,b and 7.
Scheme 4. Synthetic pathway for the formation of compounds 9a–e.
chlorides (11a,b) afforded the corresponding substituted
thiazoles 12a–c rather than the azo-tautomeric structure 13
(Scheme 5). The structures of compounds 12a–c were
deduced from the corrected analytical and spectroscopic
data. For example, the IR spectral data of compounds 12a–c
showed bands at 1713–1715 cmÀ1 because of C=O groups.
On the other hand, the colors of the later compounds are
pale yellow that refer to the absence of the azo group.
Pathological specimen. The compounds 3a, 3b, 4, 5b,
6b, 9d, 9e, and 12b exhibited similar or mild better
antifungal activity than the reference drug, ketoconazol
(Table 1).
MINIMUM INHIBITORY CONCENTRATION
The minimum inhibitory concentration activity of active
compounds 3a, 3b, 4, 5b, 6b, 9d, 9e, and 12b (represent
inhibition zone ≥16 mm) was then evaluated using the
twofold serial dilution technique (Table 2). The lowest
concentration showing no growth was taken as the
minimum inhibitory concentration.
ANTIMICROBIAL ACTIVITY
All the synthesized compounds were tested against
a penal of Gram +ve and Gram –ve bacteria, yeast,
and fungi. All of the tested compounds showed a
neglectable activity against either Gram +ve and Gram
–ve bacteria, but some compounds showed considerable
highly inhibitory effect against two fungal strains,
including Aspergillus niger and Aspergillus flavus, in
addition to three yeast strains, including Saccharomyces
cervesi, Candida albicans NRRL Y-477, and Candida
STRUCTURE ACTIVITY RELATIONSHIP
Some of the new compounds showed considerable
highly inhibitory effect against two fungal strains and
three yeast strains. The compounds 3a, 3b, 4, 5b, 6b, 9d,
Journal of Heterocyclic Chemistry
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N. A. Abdel Hafez, M. A. Elsayed, M. M. El-Shahawi, G. E. A. Awad, and K. A. Ali
Vol 000
Scheme 5. Synthetic pathway for the formation of compounds 12a–c.
Table 1
The antimicrobial activity expressed, as inhibition diameter zones in millimeters (mm), of the newly synthesized compounds against the pathological
strains based on well diffusion assay.
Aspergillus
niger
Aspergillus
flavus
Saccharomyces
cervesi
Candida albicans
NRRLY-477
Candida Pathological
specimen
Comp. no
3a
3b
4
5b
6b
9d
9e
12b
32
28
31
30
30
26
32
28
33
33
22
30
22
30
30
30
29
32
29
25
28
30
25
25
33
30
31
33
24
30
28
27
26
31
29
31
30
25
30
28
29
25
31
30
33
ketoconazole
The experiment was carried out in triplicate, and the average zone of inhibition was calculated.
Table 2
Minimum inhibitory concentration (μg/mL) against the pathological strains based on twofold serial dilution technique.
Aspergillus
Niger
Aspergillus
flavus
Saccharomyces
cervesi
Candida albicans NRRLY-
Candida Pathological
specimen
Comp. no.
477
3a
3b
4
5b
6b
9d
9e
12b
65.5
125
65.5
65.5
125
250
125
125
65.5
65.5
125
65.5
125
65.5
125
125
65.5
125
125
125
125
65.5
125
125
125
125
125
65
65.5
125
125
125
125
125
125
65.5
65.5
65.5
65.5
65.6
65.5
125
65.5
65.5
65.5
ketoconazole
The experiment was carried out in triplicate, and the average zone of inhibition was calculated.
9e, and 12b exhibited similar or mild better antifungal
activity than the reference drug, ketoconazol. Five of the
most active compounds 5b, 6b, 9d, 9e, and 12b contain
3-ethyl thiazole scaffold that may lead to enhance the
antifungal activity.
EXPERIMENTAL
All melting points were measured on a
Gallenkamp melting point apparatus (Weiss Gallenkamp,
London, UK). The infrared spectra were recorded in
Chemistry.
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New Thiazolidine-Based Heterocycles
potassium bromide disks on a Pye Unicam SP 3300 and
Shimadzu FT IR 8101 PC infrared spectrophotometers
(Pye Unicam Ltd. Cambridge, England and Shimadzu,
Tokyo, Japan, respectively). The NMR spectra were
recorded on a Varian Mercury VX-300 NMR spectrometer
2-(2-(1-(3,4-Dimethoxyphenyl)ethylidine)hydrazono)
thiazolidin-4-one (4).
White solid; Yield (87%); mp:
225–227°C (EtOH). IR (KBr, cmÀ1): v 3376 (NH), 1724
1
(C=O), H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 3.80,
3.84 (2 s, 8H, 2OCH3; CH2-thiazole), 6.98 (d, 1H,
CH-Ar), 7.38 (d, 1H, CH-Ar), 7.50 (s, 1H, CH-Ar), 11.85
(s, 1H, NH). MS m/z (%): 293 [M+] (100), 278 (16), 253
(17), 238 (7). Anal. Calcd. for C13H15N3O3S (293.34):
C, 53.23; H, 5.15; N, 14.32; S, 10.93. Found: C, 53.29;
H, 5.20; N, 14.36; S, 10.95.
2-(2-(1-(3,4-Dimethoxyphenyl)ethylidine)hydrazono)-5-
methylthiazolidin-4-one (5a). Gray solid; Yield (80%); mp:
1
(Varian, Palo Alto, CA, USA). H NMR spectra were run
at 300 MHz, and 13C NMR spectra were run at
75.46 MHz in deuterated chloroform (CDCl3) or dimethyl
sulfoxide (DMSO-d6). Chemical shifts are given in parts
per million and were related to that of the solvent. Mass
spectra were recorded on a Shimadzu GCMS-QP 1000
EX mass spectrometer (Shimadzu) at 70 eV. Elemental
analyses were carried out at the Microanalytical Centre
of Cairo University, Giza, Egypt, and recorded on
Elementar-Vario EL (Germany) automatic analyzer. The
reactions were monitored by TLC. Compounds 2b, 8a–c,
and 11a,b were prepared according to the reported
references [19–22].
188–189°C (EtOH). IR (KBr, cmÀ1): v 3372 (NH), 1742
(C=O). 1H NMR (CDCl3): δ 1.68 (d, 3H, CH3), 2.41
(s, 3H, CH3), 3.93 (s, 3H, OCH3), 3.96 (s, 3H, OCH3),
4.05 (q, 1H, CH-thiazole), 6.86 (d, 1H, CH-Ar), 7.37
(d, 1H, CH-Ar), 7.60 (s, 1H, CH-Ar), 8.45 (br., 1H,
NH). MS m/z (%): 307 [M+] (100), 292 (16), 163 (3).
Anal. Calcd. for C14H17N3O3S (307.37): C, 54.71; H,
5.57; N, 13.67; S, 10.43. Found: C, 54.77; H, 5.62; N,
13.70; S, 10.45.
Preparation of the thiosemicarbazone derivatives (3a,b).
To a mixture of 3,4-dimethoxy acetophenone (1) (1.8 g,
10 mmol) and anhydrous sodium acetate (1.64 g,
20 mmol) in absolute EtOH (15 mL), thiosemicarbazide
(2a) (0.91 g, 10 mmol) or ethyl thiosemicarbazide (2b)
(1.19 g, 10 mmol) was added. The mixture was
refluxed for 3 h, left to cool, then poured into ice water.
The formed precipitate was filtered off, dried, and
recrystallized from EtOH to afford the corresponding
thiosemicarbazones (3a,b).
1-(1-(3,4-Dimethoxyphenyl)ethylidene)thiosemicarbazide
(3a). The analytical data of compound 3a were as the
reported in the literature [23].
4-Ethyl-1-(1-(3,4-dimethoxyphenyl)ethylidene)
thiosemicarbazide (3b). Yellow solid; Yield (72%); mp:
2-(2-(1-(3,4-Dimethoxyphenyl)ethylidine)hydrazono)-3-
ethyl-5-methylthiazolidin-4-one (5b).
White solid; Yield
(80%); mp: 150–152°C (EtOH). IR (KBr, cmÀ1): v 1715
1
(C=O). H NMR (DMSO-d6): δ 1.21 (t, 3H, CH3-ethyl),
1.50 (d, 3H, CH3), 2.39 (s, 3H, CH3), 3.80 (m, 8H,
2OCH3 + CH2-ethyl), 4.21 (q, 1H, CH-thiazole), 6.99
(d, 1H, CH-Ar), 7.40 (d, 1H, CH-Ar) 7.50 (s, 1H, CH-Ar),.
MS m/z (%): 335 [M+] (16), 190 (57), 178 (52), 164 (100).
Anal. Calcd. for C16H21N3O3S (335.42): C, 57.29; H,
6.31; N, 12.53; S, 9.56. Found: C, 57.35; H, 6.36; N,
12.56; S, 9.59.
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(4-methylthiazol-2-
(3H)-ylidene)hydrazine (6a). Gray solid; Yield (88%); mp:
128–129°C (EtOH). IR (KBr, cmÀ1): v 3331 (2NH),
1581(C=N). 1H NMR (CDCl3): δ 1.31 (t, 3H, CH3),
2.25 (s, 3H, CH3), 3.73 (q, 2H, CH2), 3.93 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.99 (d, 1H, CH-Ar), 7.22
(s, 1H, CH-Ar), 7.66 (d, 1H, CH-Ar), 7.66 (s, 1H,
NH), 8.54 (s, 1H, NH). MS m/z (%): 281 [M+] (25),
179 (32), 164 (31), 148 (13), 133 (23), 103 (13). Anal.
Calcd for C13H19N3O2S (281.37): C, 55.49; H, 6.81; N,
14.93; S, 11.40. Found: C, 55.42; H, 6.75; N, 14.87;
S, 11.32.
145–147°C (EtOH). IR (KBr, cmÀ1): v 3542 (NH), 1561
(C=N). 1H NMR (CDCl3): δ 2.23 (s, 3H, CH3), 2.29
(s, 3H, CH3), 3.91 (s, 3H, OCH3), 3.95 (s, 3H, OCH3),
6.22 (s, 1H, CH-thiazole), 6.84 (d, 1H, CH-Ar), 7.20
(d, 1H, CH-Ar), 7.50 (s, 1H, CH-Ar); MS m/z (%): 291
[M+] (29), 178 (43), 137 (26), 113 (19), 107 (14). Anal.
Calcd. for C14H17N3O2S (291.37): C, 57.71; H, 5.88; N,
14.42; S, 11.00. Found: C, 57.77; H, 5.93; N, 14.47;
S, 11.03.
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(3-ethyl-4-
methylthiazol-2-(3H)-ylidene) hydrazine (6b). Yellow solid;
General procedure for the preparation of Rhodanine
Yield (78%); mp: 98–100°C (EtOH). IR (KBr, cmÀ1): v
analogues; 4, 5a,b, 6a,b, and 7.
A mixture of the
1595 (C=N). 1H NMR (CDCl3):
δ 1.34 (t, 3H,
thiosemicarbazones (3a,b) (1 mmol) and the appropriate
halo compounds including ethyl bromoacetate, ethyl
CH3-ethyl), 2.16 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.94
(m, 8H, 2OCH3 + CH2-ethyl), 5.65 (s, 1H, CH-
thiazole), 6.83 (d, 1H, CH-Ar), 7.28 (d, 1H, CH-Ar);
7.67 (s, 1H, CH-Ar); MS m/z (%): 319 [M+] (91), 178
(19), 164 (66), 149 (46), 128 (39), 114 (33.6). Anal.
Calcd. for C16H21N3O2S (319.42): C, 60.16; H, 6.63;
N, 13.16; S, 10.04. Found: C, 60.22; H, 6.68; N,
13.19; S, 10.10.
2-bromopropanoate,
chloroacetone,
and
2-
chloroacetophenone in ethanolic solution of anhydrous
sodium acetate (2 mmol) were refluxed for 2–5 h. After
cooling, the mixtures were washed with ice cold water.
The formed solids were filtered off and dried then
crystallized from EtOH to afford the corresponding of
Rhodanine analogues, 4, 5a,b, 6a,b, and 7, respectively.
Journal of Heterocyclic Chemistry
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N. A. Abdel Hafez, M. A. Elsayed, M. M. El-Shahawi, G. E. A. Awad, and K. A. Ali
Vol 000
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(4-phenylthiazol-2-
(3H)-ylidene)hydrazine (7). Gray solid; Yield (90%); mp:
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(3-ethyl-4-methyl-
5-phenylazo-thiazole-2-ylidene)hydrazine (9d).
Red solid;
188–189°C (EtOH). IR (KBr, cmÀ1): v 3275 (NH), 1562
(C=N). 1H NMR (CDCl3): δ 2.09 (s, 3H, CH3), 3.91
(s, 3H, OCH3), 3.95 (s, 3H, OCH3), 6.83–7.81 (m, 9H,
CH-Ar + CH-thiazole); 13C NMR (CDCl3): δ 12.88,
55.75, 55.85, 103.51, 108.57, 110.42, 118.92, 125.87,
127.66, 128.56, 130.68, 134.78, 146.10, 148.90, 150.09,
151.29, 170.07. MS m/z (%): 353 [M+] (100), 338 (7),
178 (6); Anal. Calcd. for C19H19N3O2S (353.44): C,
64.57; H, 5.42; N, 11.89; S, 9.07. Found: C, 64.63; H,
5.48; N, 11.94; S, 9.11.
Yield (89%); mp: 186–188°C (EtOH). IR (KBr, cmÀ1): v
1595 (C=N), 2934 (CH aliphatic). 1H NMR (CDCl3)
δ 1.37 (t, 3H, CH3), 2.27 (s, 3H, CH3), 2.73 (s, 3H, CH3),
3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.15 (q, 2H,
CH2), 6.99–7.69 (m, 8H, CH-Ar). MS m/z (%): 425 [M+]
(5), 410 (11), 341 (12), 296 (14), 178 (35), 164 (53), 104
(26), 91 (45). Anal. Calcd. for C22H25N5O2S (423.53): C,
62.39; H, 5.95; N, 16.54; S, 7.57. Found: C, 62.31; H,
5.86; N, 16.50; S, 7.51.
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(3-ethyl-4-methyl-
5-(4-methylphenylazo)-thiazole-2-ylidene)hydrazine (9e).
General procedure for the preparation of the azothiazole
Red solid; Yield (79%); mp: 195–197°C (EtOH). IR
derivatives 9a–e and 12a–c.
To
a
mixture of
1
(KBr, cmÀ1): v 1587 (C=N). H NMR (CDCl3): δ 1.44
thiosemicarbazones (3a,b) (1 mmol) and the appropriate
hydrazonoyl chlorides (1 mmol) in EtOH, TEA (1 mmol)
was added. The reaction mixture was then refluxed for
6–8 h. After cooling, the mixture was washed with ice
cold water. The formed solids were filtered and dried
then crystallized from EtOH to afford the corresponding
(t, 3H, CH3), 1.54 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.45
(s, 3H, CH3), 3.93 (s, 3H, OCH3), 3.99 (s, 3H, OCH3),
4.45 (q, 2H, CH2), 6.90–7.95 (m, 7H, CH-Ar). MS m/z
(%): 437 [M+] (2), 425 (4), 413 (23), 356 (42), 301 (11),
177 (8), 137 (34). 85 (100). Anal. Calcd. for
C23H27N5O2S (437.56): C, 63.13; H, 6.22; N, 16.01; S,
7.33; Found: C, 63.19; H, 6.27; N, 16.06; S, 7.35.
azo-thiazole derivatives 9a–e and 12a–c, respectively.
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(4-methyl-5-
2-(2-(1-(3,4-Dimethoxyphenyl)ethylidine)hydrazono)-5-
phenylazo-thiazole-2-(3H)-ylidene)hydrazine (9a).
Reddish
phenylazo-thiazolidin-4-one (12a).
Pale yellow solid;
solid; Yield (92%); mp: 125–127°C (EtOH). IR (KBr,
cmÀ1): v 3348 (NH), 1597 (C=N). 1H NMR (CDCl3):
δ 2.54 (s, 3H, CH3), 2.63 (s, 3H, CH3), 3.90 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 6.85–7.64 (m, 8H, CH-Ar);
13C NMR (CDCl3): δ 15.45, 16.61, 55.85, 55,.97,
109.73, 114.08, 121.03, 122.69, 125.70, 129.36, 130.50,
140.57, 142.66, 148.70, 151.46, 165.18, 169.42, 171.31.
MS m/z (%): 395 [M+] (7), 353 (100), 337 (12), 292 (4).
Anal. Calcd. for C20H21N5O2S (395.48): C, 60.74; H,
5.35; N, 17.71; S, 8.11. Found: C, 60.70; H, 5.39; N,
Yield (79%); mp: 163–165°C (EtOH). IR (KBr, cmÀ1):
v 3118 (NH), 1713 (C=O); MS m/z (%): 397 [M+]
(11), 305 (1), 289 (0.7), 113 (20.5), 101 (18). Anal.
Calcd. for C19H19N5O3S (397.45): C, 57.42; H, 4.82;
N, 17.62; S, 8.07; Found: C, 57.37; H, 4.75; N, 17.57;
S, 8.01.
2-(2-(1-(3,4-Dimethoxyphenyl)ethylidine)hydrazono)-3-
ethyl-5-phenylazo-thiazolidin-4-one (12b).
Pale yellow
solid; Yield (79%); mp: 170–172°C (EtOH). IR (KBr,
1
cmÀ1): v 3107 (NH), 1717 (C=O). H NMR (CDCl3): δ
17.65; S, 8.15.
1.43 (t, 3H, CH3), 2.31 (s, 3H, CH3), 3.92 (s, 3H,
OCH3), 3.98 (s, 3H, OCH3), 4.44 (q, 2H, CH2),
6.85–8.10 (m, 8H, CH-Ar). 13C NMR (CDCl3): δ 14.11,
14.69, 55.85, 62.79, 109.10, 110.29, 110.38, 119.80,
120.02, 121.94, 126.67, 128.73, 130.81, 131.42, 139.4,
148.80, 150.53, 157.03, 159.2, 160.05, 164.01. MS m/z
(%): 425 [M+] (62), 355 (55), 341 (100), 299.9 (17), 178
(6), 164 (18), 148.9 (5). Anal. Calcd. for C21H23N5O3S
(425.50): C, 59.28; H, 5.45; N, 16.46; S, 7.54. Found: C,
59.19; H, 5.39; N, 16.38; S, 7.46.
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(4-methyl-5-(4-
methylphenylazo)-thiazole-2-(3H)-ylidene)hydrazine (9b).
Reddish solid; Yield (94%); mp: 215–217°C (EtOH). IR
(KBr, cmÀ1): v 3376 (NH), 1600 (C=N). 1H NMR
(DMSO-d6): δ 2.27 (s, 3H, CH3), 2.58 (s, 3H, CH3), 3.84
(m, 9H, 2OCH3 + CH3), 3.85 (s, 3H, OCH3), 6.92–8.20
(m, 7H, CH-Ar), 10.05 (s, 1H, NH, exchangeable with
D2O); MS m/z (%): 409 [M+] (2), 305 (1), 113 (18), 101
(16). Anal. Calcd. for C21H23N5O2S (409.50): C, 61.59;
H, 5.66; N, 17.10; S, 7.83; Found: C, 61.65; H, 5.73; N,
2-(2-(1-(3,4-Dimethoxyphenyl)ethylidine)hydrazono)-5-(4-
17.13; S, 7.86.
1-(1-(3,4-Dimethoxyphenyl)ethylidine)-2-(4-methyl-5-(4-
chlorophenylazo-thiazole-2-(3H)-ylidene)hydrazine (9c).
methylphenylazo)-thiazolidin-4-one (12c).
Pale yellow
solid; Yield (69%); mp: 155–158°C (EtOH). IR (KBr,
1
Dark red solid; Yield (89%); mp: 228–230°C (EtOH). IR
(KBr, cmÀ1): v 3376 (NH), 1598 (C=N). 1H NMR
(DMSO-d6): δ 2.26 (s, 3H, CH3), 3.78–3.82 (m, 9H,
2OCH3 + CH3), 6.92–8.20 (m, 7H, CH-Ar), 10.05
(s, 1H, NH). MS m/z (%): 429 [M+] (5), 425 (100), 353
(52), 252 (47), 236 (30), 178 (7). Anal. Calcd. for
C20H20ClN5O2S (429.10): C, 55.87; H, 4.69; N, 16.29; S,
7.46; Found: C, 55.94; H, 4.74; N, 16.32; S, 7.49.
cmÀ1): v 3376 (NH), 1710 (C=O). H NMR (CDCl3): δ
1.42 (t, 3H, CH3), 2.31 (s, 3H, CH3), 2.41 (s, 3H, CH3),
3.93 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 4.48 (q, 2H,
CH2), 6.87–7.95 (m, 7H, CH-Ar). MS m/z (%): 440
[M+ + 1] (90), 439 (9), 355 (100), 341 (97), 300 (9).
Anal. Calcd. for C22H25N5O3S (439.53): C, 60.12; H,
5.73; N, 15.93; S, 7.30. Found: C, 60.15; H, 5.77; N,
15.87; S, 7.33.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
New Thiazolidine-Based Heterocycles
Antimicrobial activity.
All synthesized chemical
showed excellent activity against yeast and fungi strains
compared with ketoconazol, as reference drug.
compounds were individually tested against a panel of
Gram +ve and Gram –ve bacterial pathogens, yeast, and
fungi. Antimicrobial tests were carried out by the agar
well diffusion method [24] using 100 μL of suspension as
inoculum containing 1 × 106 CFU/mL of pathogenic
bacteria that include Staphelococcus aureus ATCC29213,
Bacillus subtilis ATCC6633 as a Gram + ve bacteria,
Escherichia coli ATCC2592, Pseudomonas aeroginosa
ATCC27953 as a Gram –ve bacteria, 1 × 106 CFU/mL
yeast that include S. cervesi, C. albicans NRRL Y-477,
and C. albicans isolated from pathological sample, and
1 × 104 spore/mL of fungi that include A. niger and
A. flavus. The tested microorganism’s inoculums were
spread on a sterile Petri dishes containing Müller–Hinton
agar. After the media had cooled and solidified, wells
(10 mm in diameter) were made in the solidified agar and
loaded with 100 μL of tested compound solution prepared
by dissolving 10 mg of the chemical compound in 1 mL
of DMSO. The inculcated plates were then incubated for
24 h at 37°C for bacteria and yeast and 48 h at 28°C for
fungi. Negative controls were prepared using DMSO
employed for dissolving the tested compound. Ten
milligrams per milliliters of Ketoconazole was used as
standard for antifungal activity. After incubation time,
antifungal activity was evaluated by measuring the zone
of inhibition against the test organisms and compared with
that of the standard. The observed zone of inhibition
is presented in Table 1. Antimicrobial activities were
expressed as inhibition diameter zones in millimeters
(mm). The experiment was carried out in triplicate, and
the average zone of inhibition was calculated.
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CONCLUSION
In conclusion, we have prepared a series of Rhodanine
analogues from the reaction of thiosemicarbazone
derivatives with α-halo carbonyl compounds and
hydrazonoyl chlorides to afford a series of highly
functionalized thiazole derivatives in good yields. Some
of the new synthesized Rhodanine analogues’ were
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet