Synthesis and antimicrobial activity of new thiazole and thiadiazole derivatives via ethyl pyruvate

Article abstract of DOI:10.1080/17415993.2019.1694678

Reaction of ethyl 2-(2-((methylthio)carbonothioyl)hydrazono)propanoate (2) and ethyl 2-(2-carbamothioyl-hydrazono)propanoate (3) with hydrazonoyl halides 4a-e afforded the corresponding thiadiazoles 5a-e. Also, treatment of compound 2 with α-ketohydrazono

Full text of DOI:10.1080/17415993.2019.1694678

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Synthesis and antimicrobial activity of new
thiazole and thiadiazole derivatives via ethyl
pyruvate
Fatma M. Saleh, Abdou O. Abdelhamid & Hamdi M. Hassaneen
To cite this article: Fatma M. Saleh, Abdou O. Abdelhamid & Hamdi M. Hassaneen (2019):
Synthesis and antimicrobial activity of new thiazole and thiadiazole derivatives via ethyl pyruvate,
Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2019.1694678
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2019.1694678
Synthesis and antimicrobial activity of new thiazole and
thiadiazole derivatives via ethyl pyruvate
Fatma M. Saleh , Abdou O. Abdelhamid and Hamdi M. Hassaneen
Faculty of Science, Department of Chemistry, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Reaction of ethyl 2-(2-((methylthio)carbonothioyl)hydrazono)pro
panoate (2) and ethyl 2-(2-carbamothioyl-hydrazono)propanoate (3)
with hydrazonoyl halides 4a-e afforded the corresponding thiadia-
zoles 5a-e. Also, treatment of compound 2 with α-ketohydrazonoyl
halides 12a-f in absolute ethanol and in the presence of tri-
ethylamine gave the corresponding thiadiazoles 13a-f; while reac-
tion of ethyl 2-(2-carbamothioyl-hydrazono)propanoate (3) with α-
ketohydrazonoyl halide 12 gave thiazole derivatives 15. Also, the
reaction of compound 3 with hydrazonoyl chloride 12f afforded thi-
azolone derivative 18. Antimicrobial studies are performed using
two-gram positive bacteria and two-gram negative bacteria. Data
revealed that thiazole derivative 17a achieved the lowest MIC val-
ues (high efficient derivative) against the sensitive bacterial strain S.
aureus with MIC value 160 µg/ml.
Received 26 September 2019
Accepted 9 November 2019
KEYWORDS
Ethyl pyruvate;
thiosemicarbazide; methyl
hydrazinecarbodithioate;
hydrazonoyl halides;
thiadiazoles; thiazoles
Introduction
Ethyl pyruvate is a simple ester of pyruvate and stable lipophilic ester obtained from the
endogenous metabolite pyruvate and has been exhibited to protect against inflammation
[
1] and to mitigate organ dysfunction in several animal models of diverse disorders, includ-
ing severe sepsis, burns and acute pancreatitis [2,3]. Also, ethyl pyruvate has been revealed
CONTACT Hamdi M. Hassaneen
hamdi_251@yahoo.com
Faculty of Science, Department of Chemistry, Cairo
University, Giza, Egypt
©
2019 Informa UK Limited, trading as Taylor & Francis Group

2
F. M. SALEH ET AL.
to possess a protective effect on acute lung injury (ALI), probably through the inhibition
of the mitogen-activated protein kinase (MAPK) pathway in lungs [4–6]. Ethyl pyruvate is
an important intermediate of organic synthesis with wide applications inhibits the growth
of cells relying predominantly on glycolysis [7], antitumor [8], antitrypanosome activity
[
9], and other industrial and pharmaceutical applications [2,10–14]. The oxazolone syn-
thesized from ethyl pyruvate widely used for the synthetic fungicides [15,16]. It is well
known that thiadiazole derivatives are formed via reaction of hydrazonoyl halides with
potassium thiocyanate [17–21] or by coupling of 1-substitutedl-2-thiocyanatoethan-1-one
with arenediazonium chlorides [22,23]. Also, thiazole derivatives were prepared via reac-
tion of thiourea with α-ketohydrazonoyl halide [24] or with phenacyl bromide [24]. We
report herein the utility of ethyl pyruvate in the synthesis of new thiadiazole and thiazole
having many functional groups and study the biological activities of some new synthesized
compounds.
Results and discussion
Refluxing of ethyl pyruvate (1A) with methyl hydrazinecarbodithioate in 2-propanol
afforded ethyl 2-(2-((methylthio)carbonothioyl)hydrazono)propanoate (2) [25–27]
(
Scheme 1). Stirring of compound 2 with the appropriate hydrazonoyl halides 4a–e in
absolute ethanol in the presence of triethylamine at room temperature afforded the cor-
responding thiadiazoles 5a–e, respectively (Scheme 2). The structures of isolated products
5
a–e were established by their spectral data and elemental analyses.
Also, treatment of ethyl 2-(2-carbamothioylhydrazono)propanoate (3) [28] with hydra-
zonoyl halides 4a–e in refluxing ethanol in the presence of triethylamine gave, in each case,
1
one isolated product which proved identical in all respects (mp, mixed mp, IR, H NMR,
1
3
C NMR and MS spectra) with the corresponding derivatives 5 (Scheme 2). Moreover,
the structures of 5a–e were confirmed by alternative synthesis. For example, thiadiazole
a was obtained via refluxing 2-hydrazono-1,3,4-thiadiazole derivative 6a (prepared from
5
Scheme 1. Synthesis of ethyl 2-(2-((methylthio)carbonothioyl)hydrazono)propanoate (2) and ethyl
-(2-carbamothioyl-hydrazono)propanoate (3).
2

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 2. Synthesis of 1,3,4-thiadiazoles 5a–e.
Scheme 3. A plausible mechanism for the formation 1,3,4-thiadiazole derivatives 5.
reaction of methyl hydrazinecarbodithioate (2) with hydrazonoyl halides 4a [29–32]) with
ethyl pyruvate in 2-propanol.
In light of these results, the mechanism outlined in Scheme 3 seems to be the most
plausible pathway for the formation of 5a–e from the reaction of the 3 or 2 with 4. The
reaction involves the initial formation of thiohydrazonates 8, 10 via 1,3-addition, which
undergoes intramolecular cyclization as soon as it is formed to yield the intermediate 9,
11 or via 1,3-dipolar cycloaddition of nitrilimines 7 to CS double bond of 3 or 2, which
afforded intermediate 9 or 11 which gave a final product 5 by elimination of ammonia or
methyl mercaptan, respectively [33,34].

4
F. M. SALEH ET AL.
Scheme 4. Synthesis of 1,3,4-thiadiazoles 13a–f.
Analogously, treatment of α-ketohydrazonoyl halides 12a–f with compound 2 in
ethanolic triethylamine yielded 1,3,4-thiadiazoles 13a–f in a good yield (Scheme 4). Struc-
tures of 13a–f were confirmed based on elemental analysis, spectral data and alternative
synthetic route. For example, treatment of ethyl 5-hydrazono-4-phenyl-4,5-dihydro-1,3,4-
thiadiazole-2-carboxylate (14) [32] with 1A in 2-propanol gave product identical in all
respect mp, mixed mp, and spectra with compound 13f.
In contrast, treatment of α-ketohydrazonoyl halide 12a with compound 3 in boil-
ing ethanol and in the presence of triethylamine gave one isolable product in each case,
and the products formulated as: ethyl 2-(2-(4-substituted-5-(phenyldiazenyl)-thiazol-2-
yl)hydrazono)propanoate (15a) (Scheme 5). Structures 15 were elucidated on the base
of elemental analyses, spectral data and alternative synthetic route. Thus, reaction of
ethyl 2-(2-carbamothioylhydrazono)propanoate (3) with ω-bromoacetophenone (16a)
in boiling ethanol gave the corresponding thiazoles 17a. Coupling of the latter com-
pound 17a with benzenediazonium chloride in ethanolic sodium acetate solution gave
a product identical in all respect (mp, mixd mp and spectra) with 15a (Scheme 5). Its
mass spectrum showed an intense peak, base peak, at m/z = 393 which corresponding
to its molecular weight. The IR spectrum showed two characteristic bands at ν 3429
−
1
and 1697 cm assignable to NH and C = O stretching frequencies, respectively. Also,
1
the H NMR spectrum revealed signals at δ 1.31 ppm (t, J = 7 Hz, 3H) and 4.27 ppm
(
(
q, J = 7 Hz, 2H) corresponding to ethoxycarbonyl group, singlet signal at 2.14 ppm
CH ) and a singlet signal at δ 11.38 ppm exchangeable with deuterium oxide assignable
3
to NH proton, in addition to signals of aromatic moiety. Similarly, compounds 17b–g
were prepared via reaction of ω-bromoacetophenone derivatives 16b–g with ethyl 2-
(
2-carbamothioylhydrazono)propanoate (3) in boiling ethanol. Coupling of the latter
compounds 17b–g with benzenediazonium chloride in ethanolic sodium acetate solution

JOURNAL OF SULFUR CHEMISTRY
5
Scheme 5. Synthesis of ethyl 4-(aryl)-5-(2-phenylhydrazono)thiazol-2(5H)-ylidene)hydrazono)-
propanoate 15a–g.
gave ethyl 4-(aryl)-5-(2-phenylhydrazono)thiazol-2(5H)-ylidene)hydrazono)-propanoate
1
5b–g (Scheme 5).
However, refluxing of compound 3 with N-phenyl-C-ethoxycarbonylmethano-hydra
zonoyl chloride 12f in ethanol in the presence of triethylamine yielded ethyl 2-((4-oxo-5-
2-phenylhydrazono)thiazolidin-2-ylidene)hydrazono)-propanoate (18) (Scheme 6). The
(
structure of compound 18 based on elemental analysis and spectral data (see Experimen-
tal). Yield% of all new synthesized compounds 5–18 was mentioned in Table 1.
Antimicrobial screening
The antibacterial and antifungal activities of new synthesized compounds 5, 13, 15, 17,
and 18 were studied by the disc diffusion method. The antibacterial activities were done
on the following pathogenic organisms; the gram-positive bacteria Staphylococcus aureus
and Bacillus subtilis, the gram negative bacteria Escherichia coli and Pseudomonas aerugi-
nosa. Moreover, antifungal activities aganist Aspergillus flavus and Candida albicans were
studied. The synthesized compounds were used at the concentration of 20 mg/mL using

6
F. M. SALEH ET AL.
Scheme 6. Synthesis of ethyl 2-(2-(4-oxo-5-(2-phenylhydrazono)-4,5-dihydrothiazol-2-yl)hydrazono)
propanoate 18.
Table 1. Yield% of all new synthesized compounds 5–18.
Compounds
Yield %
Compounds
Yield %
Compounds
Yield %
5
5
5
5
5
1
1
1
1
a
b
c
d
65
72
69
73
63
67
66
68
70
13e
13f
70
73
66
63
60
67
64
60
68
17a
17b
17c
17d
17e
17f
17g
18
77
70
66
74
73
77
73
70
15a
15b
15c
15d
15e
15f
e
3a
3b
3c
3d
15g
DMSO as a solvent. The Ampicillin 10 μL/disc was used as a standard antibacterial agent
and the Amphotericin B 20 μg/mL as standard antifungal agent. The results presented in
Table 2 all compounds show no antibacterial and antifungal activities except compounds
1
5e, 15f, 17a, 17b, 17c, and 18 however, the most potent compound exhibited antibacterial
and antifungal activities was compound 17a.
Compound 17a showed high potentiality in growth inhibition of tested microorgan-
isms with relative activity of standard antibiotics with relative activity of 42% in B. subtilis,
1
00% in S. aureus, 60% in E. coli, 50% in P. aeruginosa, and 66.7% in C. albicans. Regard-
ing the structure–activity relationship the parent compound (Ar = Ph) 17a showed high
antimicrobial activity, while the presence of electron donating groups leads to decrease the
antimicrobial activity.
In vitro susceptibility tests were performed to evaluate minimum inhibitory concen-
tration (MIC) was measured by a broth dilution method [35–37]. MIC values were
determined for the highly efficient antibacterial compounds using the most sensitive
microorganisms. Compound 17a achieved the lowest MIC value (high efficient deriva-
tive) against the sensitive bacterial strain S. aureus with MIC value 160 μg/ml, followed by

Table 2. In vitro antibacterial and antifungal activities of compounds 15, 17 and 18 (Inhibition zone in mm).a
Antimicrobial activity
+
−
Bacterial species (G )
Bacterial species (G )
Fungi
Bacillus subtilis
Staphylococcusaureus
Escherichia coli
Pseudomonasaeruginosa
Candida albicans
Compounds
Standard
IZ
0.0
RA%
IZ
0.0
RA%
IZ
0.0
RA%
IZ
RA%
IZ
0.0
RA%
0.0
Control: DMSO
Ampicillin
0.0
100
0.0
100
0.0
100
0.0
26
0.0
100
26
21
25
Amphotericin B
21
100
1
1
1
1
1
1
5e
5f
7a
7b
7c
8
0.0
9.0
11
0.0
00.0
9.0
0.0
34.6
42.0
0.0
0.0
34.6
11.0
15
21
11
11.0
14.0
52.4
71.4
100.0
52.4
52.4
66.7
0.0
9.0
15
0.0
11.0
0.0
0.0
36.0
60.0
0.0
44.0
0.0
0.0
9.0
13
0.0
10.0
0.0
0.0
34.6
50.0
0.0
38.5
0.0
0.0
0.0
14.0
0.0
14.0
0.0
0.0
0.0
66.7
0.0
66.7
0.0
−
aG = Gram negative; G+ = gram positive; R. A. = relative activity.

8
F. M. SALEH ET AL.
bacterial strain E. coli with MIC value 380 μg/ml and the highest MIC values against C.
albicans MIC with value 420 μg/ml.
Experimental
Melting points were measured with a Stuart melting point apparatus and are uncorrected.
The IR spectra were recorded using a FTIR Bruker–vector 22 spectrophotometer as KBr
1
13
pellets. The H and C NMR spectra were recorded in CDCl or DMSO–d as solvent on
3
6
Varian Gemini NMR spectrometer at 300 and 75 MHz, respectively, using TMS as internal
standard. Chemical shifts are reported as δ values in ppm. Mass spectra were recorded with
a Shimadzu GCMS–QP–1000 EX mass spectrometer in EI (70 eV) model. The elemental
analyses were performed at the Micro analytical center, Cairo University.
Synthesis of ethyl (aryl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)propanoate
(5, 13)
Method A: A mixture of ethyl 2-(2-((methylthio)carbonothioyl)hydrazono)-propanoate
(
2) [25] (0.44 gm, 5 mmol) and the appropriate hydrazonoyl halides 4a–e and 12a–f
(5 mmol) was dissolved in ethanol (50 mL). To the resulting solution triethylamine (2 mL)
was added and reaction mixture was stirred for 6 h at room temperature. The resulting
solid product that precipitated was collected, washed with ethanol and crystallized from
a suitable solvent to afford the corresponding thiadiazole derivatives 5a–e and 13a–f. The
products 5, 13 prepared together with their physical constants are listed below in yield
(
73%–63%).
Method B: To a solution of ethyl 2-(2-carbamothioylhydrazono)propanoate (3) [28]
0.95 gm, 5 mmol) and the appropriate hydrazonoyl chlorides 4a–f (5 mmol) was dissolved
(
in ethanol (50 mL), triethylamine (2 mL) was added and reaction mixture was refluxed for
h. The resulting solid product that precipitated was collected, washed with ethanol and
6
crystallized from a suitable solvent to afford the corresponding thiadiazole derivatives 5a–f
in yield (60%–52%).
Ethyl 2-((3,5-diphenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)propanoate (5a):
−
1 1
Yellow crystals (EtOH), mp 143–144°C; IR (KBr) ν 1702 (C = O) cm ; H NMR
(
300 MHz, CDCl ) δ 1.39 (t, J = 7 Hz, 3H, CH ), 2.31 (s, 3H, CH ), 4.33 (q, J = 7 Hz,
3
3
3
1
3
2
1
H, CH ) and 7.27–8.17 (m, 10H); C NMR (75 MHz, CDCl ) δ 14.2, 14.8, 61.3, 121.2,
2
3
22.8, 128.6, 128.9, 129.1, 130.6, 130.8, 137.9, 151.8, 152.2, 165.3, 167.4. MS (EI, 70 eV)
+
m/z (%): 366 (M , 14.8), 91 (100). Anal. Calcd. for C H N O S (366.4): C, 62.28; H,
1
9
18
4
2
4
.95; N, 15.29; S, 8.75. Found: C, 62.16; H, 4.88; N, 15.24; S, 8.80.
Ethyl 2-((3-phenyl-5-((E)-styryl)-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)propa-
−
1 1
noate (5b): Yellow crystals (EtOH), mp 137–138°C; IR (KBr) ν 1699 (C = O) cm ; H
NMR (300 MHz, CDCl ) δ 1.40 (t, J = 7 Hz, 3H, CH ), 2.30 (s, 3H, CH ), 4.33
3
3
3
(
7
1
q, J = 7 Hz, 2H, CH ), 7.02 (d, J = 14 Hz, 1H, CH), 7.13 (d, J = 14 Hz, 1H, CH),
2
1
3
.27–7.54 (m, 8H) and 8.10 (d, 2H); C NMR (75 MHz, CDCl ) δ 14.3, 14.7, 61.4, 118.5,
3
21.9, 126.4, 127.2, 128.7, 128.9, 129.5, 135.1, 137.6, 139.4, 151.9, 152.1, 165.1, 167.8. MS
+
(
EI, 70 eV) m/z (%): 392 (M , 100). Anal. Calcd. for C H N O S (392.5): C, 64.27; H,
2
1
20
4
2
5.14; N, 14.28; S, 8.17. Found: C, 64.13; H, 5.20; N, 14.20; S, 8.23.

JOURNAL OF SULFUR CHEMISTRY
9
Ethyl 2-((5-(furan-2-yl)-3-(4-nitrophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)hydra-
zono)-propan-oate (5c): Yellow crystals (DMF), mp 192–194°C; IR (KBr) ν 1689 (C = O)
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.39 (t, J = 7 Hz, 3H, CH ), 2.34 (s, 3H, CH ), 4.33
3
3
3
1
3
(
q, J = 7 Hz, 2H, CH ) and 6.60–8.47 (m, 7H); C NMR (75 MHz, CDCl ) δ 14.1, 14.6,
2
3
6
(
1.4, 108.2, 108.8, 110.2, 122.8, 135.9, 139.6, 140.6, 142.2, 150.7, 151.0, 153.9, 163.2. MS
+
EI, 70 eV) m/z (%): 401 (M , 100). Anal. Calcd. for C H N O S (401.4): C, 50.87; H,
1
7
15
5
5
3
.77; N, 17.45; S, 7.99. Found: C, 50.93; H, 3.70; N, 17.38; S, 7.85.
Ethyl 2-((3-(4-nitrophenyl)-5-(thien-2-yl)-1,3,4-thiadiazol-2(3H)-ylidene)hydra-
zono)-propanoate (5d): Yellow crystals (DMF), mp 186–188°C; IR (KBr) ν 1700 (C = O)
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.40 (t, J = 7 Hz, 3H, CH ), 2.34 (s, 3H, CH ), 4.34
3
3
3
1
3
(
q, J = 7 Hz, 2H, CH ) and 7.13–8.47 (m, 7H); C NMR (75 MHz, CDCl ) δ 14.0, 14.6,
2
3
6
1.5, 109.0, 109.2, 110.5, 123.9, 136.5, 139.3, 141.0, 142.8, 150.9, 151.5, 154.2, 163.5. Anal.
Calcd. for C H N O S (417.5): C, 48.91; H, 3.62; N, 16.78; S, 15.36. Found: C, 49.00; H,
1
7
15
5
4 2
3
.69; N, 16.70; S, 15.39.
Ethyl 2-((3-phenyl-5-(phenylcarbamoyl)-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)
-
1
3
(
propanoate (5e): Yellow crystals (EtOH), mp 145–146°C; IR (KBr) ν 3410 (NH), 1690,
−1 1
683 (2C = O) cm ; H NMR (300 MHz, CDCl ) δ 1.25 (t, J = 7 Hz, 3H, CH ), 2.26 (s,
3
3
13
H, CH ), 4.30 (q, J = 7 Hz, 2H, CH ), 7.20–8.00 (m, 10H) and 8.49 (s, 1H, NH); C NMR
3
2
75 MHz, CDCl ) δ 14.2, 14.4, 61.5, 120.6, 122.3, 122.5, 126.8, 127.0, 128.1, 134.7, 135.1,
3
+
1
40.8, 150.5, 151.2, 163.5, 164.2. MS (EI, 70 eV) m/z (%): 409 (M , 21.3), 77 (100). Anal.
Calcd. for C H N O S (409.5): C, 58.67; H, 4.68; N, 17.10; S, 7.83. Found: C, 58.55; H,
2
0
19
5
3
4
.78; N, 17.04; S, 7.88.
Ethyl 2-((5-benzoyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)propano-
−
1
ate (13a): Yellow crystals (EtOH), mp 162–164°C; IR (KBr) ν 1712, 1697 (2C = O) cm ;
1
H NMR (300 MHz, CDCl ) δ 1.39 (t, J = 7 Hz, 3H, CH ), 2.28 (s, 3H, CH ), 4.32 (q,
3
3
3
1
3
J = 7 Hz, 2H, CH ) and 7.27–8.35 (m, 10H); C NMR (75 MHz, CDCl ) δ 14.1, 14.7,
2
3
6
1
1.5, 122.4, 127.4, 128.5, 128.9, 130.5, 133.9, 134.3, 138.9, 152.8, 153.8, 164.9, 168.6,
82.3. MS (EI, 70 eV) m/z (%): 394 (M , 11.7), 105 (100). Anal. Calcd. for C H N O S
+
2
0
18
4
3
(
394.4): C, 60.90; H, 4.60; N, 14.20; S, 8.13. Found: C, 60.99; H, 4.58; N, 14.28;
S, 8.05.
Ethyl 2-((5-(2-naphthoyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)-pro-
panoate (13b): Yellow crystals (CH CN), mp 150–152°C; IR (KBr) ν 1720, 1709 (2C = O)
3
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.40 (t, J = 7 Hz, 3H, CH ), 2.30 (s, 3H, CH ), 4.33
3
3
3
1
3
(
6
1
q, J = 7 Hz, 2H, CH ) and 7.27–9.02 (m, 12H); C NMR (75 MHz, CDCl ) δ 14.0, 14.4,
2
3
1.3, 120.2, 121.3, 122.9, 125.3, 126.7, 127.2, 127.5, 128.0, 128.9, 130.2, 131.2, 131.3, 133.5,
36.7, 140.5, 155.6, 157.2, 168.2, 183.9. Anal. Calcd. for C H N O S (444.5): C, 64.85;
2
4
20
4
3
H, 4.54; N, 12.60; S, 7.21. Found: C, 64.93; H, 4.60; N, 12.78; S, 7.15.
Ethyl 2-((5-acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono)propanoate
−
1
(
13c): Yellow crystals (EtOH), mp 139–140°C; IR (KBr) ν 1712, 1690 (2C = O) cm ;
1
H NMR (300 MHz, CDCl ) δ 1.37 (t, J = 7 Hz, 3H, CH ), 2.26 (s, 3H, CH ), 2.65 (s, 3H,
3
3
3
1
3
CH CO), 4.30 (q, J = 7 Hz, 2H, CH ) and 7.27–8.03 (m, 5H); C NMR (75 MHz, CDCl )
3
2
3
δ 14.1, 14.7, 25.1, 61.5, 122.4, 127.4, 128.9, 138.8, 152.0, 153.7, 164.9, 169.2, 189.4. MS (EI,
+
7
0 eV) m/z (%): 332 (M , 78.8), 259 (100). Anal. Calcd. for C H N O S (332.4): C, 54.20;
1
5
16
4
3
H, 4.85; N, 16.86; S, 9.65. Found: C, 54.08; H, 4.78; N, 16.91; S, 9.70.
Ethyl 2-((3-phenyl-5-(thien-2-oyl)-1,3,4-thiadiazol-2(3H)-ylidene-hydrazono)-pro-
panoate (13d): Yellow crystals (CH CN), mp 149–150°C; IR (KBr) ν 1710, 1699 (2C = O)
3

10
F. M. SALEH ET AL.
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.40 (t, J = 7 Hz, 3H, CH ), 2.28 (s, 3H, CH ), 4.37
3
3
3
1
3
(
q, J = 7 Hz, 2H, CH ) and 7.22–8.41 (m, 8H); C NMR (75 MHz, CDCl ) δ 14.1, 14.7,
2
3
6
1.5, 122.3, 127.3, 128.4, 128.9, 136.1, 136.4, 138.5, 139.0, 152.2, 153.8, 164.9, 168.5, 173.9.
Anal. Calcd. for C H N O S (400.5): C, 53.99; H, 4.03; N, 13.99; S, 16.01. Found: C,
1
8
16
4
3 2
5
3.87; H, 4.11; N, 13.87; S, 16.14.
Ethyl 2-((5-(furan-2-oyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono) pro-
panoate (13e): Yellow crystals (CH CN), mp 190–192°C; IR (KBr) ν 1715, 1691 (2C = O)
3
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.38 (t, J = 7 Hz, 3H, CH ), 2.27 (s, 3H, CH ),
3
3
3
1
3
4
1
1
.31 (q, J = 7 Hz, 2H, CH ) and 6.65–8.05 (m, 8H); C NMR (75 MHz, CDCl ) δ 14.0,
2
3
4.6, 61.5, 121.0, 127.1, 128.8, 128.9, 135.9, 136.3, 138.1, 139.0, 152.0, 153.9, 164.4, 168.2,
+
73.9. MS (EI, 70 eV) m/z (%): 384 (M , 55.4), 95 (100). Anal. Calcd. for C H N O S
1
8
16
4
4
(
384.4): C, 56.24; H, 4.20; N, 14.58; S, 8.34. Found: C, 56.18; H, 4.09; N, 14.64;
S, 8.43.
Ethyl 5-((1-ethoxy-1-oxopropan-2-ylidene)hydrazono)-4-phenyl-4,5-dihydro-1,3,4-
thiadiazole-2-carboxylate (13f): Yellow crystals (EtOH), mp 109–110°C; IR (KBr) ν 1702,
−
1 1
1
(
5
1
692 (2C = O) cm ; H NMR (300 MHz, CDCl ) δ 1.37 (t, J = 7 Hz, 6H, 2CH ), 2.25
3
3
s, 3H, CH ), 4.30 (q, J = 7 Hz, 2H, CH ), 4.43 (q, J = 7 Hz, 2H, CH ) and 7.27–8.02 (m,
3
2
2
1
3
H); C NMR (75 MHz, CDCl ) δ 14.1, 14.6, 53.5, 61.5, 63.0, 122.5, 127.4, 128.8, 138.8,
3
+
44.1, 153.4, 158.2, 164.8, 168.9. MS (EI, 70 eV) m/z (%): 362 (M , 100). Anal. Calcd. for
C H N O S (362.4): C, 53.03; H, 5.01; N, 15.46; S, 8.85. Found: C, 53.11; H, 4.85; N,
1
6
18
4
4
1
5.33; S, 8.88.
Synthesis of ethyl 2-(2-(4-(aryl)thiazol-2-yl)hydrazono)propanoate (17)
To a solution ethyl 2-(2-carbamothioyl-hydrazono)propanoate 3 (0.95 gm, 5 mmol) in
ethanol (50 mL), the appropriate phenacyl bromides 16a–g (5.0 mmol) was added and
reaction mixture was refluxed for 6 h. The resulting solid product that precipitated was
collected and crystallized from a suitable solvent to afford the corresponding thiazole
derivatives 17a–g.
Ethyl 2-(2-(4-phenylthiazol-2-yl)hydrazono)propanoate (17a): Yellow crystals (CH
3
−
1 1
CN), mp 131–133°C; IR (KBr) ν 1700 (C = O) cm ; H NMR (300 MHz, CDCl ) δ 1.34
3
(
t, J = 7 Hz, 3H, CH ), 2.18 (s, 3H, CH ), 4.22 (q, J = 7 Hz, 2H, CH ), 7.04–7.38 (m, 6H)
3
3
2
1
3
and 9.22 (s, 1H, NH); C NMR (75 MHz, CDCl ) δ 11.5, 14.1, 61.5, 118.2, 120.1, 122.3,
29.3, 131.2, 147.7, 150.1, 151.3, 165.7; MS (EI, 70 eV) m/z (%): 289 (M , 26), 216 (100).
3
+
1
Anal. Calcd. for C H N O S (289.4): C, 58.11; H, 5.23; N, 14.52; S, 11.08. Found: C,
1
4
15
3
2
5
8.02; H, 5.31; N, 14.59; S, 10.97.
Ethyl 2-(2-(4-(p-tolyl)thiazol-2-yl)hydrazono)propanoate (17b): Yellow crystals
−
1 1
(
EtOH), mp 149–150°C; IR (KBr) ν 1706 (C = O) cm ; H NMR (300 MHz, CDCl ) δ
3
1
2
8
1
.37 (t, J = 7 Hz, 3H, CH ), 1.96 (s, 3H, CH ), 2.36 (s, 3H, 4-CH C H ), 4.30 (q, J = 7 Hz,
3
3
3
6
4
H, CH ), 6.91 (s, 1H, CH), 7.18 (d, J = 8.5 Hz, 2H, Ar), 7.64 (d, J = 8.5 Hz, 2H, Ar) and
2
1
3
.89 (s, 1H, NH); C NMR (75 MHz, CDCl ) δ 11.7, 14.1, 21.1, 61.5, 104.2, 125.7, 129.4,
3
+
31.4, 137.9, 138.3, 151.2, 164.2, 168.6. MS (EI, 70 eV) m/z (%): 303 (M , 38), 230 (100).
Anal. Calcd. for C H N O S (303.4): C, 59.39; H, 5.65; N, 13.85; S, 10.57. Found: C,
1
5
17
3
2
5
9.22; H, 5.73; N, 13.79; S, 10.63.
Ethyl 2-(2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazono)propanoate (17c): Yellow
−
1 1
crystals (MeOH), mp 107–108°C; IR (KBr) ν 1697 (C = O) cm ; H NMR (300 MHz,

JOURNAL OF SULFUR CHEMISTRY
11
CDCl ) δ 1.34 (t, J = 7 Hz, 3H, CH ), 2.03 (s, 3H, CH ), 3.80 (s, 3H, 4-CH OC H ), 4.27
3
3
3
3
6
4
(
q, J = 7 Hz, 2H, CH ), 6.80 (s, 1H, CH), 6.90 (d, J = 8.5 Hz, 2H, Ar), 7.66 (d, J = 8.5 Hz,
2
1
3
2
1
4
H, Ar) and 8.97 (s, 1H, NH); C NMR (75 MHz, CDCl ) δ 12.0, 14.0, 55.2, 61.6, 102.8,
3
+
14.1, 126.1, 127.1, 139.4, 149.7, 159.6, 163.9, 168.7. MS (EI, 70 eV) m/z (%): 319 (M ,
5), 246 (100). Anal. Calcd. for C H N O S (319.4): C, 56.41; H, 5.37; N, 13.16; S, 10.04.
1
5
17
3
3
Found: C, 56.29; H, 5.41; N, 13.20; S, 9.97.
Ethyl 2-(2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazono)propanoate (17d): Yellow crys-
−
1 1
tals (CH CN), mp 198–200°C; IR (KBr) ν 1690 (C = O) cm ; H NMR (300 MHz,
3
CDCl ) δ 1.31 (t, J = 7 Hz, 3H, CH ), 2.14 (s, 3H, CH ), 4.24 (q, J = 7 Hz, 2H, CH )
3
3
3
2
7
.02 (s, 1H, CH), 7.45 (d, J = 9 Hz, 2H, Ar), 7.87 (d, J = 9 Hz, 2H, Ar) and 9.28 (s, 1H,
1
3
NH); C NMR (75 MHz, CDCl ) δ 11.7, 14.0, 61.6, 119.8, 123.7, 127.8, 130.9, 133.1, 138.5,
3
+
1
50.6, 164.2, 168.4. MS (EI, 70 eV) m/z (%): 334 (M , 17), 261 (100). Anal. Calcd. for
C H N O S (334.3): C, 50.29; H, 4.22; N, 16.76; S, 9.59. Found: C, 50.17; H, 4.30; N,
1
4
14
4
4
1
6.68; S, 9.66.
Ethyl 2-(2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)propanoate (17e): Yellow crys-
−
1 1
tals (EtOH), mp 167–168°C; IR (KBr) ν 1701 (C = O) cm ; H NMR (300 MHz, CDCl )
3
δ 1.33 (t, J = 7 Hz, 3H, CH ), 1.91 (s, 3H, CH ), 4.27 (q, J = 7 Hz, 2H, CH ), 6.94 (s, 1H,
3
3
2
1
3
CH), 7.31 (d, J = 8 Hz, 2H, Ar), 7.65 (d, J = 8 Hz, 2H, Ar) and 9.20 (s, 1H, NH); C NMR
(
75 MHz, CDCl ) δ 11.6, 14.1, 61.6, 105.5, 127.0, 128.8, 132.7, 133.7, 138.3, 150.0, 164.1,
3
+
1
68.5. MS (EI, 70 eV) m/z (%):326 (M + 2, 2), 325 (M + 1, 10) 324 (M , 6), 250 (100). Anal.
Calcd. for C H ClN O S (323.8): C, 51.93; H, 4.36; Cl, 10.95; N, 12.98; S, 9.90. Found:
1
4
14
3
2
C, 51.80; H, 4.41; Cl, 10.88; N, 12.91; S, 9.98.
Ethyl 2-(2-(4-(4-bromophenyl)thiazol-2-yl)hydrazono)propanoate (17f): Yellow crys-
−
1 1
tals (CH CN), mp 169–170°C; IR (KBr) ν 1689 (C = O) cm ; H NMR (300 MHz,
3
CDCl ) δ 1.31 (t, J = 7 Hz, 3H, CH ), 2.14 (s, 3H, CH ), 4.22 (q, J = 7 Hz, 2H, CH ),
3
3
3
2
6
.91 (s, 1H, CH), 7.27 (d, J = 8.5 Hz, 2H, Ar), 7.55 (d, J = 8.5 Hz, 2H, Ar) and 9.18 (s, 1H,
1
3
NH); C NMR (75 MHz, CDCl ) δ 11.5, 14.2, 61.3, 115.2, 126.1, 127.9, 133.1, 134.7, 138.5,
3
+
1
50.1, 164.2, 168.6. MS (EI, 70 eV) m/z (%): 370 (M + 2, 4), 369 (M + 1, 22), 368 (M , 5),
2
96 (100). Anal. Calcd. for C H BrN O S (368.2): C, 45.66; H, 3.83; Br, 21.70; N, 11.41;
1
4
14
3
2
S, 8.71. Found: C, 45.57; H, 3.90; Br, 21.79; N, 11.33; S, 8.65.
Ethyl 2-(2-(4-(4-cyanophenyl)thiazol-2-yl)hydrazono)propanoate (17 g): Yellow crys-
−
1 1
tals (CH CN), mp 171–172°C; IR (KBr) ν 2218 (CN), 1700 (C = O) cm ; H NMR
3
(
300 MHz, CDCl ) δ 1.35 (t, J = 7 Hz, 3H, CH ), 2.10 (s, 3H, CH ), 4.29 (q, J = 7 Hz, 2H,
3
3
3
CH ), 7.12 (s, 1H, CH), 7.64 (d, J = 8.5 Hz, 2H, Ar) 7.85 (d, J = 8.5 Hz, 2H, Ar) and 9.16
2
1
3
(
1
s, 1H, NH); C NMR (75 MHz, CDCl ) δ 11.5, 14.1, 61.8, 108.3, 111.1, 118.8, 126.2, 132.5,
3
+
32.5, 138.3, 138.4, 149.5, 163.9, 168.0. MS (EI, 70 eV) m/z (%): 314 (M , 20), 241 (100).
Anal. Calcd. for C H N O S (314.4): C, 57.31; H, 4.49; N, 17.82; S, 10.20. Found: C,
1
5
14
4
2
5
7.19; H, 4.57; N, 17.90; S, 10.07.
Synthesis of ethyl 4-(aryl)-5-(2-phenylhydrazono)thiazol-2(5H)-ylidene)hydra-
zono)-propanoate 15a–g
Method A: To the appropriate solution of thiazoles 17a–g (5.0 mmol) in ethanol (100 mL),
sodium acetate (0.41 g, 5.0 mmol) was added. To the resulting cold mixture, the prepared
as usual by diazotizing aniline (0.5 mL, 5.0 mmol) in hydrochloric acid (6, 3 mL) with
sodium nitrite (0.35 g, 5.0 mmol) in water (5 mL), was added portion wise over 30 min.

12
F. M. SALEH ET AL.
The reaction mixture was stirred for further 1 h while cooling in an ice-bath. The solid
that precipitated was filtered, washed with water, dried and finally crystallized from suitable
solvent to give 15a–g.
Ethyl 2-(2-(4-phenyl-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)propanoate (15a):
−
1
Red crystals (CH CN), mp 178–180°C; IR (KBr) ν 3429 (NH), 1697 (C = O) cm ;
3
1
H NMR (300 MHz, CDCl ) δ 1.31 (t, J = 7 Hz, 3H, CH ), 2.14 (s, 3H, CH ), 4.27 (q,
3
3
3
1
3
J = 7 Hz, 2H, CH ), 7.22–8.98 (m, 10H) and 11.38 (s, 1H, NH); C NMR (75 MHz,
2
CDCl ) δ 14.1, 14.5, 55.0, 109.3, 118.2, 125.8, 128.2, 128.5, 129.6, 130.1, 132.5, 140.8, 148.3,
3
+
1
50.8, 163.8, 164.9. MS (EI, 70 eV) m/z (%): 393 (M , 65), 77 (100). Anal. Calcd. for
C H N O S (393.5): C, 61.05; H, 4.87; N, 17.80; S, 8.15. Found: C, 60.89; H, 4.77; N,
2
0
19
5
2
1
7.91; S, 8.07.
Ethyl 2-(2-(5-(phenyldiazenyl)-4-(p-tolyl)thiazol-2-yl)hydrazono)propanoate (15b):
−
1 1
Red crystals (EtOH), mp 129–130°C; IR (KBr) ν 3423 (NH), 1700 (C = O) cm ; H
NMR (300 MHz, CDCl ) δ 1.36 (t, J = 7 Hz, 3H, CH ), 2.21 (s, 3H, CH ), 2.42 (s, 3H,
3
3
3
1
3
4
-CH C H ), 3.90 (s, 1H, NH), 4.34 (q, J = 7 Hz, 2H, CH ) and 7.07–8.37 (m, 9H); C
3
6
4
2
NMR (75 MHz, CDCl ) δ 13.9, 14.1, 19.7, 21.4, 21.5, 61.8, 61.9, 122.6, 128.9, 129.0. 129.2,
3
+
1
29.6, 130.1, 131.2, 139.5, 162.7, 168.2. MS (EI, 70 eV) m/z (%): 407 (M , 96), 77 (100).
Anal. Calcd. for C H N O S (407.5): C, 61.90; H, 5.19; N, 17.19; S, 7.87. Found: C, 61.79;
2
1
21
5
2
H, 5.04; N, 17.24; S, 7.80.
Ethyl 2-(2-(4-(4-methoxyphenyl)-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)propa-
noate (15c): Red crystals (EtOH), mp 77–78°C; IR (KBr) ν 3427 (NH), 1695 (C = O)
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.30 (t, J = 7 Hz, 3H, CH ), 2.14 (s, 3H, CH ), 3.22
3
3
3
(
s, 3H, 4-CH OC H ), 4.28 (q, J = 7 Hz, 2H, CH ), 7.19–8.66 (m, 9H) and 11.77 (s, 1H,
3
6
4
2
1
3
NH); C NMR (75 MHz, CDCl ) δ 14.1, 14.3, 55.1, 55.9, 109.8, 117.6, 125.3, 128.8, 129.0,
3
+
1
1
5
29.7, 130.9, 132.4, 141.3, 148.8, 150.1, 163.0, 164.5. MS (EI, 70 eV) m/z (%): 423 (M ,
00). Anal. Calcd. for C H N O S (423.5): C, 59.56; H, 5.00; N, 16.54; S, 7.57. Found: C,
2
1
21
5
3
9.44; H, 5.12; N, 16.48; S, 7.49.
Ethyl 2-(2-(4-(4-nitrophenyl)-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)propanoate
15d): Red crystals (CH CN), mp 236–238°C; IR (KBr) ν 3422 (NH), 1690 (C = O)
(
3
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.31 (t, J = 7 Hz, 3H, CH ), 2.14 (s, 3H, CH ), 4.30
3
3
3
1
3
(
q, J = 7 Hz, 2H, CH ), 7.09–8.56 (m, 9H) and 11.78 (s, 1H, NH); C NMR (75 MHz,
2
CDCl ) δ 13.9, 14.1, 55.7, 122.4, 124.6, 127.8, 127.9, 128.0, 128.5, 134.2, 138.9, 143.5, 145.9,
3
+
1
50.1, 163.4, 166.8. MS (EI, 70 eV) m/z (%): 438 (M , 48), 77 (100). Anal. Calcd. for
C H N O S (438.5): C, 54.79; H, 4.14; N, 19.17; S, 7.31. Found: C, 54.66; H, 4.02; N,
2
0
18
6
4
1
9.25; S, 7.40.
Ethyl 2-(2-(4-(4-chlorophenyl)-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)propano-
ate (15e): Red crystals (EtOH), mp 123–124°C; IR (KBr) ν 3429 (NH), 1699 (C = O)
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.30 (t, J = 7 Hz, 3H, CH ), 2.15 (s, 3H, CH ), 4.29
3
3
3
1
3
(
q, J = 7 Hz, 2H, CH ), 7.23–8.57 (m, 9H) and 11.67 (s, 1H, NH); C NMR (75 MHz,
2
CDCl ) δ 14.0, 14.1, 55.8, 124.7, 125.0, 125.2, 127.8, 128.0, 128.6, 130.2, 132.5, 135.1, 143.4,
3
+
1
50.2, 163.2, 166.3. MS (EI, 70 eV) m/z (%): 430 (M + 2, 4), 429 (M + 1), 428 (M , 18), 77
(
100). Anal. Calcd. for C H ClN O S (427.9): C, 56.14; H, 4.24; Cl, 8.28; N, 16.37; S,
20 18 5 2
7
.49. Found: C, 56.02; H, 4.17; Cl, 8.17; N, 16.45; S, 7.38.
Ethyl 2-(2-(4-(4-bromophenyl)-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)propano-
ate (15f): Red crystals (EtOH), mp 129–130°C; IR (KBr) ν 3424 (NH), 1690 (C = O)
−
1 1
cm ; H NMR (300 MHz, CDCl ) δ 1.32 (t, J = 7 Hz, 3H, CH ), 2.17 (s, 3H, CH ), 4.20
3
3
3

JOURNAL OF SULFUR CHEMISTRY
13
1
3
(
q, J = 7 Hz, 2H, CH ), 7.39–8.49 (m, 9H) and 11.70 (s, 1H, NH); C NMR (75 MHz,
2
CDCl ) δ 14.0, 14.2, 55.7, 123.1, 124.7, 125.1, 126.9, 127.4, 128.1, 130.5, 132.8, 135.7, 142.9,
3
+
1
7
50.5, 163.1, 166.7. MS (EI, 70 eV) m/z (%): 474 (M + 2, 7), 473 (M + 1, 28), 472 (M , 23),
7 (100). Anal. Calcd. for C H BrN O S (472.4): C, 50.86; H, 3.84; Br, 16.92; N, 14.83;
2
0
18
5
2
S, 6.79. Found: C, 50.77; H, 3.78; Br, 16.85; N, 14.79; S, 6.68.
Ethyl 2-(2-(4-(4-cyanophenyl)-5-(phenyldiazenyl)thiazol-2-yl)hydrazono)propano-
ate (15 g): Red crystals (CH CN), mp 198–200°C; IR (KBr) ν 3423 (NH), 2215 (CN), 1697
3
−
1 1
(
C = O) cm ; H NMR (300 MHz, CDCl ) δ 1.25 (t, J = 7 Hz, 3H, CH ), 2.12 (s, 3H,
3
3
13
CH ), 4.18 (q, J = 7 Hz, 2H, CH ), 7.52–8.40 (m, 9H) and 11.76 (s, 1H, NH); C NMR
3
2
(
1
75 MHz, CDCl ) δ 13.9, 14.0, 55.6, 112.2, 118.3, 120.7, 124.1, 126.4, 127.4, 128.7, 130.1,
3
+
32.3, 135.8, 142.3, 150.4, 163.5, 166.5. MS (EI, 70 eV) m/z (%): 418 (M , 76), 77 (100).
Anal. Calcd. for C H N O S (418.5): C, 60.27; H, 4.34; N, 20.08; S, 7.66. Found: C, 60.12;
2
1
18
6
2
H, 4.25; N, 20.17; S, 7.58.
Alternative method for synthesis of Ethyl 2-(2-(4-phenyl-5-(phenyldiazenyl)
thiazol-2-yl)hydrazono)propanoate (15a)
A mixture of 2-oxo-N,2-diphenylacetohydrazonoyl bromide 12a (0.3 g, 1 mmol), com-
pound 3 (0.13 g, 1 mmol) and triethylamine in ethanol (20 mL) was refluxed for 3 h. The
solid was collected and crystallized from ethanol afforded identical product mp, mixed mp
and spectra with compound 15a.
Synthesis of ethyl 2-((4-oxo-5-(2-phenylhydrazono)thiazolidin-2- ylidene)
hydrazono)-propanoate (18)
To a solution ethyl 2-(2-carbamothioylhydrazono)propanoate 3 (0.95 gm, 5 mmol) and
N-phenyl-C-ethoxycarbonylmethanohydrazonoyl chloride 12f (1.13 gm, 5 mmol) was
dissolved in ethanol (50 mL), triethylamine (2 mL) was added and reaction mixture
was refluxed for 6 h. The resulting solid product that precipitated was collected and
crystallized from ethanol to afford ethyl 2-((4-oxo-5-(2-phenylhydrazono)thiazolidin-2-
ylidene)hydrazono)propanoate (14): Yellow crystals, mp 176–178°C; IR (KBr) ν 3422
−
1 1
(
NH), 1697, 1686 (2C = O) cm ; H NMR (300 MHz, CDCl ) δ 1.29 (t, J = 7 Hz, 3H,
3
CH ), 2.17 (s, 3H, CH ), 4.20 (q, J = 7 Hz, 2H, CH ), 7.01–7.37 (m, 5H), 11.55 (s, 1H,
3
3
2
1
3
NH) and 11.70 (s, 1H, NH); C NMR (75 MHz, CDCl ) δ 14.1, 14.2, 56.4, 112.9, 121.2,
3
+
1
28.5, 136.9, 142.3, 146.8, 156.3, 163.5, 166.0. MS (EI, 70 eV) m/z (%): 333 (M , 10), 307
(
100). Anal. Calcd. for C H N O S (333.4): C, 50.44; H, 4.54; N, 21.01; S, 9.62. Found:
14 15 5 3
C, 50.32; H, 4.67; N, 20.93; S, 9.49.
Antimicrobial assay
Antimicrobial activity of the tested compounds was determined using a modified Kirby-
Bauer disc diffusion method [38]. Briefly, 100 μl of the test bacteria/fungi were grown in
8
1
0 ml of fresh media until they reached a count of approximately 10 cells/ml for bacteria
5
or 10 cells/ml for fungi [39]. 100 μl of microbial suspension was spread onto agar plates
corresponding to the broth in which they were maintained.

14
F. M. SALEH ET AL.
Of the many media available, NCCLS recommends Mueller-Hinton agar due to: it
results in good batch-to-batch reproducibility. Disc diffusion method for filamentous fungi
tested by using approved standard method (M38-A) developed by the (NCCLS, 2002) [40]
for evaluating the susceptibilities of filamentous fungi to antifungal agents. Disc diffusion
method for yeasts developed by using approved standard method (M44-P) by the (NCCLS,
2
003) [41].
Minimum inhibitory concentration study
The MIC values were measured by the broth dilution method [37,42]. Five hundred micro
liters of a stock solution (10.24 mg/mL) of each tested compound in dimethyl sulfox-
ide (DMSO) were prepared and then diluted with Mueller-Hinton broth to 1024 μg/mL.
The strains were grown briefly at 37°C in Mueller-Hinton media. After 5 h of bacterial
5
growth, the bacterial culture was diluted to obtain a concentration of 5 × 10 cells/mL.
Then, 150 μL bacterial suspensions were added to each well of the flat-bottomed 96-well
tissue culture plate. Two-fold serial dilutions were carried out from the fist well to the tenth
well; the final concentrations of the compounds ranged from 1 to 512 μg/mL; and excess
media (150 μL) were discarded from the last well. The plates were incubated at 37°C for 24 h
in an electro-heating standing temperature cultivator and were read visually. The MIC of
the sample showing no turbidity was recorded as the lowest concentration of compound
that inhibited bacterial growth completely. Each assay was run in triplicate.
Conclusion
In summary, ethyl pyruvate proved to be useful precursor for convenient synthesis
of new thiadiazoles and thiazoles having many functional groups that have not been
reported hitherto. As antimicrobial results showed that ethyl 2-(2-(4-phenylthiazol-2-
yl)hydrazono)propanoate (17a) achieved the lowest MIC value (high efficient derivative)
against the sensitive bacterial strain S. aureus with MIC value 160 μg/ml.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Fatma M. Saleh http://orcid.org/0000-0003-0451-4802
Abdou O. Abdelhamid http://orcid.org/0000-0002-5380-7727
Hamdi M. Hassaneen http://orcid.org/0000-0003-0963-4192
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