Synthesis and evaluation of biological activities of 4-cyclopropyl-5-(2-fluorophenyl) arylhydrazono-2,3-dihydrothiazoles as potent antioxidant agents

Article abstract of DOI:10.1080/17415993.2015.1122009

A new series of 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-dihydrothiazole derivatives was synthesized via the reaction of prepared thiosemicarbazones with 2-bromo-1-cyclopropyl-2-(2-uorophenyl)ethanone in the presence of Et3 N as a catalyst throug

Full text of DOI:10.1080/17415993.2015.1122009

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Synthesis and evaluation of biological
activities of 4-cyclopropyl-5-(2-fluorophenyl)
arylhydrazono-2,3-dihydrothiazoles as potent
antioxidant agents
F. Ghanbari Pirbasti, Nosrat O. Mahmoodi & Jafar Abbasi Shiran
To cite this article: F. Ghanbari Pirbasti, Nosrat O. Mahmoodi & Jafar Abbasi Shiran
(2016): Synthesis and evaluation of biological activities of 4-cyclopropyl-5-(2-fluorophenyl)
arylhydrazono-2,3-dihydrothiazoles as potent antioxidant agents, Journal of Sulfur Chemistry
To link to this article: http://dx.doi.org/10.1080/17415993.2015.1122009
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Date: 16 February 2016, At: 11:51

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2015.1122009
Synthesis and evaluation of biological activities of
4-cyclopropyl-5-(2-fluorophenyl)
arylhydrazono-2,3-dihydrothiazoles as potent antioxidant
agents
F. Ghanbari Pirbasti, Nosrat O. Mahmoodi and Jafar Abbasi Shiran
Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
ABSTRACT
ARTICLE HISTORY
Received 21 August 2015
Accepted 13 November 2015
A new series of 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-
dihydrothiazole derivatives was synthesized via the reaction of
prepared thiosemicarbazones with 2-bromo-1-cyclopropyl-2-(2-
fluorophenyl)ethanone in the presence of Et3N as a catalyst through
a semi Hantzsch cyclization. The optimized reaction conditions for
this one-pot reaction were achieved. The products were obtained
in short reaction times, high yields and high purities. Antioxidant
activityofproductswasevaluatedusingDPPH(2,2-diphenyl-2-picryl-
hydrazyl) and ABTS 2,2-azinobis(3-ethylbenzothiazoline-sulfonate)
assays. Products showed higher antioxidant activity using the ABTS
method. Compounds 5c and 5g showed lower IC50 values compared
with ascorbic acid as a standard. Compounds 5a–5h possessed mod-
erate to high antioxidant activity by both methods. Also, antibac-
terial activity of 5a–5h was evaluated against gram-positive and
gram-negative bacterial strains. None of the compounds inhibited A.
hydrophila, whiletheyhadmoderatetolowinhibitoryactivityagainst
other tested bacterial strains.
KEYWORDS
Hydrazinyl thiazole;
2-bromo-1-cyclopropyl-2-(2-
fluorophenyl)ethanone;
antioxidant; DPPH; ABTS;
antibacterial
CONTACT Nosrat O. Mahmoodi
mahmoodi@guilan.ac.ir
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2015.1122009
© 2016 Taylor & Francis

2
F. G. PIRBASTI ET AL.
Introduction
Sulfur-containing heterocyles have been under investigation for a long time because of
their interesting and diverse biological properties. Also, sulfur is an important element that
is incorporated into proteins and some biomolecules.[1] Thiazoles as sulfur-containing
compounds possessed various applications in medicine. Thiazole moiety is found in
thiamine (vitamin B1). Also, some important drugs such as penicillin, sulfathiazole,
ritonavir, abafungin, bleomycine, and tiazofurin have thiazole moiety as their inte-
gral part. Thiazoles have attracted considerable attention due to their wide biologi-
cal activities such as antitrypanosomal,[2] anti-inflammatory,[3,4] antihypertensive,[5]
anti-allergic,[6] antibacterial,[7] anti-schizophrenia,[8] anti-HIV,[9] analgesic,[10] and
anti-viral.[11] Moreover, hydrazinyl thiazole derivatives exhibited interesting biological
activities including antioxidant,[12,13] antibacterial,[14] anti-malarial,[15] antitumor,[16]
and antifungal.[17] Also, hydrazinyl thiazole derivative of isatin has been used as a naked
eye chemosensor for fluoride anion detection.[18] Recently, various biological activities,
e.g. antibacterial, antifungal, antioxidant, cytotoxicity and DNA cleavage of complexes
derived from thiazoles have been studied.[19,20]
Compounds bearing fluorine atom have shown interesting biological activities.[21,22]
According to the literature, the presence of fluorine atom can increase the poten-
tial of biological activities, e.g. fluorinated Schiff bases derived from 1,2,4-triazoles
showed potent antiproliferative activity,[23] and fluorine atom enhanced insecticidal activ-
ity of 2-(3-(2,6-dichloro-4-(3,3-dichloroallyloxy)phenoxy)propoxy)-5-(trifluoromethyl)
benzo[d]oxazole.[24]
Sunlight, ultraviolet light, ionizing radiation, chemical reactions, and metabolic pro-
cesses can produce free radical species. Free radical species can react and oxidize DNA,
lipids, and proteins, and nucleic acids in living systems and result in degenerative disease
and health problems. Antioxidants are a class of compounds which trap free radicals, so
can reduce the risk for chronic diseases such as cancer and heart disease.[25]
As a part of our current studies in synthesis of thiazolyl-pyrazoline derivatives,[26]
bis-thiazoles,[27] thiazolyl-pyridazinones,[28] and 1,4-dihydropyridines bearing thiazole
moiety and possessing high antioxidant activity [29] here, we reported synthesis of new
hydrazinyl thiazoles and evaluation of their antioxidant and antibacterial activities.
Results and discussion
Chemistry
α-Halocarbonyl compounds are convenient and widely used building blocks for vari-
ous types of heterocyclization and for the Hantzsch’s thiazole synthesis.[30] 2-Bromo-1-
cyclopropyl-2-(2-fluorophenyl)ethanone (α-halocarbonyl compound) is a key moiety in
prasugrel as a platelet inhibitor drug, which is more efficient than ticlopidine and clopi-
dogrel [31] (Figure 1). Recently, it has been used in the synthesis of thiazol-2-imine
derivatives [32] so this prompted us to investigate synthesis of new thiazoles using 2-
bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone. Even though, the carbonyl group 4 is
condensed to a carbon of thiazole ring, but the cyclopropyl and 2-fluorophenyl moieties
still presented in the skeleton of target products 5 (Scheme 1).

JOURNAL OF SULFUR CHEMISTRY
3
Figure 1. Structure of prasugrel.
Scheme 1. Synthesis of 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-dihydrothiazole deriva-
tives 5a–5g.
In this study, new 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-dihydrothiazole
derivatives 5a–5h were synthesized through the reaction of carbonyl compounds
1a–1h, thiosemicarbazide 2, and 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone 4.
Thiosemicarbazone derivatives 3a–3h were prepared through the condensation of car-
bonyl compounds 1a–1h and thiosemicarbazide 2 in the presence of a few drops of AcOH
in EtOH. Then, cyclization of thiosemicarbazones 3a–3h with 2-bromo-1-cyclopropyl-2-
(2-fluorophenyl)ethanone 4 under optimized reaction conditions led to the corresponding
products 5a–5h (Scheme 1).
With the aim to obtain the optimal reaction conditions, preparation of 5a was selected
as a model reaction. Results are summarized in Table 1. The effects of different basic cata-
lysts, amounts of catalyst, and solvents were studied. According to the results, the reaction
proceeded slowly in low yield in the absence of catalyst (entry 1), while product 5a was
obtained in a higher yield and shorter reaction time in the presence of Et3N (entry 2).
Increasing the amount of catalyst showed no substantial improvement in the yield (entry
5), while the yield was decreased by reducing the amount of catalyst to 10% (entry 4).
Moreover, the effects of other polar solvents such as DMF, methanol (MeOH) and CH3CN
on the yield and time of the reaction were studied (entry 6–11). Thus, compound 5a was
obtained from the reaction of thiosemicarbazone 3a and 4 in the presence of Et3N (20
mol%) in high yield (95%) and short reaction time (30 min) in EtOH as the solvent under

4
F. G. PIRBASTI ET AL.
Table 1. Optimization of reaction condition for synthesis of 5a.
Entry
catalyst
Solvent
Condition
Time (min)
Yield%
1
2
3
4
5
6
7
8
–
EtOH
EtOH
EtOH
EtOH
EtOH
DMF
MeOH
CH3CN
EtOH
EtOH
EtOH
r.t.
r.t.
240
120
30
45
30
30
40
50
40
45
90
53
85
95
88
94
91
82
85
80
82
76
Et3N (20 mol%)
Et3N (20 mol%)
Et3N (10 mol%)
Et3N (40 mol%)
Et3N (20 mol%)
Et3N (20 mol%)
Et3N (20 mol%)
DBU (20 mol%)
piperidine (20 mol%)
NaOAc (20 mol%)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
9
10
11
reflux conditions. The formation of product 5a was indicated by a reaction color change
from yellow to dark orange within 5 min, however completion of the reaction took place
within 30 min.
The scope of this method was explored for the synthesis of new 4-cyclopropyl-5-
(2-fluorophenyl)arylhydrazono-2,3-dihydrothiazoles 5a–5h with different carbonyl com-
pounds 1a–1h under the optimized reaction conditions. The results showed that this
procedure is reliable, simple setup, reproducible, high yield, economic and products puri-
1
fied without chromatographic methods. All products were fully characterized by IR, H
NMR and 13C NMR spectra. The physicochemical properties of synthesized compounds
are presented and summarized in Table 2.
IR spectra of products 5a–5h showed characteristic absorption bands at 3320–3200,
1
1620–1600 and 1070–1050 cm−1 due to N–H, C N and C–F bonds, respectively. H
=
NMR spectra of products were in accordance with expected number, chemical shifts and
coupling constants. Aromatic protons appeared at 8.28–6.66 ppm. Also, aliphatic proton
of cyclopropyl moiety (Hc) and methylene protons appeared as multiples at 1.99–1.86
and 1.20–0.88 ppm, respectively. In addition, N–H can be endo- or exo-cyclic. However,
according to the literature [33] a signal at 14.50–11.45 ppm is related to exocyclic N–H. So,
we can propose an exo-cyclic N–H for compound 5g according to a down field signal at
12 ppm and an endo-cyclic N–H for other compounds.
13C NMR spectra of compounds 5a–5h corresponded to the expected number and types
of carbons. Aromatic and olefinic carbons appeared at 168.6–108.4 ppm and aliphatic car-
bons appeared at their expected chemical shifts at 55.9–7.8 ppm. 13C NMR spectra of
products represented C–F couplings clearly. Fluorine atom has split all carbons of the
phenyl ring. All chemical shifts and coupling constants of important carbon atoms are
summarized in Table 3.
Biology
Antioxidant activity
All products were screened for their in vitro antioxidant activity. DPPH (2,2-diphenyl-2-
picrylhydrazyl) radical and ABTS 2,2-azinobis(3-ethylbenzothiazoline-sulfonate) radical
cation are widely used, rapid, simple, and inexpensive methods to evaluate antioxidant
ability of compounds. In this research, the antioxidant activity of compounds was evaluated
using colorimetric DPPH and ABTS methods. When a compound acts as an antioxidant

JOURNAL OF SULFUR CHEMISTRY
5
Table 2. Data related to synthesized 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-dihydrothia-
zoles.
Compound
Time (min)
Yield %
5a
30
95
5b
30
94
5c
20
96
5d
35
89
m.p. (°C)
114–118
120–123
195–198
89–92
Compound
Time (min)
Yield %
5e
20
93
5f
40
90
5g
35
91
5h
30
88
m.p. (°C)
182–186
153–157
85–87
166–170
it can scavenge free radicals and lead to a decrease in absorption band at 517 and 734 nm
for DPPH and ABTS solutions, respectively. Moreover, potential antioxidant activity leads
to a rapid decrease in absorbance. ABTS is also frequently used by the food industry and
agricultural researchers to measure the antioxidant capacities of foods. ABTS is converted
to its radical cation (ABTS•+) by the addition of sodium persulfate or potassium persulfate.
ABTS•+scavenging is considered as an electron transfer reaction.[34] ABTS radical cation
is blue in color, when it reacts with an antioxidant compound the blue color changes to
yellow or colorless. Also, the DPPH radical changes from purple to colorless in reaction
with an antioxidant compound. DPPH· scavenging may be through donation of a radical
hydrogen atom (H•) to form a stable DPPH-H molecule.[35]
The antioxidant activities of compounds were screened at concentrations of
125–4000 μg/mL at 517 and 734 nm for DPPH and ABTS assays, respectively. Also, IC50

6
F. G. PIRBASTI ET AL.
Table 3. 13C NMR spectroscopy data of significant carbon atoms of 5a–5h.
Compound
5a
5b
5c
5d
5e
5f
5g
5h
C1
C2
140.8
159.9
139.1
159.9
139.9
159.9
139.9
159.9
139.4
159.9
146.3
159.9
140.0
159.9
143.3
159.9
1
1
1
1
1
1
1
1JC,F = 247 JC,F = 247 JC,F = 249 JC,F = 248 JC,F = 248 JC,F = 247 JC,F = 249 JC,F = 247
C3
120.5
120.4
116.7
118.6
116.7
120.2
116.9
119.6
2JC,F = 16 2JC,F = 16 2JC,F = 15 2JC,F = 15 2JC,F = 14 2JC,F = 15 2JC,F = 15 2JC,F = 15
C4
C5
C6
Ca,b
Cc
112.9
168.3
150.2
113.2
168.3
150.4
112.3
168.1
155.6
9.3, 9.3
8.3
112.5
168.6
157.7
10.2, 10.2
7.9
111.7
167.3
149.8
9.2, 9.2
8.3
112.9
168.1
148.9
112.0
167.9
155.2
9.3, 9.3
8.3
113.9
167.3
149.7
11.1, 11.1
11.1, 11.1
11.0, 11.0
10.8, 10.8
7.8
7.8
7.8
7.9
Cd
132.3
132.3
131.7
–
–
131.6
132.3
131.7
132.2
3JC,F = 3
124.1
3JC,F = 3
124.4
3JC,F = 1
124.8
3JC,F = 2
123.3
3JC,F = 3
124.1
3JC,F = 2
124.7
3JC,F = 2
124.2
Ce
Cf
124.4
4JC,F = 4
130.2
3JC,F = 8
116.2
4JC,F = 4
129.1
4JC,F = 4
129.1
4JC,F = 4
131.5
4JC,F = 4
131.4
4JC,F = 3
129.3
4JC,F = 3
131.3
4JC,F = 4
129.7
3JC,F = 8
3JC,F = 8
3JC,F = 8
3JC,F = 9
3JC,F = 8
3JC,F = 8
3JC,F = 8
Cg
116.0
116.0
116.5
116.5
116.0
116.4
116.1
2JC,F = 22 2JC,F = 22 2JC,F = 22 2JC,F = 21 2JC,F = 22 2JC,F = 21 2JC,F = 22 2JC,F = 22
Figure 2. DPPH radical-scavenging activity.
values (the concentration of compounds to scavenge 50% of DPPH or ABTS) were cal-
culated by plotting radical scavenging activity against concentration and obtaining a line
equation. Ascorbic acid was used as a standard. The investigation of antioxidant activ-
ity revealed that all the newly synthesized compounds showed potent to moderate radical
scavenging activity when compared with ascorbic acid as a standard. As it is depicted in
Figures 2 and 3 radical scavenging activity of products 5a–5h was dose dependent. In the
DPPH assay, compounds 5a, 5b, 5e and 5g showed higher antioxidant activity at lower con-
centration (125–500 μg/mL) in comparison with others. While, at higher concentrations
the antioxidant activity of all products was approximately equal. Moreover, compounds
5a and 5e showed a chigher antioxidant activity at low concentration (120 μg/mL) in the
ABTS assay, while higher concentrations represented potent antioxidant activity.
In addition, IC50 values of products 5a–5h were calculated (Figure 4). The IC50 values
were in the range of 1.92–0.17 and 0.96–0.08 μM for DPPH and ABTS assays, respectively.

JOURNAL OF SULFUR CHEMISTRY
7
Figure 3. ABTS radical-scavenging activity.
Figure 4. IC50 values of 5a–5h using DPPH and ABTS assays.
As it is evident, the ABTS assay showed more potent antioxidant activity. It shows that
compounds 5a–5h can donate radical electron better than the hydrogen radical. Product
5g was more active than ascorbic acid according to the DPPH assay, while compound 5c
represented better antioxidant activity when compared with ascorbic acid in the ABTS
assay. However, compounds 5a, 5c, 5e and 5g showed potent antioxidant activity. Other
compounds showed moderate activity.
Thiazole moiety has an important role in antioxidant activity.[25,12] As it is depicted
in Scheme 2 the endo- or exo- N–H readily can donate a hydrogen radical to the DPPH
radical and generate a new radical species which can resonate through the thiazole ring
=
=
and C–N–N C moieties. So, the new radical can be stable by resonance through this
=
=
structure. Although the thiazole and C–N–N C moieties have an important role in
antioxidant activity, however other parts of products can affect this activity as well. Prob-
ably, the high antioxidant activity of 5c can be due to the fused aromatic rings which can
stabilize the free radical by resonance through a longer system. Low antioxidant activity
of 5h is due to the presence of an electron-withdrawing group NO2, which resulted in
destabilization of radicals (Scheme 2).[36]

8
F. G. PIRBASTI ET AL.
Scheme 2. Proposed mechanism for antioxidant activity of compounds 5a–5h.
Antibacterial activity
The new synthesized compounds 5a–5h were screened for their in vitro antibacterial
activity against Gram-positive and Gram-negative bacterial strains including: Staphy-
lococcus aureus (S. aureus), Micrococcus luteus (M. luteus), Escherichia coli (E. coli),
Pseudomonas aeruginosa (Ps. aeruginosa), Bacillus subtilis (B. subtilis), and Aeromonas
hydrophila (A. hydrophila) using the well-diffusion method. Penicillin G and Gentam-
icin were used as positive controls. DMSO was used as a negative control and showed
no activity against mentioned bacterial strains. The antibacterial activity of products
5a–5h was screened at a concentration of 1000 μg/mL in DMSO. The experiments
were performed in triplicate. The results are presented as mean standard deviation in
millimeter.
According to Table 4 all of the compounds were inactive against A. hydrophila, while all
of the compounds showed antibacterial activity against Ps. aeruginosa. Moreover, 5a and
5f showed low antibacterial activity against S. aureus; however, most of the compounds
possessed antibacterial activity against E. coli and B. subtilis. Furthermore, 5e showed the
highest antibacterial activity against B. subtilis (14.3 0.57) among all of the compounds.
Also, 5f and 5b possessed higher antibacterial activity against M. luteus (10.6 0.57) and
E. coli (11.6 1.15), respectively. Moreover, compounds 5a and 5c showed similar activity
(10.3 0.57) against Ps. aeruginosa. In addition, the antibacterial activity of compounds
5a–5h was not comparable to standard drugs.

JOURNAL OF SULFUR CHEMISTRY
9
Table 4. Antibacterial assay of 5a–5h. Results are presented as mean SD in mm.
Compound
E. coli
A. hydrophila
Ps. aeruginosa
M. luteus
S. aureus
B. subtilis
5a
5b
5c
5d
5e
5f
5g
5h
9.3 0.57
11.6 1.15
7.6 0.57
9.3 0.57
–
–
–
–
–
–
–
–
–
10.3 0.57
8.3 0.57
10.3 0.57
9.3 0.57
9.3 0.57
9.3 0.57
–
8.6 0.57
9.3 0.57
11.3 0.57
8.6 0.57
10.3 0.57
14.3 0.57
8.6 0.57
10.3 0.57
–
8.6 0.57
8.3 0.57
7.3 0.57
7.6 0.57
10.6 0.57
8.3 0.57
7.6 0.57
54.0 1.0
46.0 1.0
–
–
–
–
9.6 0.57
–
–
9.3 0.57
8.6 0.57
45.0 1.0
32.0 1.0
9
1.0
8.6 0.57
24.0 1.0
29.6 0.57
–
Penicillin G
Gentamicin
46.6 1.52
41.3 1.57
23.0 1.0
30.0 1.0
32.0 1.0
35.3 0.57
Conclusion
In conclusion we have reported an efficient, convenient and easy setup procedure for syn-
thesis of new 4-cyclopropyl-5-(2-fluorophenyl)arylhydrazono-2,3-dihydrothiazole deriva-
tives. The optimized procedure led to high yields and high purities products in short
reaction time. The obtained data revealed that products namely 5a, 5c, 5e and 5g exhibited
promising antioxidant activity. The important role of hydrazinyl-thiazole moiety of syn-
thesized compounds in antioxidant activity was discussed. The antioxidant activity by the
ABTS method was higher than the DPPH method; this presents potential electron dona-
tion capacity of products besides their hydrogen atom transfer capacity. Products showed
moderate to low antibacterial activity.
Experimental
Materials and instruments
Starting materials containing ketones, thiosemicarbazide, and 2-bromo-1-cyclopropyl-
2-(2-fluorophenyl)ethanone were obtained from Fluka company (Switzerland) and
Merck company (Germany), antioxidant reagents were supplied from Sigma company
(Germany), and biological cultures were obtained from Merck company (Germany) and
Quelab company (Canada). All chemicals were used without further purification. All reac-
tions were monitored by TLC performed on silica gel plates (60 F254 Merck). IR spectra
were recorded on a Shimadzu IR-470 spectrophotometer in anhydrous potassium bromide
(KBr).1H NMR and 13C NMR spectra were recorded on a 400 MHz Bruker spectrometers
using CDCl3 as the solvent and chemical shifts are expressed relative to TMS. Coupling
constants were expressed in hertz (Hz). Melting points were determined using a Mettler
Fp5 apparatus and are uncorrected. Absorbance of antioxidant assays was recorded on the
Unico 2100 spectrophotometer. Elemental analyses were made by a Carlo–Erba EA1110
CNNO-S analyzer.
General procedure for synthesis of 5a–5h
Thiosemicarbazide 2 (2 mmol, 0.18 g) was added to a solution of carbonyl compound
1a–1h (2 mmol) in 10 mL EtOH as the solvent in the presence of a few drops of AcOH and
refluxed for 2 h. The mixture was cooled down and the resulting precipitate was filtered off
and dried at room temperature. Resulted thiosemicarbazone 3a-h (1 mmol) was dissolved
in EtOH (5 mL) and 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone 4 (1 mmol) was

10
F. G. PIRBASTI ET AL.
added to the mixture. The solution was refluxed in the presence of Et3N (20% mole) for
appropriate time. The progress of the reaction was monitored by TLC (n-hexane:EtOAc
7:2). After completion of the reaction, pH was controlled and the mixture was neutralized
with saturated Na2CO3 solution. The solids was filtered off and dried at room temperature.
The products obtained from EtOH:H2O recrystallization.
4-Cyclopropy-5-(2-fluorophenyl)-2-((6-methoxy-3,4-dihydronaphthalen-1(2H)-
ylidene)hydrazono)-2,3-dihydrothiazole 5a
Brown solid, yield: 95%, m.p. 114–118°C, IR (KBr, cm−1) ν: 3320 (stretch N–H), 2930,
=
=
2820 (stretch C–H ali.), 1620 (stretch C N), 1540, 1490 (stretch C C), 1320 (stretch
C–N), 1240, 1010 (stretch C–O), 1060 (stretch C–F), 890, 840, 810, 750 (OOP. C–H). 1H
NMR (CDCl3, 400 MHz) δ: 8.07 (d, J = 8.8 Hz, 1H, Hn), 7.55 (dt, J = 7.1, 1.6 Hz, 1H, Hg),
7.38–7.32 (m, 1H, He), 7.24–7.17 (m, 2H, Hd, Hf ), 6.82 (dd, J = 8.8, 2.4 Hz, 1H, Hm), 6.66
(d, J = 2.0 Hz, 1H, Hk), 3.84 (s, 3H, Hl), 2.78 (t, J = 6.0 Hz, 2H, Hh), 2.60 (t, J = 6.4 Hz,
2H, Hj), 2.00 (q, 2H, Hi), 1.94–1.87 (m, 1H, Hc), 1.00–0.91 (m, 4H, Ha, Ha’, Hb, Hb’) ppm.
13C NMR (CDCl3, 100 MHz) δ: 168.3 (C5), 160.1, 159.9 (1JC,F = 247 Hz, C2), 150.2 (C6),
146.4, 140.8 (C1), 132.3 (3JC,F = 3 Hz, Cd), 129.1 (3JC,F = 8 Hz, Cf ), 126.4, 125.0, 124.1
(4JC,F = 4 Hz, Ce), 120.5 (2JC,F = 16 Hz, C3), 116.0 (2JC,F = 22 Hz, Cg), 113.2, 112.9 (C4),
112.5, 55.3, 29.7 (Cj), 25.2 (Ci), 21.6 (Ch), 11.1 (Cb or Ca),11.1 (Ca or Cb), 7.8 (Cc) ppm.
Anal. calcd. for C23H22FN3OS: C, 67.75; H, 5.49; N, 10.36. Found: C, 67.80; H, 5.45; N,
10.30%.
4-Cyclopropy-2-((3,4-dihydronaphthalen-1(2H)-ylidene)hydrazono)-5-(2-
fluorophenyl)-2,3-dihydrothiazole 5b
Light orange solid, yield: 94%, m.p. 120–123°C, IR (KBr, cm−1) ν: 3310 (stretch N–H),
=
=
2930 (stretch C–H ali.), 1610 (stretch C N), 1540, 1480 (stretch C C), 1280 (stretch
C–N), 1060 (stretch C–F), 760, 750, 730 (OOP. C–H). H NMR (CDCl3, 400 MHz) δ:
1
8.15–8.12 (m, 1H, Hn), 7.99 (br, s, 1H, NH), 7.57 (t, J = 7.6 Hz, 1H, Hg), 7.37–7.09 (m,
6H, Hd,He, Hf , Hk, Hl, Hm), 2.80 (t, J = 5.8 Hz, 2H, Hj), 2.59 (t, J = 6.6 Hz, 2H, Hh), 2.00
(q, 2H, Hi), 1.95–1.88 (m, 1H, Hc), 1.00–0.88 (m, 4H, Ha, Ha’, Hb, Hb’) ppm. 13C NMR
(CDCl3, 100 MHz) δ: 168.3 (C5), 159.9 (1JC,F = 247 Hz, C2), 150.4 (C6), 146.2, 139.1 (C1),
132.3 (3JC,F = 3 Hz, Cd), 132.1, 129.1 (3JC,F = 8 Hz, Cf ), 128.8, 128.4, 126.3, 124.6, 124.1
(4JC,F = 4 Hz, Ce), 120.4 (2JC,F = 16 Hz, C3), 116.0 (2JC,F = 22 Hz, Cg), 113.2 (C4), 55.3,
29.4 (Cj), 25.2 (Ci), 21.5 (Ch), 11.1 (Cb or Ca),11.1 (Ca or Cb), 7.8 (Cc) ppm. Anal. calcd.
for C22H20FN3S: C, 70.02; H, 5.36; N, 11.10. Found: C, 69.98; H, 5.33; N, 11.14%.
4-Cyclopropy-5-(2-fluorophenyl)-2-((1-(naphthalen-2-yl)ethylidene)hydrazono)-2,3-
dihydrothiazole 5c
Yellow solid, yield: 96%, m.p. 195–198°C, IR (KBr, cm−1) ν: 3030 (stretch C–H ar.), 1600
=
=
(stretch C N), 1540, 1490 (stretch C C), 1340 (stretch C–N), 1070 (stretch C–F), 820,
810, 750 (OOP. C–H). 1H NMR (CDCl3, 400 MHz) δ: 8.17 (s, 1H, Ho), 8.03 (dd, J = 8.8,
1.6 Hz, 1H, Hi), 7.94–7.92 (m, 1H, Hj), 7.89–7.85 (m, 2H, Hn, Hk), 7.59–7.47 (m, 4H, Hg,
Hm, Hl, NH), 7.33–7.24 (m, 3H, Hd, He, Hf ), 2.69 (s, 3H, Hh, CH3), 1.99–1.93 (m, 1H, Hc),
1.20–1.11 (m, 4H, Ha, Ha’, Hb, Hb’) ppm. 13C NMR (CDCl3, 100 MHz) δ: 168.1 (C5), 159.9
(1JC,F = 249 Hz, C2), 155.6 (C6), 139.9 (C1), 134.2, 133.3, 132.9, 131.7 (3JC,F = 1 Hz, Cd),
131.5 (3JC,F = 8 Hz, Cf ), 128.8, 128.3, 127.7, 127.5, 127.4, 126.7, 124.8 (4JC,F = 4 Hz, Ce),

JOURNAL OF SULFUR CHEMISTRY
11
123.2, 116.7 (2JC,F = 15 Hz, C3), 116.5 (2JC,F = 22 Hz, Cg), 112.3 (C4), 15.7 (CH3), 9.3
(Cb or Ca), 9.3 (Ca or Cb), 8.3 (Cc) ppm. Anal. calcd. for C24H20FN3S: C, 71.82; H, 5.04;
N, 10.49. Found: C, 71.78; H, 5.01; N, 10.45%.
4-Cyclopropy-5-(2-fluorophenyl)-2-((1-(p-tolyl)ethylidene)hydrazono)-2,3-
dihydrothiazole 5d
Brown solid, yield: 89%, m.p. 89–92°C, IR (KBr, cm−1) ν: 3080 (stretch C–H ar.), 2910
=
=
(stretch C–H ali.), 1600 (stretch C N), 1560, 1540, 1510, 1480 (stretch C C), 1300 (stretch
C–N), 1060 (stretch C–F), 810, 750 (OOP. C–H). 1H NMR (CDCl3, 400 MHz) δ: 7.68 (d,
J = 8.4 Hz, 1H, Hi), 7.53 (dt, J = 7.6, 1.6 Hz, 1H, Hg), 7.42–7.36 (m, 1H, He), 7.27–7.13
(m, 5H, Hd, Hf , Hj, NH), 2.40 (s, 3H, Hh or Hk), 2.38 (s, 3H, Hk or Hh), 1.96–1.88
(m, 1H, Hc), 1.07–0.94 (m, 4H, Ha, Ha’, Hb, Hb’)ppm. 13C NMR (CDCl3, 100 MHz) δ:
168.6 (C5), 159.9 (1JC,F = 248 Hz, C2), 157.7 (C6), 140.4, 139.9 (C1), 130.2 (3JC,F = 8 Hz,
Cf ), 129.2, 129.2, 128.9, 126.9, 124.4 (4JC,F = 4 Hz, Ce), 118.6 (2JC,F = 15 Hz, C3), 116.2
(2JC,F = 21 Hz, Cg), 112.5 (C4), 21.3 (CH3–Ck), 14.5 (CH3–Ch), 10.2 (Ca, Cb), 7.9 (Cc)
ppm. Anal. calcd. for C21H20FN3S: C, 68.98; H, 5.55; N, 10.48. Found: C, 69.03; H, 5,50;
N, 10.52%.
4-Cyclopropy-2-((2,3-dihydro-1H-inden-1-ylidene)hydrazono)-5-(2-fluorophenyl)-2,3-
dihydrothiazole 5e
Light yellow solid, yield: 93%, m.p. 182–186°C, IR (KBr, cm−1) ν: 3050 (stretch C–H ar.),
=
2910 (stretch C–H ali.), 1610 (stretch C N), 1340 (stretch C–N), 1055 (stretch C–F), 810,
750 (OOP. C–H). 1H NMR (CDCl3, 400 MHz) δ: 7.78 (d, J = 7.6 Hz, 1H, Hm), 7.54 (dt,
J = 7.4, 1.4 Hz, 1H, Hg), 7.51–7.44 (m, 2H, Hk, Hl), 7.39 (d, J = 7.6 Hz, 1H, Hj), 7.36–7.23
(m, 4H, Hd, He, Hf , NH), 3.24–3.21 (m, 2H, Hi), 3.15–3.12 (m, 2H, Hh), 1.97–1.91
(m, 1H, Hc), 1.13–1.09 (m, 4H, Ha, Ha’, Hb, Hb’) ppm. 13C NMR (CDCl3, 100 MHz) δ:
167.3 (C5), 165.7, 159.9 (1JC,F = 248 Hz, C2), 149.8 (C6), 139.4 (C1), 135.9, 132.0, 131.6
(3JC,F = 2 Hz, Cd), 131.4 (3JC,F = 9 Hz, C ), 127.3, 125.8, 123.3 (4JC,F = 4 Hz, Ce), 122.3,
116.7 (2JC,F = 14 Hz, C3), 116.5 (2JC,F = f22 Hz, Cg), 111.7 (C4), 29.3 (Ci), 28.3 (C ), 9.2
h
(Cb or Ca), 9.2 (Ca or Cb), 8.3 (Cc) ppm. Anal. calcd. for C21H18FN3S: C, 69.43; H, 5.03;
N, 11.58. Found: C, 69.39; H, 5.01; N, 11.54%.
4-Cyclopropy-2-((1-(3,4-dimethoxyphenyl)ethylidene)hydrazono)-5-(2-fluorophenyl)-
2,3-dihydrothiazole 5f
Brown solid, yield: 90%, m.p. 153–157°C, IR (KBr, cm−1) ν: 3250 (stretch N–H), 3090
=
(stretch C–H ar.), 2950, 2830 (stretch C–H ali.), 1610 (stretch C N), 1550, 1510 (stretch
=
C C), 1330 (stretch C–N), 1240, 1020 (stretch C–O), 1060 (stretch C–F), 880, 860, 750
1
(OOP. C–H). H NMR (CDCl3, 400 MHz) δ: 7.55 (dt, J = 7.5, 1.8 Hz, 1H, Hg), 7.50
(d, J = 2 Hz, 1H, Hi), 7.41–7.31 (m, 1H, He), 7.25–7.17 (m, 3H, Hd, Hf , Hm), 6.87 (d,
J = 8.4 Hz, 1H, Hl), 3.96 (s, 3H, Hj or Hk), 3.93 (s, 3H, Hk or Hj), 2.26 (s, 3H, Hh, CH3),
1.91–1.86 (m, 1H, Hc), 1.00–0.89 (m, 4H, Ha, Ha’, Hb, Hb’) ppm. 13C NMR (CDCl3,
100 MHz) δ: 168.1 (C5), 159.9 (1JC,F = 247 Hz, C2), 150.2, 149.9, 148.9 (C6), 146.3 (C1),
132.3 (3JC,F = 3 Hz, Cd), 130.4, 129.3 (3JC,F = 8 Hz, Cf ), 124.1 (4JC,F = 3 Hz, Ce), 120.2
(2JC,F = 15 Hz, C3), 119.1, 116.0 (2JC,F = 21 Hz, Cg), 112.9 (C4), 110.3, 108.4, 55.9 (Cj or
Ck), 55.8 (Ck or Cj), 12.9 (Ch), 11.0 (Cb or Ca), 11.0 (Ca or Cb), 7.8 (Cc) ppm. Anal. calcd.
for C22H22FN3O2S: C, 64.25; H, 3.42; N, 10.24. Found: C, 64.20; H, 5.38; N, 10.19%.

12
F. G. PIRBASTI ET AL.
4-Cyclopropy-5-(2-fluorophenyl)-2-(2-(1-(4-methoxyphenyl)ethylidene)
hydrazinyl)thiazole 5g
Brown solid, yield: 91%, m.p. 85–87°C, IR (KBr, cm−1) ν: 3200 (stretch N–H), 2920, 2820
=
=
(stretch C–H ali.), 1620 (stretch C N), 1590, 1560, 1520, 1480 (stretch C C), 1300 (stretch
C–N), 1260, 1020 (stretch C–O), 1070 (stretch C–F), 850, 840, 810, 755 (OOP. C–H).
1H NMR (CDCl3, 400 MHz) δ: 12.0 (s, br, 1H, NH), 7.75 (d, J = 9.2 Hz, 2H, Hi), 7.52
(dt, J = 7.6, 1.6 Hz, 1H, Hg), 7.49–7.44 (m, 1H, He), 7.31–7.21 (m, 2H, Hd, Hf ), 6.93 (d,
J = 8.8 Hz, Hj), 3.86 (s, 3H, Hk, OCH3), 2.25 (s, 3H, Hh, CH3), 1.96–1.90 (m, 1H, Hc),
1.16–1.07 (m, 4H, Ha, Ha’, Hb, Hb’) ppm. 13C NMR (CDCl3, 100 MHz) δ: 167.9 (C5),
161.6, 159.9 (1JC,F = 249 Hz, C2), 155.2 (C6), 140.0 (C1), 131.7 (3JC,F = 2 Hz, Cd), 131.3
(3JC,F = 8 Hz, Cf ), 128.5, 128.2 (Ci), 124.7 (4JC,F = 3 Hz, Ce), 116.9 (2JC,F = 15 Hz, C3),
116.4 (2JC,F = 22 Hz, Cg), 113.9 (Cj), 112.0 (C4), 55.4 (Ck), 15.6 (Ch), 9.3 (Cb or Ca), 9.3
(Ca or Cb), 8.3 (Cc) ppm. Anal. calcd. for C21H20FN3OS: C, 66.15; H, 5.30; N, 11.05. Found:
C, 66.10; H, 5.25; N, 10.98%.
4-Cyclopropy-5-(2-fluorophenyl)-(2-((1-(4-nitrophenyl)ethylidene)hydrazono)-2,3-
dihydrothiazole 5h
Light red solid, yield: 88%, m.p. 166–170°C, IR (KBr, cm−1) ν: 3000 (stretch C–H ar.),
=
=
1615 (stretch C N), 1590, 1480 (stretch C C), 1510, 1340 (stretch NO2), 1050 (stretch
C–F), 860, 810, 750, 740 (OOP. C–H). 1H NMR (CDCl3, 400 MHz) δ: 8.28 (d, J = 6.8 Hz,
2H, Hj), 7.96 (d, J = 8.8 Hz, 2H, Hi), 7.55 (dt, J = 7.6, 1.6 Hz, 1H, Hg), 7.47–7.43 (m, 1H,
He), 7.30–7.22 (m, 2H, Hd, Hf ), 6.5–4 (br, s, 1H, NH), 2.45 (s, 3H, Hh, CH3), 1.95–1.91
(m, 1H, Hc), 1.04–1.00 (m, 4H, Ha, Ha’, Hb, Hb’) ppm. 13C NMR (CDCl3, 100 MHz)
δ: 167.3 (C5), 159.9 (1JC,F = 247 Hz, C2), 149.7 (C6), 147.7, 144.0, 143.3 (C1), 132.2
(3JC,F = 2 Hz, Cd), 129.7 (3JC,F = 8 Hz, Cf ), 126.5 (Ci), 124.2 (4JC,F = 4 Hz, Ce), 123.7
(Cj), 119.6 (2JC,F = 15 Hz, C3), 116.1 (2JC,F = 22 Hz, Cg), 113.9 (C4), 13.0 (Ch), 10.8 (Cb
or Ca), 10.8 (Ca or Cb), 7.9 (Cc) ppm. Anal. calcd. for C20H17FN4O2S: C, 60.63; H, 4.30;
N, 14.16. Found: C, 60.61; H, 4.35; N, 14.12%.
Biology
DPPH radical-scavenging activity assay
DPPH radical-scavenging activity of compounds was evaluated according to the
literature.[29] Appropriate amount of DPPH was dissolved in MeOH to give a concentra-
tion of 6.25 × 10−5 M. A series of sample solution at concentrations of 4000, 2000, 1000,
500, 250, 125 μg/mL in MeOH was prepared by two-fold serial dilution. To 0.1 mL of each
sample solution was added 3.9 mL of fresh DPPH solution and was shaken vigorously.
Samples were kept in darkness for 30 min then their absorbance was measured at 517 nm.
MeOH was used as a blank. Radical-scavenging activity was calculated as follows:
ꢀ
ꢁ
Acontrol − Asample
Radical scavengng activity % =
× 100,
Acontrol
where Acontrol is the absorbance of negative control (3.9 mL DPPH + 0.1 mL MeOH) and
sample the absorbance of the test compounds.
A

JOURNAL OF SULFUR CHEMISTRY
13
ABTS assay
The ABTS assay of compounds was evaluated according to the literature.[37] A solution
of ABTS (7.4 mM) in MeOH and a solution of potassium persulfate (K2S2O8) (2.6 mM)
as an oxidizing agent in MeOH were mixed in equal volumes and allowed to react for
12 h in the dark at room temperature to produce the ABTS radical cation (ABTS•+) stock
solution. Then, the resulted stock solution was diluted with MeOH to give an absorbance
of 1.1 0.02 at 734 nm. A series of sample solution at concentrations of 4000, 2000, 1000,
500, 250, 125 μg/mL in MeOH was prepared by two-fold serial dilution. Then, 150 μL of
the sample solution was added to 3.0 mL of the ABTS•+ solution, this mixture was shaken
and incubated in the dark for 2 h. Then, the absorbance of each solution was recorded at
734 nm. MeOH was used as a blank. Radical-scavenging activity was calculated by a similar
formula of the DPPH radical-scavenging assay.
The IC50 values of each compound for DPPH and ABTS assays were calculated by plot-
ting the inhibition percentage against concentration of the samples and the results were
expressed in μM.
Antibacterial assay
The antibacterial activity of hydrazinyl-thiazoles 5a–5h was evaluated biologically using
the well-diffusion method against S. aureus (ATCC 29213), M. luteus (ATCC 4698), E. coli
(ATCC 25922), P. aeruginosa (ATCC 27853), B. subtilis (DSM 6887), and A. hydrophila
(ATCC 7966) supplied from the Iranian biological resource center, Tehran, Iran. First,
nutrient agar and nutrient broth cultures were prepared according to manufactures’
instructions and were incubated at 37°C. After incubation for the appropriate time, a sus-
pension of 30 μL of each bacterium was added to the nutrient agar plates. Cups (5 mm in
diameter) were cut in the agar using a sterilized glass tube. Each well received 30 μL of
the test compounds at a concentration of 1000 μg/ml in DMSO. Then, plates were incu-
bated at 37°C for 24 h, after this time the zone of inhibition was measured and values are
expressed in millimeters (mm). The experiments were performed in triplicate. The results
are reported as mean standard deviation of zone of inhibition in millimeter. Antibacte-
rial activity of each hydrazinyl-thiazole was compared with penicillin G and gentamicin as
standard drugs. DMSO was used as a negative control.
Acknowledgements
The authors gratefully thank the assistance of Dr Zohreh Ramezanpour and Miss Somaie Rasouli
Dogaheh for help in running biological assays.
Disclosure statement
No potential conflict of interest was reported by the authors.
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