Sequential one-pot multicomponent synthesis of bis-aminothiazols and evaluation of their antibacterial and antioxidant activities

Article abstract of DOI:10.1002/jccs.201800140

A series of novel bis-thiazoles were synthesized through a one-pot semi-five-component reaction of the prepared α-bisbromo ketones, aldehydes, and thiosemicarbazide in the presence of p-TsOH under reflux condition. Products were obtained in reasonable yie

Full text of DOI:10.1002/jccs.201800140

Received: 13 April 2018
Revised: 19 August 2018
Accepted: 22 August 2018
DOI: 10.1002/jccs.201800140
A R T I C L E
Sequential one-pot multicomponent synthesis of bis-aminothiazols
and evaluation of their antibacterial and antioxidant activities
Jafar Parvizi1 | Nosrat O. Mahmoodi2 | Fateme Ghanbari Pirbasti2
1Department of Chemistry, University campus2,
A series of novel bis-thiazoles were synthesized through a one-pot semi-five-
University of Guilan, Rasht, Iran
2Department of Chemistry, Faculty of Sciences,
University of Guilan, Rasht, Iran
component reaction of the prepared α-bisbromo ketones, aldehydes, and thiosemi-
carbazide in the presence of p-TsOH under reflux condition. Products were
obtained in reasonable yields via an efficient, convenient, and simple setup. The
inhibitory activity on bacterial growth of the products was studied against Gram-
negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacte-
rial strains (Micrococcus luteus, Staphylococcus aureus) at different concentrations
(25, 50, 100, and 200 μg/mL at 600 nm). Most of the products showed inhibitory
activity at the concentration of 200 μg/mL. In addition, bis-thiazoles showeed high
to moderate antioxidant activity using the diphenylpicrylhydrazyl (DPPH) method.
Bis-thiazoles 6i and 6j showed higher antioxidant activity than vitamin C and
vitamin E.
Correspondence
Nosrat O. Mahmoodi, Faculty of Sciences,
Department of Organic Chemistry, University of
Guilan, PO Box 41335-1914, Rasht, Iran.
Email: mahmoodi@guilan.ac.ir;
nosmahmoodi@gmail.com
Funding information
the University of Guilan
KEYWORDS
antibacterial, antioxidant, bis-aminothiazol, bis-ketones, multicomponent
synthesis
important natural thiazoles. Moreover, many commercial
drugs contain the thiazole moiety and have various clinical
1
| INTRODUCTION
Heterocyclic compounds are a diverse family of chemical
compounds with many important biological activities. Thia-
zoles are one of the important members of heterocyclic com-
pounds with various properties and applications. The
thiazole ring as an interesting building block is found in
many natural and medicinal compounds with potential bio-
logical activities: for example, urukthapelstatin A is a cyclic
compound isolated from Thermoactinomycetaceae bacteria
showing anticancer activity against human lung cancer A549
cells.[1] Cyclic hexapeptides and venturamides A and B,
which were isolated from marine Cyanobacterium oscilla-
toria sp., possess antimalarial activity.[2] These diverse bio-
logical activities of thiazoles have attracted great attention of
researchers in the synthesis and investigation of their biolog-
ical activities such as antimycobacterial antibiotics,[3] pin1
inhibitor,[4] α-glucosidase inhibitor,[5] antioxidant,[6] anti-
liver cancer,[7] antibacterial,[8,9] antiplatelet,[10] anti-
inflammatory,[11] anti-Candida activity[12] activities, and so
on. Also, thiamine or vitamin B1 is one of the most
applications such as the anticancer drug tiazofurin, the non-
steroidal anti-inflammatory drugs fentizac and meloxicam,
the anti-HIV drug ritonavir, and the immunoregulating drug
fanetizole (Scheme 1).
In addition, some thiazole-containing compounds have
physical applications, for example, thiophene-thiazole-
functionalized conjugated oligomers have been used for the
fluorescent and colorimetric sensing of Cu2+ and Fe2+ from
water and thiazole-based iridium(III) complexes for organic
light-emitting diode (OLED) applications.[13,14] Among the
thiazole derivatives, hydrazinyl thiazoles are found to be
associated with different biological activities such as
antimalarial,[15]
antimycobacterial,[16]
β-glucuronidase
inhibitory,[17] antibacterial, and antitubercular.[18]
Finding new tools for saving energy, eco-friendliness,
atom economy, and saving time in synthetic organic chemis-
try has gained much attention of researchers, and this chal-
lenge has led to innovative and sustainable one-pot
multicomponent reactions (MCRs). A large to complex
© 2018 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2018;1–9.
http://www.jccs.wiley-vch.de
1

2
PARVIZI ET AL.
SCHEME 1 Structure of commercial drugs that possess the thiazole
moiety with various clinical applications
library of compounds without isolation of any intermediate
can be synthesized using simple procedures and in high
yields. Moreover, recently MCRs of hydrazinyl thiazoles
have been reported.[19–21]
SCHEME 2 Synthesis procedure of bis-thiazoles 6a–h
Encouraged by all of the above, as well as the limited
studies on the synthesis of bis-thiazoles in the
literature,[22–24] and in continuation of our ongoing research
program on the synthesis of mono- and bis-thiazoles and
screening for their biological activities,[25–33] we report in
this paper the one-pot semi-five-component, efficient, and
rapid method for the synthesis of new bis-thiazoles and
screening otheir antibacterial and antioxidant activities.
work-up and straightforward method not involving chro-
matographic purification.
The structure of the products was elucidated by their FT-
IR, 1H NMR, 13C NMR spectra and elemental analysis. The
IR spectra of products 6a–l showed characteristic absorption
bands at 3,450–3,414 and 1,628–1,603 cm−1 due to N–H
and C=N stretches, respectively.
Also, in the 1H and 13C NMR spectra of 6a–l, the
expected number, chemical shifts, and coupling constants of
various protons appeared. The N-H signal appeared as exo-
cyclic at 12.68–11.27 ppm, which is incomplete agreement
with the literature (Table 2).[35]
2
| RESULTS AND DISCUSSION
2.1 | Chemistry
In addition, the presence of a signal at 7.62–6.71 con-
firmed the presence of thiazole ring (C=H). Signals due to
the aromatic and aliphatic protons appeared at 8.32–6.83 and
5.22–1.25 ppm, respectively. The expected number and
types of carbons appeared in the 13C NMR spectra. Aromatic
and aliphatic carbons appeared in range 178.40–96.68 and
70.09–19.04 ppm, respectively.
Bis-bromo ketones 3a–h were prepared according to the lit-
erature[34] and were applied in one-pot semi-five-component
reaction of 2 equiv of aldehydes 4a–d with thiosemicarba-
zide 5 in EtOH in the presence of p-TsOH (10 mol%) under
reflux condition (Scheme 2). According to Table 1, suitable
reaction condition for the synthesis of bis-thiazole 6a as
model reaction was considered. According to entry 1, in the
absence of a catalyst at r.t., the product 6a was obtained in
55% yield during 12 hr. The same was performed with a
slightly higher yield and shorter reaction time under reflux
condition (entry 2). However, the yield of 6a increased to
70% in the presence of 5 mol% of the catalyst during 8 hr
(entry 3). Moreover, increasing the amount of catalyst led to
the formation of product 6a in higher yield in a shorter reac-
tion time (entry 4). Although products 6a was obtained in
high yield (80%) in 4 hr in CH3CN as solvent (entry 7),
using EtOH as green solvent (entry 4) was a better choice.
The reaction proceeded through the condensation of alde-
hydes 4a–d with thiosemicarbazide 5 followed by nucleo-
philic addition to bromo-ketones 3a–h through Hantzsch
reaction and subsequent intramolecular cyclization. Under
the optimized condition, bis-products 6a–l were obtained in
reasonable yields, through a simple, eco-friendly, convenient
2.2 | Biology
2.2.1
| Antibacterial activity
Pathogenic bacteria have an important role in the creation of
unknown diseases; also, bacterial resistance to available anti-
microbial drugs has become a challenge nowadays.[36] So,
exploring new, cheaper, and effective antibacterial com-
pounds is highly required. In vitro antibacterial activity of
bis-thiazoles 6a–l was investigated against Gram-positive
bacteria strains including Micrococcus luteus and Staphylo-
coccus aureus and Gram-negative bacteria strains including
Escherichia coli and Pseudomonas aeruginosa. Bacterial
inhibition percentages of the products at different concentra-
tions of 25, 50, 100, and 200 μg/mL in DMSO were studied
at 600 nm. Penicillin was used as positive control.
According to Figure 1, only products 6h and 6i inhibited
the growth of P. aeruginosa by 85 and 72%, respectively, at

PARVIZI ET AL.
3
TABLE 1 Optimization of the synthesis of 6a
Entry
Catalyst
—
Amount of catalyst (Mol%)
Solvent
EtOH
Condition
r.t.
Time (hr)
Yield (%)
1
2
3
4
5
6
7
8
—
—
5
12
10
8
55
57
70
80
60
70
80
70
—
EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
EtOH
10
10
10
10
10
EtOH
4
EtOH:H2O
DMF
6
6
CH3CN
MeOH
4
5
TABLE 2 Structure and physical properties 6a-l
Compound Product structure
6a
Color
Melting point Yield (%)
Brown
225–229
80
80
80
75
6b
6c
6d
Dark yellow 228–231
Brown
Cream
222–226
232–235
6e
6f
Brown
227–231
77
85
Dark brown 224–228
6g
6h
Dark
214–217
80
83
Dark brown 215–219
6i
6j
Brown
230–232
85
83
Dark yellow 227–230
6k
6l
Cream
Cream
230–233
225–229
90
85

4
PARVIZI ET AL.
Antibacteriala activity of producta against Sa.
Antibacterial activity of products against Psa.
100
80
60
40
20
0
100
80
60
40
20
0
25
25
50
50
100
200
100
200
Products
FIGURE 3 Inhibition percentages of products against S. aureus
Products
FIGURE 1 Inhibition percentages of products against P. aeruginosa
Antibacterial activity of products against Ml
.
Antibacterial activity of products against Ec.
100
80
60
40
20
0
100
80
60
40
20
0
25
25
50
50
100
200
100
200
Products
FIGURE 4 Inhibition percentages of products against M. luteus
FIGURE 2 Inhibition percentages of products against E. coli
by more than 90% at the concentration of 200 μg/mL. Addi-
tionally, products 6a and 6h showed antibacterial activity
against M. luteus at all tested concentrations. Also, all tested
concentrations of penicillin inhibited the growth of M. luteus
completely.
the concentration of 200 μg/mL. Also, penicillin inhibited
100% growth of P. aeruginosa at the concentrations of
50, 100 and 200 μg/mL.
Moreover, most of the products showed inhibition
against E. coli. Product 6h inhibited the growth of E. coli
completely at the concentration of 200 μg/mL; also, the
products 6i–k inhibited over 90% of bacterial growth at the
concentration of 200 μg/mL. Furthermore, product 6h
showed antibacterial activity at all tested concentrations
from 30 to 100%. However, products 6e–g showed no anti-
bacterial activity against E. coli. Also, at the concentration
of 100 μg/mL, product 6k showed the highest inhibitory
activity (85%). Furthermore, penicillin inhibited the growth
of E. coli completely at the concentration of 100 and
200 μg/mL and by 97 and 38% at the concentrations of
50 and 25 μg/mL, respectively (Figure 2).
Products 6d, 6g–j, and 6l showed inhibitory activity
against S. aureus. Products 6h–i possessed inhibitory activ-
ity at higher concentrations: for example, 100 and 200 μg/
mL. Furthermore, product 6j had the highest inhibitory
activity (79%) at the concentration of 200 μg/mL. Penicillin
as a positive control inhibited the growth of S. aureus
completely (Figure 3).
In our recent study, it was observed that benzyl linkage
has a potent influence on the antibacterial activity. Similar
results were observed in this study for products 6i and 6l.[28]
Moreover, the only structural difference between these iso-
mers (6i and 6l) is the linkage position on the benzyl ring,
namely para and meta connections, respectively. However,
this tiny difference had a major effect on the antibacterial
activity: for example, 6i with the para-substituted linkage
showed antibacterial activity against all four bacterial strains,
while 6l with meta-substituted linkage showed antibacterial
activity against E. coli and S. aureus. It can be suggested
that the symmetry of 6i has a positive effect on its antibacter-
ial activity. In addition, 6j showed good antibacterial activ-
ity, especially against E. coli, S. aureus, and M. luteus,
which may be due to incorporation of the heterocyclic furyl
moiety. Also, 6i and 6l with good antibacterial activity pos-
sess the furyl moiety. Recently it was shown that the pres-
ence of Cl substituent has a positive effect on the
antibacterial activity, and in this study the Cl-substituted
product 6h showed high antibacterial activity.[37]
According to Figure 4, most of the products possessed
antibacterial activity against M. luteus. Product 6a inhibited
the growth of M. luteus completely at the concentrations of
50, 100, and 200 μg/mL and by 96% at the concentration of
50 μg/mL. Moreover, products 6a and 6i–j showed high
antibacterial activity and inhibited the growth of M. luteus
Interestingly, most of the products possessed antibacter-
ial activity against the Gram-negative bacterial strain E. coli,
especially products 6h–k. All bacteria have an inner cell
membrane; however, this layer is unique in Gram-negative

PARVIZI ET AL.
5
IC50 values in μM
6a
6b
6c
6d
6e
6f
4
3.5
3
Antioxidant activity
3.505
100
90
80
70
60
50
40
30
20
10
0
3.019
3.022
2.59
2.966
2.611
2.28
2.5
2
1.68
1.405
1.257
1.5
1
0.97
0.74
0.2349
0.1648
6g
6h
6i
0.5
0
6j
Compounds
2000
1000
500
250
125
62.5
6k
6l
Concentration at µg/ml
FIGURE 6 IC50 values of 6a–l and standards
FIGURE 5 Antioxidant activity of 6a–l using DPPH method
compounds that trap free radicals, so they can reduce the risk
of diseases.[41]
bacteria. A lipopolysaccharide layer (outer layer) is present
in Gram-negative bacteria, and this outer layer excludes cer-
tain drugs and antibiotics from penetrating the cell, partially
accounting for why Gram-negative bacteria are generally
more resistant to antibiotics than are Gram-positive bacteria.
So, the synthesis and finding of new compounds with the
ability to inhibit Gram-negative bacteria are important.
Among various antioxidant assays, the diphenylpicrylhy-
drazyl (DPPH) assay is a fast and simple method. DPPH is a
stable free radical of violet color and turns to yellow to col-
orless in the presence of an antioxidant compound on receiv-
ing a radical hydrogen atom. DPPH violet solution has a
sharp absorption band at 517 nm, and this band decreases as
the reduced form of DPPH increases. The radical scavenging
activity of new bis-thiazoles 6a–l was evaluated at a concen-
tration of 2,000–62.5 μg/mL at 517 nm. Also, the IC50
values (i.e., the concentration of products to scavenge 50%
of DPPH radical concentration) were calculated from a linear
equation. Vitamin C (ascorbic acid) and vitamin E (α-
tocopherol) were used as standards. According to Figure 5,
all new bis-thiazoles revealed potent to moderate antioxidant
activity. Bis-thiazoles 6i–j possessed radical scavenging
activity of >50% at concentrations of 250 and 125 μg/mL,
respectively. Also, bis-thiazoles 6c and 6f showed potent
antioxidant activity at concentrations of 1,000 and 500 μg/
mL, respectively.
According to Figure 6, the higher antioxidant activity is
reflected in lower IC50 values. Interestingly, bis-thiazoles
6i–j had the lowest IC50 values (234.9 and 164.8 μM) and
their antioxidant activity was higher than that of vitamin C
(0.970 μM) and vitamin E (740 μM). The IC50 values of
other products were higher than those of the standards. The
antioxidant activity of bis-thiazoles can be ordered as fol-
lows: 6j, 6i, 6c, 6f, 6h, 6b, 6e, 6l, 6k, 6a, 6d, and 6g.
Recently, we discussed mechanism of the antioxidant activ-
ity of hydrazinylthiazoles and the important role of the endo- or
exo-N-H of thiazole. Also, if the structure of compound stabi-
lizes the formed radical through resonance, the antioxidant
activity can be improved. Besides, N-H and N=C-C=NH moi-
eties in other parts of compounds can affect the antioxidant
activity. Some proposed radical structures and resonance of
radical through the structure of bis-thiazole 6i are depicted in
Scheme 3. Ultimately, compounds 6a–l, especially 6i–j, can be
introduced as potent antioxidant compounds similar to our
recently synthesized hydrazinylthiazoles.[26,27]
Recently, Singh and coworkers studied antibacterial
activity of 2,4-disubstitued thiazoles.[38] According to their
results, none of the products was active against E. coli while
in our study most of the products were active against E. coli.
Also, the above authors found a few products were active
against P. aeruginosa like in our study. In another study,
3-(1-phenyl-4-((2-[4-arylthiazol-2-yl]hydrazono)methyl)-
1H-pyrazol-3-yl)-2H-chromen-2-one exhibited moderate to
excellent antibacterial activity against S. aureus, B. subtilis,
E. coli, and P. aeruginosa with zones of inhibition of 8–22,
7–18, 8–22, and 8–20 mm and MICs of 50–200, 50–200,
125–200, and 50–200 μg/mL, respectively.[39] Also, these
products showed good antibacterial activity against E. coli
like our products. However, these compounds showed better
antibacterial activity against P. aeruginosa and S. aureus
than our products because of the presence of the coumarinyl
moiety. Moreover, in our recent study,[26] 2,4-disubstituted
hydrazinyl-thiazoles showed antibacterial activity against
S. aureus, M. luteus, E. coli, P. aeruginosa, B. subtilis, and
A. hydrophila with the zones of inhibition of 6–11, 7–10,
9–13, 7–17, 6–21, and 6–11 mm, respectively, and these
products showed antibacterial activity against E. coli.
2.3 | Antioxidant activity
Sunlight, ultraviolet light, ionizing radiation, chemical reac-
tions, and metabolic processes can produce free-radical spe-
cies which can react and oxidize DNA, lipids, proteins, and
nucleic acids in living systems and result in degenerative
disease and health problems such as chronic diseases, car-
diovascular diseases, metabolic syndrome, cancer, and some
neurodegenerative diseases.[40] Antioxidants are a class of

6
PARVIZI ET AL.
spectrophotometer Unico 2100 and UV–vis spectrophotome-
ter NANOCOLOR® UV/VIS Macherey Nagel, respectively.
Bacterial strains were supplied generously by the Depart-
ment of Biology, Faculty of Sciences, University of Guilan.
4.2 | General procedure for the synthesis of bis-
thiazoles 6a–h
Compounds 3a–h were prepared according to literature.[30,34]
The prepared α-bromo ketones 3a–h (1 mmol), alde-
hydes 4a–d (2 mmol), and thiosemicarbazide 5 (2 mmol)
were added to a flask and refluxed in EtOH in the presence
of p-TsOH (10 mol%) for 4 hr. After the required time, the
reaction was cooled and filtered. The crude product was
washed with warm EtOH.
4.2.1
| 1,4-Bis(4-(2-(2-([E]-benzylidene)hydrazinyl)thiazol-
4-yl)phenoxy)butane (6a)
Brown solid, Yield: 80%; m.p.: 225–229ꢀC, FT-IR (KBr
cm−1): 3,445 (stretch, N–H), 3,136 (stretch, C–H aromatic),
2,935 (stretch, C–H aliphatic), 1,604 (stretch, C=N), 1,569,
1,509, (stretch, C=C), 1463 (bending, C–H, CH2), 1255, 1029
(stretch, C–O), 1171, 1119 (bending, C–N), 832, 653 (OOP,
C–H). 1H NMR (400 MHz, DMSO-d6): δ; 12.04 (s, 2H, NH,
Hf), 7.54 (s, 2H, Hg), 7.5 (d, J = 7.2 Hz, 4H, Hh), 7.35 (d,
J = 8.0 Hz, 4H, Hd), 7.28–7.22 (m, 6H, Hi, HJ), 6.88 (s, 2H,
He), 6.83 (d, J = 8.0 Hz, 4H, Hc), 3.58 (t, J = 6.8 Hz, 4H, Hb),
2.10–2.11 (m, 4H, Ha) ppm. 13C NMR (100 MHz, DMSO-
d6): δ; 176.13(C4), 136.99 (C1), 133.60 (C3), 129.4, 127.35,
124.02, 123.86, 121.23, 120.36, 119.22, 118.52, 112.24,
68.07 (Cb), 31.84 (Ca) ppm. Anal.calcd for C36H32N6O2S2: C,
67.06; H, 5.00; N, 13.03. Found: C, 67.10; H, 4.86; N, 13.07.
SCHEME 3 Proposed mechanism of antioxidant activity of bis-thiazole 6i
3
| CONCLUSIONS
In conclusion, a one-pot, multicomponent, efficient, eco-
friendly, productive, and simple (setup and work-up) synthesis
was applied for the synthesis of new bis-thiazoles. Also, the
novel bis-thiazoles showed antibacterial activity against
Gram-positive and Gram-negative bacterial strains. The anti-
bacterial activity of product 6h was comparable to that of peni-
cillin at the concentration of 200 μg/mL against E. coli and
M. luteus. Specifically, most of the products showed antibac-
terial activity against the Gram-negative E. coli. In addition,
bis-thiazoles 6i and j showed high antioxidant activity, even
higher than those of vitamin C and vitamin E. Moreover, other
bis-thiazoles showed good antioxidant activity. The results of
antibacterial and antioxidant activities of bis-thiazoles should
encourage the investigation of other biological activities.
4.2.2
| 1,4-Bis(4-(2-(2-([E]-4-chlorobenzylidene)hydrazinyl)
thiazol-4-yl)phenoxy)butane (6b)
Dark yellow solid, Yield: 80%; m.p.: 228–231ꢀC, FT-IR
(KBr, cm−1 ): 3,447 (stretch, N–H), 3,015 (stretch, C–H aro-
matic), 2925, 2857 (stretch, C–H aliphatic), 1615 (stretch,
C=N), 1593, 1504 (stretch, C=C), 1459 (bending, C–H and
CH2), 1270, 1070 (stretch, C–O), 1172 (stretch, C–N),
4
| EXPERIMENTAL
1
837, 814, 761 (OOP, C–H). H NMR (400 MHz, DMSO-
d6): δ; 12.50 (brs, 2H, NH, Hf), 8.06 (s, 2H, Hg), 7.72 (d,
J = 8.4 Hz, 4H, Hh), 7.53 (d, J = 8.6 Hz, 4H, Hd), 7.50 (d,
J = 8.4, 4H, Hi), 7.14 (S, 2H, He), 7.22 (d, J = 8.6 Hz, 4H,
Hc), 4.03 (t, J = 6.4 Hz, 4H, Hb), 1.70–1.54 (m, 4H, Ha)
ppm. 13C NMR (100 MHz, DMSO-d6): δ; 169.87 (C4),
159.12 (C1), 150.92 (C3), 146.18 (Cg), 138.12 (C6), 133.49
(C5), 130.73, 129.46, 128.55, 125.98, 114.40, 110.00, 68.99
(Cb), 31.18 (Ca) ppm. Anal. calcd for C36H30Cl2N6O2S2: C,
60.58; H, 4.24;N, 11.78. Found: C, 60.50; H, 4.30; N, 11.71.
4.1 | Materials and methods
Chemicals were purchased from Sigma and Merck chemical
companies. Solvents were supplied from local manufac-
turers. FT- IR spectra were recorded with a Shimadzu
470 spectrometer. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded with a Bruker 400 DRX-
Avance NMR spectrometer. Deuterated DMSO and TMS
were used as solvent and internal standard, respectively.
Melting points were determined with an Electrothermal
model 9100 apparatus and are uncorrected. Elemental analy-
sis was carried out using a Carlo-ErbaEA1110 CNNO-S
analyzer. Absorbance of the products during antioxidant and
antibacterial activity studies was measured on a visible
4.2.3
| 1,4-Bis(4-(2-(2-([E]-4-methoxybenzylidene)hydrazinyl)
thiazol-4-yl)phenoxy)butane (6c)
Brown solid, Yield: 80%; m.p.: 222–226ꢀC, FT-IR (KBr,
cm−1): 3,416 (stretch, N–H), 3061 (stretch, C–H aromatic),

PARVIZI ET AL.
7
4.2.6
|
1,5-Bis(4-(2-(2-([E]-4-methoxybenzylidene)hydrazinyl)
2930, 2860 (stretch, C–H aliphatic), 1603 (stretch, C=N),
1503 (stretch, C=C), 1461–1386 (bending, C–H, CH2),
1251, 1012 (C–O stretch), 1186 (C–N stretch), 830, 752
thiazol-4-yl)phenoxy)pentane (6f )
Dark brown solid, Yield: 85%; m.p.: 224–228ꢀC, FT-IR
(KBr, cm−1): 3,416 (stretch, N–H), 3061 (stretch, C–H aro-
matic), 2930, 2850 (stretch, C–H aliphatic), 1603 (stretch,
C=N), 1567, 1505 (stretch, C=C), 1466 (bending, C–H,
CH2), 1243, 1029 (stretch, C–O), 1173 (bending, C–N),
1
(OOP, C-H). H NMR (400 MHz, DMSO-d6): δ; 11.51 (s,
2H, NH, Hf), 7.50 (d, J = 7.2 Hz, 4H, Hd), 7.35 (s, 2H, Hg),
7.31 (d, J = 8.4 Hz, 4H, Hh), 7.18 (s, 2H, He), 6.86 (d,
J = 8.4, 4H, Hi), 6.70 (d, J = 7.2 Hz, 4H, Hc), 4.15 (t,
J = 6.0 Hz, 4H, Hb), 3.63 (s, 6H, Hj), 2.01–1.88 (m, 4H, Ha)
ppm.. 13C NMR (100 MHz, DMSO-d6): δ; 164.18 (C4),
161.87 (C6), 160.92 (C1), 145.84 (C3), 138.34 (Cg), 132.47,
130.09, 128.62, 126.33, 125.99, 123.41, 114.84 (Ce), 67.89
(Cb), 55.88 (Cj), 21.26 (Ca) ppm. Anal.calcd for
C38H36N6O4S2: C, 64.70; H, 5.15; N, 11.92. Found: C,
64.74; H, 5.21; N, 11.85.
1
834, 764 (OOP, C–H). H NMR (400 MHz, DMSO-d6): δ;
11.71 (s, 2H, NH, Hg), 8.06 (s, 2H, Hh), 8.01 (d, J = 7.4 Hz,
4H, Hi), 7.90 (d, J = 7.4 Hz, 4H, He), 7.84 (s, 2H, Hf), 7.61
(d, J = 7.4 Hz, 4H, Hj,), 7.50 (d, J = 7.4 Hz, 4H, Hd), 4.14
(t, J = 8.2 Hz 4H, Hc), 3.80 (s, 6H, Hk), 2.27–2.22 (m, 4H,
Hb), 1.82 (s, 2H, Ha) ppm.. 13C NMR (100 MHz, DMSO-
d6): δ; 167.40 (C4), 160.20 (C6), 157.41 (C1), 150.20 (C3),
145.94 (Ch), 138.28, 132.47, 128.60, 125.99, 115.35, 114.85
(Cd or Cj), 102.73 (Cf), 65.70 (Cc), 55.74 (Ck), 28.60
(Cb),21.27 (Ca) ppm. Anal. calcd for C39H38N6O4S2: C,
65.16; H, 5.33; N, 11.69, Found: C, 65.18; H,
5.34; N, 11.70.
4.2.4
| 1,5-Bis(4-(2-(2-([E]-benzylidene)hydrazinyl)thiazol-
4-yl)phenoxy)pentane (6d)
Cream solid, Yield: 75%; m.p.: 232–235ꢀC, FT-IR (KBr,
cm−1): 3,417 (stretch, N-H), 3064 (stretch, C–H aromatic),
2922, 2855 (stretch, C–H aliphatic), 1628 (stretch, C=N),
1491 (stretch, C=C), 1241, 1005 (stretch, C–O), 1119
4.2.7
| 1,6-Bis(4-(2-(2-([E]-benzylidene)hydrazinyl)thiazol-
4-yl)phenoxy)hexane (6g)
Brown solid, Yield: 80%; m.p.: 214–217ꢀC, FT-IR (KBr,
cm−1): 3,416 (stretch, N–H), 3062 (stretch, C–H aromatic),
2934, 2855 (stretch, C–H aliphatic), 1604 (stretch, C=N),
1553, 1489 (stretch, C=C), 1466 (bending, C–H, CH2),
1247, 1008 (stretch, C–O), 1174, 1115 (bending, C–N),
1
(stretch, C–N), 815, 715 (OOP, C–H). H NMR (400 MHz,
DMSO-d6): δ; 12.03 (s, 2H, NH, Hg), 7.99 (s, 2H, Hh), 7.86
(d, J = 7.2 Hz, 4H, Hi), 7.60 (d, J = 8.8 Hz, 4H, He), 7.42 (t,
J = 7.6 Hz, 4H, Hj), 7.33–7.29 (m, 4H, Hk, Hf), 7.01 (d,
J = 8.8 Hz, 4H, Hd), 4.06 (t, J = 6.4 Hz, 4H, Hc), 1.86–1.79
(m, 4H, Hb), 1.62–1.60 (m, 2H, Ha) ppm.13C NMR
(100 MHz, DMSO-d6): δ; 178.4 (C4), 168.82 (C1), 159.07
(C3), 142.79 (Ch), 138.63 (C5), 134.66, 129.34, 128.73,
127.77, 126.03, 115.06, 102.33 (Cf), 67.94 (Cc), 28.90 (Cb),
21.26 (Ca) ppm. Anal. calcd For C37H34N6O2S2: C,
67.45; H, 5.20; N, 12.80. Found: C, 67.40; H,
5.14; N, 12.72.
1
823, 752 (OOP, C–H). H NMR (400 MHz, DMSO-d6): δ;
12.09 (brs, 2H, NH, Hg), 8.00 (s, 2H, Hh), 7.86 (d,
J = 7.8 Hz, 4H, He), 7.60 (d, J = 8.8 Hz, 4H, Hi), 7.42 (t,
J = 7.6, 4H, Hj), 7.33–7.29 (m, 4H, Hk, Hh,), 7.00 (d,
J = 7.8 Hz, 4H, Hd), 4.03 (t, J = 6.4 Hz, 4H, Hc), 1.77–1.75
(m, 4H, Hb), 1.50 (s, 4H, Ha) ppm. 13C NMR (100 MHz,
DMSO-d6): δ; 170.60 (C4), 156.13 (C1), 150.89 (C3),
146.13 (Ch), 133.62 (C5), 129.46, 127.23, 123.89, 121.36,
119.22, 118.52, 102.79 (Cf), 68.00 (Cc), 29.22 (Cb), 25.73
(Ca) ppm. Anal. calcd for C38H36N6O2S2: C, 67.77; H,
5.39; N, 12.41, Found: C, 68.84; H, 5.45; N, 12.50.
4.2.5
| 1,5-Bis(4-(2-(2-([E]-4-chlorobenzylidene)hydrazinyl)
thiazol-4-yl)phenoxy)pentane (6e)
Brown solid, Yield: 77%; m.p.: 227–231ꢀC, FT-IR (KBr,
cm−1): 3,414 (stretch, N–H), 3082 (stretch, C–H aromatic),
2922, 2867 (stretch, C–H aliphatic), 1615 (stretch, C=N),
1510, 1449, (stretch, C=C), 1449 (bending, C–H, CH2),
1254, 1033 (stretch, C–O), 1187 (bending, C–N), 813, 754
4.2.8
| 1,6-Bis(4-(2-(2-([E]-4-chlorobenzylidene)hydrazinyl)
thiazol-4-yl)phenoxy)hexane (6h)
Dark brown solid, Yield: 83%; m.p.: 215–219ꢀC, FT-IR
(KBr, cm−1): 3,415 (stretch, N–H), 3063 (stretch, C–H aro-
matic), 2927, 2858 (stretch, C–H aliphatic), 1614 (stretch,
C=N), 1575, 1,476 (stretch, C=C), 1433 (bending,C–H,
CH2), 1216, 1005 (stretch, C–O), 1161, 1111 (bending, C–
N), 869, 783, 753 (OOP, C–H). 1H NMR (400 MHz,
DMSO-d6): δ; 11.27 (s, 2H, NH, Hg), 7.48 (s, 2H, Hh), 7.31
(d, J = 7.8 Hz, 4H, Hi), 7.26 (d, J = 6.8 Hz, 4H, He), 7.18
(d, J = 7.8, 4H, Hj), 6.88 (d, J = 6.8 Hz, 4H, Hd), 6.71 (s,
2H, Hf,), 4.00–3.95 (m, 4H, Hc), 3.56 (s, 4H, Hb), 1.31–1.28
(m, 4H, Ha) ppm. 13C NMR (100 MHz, DMSO-d6): δ;
170.60 (C4), 164.09 (C1), 160.01 (C3), 145.84 (Ch), 138.62
(C6), 132.47, 130.49, 129.12, 128.62, 125.82, 115.32,
101.32 (Cf), 68.47 (Cc), 28.18 (Cb), 25.56 (Ca) ppm. Anal.
1
(OOP, C–H). H NMR (400 MHz, DMSO-d6): δ; 11.45 (s,
2H, NH, Hg), 8.05 (s, 2H, Hh), 7.78 (d, J = 8.8 Hz, 4H, Hi),
7.68 (d, J = 7.2 Hz, 4H, He), 7.51–7.41 (m, 4H, Hj), 7.14 (d,
J = 7.2 Hz, 4H, Hd,), 7.00 (s, 2H, Hf), 4.05 (t, J = 6.00 Hz,
4H, Hc), 2.1 (s, 4H, Hb), 1.83–1.80 (m, 2H, Ha) ppm. 13C
NMR (100 MHz, DMSO-d6): δ; 172.65 (C4), 160.82 (C1),
152.33 (C3), 145.68 (Ch), 138.43 (C5), 136.68, 131.68,
129.87, 128.65, 125.98, 115.06, 106.87 (Cf), 56.50 (Cc),
21.27 (Cb), 19.04 (Ca) ppm. Anal. calcd for
C37H32Cl2N6O2S2: C, 61.07; H, 4.43; N, 11.59 Found: C,
61.13; H, 4.34; N, 11.53.

8
PARVIZI ET AL.
calcd for C38H34Cl2N6O2S2: C, 61.48; H, 4.68; N, 11.30,
Found: C, 61.54; H, 4.58; N, 11.39.
114.73, 67.89 (Cc), 55.78, (Ck), 30.28, (Cb), 21.26, (Ca)
ppm. Anal. calcd for C40H40N6O4S2: C, 61.52; H, 4.52; N,
13.45, Found: C, 61.61; H, 4.60; N, 13.51.
4.2.9
| 1,4-Bis((4-(2-([E]-2-(furan-2-ylmethylene)hydrazinyl)
thiazol-4-yl)phenoxy)methyl)benzene (6i)
4.2.12
| 1,4-Bis((3-(2-(2-((E)-furan-2-ylmethylene)hydrazinyl)
Brown solid, Yield: 85%; m.p.: 230–232ꢀC, FT-IR (KBr,
cm−1): 3,414 (stretch, N–H), 3064 (stretch, C–H aromatic),
2930, 2861 (stretch, C–H aliphatic), 1611 (stretch, C=N),
1486 (stretch, C=C), 1438 (bending, C–H, CH2), 1216,
1005 (stretch, C–O), 1158, 1118 (bending, C–N), 873, 817,
787 (OOP, C–H). 1H NMR (400 MHz, DMSO-d6): δ;
11.039 (s, 2H, NH, Hf), 8.16 (s, 2H, Hg), 7.95 (d,
J = 8.0 Hz, 2H, Hj), 7.70 (d, J = 6.8 Hz, 4H, Hd), 7.53 (s,
4H, Ha), 7.35 (s, 2H, He), 7.13 (d, J = 8.0 Hz, 4H, Hc),
6.47–6.41 (m, 4H, Hi, Hh), 5.24 (s, 4H, Hb) ppm. 13C NMR
(100 MHz, DMSO-d6): δ; 170.61 (C5), 163.02 (C2), 159.95
(C4), 155.35 (C6), 152.11, 147.93, 145.32, 142.69, 139.65,
136.66, 130.96, 127.79, 115.36, 100.98 (Ce), 68.26 (Cb)
ppm. Anal. calcd for C36H28N6O4S2: C, 64.33; H, 4.20; N,
12.49, Found: C, 64.27; H, 4.22; N, 12.31.
thiazol-4-yl)phenoxy)methyl)benzene (6l)
Cream solid, Yield: 85%; m.p.: 225–229ꢀC, FT-IR (KBr,
cm−1): 3,415 (stretch, N–H), 3058 (stretch, C–H aromatic),
2925, 2860 (stretch, C–H aliphatic), 1620 (stretch, C=N),
1615 (stretch, C–C aromatic), 1442 (bending, C–H, CH2),
1275, 1026 (stretch, C–O), 1140 (bending, C–N), 839, 766
1
(OOP, C–H). H NMR (400 MHz, DMSO-d6): δ; 12.03 (s,
2H, NH, Hf), 8.18 (s, 2H, Hg), 7.93 (d, J = 8.8 Hz, 2H, Hh),
7.75 (s, 4H, Ha), 7.04 (s, 2H, Hl), 6.98 (s, 2H, Hk,),
6.95–6.92 m, 6H, Hc, Hd, He), 7.87–6.83 (m, 4H, Hi, Hj),
4.14 (s, 4H, Hb) ppm.13C NMR (100 MHz, DMSO-d6): δ;
169.87 (C5), 159.12 (C2), 157.46, 150.92, 146.18, 138.76,
136.29, 129.58, 126.66, 125.08, 124.20, 121.30, 119.70,
114.69, 113.39, 107.76 (Ck), 67.45 (Cb) ppm. Anal. calcd
for C36H28N6O4S2: C, 64.27; H, 4.20; N, 12.49, Found: C,
64.36; H, 4.28; N, 12.32.
4.2.10
| 1,4-Bis(3-(2-(2-([E]-furan-2-ylmethylene)hydrazinyl)
thiazol-4-yl)phenoxy)butane (6j)
Dark yellow solid, Yield: 83%; m.p.: 227–230ꢀC, FT-IR
(KBr, cm−1): 3,447 (stretch, N–H), 3,160 (stretch,C–H aro-
matic), 2933, 2863 (stretch, C–H aliphatic), 1603 (stretch,
C=N), 1568, 1510 (stretch, C=C), 1463 (bending, C–H,
CH2), 1252, 1026 (stretch, C–O), 1171, 1118 (bending, C–N),
4.3 | Antibacterial assay
In vitro antibacterial activity of bis-thiazoles was expressed
as inhibition percentage against Gram-positive bacteria
strains including M. luteus and S. aureus and Gram-negative
bacteria strains including E. coli and P. aeruginosa at
600 nm. Nutrient agar and nutrient broth cultures were pre-
pared according to manufacturer's instructions and were
incubated at 37ꢀC for appropriate times. The antibacterial
activity of products was investigated at concentrations of
25, 50, 100, and 200 μg/mL in DMSO. Cultures were incu-
bated at 37ꢀC for 24 hr; after this time, the absorbance was
recorded at 600 nm. DMSO was used as negative control
and penicillin was used as positive control.
1
833 (OOP, C–H). H NMR (400 MHz, DMSO-d6): δ; 11.88
(s, 2H, NH, Hf), 7.68 (s, 2H, Hg), 7.49 (d, J = 7.2 Hz, 2H, Hj),
7.31 (t, J = 6.4, 2H, Hd), 7.27–7.23 (m, 4H, Hl, He), 7.17 (s,
2H, Hk), 6.7 (d, J = 7.2 Hz, 2H, Hc), 6.89–6.85 (m, 4H, Hh,
Hj), 3.99 (s, 4H, Hb), 2.27 (s, 4H, Ha) ppm. 13C NMR
(100 MHz, DMSO-d6): δ; 173.32 (C4), 160.92 (C1), 154.82
(C3), 150.00 (C5), 144.84, 139.12, 135.17, 130.09, 128.00,
121.65, 118.00, 111.82, 108.49, 96.68, 70.09 (Cb), 26.65, (Ca)
ppm. Anal. calcd for C32H28N6O4S2: C, 65.55; H, 5.47; N,
11.47, Found: C, 65.63; H, 5.51; N, 11.56.
4.4 | Antioxidant assay
4.2.11
| 1,6-Bis(3-(2-(2-([E]-4-methoxybenzylidene)
hydrazinyl)thiazol-4-yl)phenoxy)hexane (6k)
Antioxidant activity of bis-thiazoles was investigated using
the DPPH method according to our recent research.[26]
DPPH solution (3.9 mL, 6.25 × 10−5 M in MeOH) was
added to bis-thiazole solution (0.1 mL at different concentra-
tions of 2,000, 1,000, 500, 250, 125, and 62.5 μg/mL in
MeOH) and was shaken vigorously. Samples were kept in
darkness for 30 min and then their absorbance was measured
at 517 nm. MeOH was used as blank. The absorbance of
negative control (containing all reagents except test com-
pounds) was also measured. DPPH radical scavenging activ-
ity was calculated as follows:
Cream solid, Yield: 90%; m.p.: 230–233ꢀC, FT-IR (KBr,
cm−1): 3,450 (stretch, N–H), 3070 (stretch, C–H aromatic),
2939, 2863 (stretch, C–H aliphatic), 1607 (stretch,C=N),
1571, 1509 (stretch, C=C), 1457 (bending, C–H, CH2),
1250, 1029 (stretch, C–O), 1170, 1121 (bending, C–N),
1
875, 831, 783 (OOP, C–H). H NMR (400 MHz, DMSO-
d6): δ; 11.71 (s, 2H, NH, Hg), 7.98 (s, 2H, Hh), 7.9 (d,
J = 7.8 Hz, 4H, Hj), 7.73 (t, J = 7.0 Hz, 2H, He), 7.50 (d,
J = 8.0 Hz, 2H, Hf), 7.25 (s, 2H, Hm), 7.14 (d, J = 7.6, 2H,
Hd), 7.06 (d, J = 7.8 Hz, 4H, Hj), 7.00 (s, 2H, Hl), 3.81 (t,
J = 6.8, 4H, Hc), 3.55 (s, 6H, Hk), 2.36–2.27 (s, 4H, Hb),
1.30–1.19 (m, 4H, Ha) ppm. 13C NMR (100 MHz, DMSO-
d6): δ; 167.47 (C4), 161.88, 160.74, 158.68, 152.87, 149.17,
146.06, 138.20, 132.20, 130.09, 129.65, 128.57, 125.99,
A control−A sample
Radical scavenging activity% ¼
× 100:
Acontrol

PARVIZI ET AL.
9
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J. Heterocycl. Chem. 2017, 54, 2686.
[25] J. Parvizi, N. O. Mahmoodi, F. Ghanbari Pirbasti, J. Sulfur. Chem. 2017,
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ACKNOWLEDGMENT
The authors thank the University of Guilan for financial
support.
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SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
How to cite this article: Parvizi J, Mahmoodi NO,
Pirbasti FG. Sequential one-pot multicomponent syn-
thesis of bis-aminothiazols and evaluation of their
antibacterial and antioxidant activities. J Chin Chem
Soc.
2018;1–9.
https://doi.org/10.1002/jccs.
201800140
[22] F. M. Abdelrazek, S. M. Gomha, P. Metz, M. M. Abdalla, J. Heterocyclic.
Chem. 2017, 54, 618.