Microwave Assisted Synthesis and Biological Activity of Novel Bis{2-[2-(substituted benzylidene)hydrazinyl]thiazole} Derivatives

Article abstract of DOI:10.1134/S1070363218030301

Abstract—New 4,4'-(4,6-dimethoxy-1,3-phenylene)bis{2-[2-(substituted benzylidene)hydrazinyl]thiazole} derivatives (5a–5j) have been synthesized from the corresponding 1,1'-(4,6-dimethoxy-1,3-phenylene)bis(2,2- dibromoethanone) and substituted thiosemicarbazones by the conventional method and under microwave irradiation. Structures of the synthesized compounds were characterized by FT-IR, 1H, and 13C NMR and Mass spectra. The products were evaluated for their in vitro antibacterial activity against Gram-positive and Gramnegative stains. Some of the compounds 5b, 5f, 5h demonstrated high activity against B. subtilis (+ve), compound 5c exhibited high activity against E. coli (–ve) and P. aeruginosa (–ve) stains. Among the titled compounds also evaluated for their in vitro antimycobacterial activity, the product 5b demonstrated pronounced antimycobacterial activity against M. bovis stain.

Full text of DOI:10.1134/S1070363218030301

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ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 3, pp. 580–586. © Pleiades Publishing, Ltd., 2018.
Microwave Assisted Synthesis and Biological Activity
of Novel Bis{2-[2-(substituted benzylidene)hydrazinyl]thiazole}
Derivatives1
N. H. Kumar Babaa, D. Ashokb*, Boddu Ananda Raob,
Madderla Sarasijac, and N. Y. S. Murthyd
a Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad, Telangana, 500085 India
b Green and Medicinal Chemistry Laboratory, Department of Chemistry,
Osmania University, Hyderabad, Telangana, 500007 India
*е-mail: ashokdou@gmail.com
c Department of Chemistry, Satavahana University, Karimnagar, Telangana, 505001 India
d Department of Chemistry, Anurag Group of Institutions, Hyderabad, Telangana, 501301 India
Received January 23, 2018
Abstract—New 4,4'-(4,6-dimethoxy-1,3-phenylene)bis{2-[2-(substituted benzylidene)hydrazinyl]thiazole}
derivatives (5a–5j) have been synthesized from the corresponding 1,1'-(4,6-dimethoxy-1,3-phenylene)bis(2,2-
dibromoethanone) and substituted thiosemicarbazones by the conventional method and under microwave
irradiation. Structures of the synthesized compounds were characterized by FT-IR, 1H, and 13C NMR and Mass
spectra. The products were evaluated for their in vitro antibacterial activity against Gram-positive and Gram-
negative stains. Some of the compounds 5b, 5f, 5h demonstrated high activity against B. subtilis (+ve),
compound 5c exhibited high activity against E. coli (–ve) and P. aeruginosa (–ve) stains. Among the titled
compounds also evaluated for their in vitro antimycobacterial activity, the product 5b demonstrated
pronounced antimycobacterial activity against M. bovis stain.
Keywords: thiazole, microwave irradiation, anti-bacterial, antimycobacterial
DOI: 10.1134/S1070363218030301
INTRODUCTION
aches to the target compounds: conventional and
microwave assisted synthesis. The synthesized com-
pounds were tested for their in vitro antibacterial and
antimycobacterial activity.
Synthesis of thiazole analogues is the hot topic due
to their broad range of biological and pharmaceutical
properties, such as antibacterial [1-3], hypertension
[4], anti-HIV [5], antiviral [6, 7], anti-inflammatory
[8], and anticancer [9, 10]. Thiosemicarbazones are of
considerable importance in medicinal chemistry
[11, 12], and synthesis of sulfur and nitrogen containing
heterocyclic compounds such as thiazoles [13–16]. Bis-
heterocyclic compounds have demonstrated higher
biological activity than their monoheterocyclic
analogues [17, 18]. The above information encouraged
us to synthesize a symmetrical molecular system of bis
RESULTS AND DISCUSSION
The synthetic pathway to the target compounds 5a–
5j (Scheme 1) started with accumulation of 2,4-
diacteylresorcinol (RDA) (1) according to the
developed earlier procedure [22]. Upon methylation by
MeI the compound 1 in the presence of K2CO3 at room
temperature gave the corresponding product 2 which
was subjected to bromination in CHCl3 at –10°C. Thus
obtained 1,1'-(4,6-dimethoxy-1,3-phenylene)bis(2,2-di-
bromoethanone) (3) was treated with various thiosemi-
carbazones derivatives 4a–4j in ethanol under micro-
wave irradiation to accumulate 4,4'-(4,6-dimethoxy-1,3-
{2-[2-(substituted
benzylidene)hydrazinyl]thiazole}
derivatives 5a–5j starting with 2,4-diaceteylresorcinol
(RDA) (Scheme 1). Such synthesis of new heterocyclic
compounds from RDA became the development of our
earlier studies [19–21]. Here we present two appro-
phenylene)bis{2-[2-(substituted
benzylidene)hyd-
razinyl]thiazole} derivatives 5a–5j, accordingly. The
alternative conventional method led to relatively low
1 The text was submitted by the authors in English.
580

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MICROWAVE ASSISTED SYNTHESIS AND BIOLOGICAL ACTIVITY
581
Scheme 1. Synthesis of 4,4'-(4,6-dimethoxy-1,3-phenylene)bis{2-[2-(substituted benzylidene)hydrazinyl]thiazole}
derivatives 5a–5j.
MeO
Br
OMe
Br
MeO
OMe
HO
OH
Br2, CHCl3
K2CO3, MeI, DMF
0°C, room temperature,
16 h
−10°C, 1 h
Br
Br
O
O
O
O
O
O
2
3
1
Method B
Method A
EtOH,
EtOH,
H
N
NH2
Reflux, 8−15 h
MWI, 5−15 min
Ar
N
S
4a−4j
MeO
N
OMe
N
S
S
NH
HN
N
N
Ar
Ar
5a−5j
Ar = phenyl (5a), 2-hydroxyphenyl (5b), 3-hydroxyphenyl (5c), 4-methoxyphenyl (5d), 2-bromophenyl (5e), 3-bromophenyl
(5f), 2-chlorophenyl (5g), 4-chlorophenyl (5h), 2-nitrophenyl (5i), 3-nitrophenyl (5j).
yields (65–80%) upon lengthy procedure. The follow-
ing optimization of the process was evaluated for the
compound 5a (Table 1). The optimized conditions
allowed to synthesize the derivatives 5a–5j in 80–92%
yields within 5–15 min (Table 2). Chemical structures
of the newly synthesized compounds 3 and 5a–5j were
negative bacterial strains of Escherichia coli and
Pseudomonas aeruginosa, and Gram-positive bacterial
strains of Bacillus subtilis and Staphylococcus aureus
at concentrations of 50 and 100 µg/mL using agar well
diffusion method according to the literature protocol
[23].
1
elucidated from FT-IR, H, and 13C NMR, and Mass
Compounds 5b, 5f, 5h demonstrated activity
against Bacillus subtilis higher than the standard drug
spectra. The FTIR spectrum of compound 5a revealed
three bands for the NH, C=N and C=C bonds at 3462,
1618, and 1495 cm–1, respectively. The 1H NMR
spectrum of compound 5a demonstrated characteristic
signals of the thiazole ring proton at 7.26 ppm, CH=N
proton at 8.09 ppm, and the signal at 4.02 ppm was
assigned to the methoxy protons. Signals of carbon
atoms of same groups were recorded at 106.07, 143.49
and 56 ppm in 13C spectra, respectively. The mass
spectrum of compound 5a exhibited the peak at 541.4,
which corresponded to the [M + H]+ ion.
Table 1. Variety of conditions tested in the synthesis of
compound 5a
Conventional method
time, h yield, %a
MWI method
time, min yield, %a
Solvent
DMSO
16
18
24
8
65
63
45
80
55
20
30
40
10
50
82
78
55
92
65
DMF
THF
Ethanol
Biological activity. Antibacterial activity. The in
vitro antimicrobial activity of all synthesized
compounds 5a–5j (Table 3) was studied against Gram-
1,4-Dioxane
a Isolated yield.
24
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582
KUMAR BABA et al.
Table 2. Yields of the synthesized compounds 5a–5j under
optimized conditions
Antimycobacterial activity. The in vitro antimyco-
bacterial activity of the synthesized compounds 5a–5j
(Table 4) was studied against Mycobacterium bovis
stain. Only compound 5b demonstrated higher activity
against M. bovis stain than the standard Isoniazid +
Rifampicin.
Conventional
MWI method
method
Compound mp, °C
time, yield,
time,
min
yield,
a
a
h
%
%
5a
5b
5c
5d
5e
5f
248–250
8
80
70
69
72
76
75
71
73
65
68
5
92
86
85
90
88
86
82
84
80
82
EXPERIMENTAL
186–188 12
193–195 12
260–262 12
180–182 12
184–186 12
220–222 10
255–257 10
250–252 15
244–246 15
15
15
10
10
10
10
10
15
15
All reagents and solvents were purchased from
commercial sources. IR spectra were recorded on a
Shimadzu FTIR-8400S spectrophotometer. H and 13C
1
NMR spectra were measured on a Bruker Avance 300
spectrometer using DMSO-d6 and CDCl3 solvents and
TMS as internal standard. Mass spectra were measured
on a Shimadzu LCMS2020 spectrometer. Elemental
analyses were performed on a Carlo Erba EA1106
elemental analyzer. Melting points were determined in
open capillary tubes on a Stuart SMP3 melting point
apparatus. All reactions were carried out under the
atmosphere of Ar. Microwave assisted reactions were
carried out in an Anton Paar Monowave 300
microwave (850 W, 2.45 GHz) with a maximum
delivered power of 850 W in 10 W increments (pulsed
irradiation). Analytical TLC was performed on pre-
5g
5h
5i
5j
a Isolated yield.
Norfloxacin at both concentrations. In case of Gram-
negative bacterial strains, 5c was more active against
Escherichia coli and Pseudomonas aeruginosa strains
than Ofloxacin at both concentrations.
Table 3. Antibacterial activity of the synthesized compounds 5a–5j
Zone of inhibition after 24 h, mm
gram-negative bacteria
Escherichia coli Pseudomonas aeruginosa
concentration, µg/mL
gram-positive bacteria
Compound
Staphylococcus aureus
Bacillus subtilis
50
3.0
3.0
2.0
2.5
2.0
3.0
3.0
2.5
2.0
2.0
5.0
–
100
6.0
4.0
3.0
4.0
3.0
5.0
5.0
4.0
3.0
3.0
8.0
–
50
2.0
4.5
3.0
2.0
3.0
5.0
2.0
4.5
2.5
2.0
4.0
–
100
3.0
6.5
5.0
3.0
4.5
6.0
3.0
6.0
4.0
3.0
6.0
–
50
2.5
5.0
7.0
2.5
3.0
3.0
2.5
2.5
4.0
4.0
–
100
4.0
6.0
9.0
4.0
4.0
4.0
4.0
3.0
5.0
5.0
–
50
2.5
4.0
5.5
3.0
3.0
2.5
3.0
2.5
2.5
3.5
–
100
4.0
8.0
9.0
4.0
5.0
4.0
4.0
4.0
5.0
5.0
–
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
Norfloxacin
Ofloxacin
7.0
8.0
5.0
9.0
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MICROWAVE ASSISTED SYNTHESIS AND BIOLOGICAL ACTIVITY
583
60
Table 4. Antimycobacterial activity of the compounds 5a–5j
coated Merck F254 silica gel plates, and visualized by
exposing to iodine vapour and under UV light.
Zone of inhibition,
mm
Synthesis of 1,1'-(4,6-dimethoxy-1,3-phenylene)-
diethanone (2) [24]. To a stirred solution of 1,1'-(4,6-
dihydroxy-1,3-phenylene)diethanone (1) (1.0 g,
5.15 mmol) in N,N-dimethylformamide (20 mL) was
added potassium carbonate (3.5 g, 25.75 mmol). The
mixture was cooled down to 0°C and MeI (0.97 mL,
15.45 mmol) was added dropwise. The reaction mix-
ture was stirred slowly at room temperature for
16 h. Ice water was added to the reaction mixture and
the resulting solid was filtered off, washed with diethyl
ether and dried under vacuum to affords 1,1'-(4,6-
dimethoxy-1,3-phenylene)diethanone (2) [24] as white
solid. Yield 87%, mp 164–166°С.
Compound
Mycobacterium bovis
5a
5b
5c
5d
5e
5f
14.068
41.120
26.897
19.459
21.821
34.496
21.455
30.848
9.830
5g
5h
5i
Synthesis of 1,1'-(4,6-dimethoxy-1,3-phenylene)
bis(2,2-dibromoethanone) (3). To a stirred solution of
1,1'-(4,6-dimethoxy-1,3-phenylene)diethanone (2) (1.0 g,
0.0045 moles) in CHCl3 (10 mL) was added Br2
(0.92 mL, 0.018 mol) in CHCl3 solution (5 mL) at
–10°C, and the following stirring was continued for 1 h.
The reaction mixture was quenched with crushed ice
and extracted with CH2Cl2 (2×20 mL). The combined
organic layers were dried over anhydrous sodium
sulfate, concentrated and purified by silica gel (60–
120 mesh) column chromatography (gradient elution
with 10 to 15% EtOAc/Hexane) to afford compound 3
as off-white solid. Yield 90%, mp 160–165°С. IR spec-
trum, ν, cm–1: 3016 (Ar-CH), 2954 (C–H), 1672 (C=O),
5j
5.597
Isoniazid + Rifampicin
40.000
carbazone 4a–4j (0.782 mmol) in ethanol (5 mL). The
reaction mixture was refluxed for 8–15 h. Upon com-
pletion of the reaction, the mixture was concentrated
under rota vacuo and the crude product was purified
by column chromatography using basic alumina
(gradient elution with 30 to 40% EtOAc/Hexane) to
yield the desired solid compounds 5a–5j respectively.
Microwave irradiation method B. A microwave
tube was filled with the mixture of 1,1'-(4,6-dimethoxy-
1,3-phenylene)bis(2,2-dibromoethanone) 3 (0.150 g,
0.279 mmol), a substituted thiosemicarbazone 4a–4j
(0.782 mmol) and ethanol (10 mL), and subjected to
MWI (Monowave-300 reactor) at 100 W for 5–15 min.
Upon completion of the reaction, the mixture was
concentrated under rota vacuo and the crude product
was purified by column chromatography using basic
alumina (gradient elution with 30 to 40% EtOAc/
Hexane) to yield the desired solid compounds 5a–5j,
respectively.
1
1558 (C=C). Н NMR spectrum, δ, ppm: 4.06 s (6H,
2OCH3), 6.89 s (1H, Ar-H), 7.38 s (2H, Ar-H), 8.20 s
(1H, Ar-H). 13C NMR spectrum, δC, ppm: 56.9, 68.9,
96.6, 117.2, 133.9, 164.2, 189.5. Found, %: C 26.74; H
1.83. C12H10Br4O4. Calculated, %: C 26.80; H 1.87. M
539.0 [M + H]+.
General procedure for synthesis of compounds
4a–4j [25–27]. The appropriate thiosemicarbazide
(1.0 g, 10.97 mmol) and aldehyde (12.07 mmol) were
dissolved in ethanol (10 mL) and acetic acid
(0.2 mmol) was added to the solution. The reaction
mixture was refluxed for 5–6 h and then cooled down
to room temperature. The resulting precipitate was
filtered off, washed with ether and recrystallized from
ethanol to obtain the corresponding thiosemicarbazones.
4,4'-(4,6-Dimethoxy-1,3-phenylene)bis[2-(2-benzyl-
idenehydrazinyl)thiazole] (5a). White solid. IR spec-
trum, ν, cm–1: 3462 (NH), 1618 (HC=N, azomethine),
1
1495 (C=N, thiazole), 1367 (C–N), 754 (C–S). Н
NMR spectrum, δ, ppm: 4.0 s (6H, 2OCH3), 6.83 s
(1Н, Ar-H), 7.26 s (2H, thiazole-H), 7.35–7.50 m (6H,
Ar-H),7.68 d (4H, Ar-H, J = 6.9 Hz), 8.09 s (2Н,
NH=CH), 8.64 s (1H, Ar-H). 13C NMR spectrum, δC,
ppm: 56.0, 96.3, 106.1, 113.8, 126.6, 126.8, 128.9,
General procedure for the synthesis of com-
pounds 5a–5j. Conventional heating method A. To a
stirred solution of 1,1'-(4,6-dimethoxy-1,3-phenylene)-
bis(2,2-dibromoethanone) 3 (0.150 g, 0.279 mmol) in
ethanol (5 mL), was added a substituted thiosemi-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 3 2018