Novel Substituted Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Molecular Docking Study, and Investigation of Their In Vitro Antifungal Activities

Article abstract of DOI:10.1002/jhet.3653

In this study, a new series of substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized. To this end, first 2-amino-1,3,4-thiadiazole derivatives (compounds 2a and 2b), the starting materials, were synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1-b][1,3,4]thiadiazole derivatives (4–16), the target compounds, were synthesized from reactions of 2-amino-1,3,4-thiadiazole derivatives (2a and 2b) with 2-bromoacetophenone derivatives (3a–3i) (in yields of 52% to 71%). All of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, Fourier transform infrared, elemental analysis, mass spectroscopy, and X-ray diffraction analysis (compounds 4–12, 14, and 15) techniques. In vitro antifungal activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibition, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target compounds were determined against some plant pathogens. According to the results of the biological activity tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical calculations were performed to support the experimental results. The geometric parameters of selected compounds (5, 6, and 8) were optimized using the density functional theory B3LYP/6-31G(d) method in the Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital–lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were performed for antifungal activity studies of the selected compounds and to determine whether or not these compounds could be inhibitor agents for the 2RKV protein structure.

Full text of DOI:10.1002/jhet.3653

Month 2019
Novel Substituted Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives:
Synthesis, Characterization, Molecular Docking Study, and Investigation
of Their In Vitro Antifungal Activities
a
Mustafa Er,
Hakan Tahtaci,a Tuncay Karakurt,b and Abdurrahman Onaranc
*
aDepartment of Chemistry, Faculty of Science, Karabuk University, 78050, Karabuk, Turkey
bDepartment of Chemical Engineering, Faculty of Engineering and Architecture, Ahi Evran University, 40100, Kırşehir,
Turkey
cDepartment of Plant Protection, Faculty of Agriculture, Gaziosmanpasa University, 60250, Tokat, Turkey
*E-mail: mustafaer@karabuk.edu.tr
Received January 9, 2019
DOI 10.1002/jhet.3653
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
In this study, a new series of substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized.
To this end, first 2-amino-1,3,4-thiadiazole derivatives (compounds 2a and 2b), the starting materials, were
synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1-b][1,3,4]thiadiazole deriva-
tives (4–16), the target compounds, were synthesized from reactions of 2-amino-1,3,4-thiadiazole derivatives
(2a and 2b) with 2-bromoacetophenone derivatives (3a–3i) (in yields of 52% to 71%). All of the synthesized
compounds were characterized by 1H NMR, 13C NMR, Fourier transform infrared, elemental analysis, mass
spectroscopy, and X-ray diffraction analysis (compounds 4–12, 14, and 15) techniques. In vitro antifungal
activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibi-
tion, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target
compounds were determined against some plant pathogens. According to the results of the biological activity
tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical
calculations were performed to support the experimental results. The geometric parameters of selected com-
pounds (5, 6, and 8) were optimized using the density functional theory B3LYP/6-31G(d) method in the
Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital–
lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were
performed for antifungal activity studies of the selected compounds and to determine whether or not these
compounds could be inhibitor agents for the 2RKV protein structure.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
bridgehead nitrogen atom, are referred to as
imidazo[2,1-b][1,3,4]thiadiazoles [11]. Imidazo[2,1-b]
[1,3,4]thiadiazoles and their derivatives are widely
used in medicine, pharmaceutics, and pharmaceutical
chemistry because of their numerous biological
activities, including antimicrobial [12,13], antifungal
[14], antibacterial [15–17], anti-inflammatory,[18–20]
antitubercular [21–24], analgesic [25], and diuretic [26]
activities.
Imidazo[2,1-b][1,3,4]thiadiazole and its derivatives are
known to have high anticancer activity. As is known,
cancer is a disease in which cells divide uncontrollably
and invade surrounding tissues. There are different
Among the most commonly used heterocyclic
compounds in pharmaceutics and clinical drugs are
imidazole, 1,3,4-thiadiazole, and their derivatives. In
recent years, synthesis and characterization studies of
bioactive compounds such as imidazole and 1,3,4-
thiadiazole have been steadily increasing [1–5]. The
synthesis of compounds containing these bioactive
groups together with various biological activities has
received much interest as well [6–10].
These heterocyclic systems, in which imidazole and
1,3,4-thiadiazole rings are fused to each other with a
© 2019 Wiley Periodicals, Inc.

M. Er, H. Tahtaci, T. Karakurt, and A. Onaran
Vol 000
assumptions regarding the causes of this disease. According
to one hypothesis, TGFβ receptors cause metastasis because
of loss of heterozygosity. The signaling pathway of the
TGFβ receptors must be inhibited to stop the metastasis of
cancer cells. The intracellular part of TGFβ receptors is the
starting point of the signaling pathway, which supports
metastasis [27–31].
In this part of the TGFβ receptor, phosphate groups in
adenosine triphosphate (ATP) are transferred to the TGFβ
receptor, which constitutes the first stage of the signal
that triggers metastasis. Since the structure of
imidazo[2,1-b][1,3,4]thiadiazole derivatives is similar to
that of ATP, they stop the phosphorylation reaction by
binding to TGFβ receptors instead of ATP molecules,
thereby creating an anticancer effect [32,33].
The sharp absorption bands observed around 2220–2260
cmꢀ1 that belong to the nitrile groups (C≡N) disappeared
in the IR spectra of 2-amino-1,3,4-thiadiazole derivatives
(2a,b). It was observed that symmetric and asymmetric
absorption bands appeared instead as two separate bands
belonging to the –NH2 group of 2-amino-1,3,4-
thiadiazole derivatives (2a and 2b) in the 3271–3112
cmꢀ1 range, which indicates that these compounds were
formed.
The –NH2 group proton signals of compounds 2a and
2b bonded to the 1,3,4-thiadiazole ring from the C2
1
position in H NMR spectra were observed as a singlet
corresponding to two protons in the range of 7.14–7.03
ppm. Proton peaks belonging to the –NH2 group of these
compounds (2a and 2b) disappeared as a result of proton-
deuterium exchange performed with D2O.
In addition to anticancer activity, imidazo[2,1-b][1,3,4]
thiadiazole derivatives have antimicrobial activity as well.
Pathogens gain resistance to antimicrobial drugs over
time, which leads to new problems. For this reason, it is
necessary to design and synthesize new antimicrobial
drugs to protect against epidemics [34].
The structures of compounds 2a and 2b were confirmed
by the 13C NMR spectra. In the 13C NMR spectra of these
compounds, C2 carbon signals belonging to the thiadiazole
ring were observed at 157.12 and 156.39 ppm for
compounds 2a and 2b, respectively. The C5 carbon
signals of the same ring were recorded as 169.33 and
169.78 ppm, respectively. In the 13C NMR spectra, it was
seen that resonance values belonging to carbons of the
thiadiazole ring of these compounds were highly
compatible with this type of compound in the literature
[12,40]. Other 13C NMR spectral data of the molecule
verified the suggested structure.
In the final step, imidazo[2,1-b][1,3,4]thiadiazole
derivatives (4–16), the target compounds, were
synthesized from reactions of 2-amino-1,3,4-thiadiazole
derivatives (2a and 2b) with 2-bromoacetophenone
derivatives (3a–3i) in absolute ethyl alcohol. The
synthetic pathway is shown in Scheme 1.
The most important evidence for the formation of
imidazo[2,1-b][1,3,4]thiadiazole derivatives in the IR
spectra of these compounds is the disappearance of
symmetric and asymmetric absorption bands belonging to
the –NH2 group in 2-amino-1,3,4-thiadiazole derivatives
(2a and 2b) observed in the 3271–3112 cmꢀ1 range.
Furthermore, the –NH2 group proton signals observed in
the 7.14–7.03 ppm range in the initial compounds (2a
and 2b) disappeared in the 1H NMR spectra of these
compounds. Instead, C5–H signals were observed as a
singlet corresponding to one proton in the 8.93–8.50 ppm
range, which indicates ring cyclization and is the most
important evidence for the formation of imidazo[2,1-b]
[1,3,4]thiadiazole derivatives (4–16). These values are
consistent with those of similar studies in the literature
[12,41].
In light of the aforementioned important data, this study
aims to synthesize imidazo[2,1-b][1,3,4]thiadiazole
derivatives
with
potential
biological
activities,
characterize them via various spectroscopic methods, and
investigate the antifungal activities of these compounds.
Another purpose of the study is to calculate the
optimized structures and highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular
orbital (LUMO) energy values of the most actives
compounds (5, 6, and 8) among the synthesized
compounds using the density functional theory (B3LYP)
[35,36] theory with 6-31G(d) basis set, which is a
quantum chemical calculation, in the Gaussian 09
program [37]. The study further aims to determine
whether or not these optimized compounds could be
candidate inhibitor agents for the 2RKV Fusarium
graminearum protein structure using the molecular
docking simulation method.
RESULTS AND DISCUSSION
Chemistry.
In this study, 2-amino-1,3,4-thiadiazole
derivatives (2a and 2b) were first synthesized. 2-Amino-
1,3,4-thiadiazole derivatives (2a and 2b) were obtained
from reactions of nitrile compounds (1a and 1b) with
thiosemicarbazide in trifluoroacetic acid with high yields
(82% and 79%, respectively). The nitrile derivatives (1a
and 1b) used as starting materials to synthesize
imidazo[2,1-b][1,3,4]thiadiazole derivatives (4–16) were
commercially obtained, while 2-amino-1,3,4-thiadiazole
derivatives (2a and 2b) were obtained as specified in the
literature [38,39].
Further, important evidence indicating ring cyclization
in imidazo[2.1-b][1,3,4]thiadiazole derivatives (4–16) is
the observation of signals in the ranges of 113.52–109.61
ppm and 146.18–143.14 ppm in the 13C NMR spectra,
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Month 2019
Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Mo-
lecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
Scheme 1. The synthetic route for the synthesis of substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (4–16). Reagent and conditions: i:
trifluoroacetic acid, 60°C, reflux, 3 h; ii: absolute ethanol, reflux, 12–16 h. [Color figure can be viewed at wileyonlinelibrary.com]
corresponding to C5 and C6 carbons, respectively. Peaks
belonging to C2 and C8 carbons in these compounds were
observed in the 165.15–163.26 ppm and 145.32–140.89
Rhizoctonia solani. Fungicides with 50% Manep, 80%
Thiram, and 80% Captan active substances, used as a
positive control, showed activity against all fungi at the
recommended doses. Some compounds showed the same
degree of effect as the positive control (Table 2 and
Figs 2 and 3). Dimethyl sulfoxide (DMSO), used as the
negative control, showed no antifungal activity. PI values
were determined considering the mycelium development
in the negative control. The PI value of test fungi for
1000 μg/mL varied from 55% to 100% for M. fructigena,
from 0% to 72% for R. solani, from 52% to 88% for A.
solani, from 52% to 86% for V. dahliae, from 0% to 68%
for S. sclerotiorum, and from 65% to 100% for F.
oxysporum f.sp. melonis. MFC, MIC, and LD50 values of
compounds against the fungi were also calculated
(Table 3). MFC values varied from >250 to >1000
μg/mL. These values varied depending on activities of
compounds against test fungi. Similarly, MIC values
varied depending on reactions of test fungi against
compounds. These activity values varied between 31.25
and 1000 μg/mL for MIC (Table 3). LD50 values varied
between doses of 253 and 1235 μg/mL. These values
were calculated to be 397 to 986 μg/mL for M.
fructigena, 561 to 1235 μg/mL for R. solani, 367 to 880
μg/mL for A. solani, 610 to 1062 μg/mL for V. dahliae,
728 to 1173 μg/mL for S. sclerotiorum, and 253 to 634
μg/mL for F. oxysporum f.sp. melonis.
1
ppm ranges, respectively. Other H NMR and 13C NMR
spectral data of these compounds are presented in the
1
experimental part of this study in detail. The H NMR
and 13C NMR spectra of all synthesized compounds are
given in the Supporting Information.
The mass spectra belonging to the synthesized
compounds were observed as expected with molecular
ion peaks.
In addition, the structures of compounds 4–12, 14, and
15 were confirmed by X-ray diffraction analysis. The
crystal structures and crystallographic data of these
compounds are shown in Figure 1 and Table 1,
respectively. Rotational disorder was observed for the F
atoms of crystals 5, 8, and 12. Bond lengths, bond
angles, and packing structures of compounds 4–12, 14,
and 15 are given in the Supporting Information.
In vitro antifungal activity studies.
In vitro antifungal
activity values of all synthesized compounds were
determined. Inhibition zones, percentage of inhibition
(PI), minimum fungicidal activity (MFC), minimum
inhibitory concentration (MIC), and lethal dose (LD50)
values of compounds were determined against some plant
pathogens (Tables 2 and 3 and Figs 2 and 3). Varying
activities were observed for 500 and 1000 μg/mL doses
of all used compounds. The activity rate increased with
increasing dose. The fungus that was most sensitive to
the compounds was Fusarium oxysporum f.sp. melonis,
followed by Alternaria solani, Monilia fructigena,
Verticillium dahliae, Sclerotinia sclerotiorum, and
Molecular docking studies. Molecular docking studies
of compounds 5, 6, and 8 were performed using the
AutoDock Vina [42] program. AutoDock Tools were
used for creating docking data entry files, and receptor–
ligand interactions were demonstrated with Discover
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M. Er, H. Tahtaci, T. Karakurt, and A. Onaran
Vol 000
Figure 1. The crystal structures of compounds 4–12, 14, and 15. [Color figure can be viewed at wileyonlinelibrary.com]
Studio Visualizer 2017 software [43]. Molecular docking
studies were conducted using Coenzyme A with a
resolution of 1.6 A and T-2 mycotoxin (ZBA) and X-ray
crystal structures of trichothecene 3-O-acetyltransferase
(PDB ID: 2RKV) in complex form. Before proceeding to
calculations, the crystal structures of 2RKV and all ligand
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lecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
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M. Er, H. Tahtaci, T. Karakurt, and A. Onaran
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Table 3
Antifungal activity values (MFC, MIC, and LD50) of target compounds (4–16).
MFC, MIC, and LD50 values (μg/mL)
Compounds
Values
MFC
Mf
>1000
250
722
>500
125
446
>500
125
470
>1000
250
Rs
As
Vd
Ss
FOM
>500
4
5
6
7
8
9
>1000
>1000
ND
>1000
>500
ND
>1000
>500
ND
>1000
>500
ND
>1000
>500
ND
>1000
500
1009
>1000
>250
1170
>1000
>250
1080
>1000
>250
1235
>1000
>250
1055
>1000
>250
1166
>1000
>250
1094
1000
125
>1000
125
665
>1000
125
>1000
250
921
>1000
500
953
>1000
250
1027
>1000
500
1048
>1000
250
714
>1000
125
787
>1000
500
1062
>1000
250
931
>1000
250
872
>1000
500
990
>1000
250
889
>1000
125
610
>1000
125
749
>2000
500
1766
3000
>31.25
1377
>2000
62.5
1534
>1000
250
1133
>1000
500
1173
>1000
>1000
ND
>1000
500
1161
>1000
500
1070
>1000
250
728
>1000
250
902
>1000
500
1100
>1000
1000
ND
>1000
1000
ND
>1000
500
1086
>1000
500
1062
>1000
500
1039
2000
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
MFC
MIC
LD50
62.5
407
>1000
125
598
>1000
125
525
>250
31.25
253
716
>1000
62.5
707
>1000
125
592
>1000
62.5
622
>500
735
>500
62,5
397
>1000
125
627
>100
125
726
>1000
250
694
>1000
250
889
>1000
250
986
>1000
250
>500
62.5
387
>500
31.25
62.5
367
>1000
125
880
>1000
125
767
>1000
125
739
>1000
125
681
>1000
125
830
>500
31.25
499
>500
485
>500
125
538
>500
31.25
395
>500
10
11
12
31.25
345
>250
13
31.25
275
>1000
125
634
>1000
125
14
803
15
>1000
>125
693
>1000
250
916
>2000
125
1188
3000
62.5
843
2000
580
>500
16
31.25
420
2000
62.5
604
3000
31.25
649
62.5
561
>2000
250
1388
3000
>62.5
1250
>2000
125
482
>2000
125
1682
3000
1C+
2C+
3C+
62.5
844
3000
31.25
615
>2000
250
62.5
679
2000
250
>1000
>31.25
510
31.25
572
1294
1497
927
ND, not determined; LD50, lethal dose; MFC, minimum fungicidal concentration; MIC, minimum inhibitory concentration; C+: Manep (1), Thiram (2),
and Captan (3) positive control; Mf, Monilia fructigena; Rs, Rhizoctonia solani; As, Alternaria solani; Vd, Verticillium dahliae; Ss, Sclerotinia
sclerotiorum; FOM, Fusarium oxysporum f.sp. melonis.
compounds were prepared using protein and ligand
preparation wizards in the PyRx package [44]. Prior to
the docking process, first water and heteroatoms other
than the natural ligand (ZBA) were removed, and
hydrogen atoms and Gasteiger charges were added to the
2RKV protein structure.
Molecular docking studies were performed to see
possible bonding modes of the synthesized compounds.
Coenzyme A and T-2 mycotoxin (ZBA, natural ligand)
and X-ray crystal structures of trichothecene 3-O-
acetyltransferase were used in the calculations. The
biological activity test results showed that compounds 5,
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Month 2019
Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Mo-
lecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
Figure 2. Percentage inhibition of compounds against M. fructigena (Mf), R. solani (RS), and A. solani (AS) for 500 and 1000 μg/mL; C+: Manep (1),
Thiram (2), and Captan (3) positive control; Cꢀ: negative control. According to negative control, mycelial growth was calculated percentage inhibition
values. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3. Percentage inhibition of compounds against V. dahliae (VD), S. sclerotiorum (SS), and F. oxysporum melonis (FOM) for 500 and 1000 μg/mL;
C+: Manep (1), Thiram (2), and Captan (3) positive control; Cꢀ: negative control. According to negative control, mycelial growth was calculated percent-
age inhibition values. [Color figure can be viewed at wileyonlinelibrary.com]
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M. Er, H. Tahtaci, T. Karakurt, and A. Onaran
Vol 000
Table 4
more specifically with hydrogen bonding and alkyl
interactions. As seen in Figure 4, the O atom of the
receptor and the reference ZBA ligand formed hydrogen
bonds with lengths of 2.49, 2.58, 2.17, and 2.82 Å with
amino acids TYR413, THR366, HIS156i, and LEU365
of the receptor, respectively. N and F atoms of ligand 5
formed hydrogen bonds with lengths of 2.37 and 2.19 Å
with TYR413 and MET161 of the receptor, respectively.
All of the three ligands yielded values similar to the
reference ligand (ZBA) according to their bonding
affinities as shown in Table 4. In conclusion, it is
possible to say that ligands 5, 6, and 8 could be candidate
inhibitor molecules for the 2RKV target structure. Also,
as seen in Table 4 and stated in the literature [39], high
HOMO energy values resulted in high docking scores.
The findings obtained in this study suggest that these
compounds could be new potential inhibitors with
biological activity for the 2RKV protein structure and
used in in vitro studies.
Docking scores and highest occupied molecular orbital (HOMO) energies
of compounds 5, 6, and 8 and natural ligand ZBA.
Comp. no.
DScore (kcal/mol)
E
HOMO (eV)
ZBA
ꢀ8.5
ꢀ7.4
ꢀ7.1
ꢀ7.4
ꢀ6.69
ꢀ5.72
ꢀ5.22
ꢀ5.74
5
6
8
6, and 8 were the most active against the M. fructigena
disease. Docking studies were performed for these three
ligands. Table 4 shows the docking scores and HOMO
energies of compounds 5, 6, and 8 and natural ligand
ZBA; Figures 4–7 show docking studies for the active
bonding zones of the target protein.
It was seen that the ligand bonded to the active bonding
sites of receptors with weak, noncovalent interactions and
Figure 4. The 3D and 2D presentation of docking results of the ZBA ligand in the active region of the 2RKV protein. [Color figure can be viewed at
wileyonlinelibrary.com]
Figure 5. The 3D and 2D presentation of docking results of ligand 5 in the active region of the 2RKV protein. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2019
Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Mo-
lecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
Figure 6. The 3D and 2D presentation of docking results of ligand 6 in the active region of the 2RKV protein. [Color figure can be viewed at
wileyonlinelibrary.com]
Figure 7. The 3D and 2D presentation of docking results of ligand 8 in the active region of the 2RKV protein. [Color figure can be viewed at
wileyonlinelibrary.com]
CONCLUSIONS
EXPERIMENTAL
The H NMR and 13C NMR spectra of the compounds
were measured in DMSO-d6 using an Agilent NMR
VNMRS spectrometer at 400 and 100 MHz, respectively.
Chemical shift values are given in ppm (δ) with
tetramethylsilane as internal standard. The IR spectra
were recorded in a Bruker Optics Alpha FTIR in
attenuated total reflection (ATR). The mass spectra were
measured with a Thermo TSQ Quantum Access Max LC-
MS/MS spectrometer. Elemental analyses were performed
on a LECO 932 CHNS (Leco-932, St. Joseph, MI, USA)
instrument, and the results were within 0.4% of the
theoretical values. Melting points were recorded on a
Thermo Scientific IA9000 series apparatus and were
uncorrected. All of the chemicals were obtained from
Sigma Aldrich Chemicals.
1
Imidazo[2,1-b][1,3,4]thiadiazole derivatives, the target
compounds of this study, were synthesized using simple
reaction methodologies. All of the synthesized
compounds were characterized using various analysis
methods.
Biological activity tests were applied to the target
compounds. According to the results obtained, all of the
synthesized compounds showed moderate to high levels
of antifungal activity against various plant pathogens.
After calculating the stable structures of the selected
compounds (5, 6, and 8), docking simulation processes
were used for HOMO–LUMO energies and possible
bonding models and confirmations for the molecule. It
was found that the HOMO energy values and affinity
energy values of the compounds were proportional.
All of the findings obtained in this study indicate that
these compounds could be new potential inhibitors for
the 2RKV protein structure.
Computational details.
Molecular docking studies
were performed using the AutoDock Vina [42] and
Discover Studio Visualizer 4.5 [43] programs. Optimized
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Vol 000
structures and HOMO energy values of all ligands were
calculated using the 6-32G(d) base set density functional
theory (B3LYP) theory with the Gaussian 09 program.
DMF-EtOH, 1:3). IR (ATR, cmꢀ1): 3271–3112 (–NH2),
3067 (Ar–CH), 2954 (Aliph. CH), 1602 (C═N). H NMR
1
(400 MHz, DMSO-d6) δ (ppm): 4.32 (s, 2H, –CH2),
Phenyl–H [7.54 (d, J = 8.0 Hz, 2H), 8.16 (d, J = 8.0 Hz,
2H)], 7.14 (s, 2H, NH2). 13C NMR (100 MHz,
DMSO-d6, δ ppm): 35.59 (–CH2), Phenyl–C [124.42
(CH), 130.67 (CH), 146.54 (C), 147.08 (C)],
Thiadiazole–C [156.39 (C), 169.78 (C)]. MS: m/z 237.06
(M+1, 100). Anal. Calcd. for C9H8N4O2S: C, 45.75; H,
Crystallographic analysis.
X-ray diffraction data of
crystals were collected with a Bruker AXS APEX CCD
[45] diffractometer using MoKα beams. The crystal was
kept at 293(2) K during data collection. Using Olex2
[46], the structure was solved with the ShelXT [47]
structure solution program using direct methods and
refined with the ShelXL [48] refinement package using
least squares minimization.
3.41; N, 23.72. Found: C, 45.68; H, 3.35; N, 23.65.
General procedure for the synthesis of imidazo[2,1-b][1,3,4]
thiadiazole derivatives (4–16). In a two-necked flask, 2-
amino-1,3,4-thiadiazole derivatives (2a–b) (4 mmol) were
dissolved in absolute ethanol (30 mL). 2-
Bromoacetophenone derivatives (3a–i) (4 mmol) were
dissolved in absolute ethanol (20 mL) and then added
drop by drop to this solution at room temperature with
the assistance of a dropping funnel. Then, the mixture
was refluxed and stirred for 12–16 h. The progress of
reaction was monitored by thin-layer chromatography at
appropriate time intervals. The excess of solvent was
removed under reduced pressure and neutralized by
aqueous sodium carbonate (Na2CO3) solution. The
solution was filtered and washed with deionized water.
The solid matter was recrystallized from acetone. The
synthesized compounds were dried with P2O5 in a
vacuum oven. The physical properties and spectral data
derived from the obtained products are listed below.
Fungi culture. M. fructigena (isolated from apple in
Gümüşhane, Turkey), R. solani (isolated from potato in
Tokat, Turkey), A. solani (isolated from tomato in Antalya,
Turkey), V. dahliae (isolated from tomato in Antalya,
Turkey), S. sclerotiorum (isolated from cucumber in An-
talya, Turkey), and F. oxysporum f.sp. melonis (isolated
from melon in Hatay, Turkey) plant pathogens were used
for in vitro antifungal activity study. The pathogens were
grown on a potato dextrose agar medium at 22°C 2°C
for about 7 days.
Synthesis. General procedure for the synthesis of
2-amino-1,3,4-thiadiazole derivatives (2a–b).
Compounds
2a–b were synthesized according to a method given in
the literature [38,39].
In a round-bottomed flask, compounds (1a–b) (0.1 mol)
and thiosemicarbazide (0.15 mol) in trifluoroacetic acid (50
mL) at 60°C were stirred for 3 h. The progress of the
reaction was monitored by thin-layer chromatography at
appropriate time intervals. After completion of the
reaction, the mixture was poured into 500 mL of ice-cold
water and neutralized with ammonia. The solution was
filtered, and the solid matter was obtained. It was washed
with deionized water, ethanol, and diethyl ether,
respectively. The solid was recrystallized from the
appropriate solvent. The physical properties and spectral
data derived from the obtained products are listed below.
2-(3-Fluorobenzyl)-6-phenylimidazo[2,1-b][1,3,4]
thiadiazole (4).
Brownish crystals, yield 0.77 g (62%),
mp 134–136°C (from Acetone). IR (ATR, cmꢀ1): 3112
1
(Ar–CH), 2922 (Aliph. CH), 1596 (C═N). H NMR (400
MHz, DMSO-d6, δ ppm): 4.46 (s, 2H, –CH2), 3F–Ar–H
[7.14 (t, J = 16.0 Hz, 1H), 7.25 (t, J = 16.0 Hz, 2H), 7.41
(q, J = 12.0 Hz, 1H)], Phenyl–H [7.24 (t, J = 12.0 Hz,
1H), 7.38 (t, J = 12.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H)],
Imidazole–H [8.63 (s, 1H)]. 13C NMR (100 MHz,
DMSO-d6, δ ppm): 36.85 (–CH2), 3F–Ar–C [114.69
(CH), 116.58 (CH), 125.07 (CH), 131.23 (CH), 139.15
(C), 161.47 (C)], Phenyl–C [125.75 (CH), 127.71 (CH),
129.09 (CH), 134.33 (C)], Imidazole–C [110.77 (CH),
145.38 (C)], Thiadiazole–C [145.32 (C), 163.89 (C)].
MS: m/z 309.64 (M+, 100). Anal. Calcd. for C17H12FN3S:
C, 66.00; H, 3.91; N, 13.58. Found: C, 65.95; H, 3.97;
N, 13.50.
5-(3-Fluorobenzyl)-1,3,4-thiadiazol-2-amine
(2a).
White crystals, yield: 17.16 g (82%), mp 201–203°C
(from DMF-EtOH, 1:4). IR (ATR, cmꢀ1): 3265–3114 (–
NH2), 3059 (Ar–CH), 2958 (Aliph. CH), 1604 (C═N).
1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.16 (s, 2H, –
CH2), Phenyl–H [7.11–7.07 (m, 3H), 7.35 (q, J = 12.0
Hz, 1H)], 7.03 (s, 2H, NH2). 13C NMR (100 MHz,
DMSO-d6, δ ppm): 35.39 (–CH2), Phenyl–C [114.001
(CH), 115.98 (CH), 125.27 (CH), 131.06 (CH), 141.29
(C), 163.83 (C)], Thiadiazole–C [157.12 (C), 169.33
(C)]. MS: m/z 209.82 (M+, 100). Anal. Calcd. for
C9H8FN3S: C, 51.66; H, 3.85; N, 20.08. Found: C,
51.62; H, 3.78; N, 20.18.
6-(4-Bromophenyl)-2-(3-fluorobenzyl)imidazo[2,1-b]
[1,3,4]thiadiazole (5).
Light yellow crystals, yield 1.01
g (65%), mp 156–157°C (from Acetone). IR (ATR, cmꢀ1):
1
3113 (Ar–CH), 2927 (Aliph. CH), 1595 (C═N). H NMR
(400 MHz, DMSO-d6, δ ppm): 4.46 (s, 2H, –CH2), 3F–
Ar–H [7.13 (t, J = 16.0 Hz, 1H), 7.24 (t, J = 16.0 Hz,
2H), 7.40 (q, J = 12.0 Hz, 1H)], Phenyl–H [7.56 (d, J =
8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H)], Imidazole–H
5-(4-Nitrobenzyl)-1,3,4-thiadiazol-2-amine (2b).
White
crystals, yield: 18.66 g (79%), mp 181–182°C (from
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Mo-
lecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
[8.68 (s, 1H)]. 13C NMR (100 MHz, DMSO-d6, δ ppm):
36.85 (–CH2), 3F–Ar–C [114.70 (CH), 116.58 (CH),
125.75 (CH), 131.22 (CH), 139.08 (C), 161.47 (C)],
Phenyl–C [120.57 (C), 127.04 (CH), 132.02 (C), 133.61
(CH)], Imidazole–C [111.22 (CH), 145.58 (C)],
Thiadiazole–C [144.21 (C), 163.89 (C)]. MS: m/z 389.54
(M+1, 100). Anal. Calcd. for C17H11BrFN3S: C, 52.59;
H, 2.86; N, 10.82. Found: C, 52.49; H, 2.88; N, 10.89.
OCH3), 3F–Ar–C [114.52 (CH), 116.56 (CH), 125.73
(CH), 131.22 (CH), 139.21 (C), 161.47 (C)], Phenyl–C
[114.88 (CH), 126.40 (C), 126.99 (CH), 159.11 (C)],
Imidazole–C [109.61 (CH), 145.44 (C)], Thiadiazole–C
[145.02 (C), 163.65 (C)]. MS: m/z 339.79 (M+, 100).
Anal. Calcd. for C18H14FN3OS: C, 63.70; H, 4.16; N,
12.38. Found: C, 63.77; H, 4.07; N, 12.29.
2-(3-Fluorobenzyl)-6-(4-nitrophenyl)imidazo[2,1-b]
6-(4-Chlorophenyl)-2-(3-fluorobenzyl)imidazo[2,1-b]
[1,3,4]thiadiazole (9).
Yellow crystals, yield 0.74 g
[1,3,4]thiadiazole (6).
Light yellow crystals, yield 0.98
(52%), mp 226–228°C (from Acetone). IR (ATR, cmꢀ1):
3122 (Ar–CH), 2925 (Aliph. CH), 1592 (C═N), 1514–
g (71%), mp 155–157°C (from Acetone). IR (ATR, cmꢀ1):
1
1
3109 (Ar–CH), 2925 (Aliph. CH), 1596 (C═N). H NMR
1333 (–NO2). H NMR (400 MHz, DMSO-d6, δ ppm):
(400 MHz, DMSO-d6, δ ppm): 4.46 (s, 2H, –CH2), 3F–
Ar–H [7.13 (t, J = 16.0 Hz, 1H), 7.24 (t, J = 16.0 Hz,
2H), 7.40 (q, J = 16.0 Hz, 1H)], Phenyl–H [7.43 (d, J =
8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H)], Imidazole–H
[8.67 (s, 1H)]. 13C NMR (100 MHz, DMSO-d6, δ ppm):
36.84 (–CH2), 3F–Ar–C [114.70 (CH), 116.37 (CH),
125.75 (CH), 131.21 (CH), 139.09 (C), 161.47 (C)],
Phenyl–C [126.72 (CH), 129.12 (CH), 132.05 (C),
133.25 (C)], Imidazole–C [111.19 (CH), 145.56 (C)],
Thiadiazole–C [144.18 (C), 163.89 (C)]. MS: m/z 343.68
(M+, 100). Anal. Calcd. for C17H11ClFN3S: C, 59.39; H,
3.22; N, 12.22. Found: C, 59.48; 49; H, 3.27; N, 12.14.
4.49 (s, 2H, –CH2), 3F–Ar–H [7.14 (t, J = 16.0 Hz, 1H),
7.26 (t, J = 16.0 Hz, 2H), 7.42 (q, J = 12.0 Hz, 1H)],
Phenyl–H [8.08 (d, J = 8.0 Hz, 2H), 8.25 (d, J = 8.0 Hz,
2H)], Imidazole–H [8.93 (s, 1H)]. 13C NMR (100 MHz,
DMSO-d6, δ ppm): 36.87 (–CH2), 3F–Ar–C [114.75
(CH), 116.63 (CH), 125.67 (CH), 131.24 (CH), 138.98
(C), 161.47 (C)], Phenyl–C [124.67 (CH), 125.79 (CH),
138.90 (C), 146.53 (C)], Imidazole–C [113.52 (CH),
143.14 (C)], Thiadiazole–C [140.89 (C), 163.89 (C)].
MS: m/z 354.77 (M+, 100). Anal. Calcd. for
C17H11FN4O2S: C, 57.62; H, 3.13; N, 15.81. Found: C,
57.71; H, 3.12; N, 15.74.
2-(3-Fluorobenzyl)-6-(4-fluorophenyl)imidazo[2,1-b]
4-(2-(3-Fluorobenzyl)imidazo[2,1-b][1,3,4]thiadiazol-6-
[1,3,4]thiadiazole (7).
White crystals, yield 0.84 g
yl)benzonitrile (10).
White crystals, yield 0.94 g (70%),
(64%), mp 148–150°C (from Acetone). IR (ATR, cmꢀ1):
mp 186–187°C (from Acetone). IR (ATR, cmꢀ1): 3137
(Ar–CH), 2920 (Aliph. CH), 2211 (C≡N), 1596 (C═N).
1H NMR (400 MHz, DMSO-d6, δ ppm): 4.47 (s, 2H, –
CH2), 3F–Ar–H [7.13 (t, J = 16.0 Hz, 1H), 7.25 (t, J =
16.0 Hz, 2H), 7.41 (q, J = 12.0 Hz, 1H)], Phenyl–H
[7.83 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.0 Hz, 2H)],
Imidazole–H [8.84 (s, 1H)]. 13C NMR (100 MHz,
DMSO-d6, δ ppm): 36.87 (–CH2), 119.48 (C≡N), 3F–
Ar–C [114.73 (CH), 116.40 (CH), 125.52 (CH), 131.31
(CH), 138.98 (C), 161.46 (C)], Phenyl–C [125.79 (CH),
131.23 (CH), 133.17 (C), 138.83 (C)], Imidazole–C
[109.72 (CH), 146.18 (C)], Thiadiazole–C [143.51 (C),
165.15 (C)]. MS: m/z 334.79 (M+, 100). Anal. Calcd. for
C18H11FN4S: C, 64.66; H, 3.32; N, 16.76. Found: C,
64.58; H, 3.25; N, 16.69.
1
3117 (Ar–CH), 2985 (Aliph. CH), 1587 (C═N). H NMR
(400 MHz, DMSO-d6, δ ppm): 4.45 (s, 2H, –CH2), 3F–
Ar–H [7.12 (t, J = 16.0 Hz, 1H), 7.25 (t, J = 12.0 Hz,
2H), 7.41 (q, J = 16.0 Hz, 1H)], Phenyl–H [7.19 (dd, J =
12.0, 6.0 Hz, 2H), 7.85 (dd, J = 12.0, 6.0 Hz, 2H)],
Imidazole–H [8.60 (s, 1H)]. 13C NMR (100 MHz,
DMSO-d6, δ ppm): 36.83 (–CH2), 3F–Ar–C [114.68
(CH), 116.57 (CH), 125.73 (CH), 131.28 (CH), 139.11
(C), 161.47 (C)], Phenyl–C [115.84 (CH), 127.02 (C),
130.89 (CH), 163.15 (C)], Imidazole–C [110.61 (CH),
145.36 (C)], Thiadiazole–C [144.48 (C), 164.14 (C)].
MS: m/z 327.79 (M+, 100). Anal. Calcd. for
C17H11F2N3S: C, 62.37; H, 3.39; N, 12.84. Found: C,
62.31; H, 3.44; N, 12.93.
2-(3-Fluorobenzyl)-6-(4-methoxyphenyl)imidazo[2,1-b]
6-([1,1′-Biphenyl]-4-yl)-2-(3-fluorobenzyl)imidazo[2,1-b]
[1,3,4]thiadiazole (8).
Orange crystals, yield 0.91 g
[1,3,4]thiadiazole (11).
Light yellow crystals, yield
(67%), mp 156–158°C (from Acetone). IR (ATR, cmꢀ1):
3123 (Ar–CH), 2926 (Aliph. CH), 1596 (C═N), 1099 (–
1.03 g (67%), mp 173–175°C (from Acetone). IR (ATR,
cmꢀ1): 3122 (Ar–CH), 2923 (Aliph. CH), 1595 (C═N).
1H NMR (400 MHz, DMSO-d6, δ ppm): 4.47 (s, 2H, –
CH2), 3F–Ar–H [7.15 (t, J = 16.0 Hz, 1H), 7.25 (t, J =
16.0 Hz, 2H), 7.34 (t, J = 12.0 Hz, 1H)], Phenyl–H [7.69
(d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H)], Phenyl–
Phenyl–H [7.47–7.39 (m, 3H), 7.68 (d, J = 8.0 Hz, 2H)],
Imidazole–H [8.69 (s, 1H)]. 13C NMR (100 MHz,
1
OCH3). H NMR (400 MHz, DMSO-d6, δ ppm): 3.75 (s,
3H, –OCH3), 4.45 (s, 2H, –CH2), 3F–Ar–H [7.14 (t, J =
16.0 Hz, 1H), 7.24 (t, J = 16.0 Hz, 2H), 7.41 (q, J = 12.0
Hz, 1H)], Phenyl–H [6.95 (d, J = 8.0 Hz, 2H), 7.74 (d, J
= 8.0 Hz, 2H)], Imidazole–H [8.50 (s, 1H)]. 13C NMR
(100 MHz, DMSO-d6, δ ppm): 36.82 (–CH2), 55.57 (–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Er, H. Tahtaci, T. Karakurt, and A. Onaran
Vol 000
DMSO-d6, δ ppm): 36.87 (–CH2), 3F–Ar–C [114.70 (CH),
116.59 (CH), 125.61 (CH), 131.24 (CH), 140.17 (C),
161.48 (C)], Phenyl–C [125.79 (CH), 127.85 (CH),
131.24 (CH), 139.16 (C)], Phenyl–Phenyl–C [125.76
(CH), 126.90 (CH), 127.35 (CH), 129.36 (C)],
Imidazole–C [110.95 (CH), 145.47 (C)], Thiadiazole–C
[145.04 (C), 164.21 (C)]. MS: m/z 385.89 (M+, 100).
Anal. Calcd. for C23H16FN3S: C, 71.67; H, 4.18; N,
10.90. Found: C, 71.62; H, 4.14; N, 10.88.
Phenyl–H [7.84 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.0 Hz,
2H)], Imidazole–H [8.86 (s, 1H)]. 13C NMR (100 MHz,
DMSO-d6, δ ppm): 36.83 (–CH2), 119.46 (C≡N), pNO2–
Ar–C [124.34 (CH), 131.02 (CH), 146.18 (C), 147.32
(C)], Phenyl–C [112.97 (C), 125.54 (CH), 133.21 (CH),
138.80 (C)], Imidazole–C [109.76 (CH), 144.10 (C)],
Thiadiazole–C [143.62 (C), 164.30 (C)]. MS: m/z 384.84
(M+ + Na). Anal. Calcd. for C18H11N5O2S: C, 59.82; H,
3.07; N, 19.38. Found: C, 59.88; H, 3.00; N, 19.30.
6-([1,1′-Biphenyl]-4-yl)-2-(4-nitrobenzyl)imidazo[2,1-b]
2-(3-Fluorobenzyl)-6-(4-(naphthalen-2-yl)phenyl)
[1,3,4]thiadiazole (15).
Light yellow crystals, yield
imidazo[2,1-b][1,3,4]thiadiazole
(12).
Brownish
1.09 g (66%), mp 230–231°C (from Acetone). IR (ATR,
crystals, yield 1.18 g (68%), mp 146–148°C (from
Acetone). IR (ATR, cmꢀ1): 3124 (Ar–CH), 2916 (Aliph.
CH), 1587 (C═N). 1H NMR (400 MHz, DMSO-d6, δ
ppm): 4.48 (s, 2H, –CH2), 3F–Ar–H [7.15 (t, J = 16.0
Hz, 1H), 7.25 (t, J = 16.0 Hz, 2H), 7.43–7.39 (m, 1H)],
Naphthyl–H [7.51–7.45 (m, 2H), 7.92–7.86 (m, 3H), 7.98
(d, J = 8.0 Hz, 1H), 8.37 (s, 1H)], Imidazole–H [8.75 (s,
1H)]. 13C NMR (100 MHz, DMSO-d6, δ ppm): 36.87 (–
CH2), 3F–Ar–C [114.72 (CH), 116.61 (CH), 125.77
(CH), 131.24 (CH), 139.06 (C), 161.48 (C)], Naphthyl–C
[123.16 (CH), 123.86 (CH), 126.23 (CH), 126.89 (CH),
128.07 (CH), 128.36 (CH), 128.62 (CH), 131.81 (C),
132.81 (C), 133.68 (C)], Imidazole–C [111.32 (CH),
145.62 (C)], Thiadiazole–C [145.36 (C), 164.25 (C)].
MS: m/z 359.71 (M+, 100). Anal. Calcd. for C21H14FN3S:
C, 70.18; H, 3.93; N, 11.69. Found: C, 70.12; H, 3.89;
N, 11.66.
cmꢀ1): 3109 (Ar–CH), 2950 (Aliph. CH), 1587 (C═N),
1
1509–1336 (–NO2). H NMR (400 MHz, DMSO-d6, δ
ppm): 4.64 (s, 2H, –CH2), pNO2–Ar–H [7.69 (d, J = 8.0
Hz, 2H), 8.23 (d, J = 8.0 Hz, 2H)], Phenyl–H [7.69 (d, J
= 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H)], Phenyl–
Phenyl–H [7.34 (t, J = 12.0 Hz, 1H), 7.44 (t, J = 12.0
Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H)], Imidazole–H [8.70 (s,
1H)]. 13C NMR (100 MHz, DMSO-d6, δ ppm): 36.82 (–
CH2), pNO2–Ar–C [124.35 (CH), 130.99 (CH), 145.45
(C), 147.30 (C)], Phenyl–C [127.86 (CH), 129.39 (CH),
133.44 (C), 139.34 (C)], Phenyl–Phenyl–C [125.62 (CH),
126.90 (CH), 127.36 (CH), 140.16 (C)], Imidazole–C
[110.99 (CH), 145.13 (C)], Thiadiazole–C [144.26 (C),
163.31 (C)]. MS: m/z 412.84 (M+, 100). Anal. Calcd. for
C23H16N4O2S: C, 66.97; H, 3.91; N, 13.58. Found: C,
66.90; H, 3.84; N, 13.61.
6-(4-(Naphthalen-2-yl)phenyl)-2-(4-nitrobenzyl)
2-(4-Nitrobenzyl)-6-phenylimidazo[2,1-b][1,3,4]
imidazo[2,1-b][1,3,4]thiadiazole (16).
Yellow solid,
thiadiazole (13).
White solid, yield 0.82 g (61%), mp
230–231°C (from Acetone). IR (ATR, cmꢀ1): 3126 (Ar–
CH), 2924 (Aliph. CH), 1599 (C═N), 1520–1336 (–
yield 1.1 g (71%), mp 183–185°C (from Acetone). IR
(ATR, cmꢀ1): 3108 (Ar–CH), 2939 (Aliph. CH), 1586
(C═N), 1510–1333 (–NO2). 1H NMR (400 MHz,
DMSO-d6, δ ppm): 4.65 (s, 2H, –CH2), pNO2–Ar–H
[7.70 (d, J = 8.0 Hz, 2H), 8.24 (d, J = 8.0 Hz, 2H)],
Naphthyl–H [7.51–7.44 (m, 2H), 7.93–7.87 (m, 3H), 7.98
(d, J = 8.0 Hz, 1H), 8.37 (s, 1H)], Imidazole–H [8.77 (s,
1H)]. 13C NMR (100 MHz, 00 DMSO-d6, δ ppm): 36.84
(–CH2), pNO2–Ar–C [124.36 (CH), 131.01 (CH), 145.62
(C), 147.32 (C)], Naphthyl–C [123.18 (CH), 123.85
(CH), 126.25 (CH), 126.90 (CH), 128.08 (CH), 128.36
(CH), 128.63 (CH), 131.77 (C), 132.83 (C), 133.66 (C)],
Imidazole–C [111.37 (CH), 145.46 (C)], Thiadiazole–C
[144.25 (C), 163.36 (C)]. MS: m/z 386.73 (M+, 100).
Anal. Calcd. for C21H14N4O2S: C, 65.27; H, 3.65; N,
14.50. Found: C, 65.21; H, 3.57; N, 14.41.
1
NO2). H NMR (400 MHz, DMSO-d6, δ ppm): 4.63 (s,
2H, –CH2), pNO2–Ar–H [7.69 (d, J = 8.0 Hz, 2H), 8.23
(d, J = 8.0 Hz, 2H)], Phenyl–H [7.25 (t, J = 16.0 Hz,
1H), 7.38 (t, J = 16.0 Hz, 2H) 7.83 (d, J = 8.0 Hz, 2H)],
Imidazole–H [8.64 (s, 1H)]. 13C NMR (100 MHz,
DMSO-d6, δ ppm): 36.81 (–CH2), pNO2–Ar–C [124.35
(CH), 130.99 (CH), 145.49 (C), 147.31 (C)], Phenyl–C
[125.08 (CH), 127.74 (CH), 129.10 (CH), 134.29 (C)],
Imidazole–C [110.82 (CH), 145.31 (C)], Thiadiazole–C
[144.26 (C), 163.26 (C)]. MS: m/z 337.32 (M+1, 100).
Anal. Calcd. for C17H12N4O2S: C, 60.70; H, 3.60; N,
16.66. Found: C, 60.61; H, 3.55; N, 16.61.
4-(2-(4-Nitrobenzyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)
benzonitrile (14).
Light yellow crystals, yield 0.93 g
In vitro antifungal activity. Antifungal activities of the
compounds were determined using the disc diffusion
method [49]. The compounds were dissolved in DMSO.
In a laminar flow cabin, Whatman No. 1 sterile filter
paper discs (6 mm) were impregnated with 50 μL of the
compounds (corresponding to 500 and 1000 μg/mL of
(64%), mp 223–225°C (from Acetone). IR (ATR, cmꢀ1):
3099 (Ar–CH), 2947 (Aliph. CH), 2221 (C≡N), 1606
(C═N), 1520–1349 (–NO2). 1H NMR (400 MHz,
DMSO-d6, δ ppm): 4.64 (s, 2H, –CH2), pNO2–Ar–H
[7.68 (d, J = 8.0 Hz, 2H), 8.22 (d, J = 8.0 Hz, 2H)],
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Mo-
lecular Docking Study, and Investigation of Their In Vitro Antifungal Activities
[3] Patel, H. M.; Sing, B.; Bhardwaj, B.; Palkar, M.; Shaikh, M.
S.; Rane, R.; Alwan, W. S.; Gadad, A. K.; Noolvi, M. N.; Karpoormath,
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Journal of Heterocyclic Chemistry
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M. Er, H. Tahtaci, T. Karakurt, and A. Onaran
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SUPPORTING INFORMATION
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet