Design and Synthesis of Some New Benzimidazole Containing Pyrazoles and Pyrazolyl Thiazoles as Potential Antimicrobial Agents

Article abstract of DOI:10.1002/jhet.3435

A new class of bis heterocycles-benzimidazolyl pyrazoles were prepared from the Michael acceptor (E)-3-(1H-benzimidazol-2-yl)-1-aryl-prop-2-en-1-one. The thiamide group was exploited to develop thiazole ring on treatment with p-fluorophenacyl bromide to get tris heterocycles. All the lead compounds were tested for antimicrobial activity. The compound 7d having nitro substituent on the aromatic ring showed greater antimicrobial activity particularly against Pseudomonas aeruginosa and Penicillium chrysogenum.

Full text of DOI:10.1002/jhet.3435

Month 2018 Design and Synthesis of Some New Benzimidazole Containing Pyrazoles
and Pyrazolyl Thiazoles as Potential Antimicrobial Agents
Nemallapudi Bakthavatchala Reddy,a
Grigory V. Zyryanov,a,e Guda Mallikarjuna Reddy,a,b Avula Balakrishna,c
Adivireddy Padmaja,d Venkatapuram Padmavathi,d Cirandur Suresh Reddy,d Jarem Raul Garcia,b and
a
*
Gundala Sravya
aChemical Engineering Institute, Ural Federal University, Yekaterinburg 620002, Russia
bDepartment of Chemistry, State University of Ponta Grossa, Ponta Grossa 84030–900, Parana, Brazil
cRajeev Gandhi Memorial College of Engineering and Technology (Autonomous), Nandyal 518501, Andhra Pradesh, India
dDepartment of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
eUral Division of the Russian Academy of Sciences, I. Ya. Postovskiy Institute of Organic Synthesis, 22 S. Kovalevskoy
Street, Yekaterinburg 620219, Russia
*E-mail: sravyas72@yahoo.com
Received July 31, 2018
DOI 10.1002/jhet.3435
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new class of bis heterocycles-benzimidazolyl pyrazoles were prepared from the Michael acceptor
(E)-3-(1H-benzimidazol-2-yl)-1-aryl-prop-2-en-1-one. The thiamide group was exploited to develop
thiazole ring on treatment with p-fluorophenacyl bromide to get tris heterocycles. All the lead compounds
were tested for antimicrobial activity. The compound 7d having nitro substituent on the aromatic ring
showed greater antimicrobial activity particularly against Pseudomonas aeruginosa and Penicillium
chrysogenum.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
heterocyclic pharmacophores,
functions as a cannabinoid receptor and is utilized to treat
obesity; fomepizole inhibits alcohol dehydrogenase; and
sildenafil inhibits phosphodiesterase [14] (Fig. 1).
Among
the
benzimidazole ring system is quite common, which was
first synthesized by Hoebrecker and subsequent
exploration by Ladnberg and Wundt during late 1870s
[1–3]. Such a heterocyclic scaffolds “benzimidazole” has
been known as a “major scaffold” considering for their
broad spectrum of biological profiles and empathies
towards different targets [4,5]. The benzimidazole
nucleus is considered as an important heterocyclic system
due to its presence in a wide range of bioactive
compounds [6]. Bendamustine [7] and Veliparib [8] are
benzimidazole-based drugs approved for the cancers
treatment (Fig. 1). The different substitutions on
benzimidazole and its derivatives have been luring
researchers throughout the world to investigate their
therapeutic potential [9–12]. The compounds with
pyrazole moieties are the most prominent class in active
pharmaceutical drugs and agrochemicals in controlling
infections, diseases, and pests [13]. In recent years,
several drugs have been developed from pyrazole
derivatives. For example, celecoxib demonstrates anti-
inflammatory effects and inhibits COX-2; rimonabant
Moreover, pyrazole derivatives have showed significant
biological activities, such as antimicrobial [15], analgesic
[16], anti-inflammatory [17], and anticancer [18]
activities. The significance of thiazoles is emphasized by
the fact that various drugs originate from them, such as
antifungal agent (ravuconazole) [19] and antiulcer agent
(nizatidine) [20] (Fig. 1). Besides, thiazolyl group is of
great importance as it appears frequently in the structures
of various natural products and biologically active
compounds like thiamine (vitamin B) and also in some
antibiotic drugs like penicillin, micrococcin [21], and
many metabolic products of fungi and primitive marine
animals. In addition, pyrazolyl thiazole scaffolds have
been receiving several medical and pharmaceutical
applications. They have potent antiviral [22], anti-
inflammatory [23], and antimicrobial activities [24,25] as
well as EP1 receptor antagonists [26,27]. Motivated by the
aforesaid findings and pursuing our studies on different
five-membered heterocycles [28], we were designed to
synthesize a new series of benzimidazole linked pyrazolyl
thiazoles and tested them as antimicrobial agents.
© 2018 Wiley Periodicals, Inc.

N. Bakthavatchala Reddy, G. V. Zyryanov, G. Mallikarjuna Reddy, A. Balakrishna,
A. Padmaja, V. Padmavathi, C. Suresh Reddy, J. R. Garcia, and G. Sravya
Vol 000
Figure 1. Drugs containing benzimidazole, pyrazole, and thiazole units. [Color figure can be viewed at wileyonlinelibrary.com]
RESULTS AND DISCUSSION
Hx are trans, and HM and HX are geminal. In addition,
two broad singlets were observed at δ 10.14 and
8.49 ppm due to NH and NH2, respectively, which
disappeared on deuteration.
A new class of bis and tris heterocycles—4,5-dihydro-
5-(1H-benzimidazol-2-yl)-3-aryl-pyrazole-1-
carbothioamide (4), 5-(1H-benzimidazol-2-yl)-3-aryl-1H-
pyrazole-1-carbothioamide (5), 2-(5-(1H-benzimidazol-2-
yl)-3-aryl-1H-pyrazol-1-yl)-4-(4-fluorophenyl)thiazole (7)
—were synthesized from (E)-3-(1H-benzimidazol-2-yl)-1-
aryl-prop-2-en-1-one (3) (Scheme 1). In fact, the
compound 3 was prepared by the Claisen–Schmidt
reaction of benzimidazole-2-carboxaldehyde (1) and aryl
ketones (2) in the presence of NaOH in methanol. The
compound 4 was prepared by the reaction of 3 with
thiosemicarbazide in the presence of NaOH in ethanol.
Oxidation of 4 with chloranil in xylene produced the
aromatized product 5. The 1H-NMR spectrum of 5a
showed a singlet at δ 6.31 and two broad singlets at 8.57
and 10.08 ppm due to C4–H, NH2, and NH, respectively.
The signals due to highly acidic protons disappeared
when D2O was added. Moreover, exploitation of
compound
5
furnished compound 7. Thus, the
cyclocondensation reaction of 5 with p-fluorophenacyl
bromide (6) resulted in 2-(5-(1H-benzimidazol-2-yl)-3-
aryl-1H-pyrazol-1-yl)-4-(4-fluorophenyl)thiazole (7). The
1H-NMR spectrum of 7a displayed a singlet at δ 6.37 and
a broad singlet at 10.10 ppm due to C4–H and NH.
Another singlet corresponding to C5–H was observed at
downfield region and merged with aromatic protons. The
structures of all the compounds were further confirmed
by IR, 13C-NMR, mass spectra, and elemental analyses.
1
The H-NMR spectrum of 4a exhibited an AMX splitting
pattern for pyrazoline ring protons. The three doublets of
doublets appeared at δ 4.14, 3.93, and 3.51 ppm were
assigned to HA, HM, and HX, respectively. The coupling
constant values JAM
= 12.3, JMX = 10.3, and
JAX = 6.3 Hz indicated that HA and HM are cis, HA and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design and Synthesis of Some New Benzimidazole Containing Pyrazoles and
Pyrazolyl Thiazoles as Potential Antimicrobial Agents
Scheme 1. [Color figure can be viewed at wileyonlinelibrary.com]
Antibacterial activity. The compounds 4, 5, and 7 were
screened for antibacterial activity at four different
concentrations 12.5, 25, 50, and 100 μg per well against
Staphylococcus aureus, Bacillus subtilis (Gram-positive
were more effective. On the other hand, the non-
aromatized (4a–g) compounds were inactive. This may be
due to the greater electron withdrawing capacity of the
aromatized compounds. Moreover, it was observed that
pyrazolyl thiazole containing tris heterocycles displayed
slightly higher activity than the respective pyrazole
containing bis heterocycles.
Antifungal activity. All the tested compounds inhibited
the spore germination against tested fungi. In general, most
of the compounds showed slightly higher antifungal
activity towards Aspergillus niger than Penicillium
chrysogenum. Among all the compounds, 7d displayed
bacteria),
Pseudomonas
aeruginosa,
Klebsiella
pneumoniae
(Gram-negative
bacteria),
and
Chloramphenicol, which was used as standard drug. The
results of antibacterial activity shown in Table S1 specified
that Gram-negative bacteria were more vulnerable towards
the tested compounds than Gram-positive ones. It was
observed that bis and tris heterocyclic compounds (5 and
7) showed slightly higher activity than the respective
mono heterocyclic system (4). This may be due to the
presence of electron withdrawing groups (NO2, F, Cl, and
Br) in bis heterocyclic compounds. The compounds
having electron withdrawing groups (5d, 5e, 5f, 5g, 7d,
7e, 7f, and 7g) were more active than those having
donating groups (OCH3 and CH3). In fact, the compound
5d showed excellent activity against P. aeruginosa when
compared with the standard drug Chloramphenicol (Table
S1 and Fig. S2). This may be due to the presence of more
electronegative chlorine on the aromatic ring. Among bis
heterocyclic compounds, aromatized derivatives (5a–g)
greater
inhibitory
activity
particularly
against
P. chrysogenum when compared with the standard drug
Ketoconazole (Table S2 and Fig. S3). Moreover,
compounds 5d, 5e, 5f, 5g, 7e, 7f, and 7g exhibited good
activity. In fact, compounds having pyrazole and thiazole
in combination with benzimidazole displayed high
inhibitory activity than others.
Minimum inhibitory concentration, minimum bactericidal
concentration, and minimum fungicidal concentration of the
compounds 5d, 7d, and 7e.
The minimum inhibitory
concentration (MIC), minimum bactericidal concentration
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Bakthavatchala Reddy, G. V. Zyryanov, G. Mallikarjuna Reddy, A. Balakrishna,
A. Padmaja, V. Padmavathi, C. Suresh Reddy, J. R. Garcia, and G. Sravya
Vol 000
(MBC), and minimum fungicidal concentration (MFC)
values of the compounds tested are listed in Table S3.
MIC is the lowest concentration of an antimicrobial that
will inhibit the visible growth of a microorganism. (But it
is not sure that the microorganisms are completely
killed.) The MBC/MFC is the lowest concentration of
antibiotic required to kill a particular bacterium/fungi.
The MBC/MFC involves an additional set of steps
performed once the MIC is determined. The
was used as diluents. The 24-h old culture of the test
bacteria S. aureus, B. subtilis, P. aeruginosa, and
K. pneumoniae and the test fungi A. niger and
P. chrysogenum was diluted 100 folds in NB (100-μL
bacterial cultures in 10-mL NB). The stock solution of
the synthesized compounds was prepared in DMSO by
dissolving 5 mg of the compound in 1 mL of DMSO.
Increasing concentrations of the test samples (1.25, 2.5,
5, 10, 20, and 40 μL of stock solution contains 6.25,
12.5, 25, 50, 100, and 200 μg of the compounds) were
added to the test tubes containing the bacterial and fungal
cultures. All the tubes were incubated at 37°C for 24 h
for bacteria and at 28°C for 48 h for fungi. The tubes
were examined for visible turbidity and using NB as
control. Control without test samples and with solvent
was assayed simultaneously. The lowest concentration
that inhibited visible growth of the tested organisms was
recorded as MIC.
To determine the MBC [34] and MFC [35] for each set
of test tubes in the MIC determination, a loopful of broth
was collected from those tubes that did not show any
growth and inoculated on sterile NB (for bacteria) and
Potato Dextrose Agar (PDA) (for fungi) by streaking.
Plates inoculated with bacteria and fungi were incubated
at 37°C for 24 h and at 28°C for 48 h, respectively. After
incubation, the lowest concentration was noted as MBC
(for bacteria) or MFC (for fungi) at which no visible
growth was observed.
antimicrobials
are
usually
regarded
as
bactericidal/fungicidal if the MBC/MFC is not greater
than four times the MIC [29]. The compound 7d
exhibited low MIC values when compared with 5d and
7e. In addition, MBC value in 7d is 2 × MIC in case of
P. aeruginosa, and MFC value is 2 × MIC in case of
P. chrysogenum. However, the other compounds showed
bactericidal and fungicidal effects greater than 2 × MIC.
The structure–antimicrobial activity relationship of the
synthesized compounds revealed that tris heterocyclic
compounds have greater activity than the corresponding
bis heterocycles. Among tris heterocyclic systems, the
nitro substituted 7d displayed excellent antibacterial
activity against P. aeruginosa with an inhibition zone of
34 mm at 100 μg per well and MIC and MBC of 6.25
and 12.5 μg/mL, respectively. The compound 5d also
displayed
strong
antifungal
activity
against
P. chrysogenum with an inhibition zone of 41 mm at
100 μg per well and MIC and MFC of 12.5 and
25 μg/mL, respectively. Moreover, it was observed that
the compounds having nitro substituent on aromatic ring
enhanced the activity when compared with electron
donating compounds.
CONCLUSION
Experimental procedure for antimicrobial activity. The
in vitro antimicrobial studies were carried out by agar
well diffusion method against test organisms [30,31].
Nutrient broth (NB) plates were swabbed with 24-h old
broth culture (100 μL) of test bacteria. Using the sterile
cork borer, wells (6 mm) were made into each petriplate.
The compounds were dissolved in dimethyl sulfoxide
(DMSO) of 5 mg/mL, and from this, 2.5, 5, 10, and
20 μL (12.5, 25, 50, and 100 μg per well) were added
into the wells by using sterile pipettes. Simultaneously,
the standard antibiotics, Chloramphenicol for antibacterial
activity and Ketoconazole for antifungal activity (as
positive control), were tested against the pathogens. The
samples were dissolved in DMSO, which showed that no
zone of inhibition acts as negative control. The plates
were incubated at 37°C for 24 h for bacteria and at 28°C
for 48 h for fungi. After appropriate incubation, the
diameter of zone of inhibition of each well was
measured. Duplicates were maintained, and the average
values were calculated for eventual antimicrobial activity.
Broth dilution test is used to determine MIC of the
aforementioned samples [32,33]. Freshly prepared NB
In conclusion, we have prepared a new class of bis
heterocycles-benzimidazolyl pyrazoles from the Michael
acceptor (E)-3-(1H-benzimidazol-2-yl)-1-aryl-prop-2-en-
1-one. The thiamide group was exploited to develop
thiazole ring on treatment with p-fluorophenacyl bromide
to get tris heterocycles. All the lead compounds were
tested for antimicrobial activity. The compound 7d
having nitro substituent on the aromatic ring showed
greater antimicrobial activity particularly against
P. aeruginosa and P. chrysogenum.
EXPERIMENTAL
Melting points were determined in open capillaries on a
1
Mel-Temp apparatus and are uncorrected. The H-NMR
spectra were recorded in CDCl3/DMSO-d6 on a Jeol
JNM λ-400 MHz spectrometer. The 13C-NMR spectra
were recorded in CDCl3/DMSO-d6 on a Jeol JNM
spectrometer operating at λ-100 MHz. High-resolution
mass spectra were recorded on Micromass Q-TOF
micromass spectrometer using electro spray ionization.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design and Synthesis of Some New Benzimidazole Containing Pyrazoles and
Pyrazolyl Thiazoles as Potential Antimicrobial Agents
All chemical shifts were reported in δ (ppm) using TMS as
an internal standard. The microanalyses were performed on
a Perkin-Elmer 240C elemental analyzer. The temperature
was measured by flexible probe throughout the reaction.
General procedure for the synthesis of 4,5-dihydro-5-(1H-
benzimidazol-2-yl)-3-aryl-pyrazole-1-carbothioamide
(4a–g). An equimolar (1 mmol) mixture of compound 3
[M + Na]; Anal. Calcd for C18H17N5OS: C, 61.52; H,
4.88; N, 19.93%; found: C, 61.63; H, 4.90; N, 20.15%.
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-(p-nitrophenyl)
pyrazole-1-carbothioamide (4d). Yellow solid; yield 84%;
m.p. 172–174°C; IR (KBr) (cmꢀ1): 3426, 3333 (NH2),
3231 (NH), 1570 (C¼N), 1338 (C¼S); 1H-NMR
(400 MHz, DMSO-d6):
δ
3.65 (dd, 1H, HX,
and thiosemicarbazide, ethanol (3 mL), and sodium
hydroxide (1.5 mmol) was added. It was refluxed for 7–
8 h. After completion of the reaction (monitored by
TLC), the contents of the flask were poured onto crushed
ice. The separated solid was collected by filtration and
purified by recrystallization from isopropyl alcohol.
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-phenylpyrazole-1-
carbothioamide (4a). Yellow solid; yield 76%; m.p. 146–
JAX = 6.8 Hz, JMX = 10.8 Hz), 4.12 (dd, 1H, HM,
JAM = 12.8 Hz, JMX = 10.8 Hz), 4.52 (dd, 1H, HA,
JAM = 12.8 Hz, JAX = 6.8 Hz), 8.65 (bs, 2H, NH2), 7.26–
8.37 (m, 8H, Ar–H), 10.48 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 45.2 (C-4), 58.8 (C-5), 119.4,
127.6, 132.3, 132.9, 135.0, 139.3, 142.3, 144.8, 155.7
(aromatic carbons), 175.3 (C¼S) ppm; MS (m/z):
389.3875 [M + Na]; Anal. Calcd for C17H14N6O2S: C,
55.73; H, 3.85; N, 22.94%; found: C, 55.81; H, 3.87; N,
148°C; IR (KBr) (cmꢀ1): 3445, 3336 (NH2), 3229 (NH),
1584 (C¼N), 1365 (C¼S); 1H-NMR (400 MHz,
DMSO-d6): δ 3.51 (dd, 1H, HX, JAX = 6.3 Hz,
JMX = 10.3 Hz), 3.93 (dd, 1H, HM, JAM = 12.3 Hz,
JMX = 10.3 Hz), 4.14 (dd, 1H, HA, JAM = 12.3 Hz,
JAX = 6.3 Hz), 8.49 (bs, 2H, NH2), 7.21–7.71 (m, 9H,
Ar–H), 10.14 (bs, 1H, NH) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ 43.6 (C-4), 57.2 (C-5), 118.5, 126.6, 131.1,
131.9, 133.7, 137.8, 140.8, 143.5, 154.4 (aromatic
carbons), 174.3 (C¼S) ppm; MS (m/z): 344.3888
[M + Na]; Anal. Calcd for C17H15N5S: C, 63.53; H, 4.70;
23.18%.
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-(p-fluorophenyl)
pyrazole-1-carbothioamide (4e). Yellow solid; yield 81%;
m.p. 166–168°C; IR (KBr) (cmꢀ1): 3437, 3329 (NH2),
3237 (NH), 1572 (C¼N), 1333 (C¼S); 1H-NMR
(400 MHz, DMSO-d6):
δ
3.02 (dd, 1H, HX,
JAX = 6.7 Hz, JMX = 10.7 Hz), 4.03 (dd, 1H, HM,
JAM = 12.6 Hz, JMX = 10.7 Hz), 4.46 (dd, 1H, HA,
JAM = 12.6 Hz, JAX = 6.7 Hz), 8.60 (bs, 2H, NH2), 7.25–
8.08 (m, 8H, Ar–H), 10.39 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 44.8 (C-4), 58.2 (C-5), 119.3,
127.4, 132.1, 132.5, 134.8, 139.0, 142.1, 144.5, 155.4
(aromatic carbons), 175.0 (C¼S) ppm; MS (m/z):
362.3789 [M + Na]; Anal. Calcd for C17H14FN5S: C,
60.16; H, 4.16; 5.88; N, 20.64%; found: C, 60.24; H,
N, 21.79%; found: C, 63.62; H, 4.71; N, 21.92%.
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-p-tolylpyrazole-1-
carbothioamide (4b). Yellow solid; yield 72%; m.p. 137–
139°C; IR (KBr) (cmꢀ1): 3438, 3332 (NH2), 3236 (NH),
1575 (C¼N), 1333 (C¼S); 1H-NMR (400 MHz,
DMSO-d6): δ 2.36 (s, 3H, Ar–CH3), 3.49 (dd, 1H, HX,
JAX = 6.1 Hz, JMX = 10.2 Hz), 4.07 (dd, 1H, HM,
JAM = 12.1 Hz, JMX = 10.2 Hz), 4.87 (dd, 1H, HA,
JAM = 12.1 Hz, JAX = 6.1 Hz), 8.32 (bs, 2H, NH2), 7.22–
7.76 (m, 8H, Ar–H), 10.08 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 21.8 (Ar–CH3), 43.1 (C-4),
56.5 (C-5), 118.3, 126.2, 130.4, 131.2, 133.5, 137.4,
140.5, 143.2, 154.1 (aromatic carbons), 173.9 (C¼S)
ppm; MS (m/z): 358.4147 [M + Na]; Anal. Calcd for
C18H17N5S: C, 64.45; H, 5.11; N, 20.88%; found: C,
4.18; N, 20.81%.
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-(p-chlorophenyl)
pyrazole-1-carbothioamide (4f). Yellow solid; yield 79%;
m.p. 158–160°C; IR (KBr) (cmꢀ1): 3427, 3319 (NH2),
3228 (NH), 1561 (C¼N), 1322 (C¼S); 1H-NMR
(400 MHz, DMSO-d6):
δ
3.58 (dd, 1H, HX,
JAX = 6.5 Hz, JMX = 10.5 Hz), 3.98 (dd, 1H, HM,
JAM = 12.5 Hz, JMX = 10.5 Hz), 4.32 (dd, 1H, HA,
JAM = 12.5 Hz, JAX = 6.5 Hz), 8.58 (bs, 2H, NH2), 7.24–
7.87 (m, 8H, Ar–H), 10.26 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 44.1 (C-4), 57.9 (C-5), 119.1,
127.2, 131.6, 132.3, 134.5, 138.7, 141.7, 144.1, 155.2
(aromatic carbons), 174.8 (C¼S) ppm; MS (m/z):
378.8351 [M + Na]; Anal. Calcd for C17H14ClN5S: C,
57.38; H, 3.97; N, 19.68%; found: C, 57.49; H, 4.00; N,
64.55; H, 5.12; N, 21.06%.
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-(p-methoxyphenyl)
pyrazole-1-carbothioamide (4c). Yellow solid; yield 70%;
m.p. 140–142°C; IR (KBr) (cmꢀ1): 3440, 3331 (NH2),
3239 (NH), 1578 (C¼N), 1339 (C¼S); 1H-NMR
(400 MHz, DMSO-d6):
δ
3.45 (dd, 1H, HX,
19.86%.
JAX = 6.1 Hz, JMX = 10.2 Hz), 3.88 (dd, 1H, HM,
JAM = 12.1 Hz, JMX = 10.2 Hz), 3.81 (s, 3H, Ar–OCH3),
4.01 (dd, 1H, HA, JAM = 12.1 Hz, JAX = 6.1 Hz), 8.27
(bs, 2H, NH2), 7.06–7.95 (m, 8H, Ar–H), 10.02 (bs, 1H,
NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 42.9 (C-
4), 56.7 (Ar–OCH3), 56.1 (C-5), 118.1, 126.1, 130.0,
131.1, 133.2, 137.3, 140.1, 143.0, 153.9 (aromatic
carbons), 173.5 (C¼S) ppm; MS (m/z): 374.4163
4,5-Dihydro-5-(1H-benzimidazol-2-yl)-3-(p-bromophenyl)
pyrazole-1-carbothioamide (4g). Yellow solid; yield 78%;
m.p. 152–154°C; IR (KBr) (cmꢀ1): 3447, 3339 (NH2),
3248 (NH), 1582 (C¼N), 1343 (C¼S); 1H-NMR
(400 MHz, DMSO-d6):
δ
3.54 (dd, 1H, HX,
JAX = 6.3 Hz, JMX = 10.4 Hz), 3.96 (dd, 1H, HM,
JAM = 12.4 Hz, JMX = 10.4 Hz), 4.20 (dd, 1H, HA,
JAM = 12.4 Hz, JAX = 6.3 Hz), 8.54 (bs, 2H, NH2), 7.23–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Bakthavatchala Reddy, G. V. Zyryanov, G. Mallikarjuna Reddy, A. Balakrishna,
A. Padmaja, V. Padmavathi, C. Suresh Reddy, J. R. Garcia, and G. Sravya
Vol 000
1
7.79 (m, 8H, Ar–H), 10.19 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 43.8 (C-4), 57.5 (C-5), 118.7,
127.0, 131.2, 132.0, 134.1, 138.2, 141.1, 143.8, 154.9
(aromatic carbons), 174.6 (C¼S) ppm; MS (m/z):
423.2864 [M + Na]; Anal. Calcd for C17H14BrN5S: C,
51.01; H, 3.53; N, 17.50%; found: C, 51.14; H, 3.54; N,
17.69%.
(NH), 1560 (C¼N), 1321 (C¼S); H-NMR (400 MHz,
DMSO-d6): δ 6.92 (s, 1H, C4–H), 7.32–8.15 (m, 8H,
Ar–H), 8.74 (bs, 2H, NH2), 10.19 (bs, 1H, NH) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 104.8 (C-4), 116.8,
124.6, 128.9, 129.7, 130.6, 131.1, 134.7, 142.8, 151.6,
153.3 (aromatic carbons), 177.6 (C¼S) ppm; MS (m/z):
387.3721 [M + Na]; Anal. Calcd for C17H12N6O2S:
56.04; H, 3.32; N, 23.06%; found: C, 56.15; H, 3.35; N,
General procedure for the synthesis of 5-(1H-benzimidazol-
2-yl)-3-aryl-1H-pyrazole-1-carbothioamide
(5a–g).
A
23.39%.
5-(1H-benzimidazol-2-yl)-3-(p-fluorophenyl)-1H-pyrazole-1-
solution of compound
4 (1 mmol) and chloranil
carbothioamide (5e).
Yellow solid; yield 83%; m.p.
(1.2 mmol) in xylene (10 mL) was refluxed for 24 h.
Then it was treated with 5% NaOH solution. The organic
layer was separated, repeatedly washed with water,
and dried over an Na2SO4. The solvent was removed
in vacuo. The solid obtained was purified by
recrystallization from isopropyl alcohol.
5-(1H-benzimidazol-2-yl)-3-phenyl-1H-pyrazole-1-
carbothioamide (5a). Yellow solid; yield 78%; m.p. 141–
162–164°C; IR (KBr) (cmꢀ1): 3422, 3314 (NH2), 3223
1
(NH), 1566 (C¼N), 1321 (C¼S); H-NMR (400 MHz,
DMSO-d6): δ 6.90 (s, 1H, C4–H), 7.30–8.14 (m, 8H,
Ar–H), 8.71 (bs, 2H, NH2), 10.17 (bs, 1H, NH) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 104.5 (C-4), 116.5,
124.3, 128.6, 129.4, 130.3, 130.8, 134.0, 141.9, 142.5,
151.3, 153.0 (aromatic carbons), 177.4 (C¼S) ppm; MS
(m/z): 360.3633 [M + Na]; Anal. Calcd for C17H12FN5S:
C, 60.52; H, 3.59; N, 20.76%; found: C, 63.62; H, 3.61;
143°C; IR (KBr) (cmꢀ1): 3437, 3329 (NH2), 3237 (NH),
1571 (C¼N), 1332 (C¼S); 1H-NMR (400 MHz,
DMSO-d6): δ 6.31 (s, 1H, C4–H), 7.28–7.99 (m, 9H,
Ar–H), 8.57 (bs, 2H, NH2), 10.08 (bs, 1H, NH) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 103.6 (C-4), 115.5,
123.7, 127.4, 128.4, 129.1, 129.8, 133.1, 140.9, 141.7,
150.5, 152.3 (aromatic carbons), 176.7 (C¼S) ppm; MS
(m/z): 342.3745 [M + Na]; Anal. Calcd for C17H13N5S:
C, 63.93; H, 4.10; N, 21.93%; found: C, 64.09; H, 4.12;
N, 20.89%.
5-(1H-benzimidazol-2-yl)-3-(p-chlorophenyl)-1H-pyrazole-1-
carbothioamide (5f).
Yellow solid; yield 81%; m.p.
158–160°C; IR (KBr) (cmꢀ1): 3417, 3309 (NH2), 3207
1
(NH), 1551 (C¼N), 1312 (C¼S); H-NMR (400 MHz,
DMSO-d6): δ 6.87 (s, 1H, C4–H), 7.29–8.12 (m, 8H,
Ar–H), 8.69 (bs, 2H, NH2), 10.14 (bs, 1H, NH) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 104.1 (C-4), 116.2,
124.0, 128.3, 129.1, 130.0, 129.6, 133.7, 141.6, 142.2,
151.0, 152.7 (aromatic carbons), 177.1 (C¼S) ppm; MS
(m/z): 376.8192 [M + Na]; Anal. Calcd for C17H12ClN5S:
C, 60.45; H, 3.58; N, 20.73%; found: C, 60.60; H, 3.59;
N, 22.20%.
5-(1H-benzimidazol-2-yl)-3-p-tolyl-1H-pyrazole-1-
carbothioamide (5b).
Yellow solid; yield 74%; m.p.
149–152°C; IR (KBr) (cmꢀ1): 3438, 3330 (NH2), 3239
1
(NH), 1574 (C¼N), 1333 (C¼S); H-NMR (400 MHz,
DMSO-d6): δ 2.36 (s, 3H, Ar–CH3), 6.70 (s, 1H, C4–H),
7.23–8.06 (m, 8H, Ar–H), 8.51 (bs, 2H, NH2), 10.05 (bs,
1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 21.5
(Ar–CH3), 103.5 (C-4), 115.3, 123.1, 127.3, 127.1,
129.0, 128.6, 132.7, 140.6, 141.5, 150.1, 151.9 (aromatic
carbons), 176.4 (C¼S) ppm; MS (m/z): 356.4011
N, 20.90%.
5-(1H-benzimidazol-2-yl)-3-(p-bromophenyl)-1H-pyrazole-1-
carbothioamide (5g).
Yellow solid; yield 78%; m.p.
153–155°C; IR (KBr) (cmꢀ1): 3459, 3352 (NH2), 3258
1
(NH), 1592 (C¼N), 1353 (C¼S); H-NMR (400 MHz,
DMSO-d6): δ 6.78 (s, 1H, C4–H), 7.27–8.08 (m, 8H,
Ar–H), 8.62 (bs, 2H, NH2), 10.10 (bs, 1H, NH) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 103.9 (C-4), 115.9,
123.7, 128.0, 127.6, 129.7, 129.3, 133.4, 141.3, 141.9,
150.7, 152.4 (aromatic carbons), 176.9 (C¼S) ppm; MS
(m/z): 421.2699 [M + Na]; Anal. Calcd for C17H12BrN5S:
C, 53.42; H, 3.16; N, 18.32%; found: C, 53.51; H, 3.17;
N, 18.52%.
[M + Na]; Anal. Calcd for C18H15N5S: C, 64.84; H, 4.53;
N, 21.01%; found: C, 64.95; H, 4.55; N, 21.22%.
5-(1H-benzimidazol-2-yl)-3-(p-methoxyphenyl)-1H-pyrazole-
1-carbothioamide (5c).
126–128°C; IR (KBr) (cmꢀ1): 3443, 3335 (NH2), 3244
Yellow solid; yield 72%; m.p.
1
(NH), 1577 (C¼N), 1338 (C¼S); H-NMR (400 MHz,
DMSO-d6): δ 3.81 (s, 3H, Ar–OCH3), 6.63 (s, 1H, C4–H),
7.21–8.01 (m, 8H, Ar–H), 8.49 (bs, 2H, NH2), 10.02 (bs,
1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 103.2
(C-4), 57.2 (Ar–OCH3), 115.0, 122.7, 127.0, 126.8,
128.4, 128.3, 132.5, 140.4, 141.1, 149.3, 151.6 (aromatic
carbons), 176.1 (C¼S) ppm; MS (m/z): 372.3981
General procedure for the synthesis of 2-(5-(1H-
benzimidazol-2-yl)-3-aryl-1H-pyrazol-1-yl)-4-(4-fluorophenyl)
thiazole (7a–g). A solution of compound 5 (1 mmol) in
ethanol (10 mL) and p-fluorophenacyl bromide (8)
(1 mmol) was added and refluxed for 5 h. The solid
separated on cooling was filtered and purified by column
[M + Na]; Anal. Calcd for C18H15N5OS: C, 61.87; H,
4.33; N, 20.04%; found: C, 61.99; H, 4.34; N, 20.21%.
5-(1H-benzimidazol-2-yl)-3-(p-nitrophenyl)-1H-pyrazole-1-
chromatography using ethyl acetate/hexane (1:1) as eluent.
2-(5-(1H-benzimidazol-2-yl)-3-phenyl-1H-pyrazol-1-yl)-4-(4-
fluorophenyl)thiazole (7a).
Yellow solid (73%); m.p.
carbothioamide (5d).
Yellow solid; yield 86%; m.p.
170–172°C; IR (KBr) (cmꢀ1): 3243 (NH), 1638 (C¼C),
167–169°C; IR (KBr) (cmꢀ1): 3426, 3315 (NH2), 3222
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design and Synthesis of Some New Benzimidazole Containing Pyrazoles and
Pyrazolyl Thiazoles as Potential Antimicrobial Agents
1
1579 (C¼N); H-NMR (400 MHz, DMSO-d6): δ 6.37 (s,
Anal. Calcd for C25H15F2N5S: C, 65.92; H, 3.32; N,
15.38%; found: C, 66.06; H, 3.33; N, 15.56%.
2-(5-(1H-benzimidazol-2-yl)-3-(p-chlorophenyl)-1H-pyrazol-
0
1H, C4–H), 7.36–8.00 (m, 14H, Ar–H, C5 –H), 10.10 (bs,
1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 104.8
(C-4), 108.6 (C-50), 115.8, 116.7, 123.7, 127.4, 128.7,
129.4, 129.7, 130.3, 131.0, 133.1, 141.6, 142.5, 149.5,
154.8, 160.8, 163.7 (aromatic carbons) ppm; MS (m/z):
460.4816 [M + Na]. Anal. Calcd for C25H16FN5S: C,
68.63; H, 3.69; N, 16.01%; found: C, 63.75; H, 3.70; N,
1-yl)-4-(4-fluorophenyl)thiazole (7f).
Yellow solid; yield
78%; m.p. 199–201°C; IR (KBr) (cmꢀ1): 3233 (NH),
1632 (C¼C), 1571 (C¼N); 1H-NMR (400 MHz,
DMSO-d6): δ 6.83 (s, 1H, C4–H), 7.29–8.18 (m, 14H,
Ar–H, C5 –H), 10.14 (bs, 1H, NH) ppm; 13C-NMR
0
(100 MHz, DMSO-d6): δ 105.0 (C-4), 109.3 (C-50),
116.2, 117.1, 124.0, 128.0, 129.1, 129.5, 129.8, 130.3,
131.2, 133.9, 142.2, 143.1, 150.0, 155.1, 161.2, 163.2
(aromatic carbons) ppm; MS (m/z): 494.9273 [M + Na].
Anal. Calcd for C25H15ClFN5S: C, 63.62; H, 3.20; N,
16.22%.
2-(5-(1H-benzimidazol-2-yl)-3-p-tolyl-1H-pyrazol-1-yl)-4-(4-
fluorophenyl)thiazole (7b). Yellow solid; yield 75%; m.p.
155–176°C; IR (KBr) (cmꢀ1): 3246 (NH), 1641 (C¼C),
1
1581 (C¼N); H-NMR (400 MHz, DMSO-d6): δ 6.75 (s,
0
1H, C4–H), 7.24–8.11 (m, 14H, Ar–H, C5 –H), 10.07 (bs,
14.84%; found: C, 63.73; H, 3.21; N, 15.06%.
2-(5-(1H-benzimidazol-2-yl)-3-(p-bromophenyl)-1H-pyrazol-
1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 104.5
(C-4), 108.3 (C-50), 115.7, 116.5, 123.2, 127.1, 128.2,
128.8, 129.0, 129.7, 130.7, 131.8, 141.4, 142.3, 149.3,
154.4, 160.5, 163.0 (aromatic carbons) ppm; MS (m/z):
474.5086 [M + Na]. Anal. Calcd for C26H18FN5S: C,
69.16; H, 4.02; N, 15.51%; found: C, 69.26; H, 4.05; N,
1-yl)-4-(4-fluorophenyl)thiazole (7g).
Yellow solid; yield
76%; m.p. 188–190°C; IR (KBr) (cmꢀ1): 3256 (NH),
1647 (C¼C), 1588 (C¼N); 1H-NMR (400 MHz,
DMSO-d6): δ 6.81 (s, 1H, C4–H), 7.27–8.15 (m, 14H,
Ar–H, C5 –H), 10.11 (bs, 1H, NH) ppm; 13C-NMR
0
(100 MHz, DMSO-d6): δ 108.9 (C-4), 112.5 (C-50),
116.0, 116.9, 123.8, 127.6, 128.9, 129.3, 129.6, 130.0,
131.1, 133.4, 142.0, 142.9, 149.8, 154.8, 161.0, 163.6
(aromatic carbons) ppm; MS (m/z): 539.3773 [M + Na].
Anal. Calcd for C25H15BrFN5S: C, 58.15; H, 2.93; N,
13.56%; found: C, 58.27; H, 2.94; N, 13.78%.
15.72%.
2-(5-(1H-benzimidazol-2-yl)-3-(p-methoxyphenyl)-1H-
pyrazol-1-yl)-4-(4-fluorophenyl)thiazole (7c). Yellow solid;
yield 72%; m.p. 166–168°C; IR (KBr) (cmꢀ1): 3252
1
(NH), 1645 (C¼C), 1585 (C¼N); H-NMR (400 MHz,
DMSO-d6): δ 6.72 (s, 1H, C4–H), 7.20–8.07 (m, 14H,
Ar–H, C5 –H), 10.05 (bs, 1H, NH) ppm; 13C-NMR
0
(100 MHz, DMSO-d6): δ 104.1 (C-4), 108.0 (C-50),
115.4, 116.2, 122.4, 126.9, 127.6, 128.3, 128.8, 129.4,
130.4, 131.4, 141.0, 142.0, 149.0, 154.0, 160.1,
162.7 (aromatic carbons) ppm; MS (m/z): 490.5072
[M + Na]. Anal. Calcd for C26H18FN5OS: C, 66.79; H,
Acknowledgments. The authors G. Sravya and N.
Bakthavatchala Reddy are thankful to Sri Padmavathi Mahila
Viswavidyalayam, Tirupati, for evaluating the antimicrobial
activity and also thankful to Ural Federal University,
Yekaterinburg, Russia, for providing lab facilities.
3.88; N, 14.98%; found: C, 66.91; H, 3.89; N, 15.19%.
2-(5-(1H-benzimidazol-2-yl)-3-(p-nitrophenyl)-1H-pyrazol-1-
yl)-4-(4-fluorophenyl)thiazole (7d).
Yellow solid; yield
REFERENCES AND NOTES
77%; m.p. 215–217°C; IR (KBr) (cmꢀ1): 3242 (NH),
1636 (C¼C), 1577 (C¼N); 1H-NMR (400 MHz,
DMSO-d6): δ 6.89 (s, 1H, C4–H), 7.35–8.24 (m, 14H,
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0
(100 MHz, DMSO-d6): δ 105.6 (C-4), 109.9 (C-50),
116.7, 117.8, 124.6, 128.5, 129.6, 129.9, 130.4, 130.9,
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2-(5-(1H-benzimidazol-2-yl)-3-(p-fluorophenyl)-1H-pyrazol-
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1634 (C¼C), 1576 (C¼N); 1H-NMR (400 MHz,
DMSO-d6): δ 6.87 (s, 1H, C4–H), 7.31–8.20 (m, 14H,
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(100 MHz, DMSO-d6): δ 105.2 (C-4), 109.6 (C-50),
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131.3, 134.2, 142.5, 143.4, 150.2, 155.3, 161.4, 163.5
(aromatic carbons) ppm; MS (m/z): 478.4722 [M + Na].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Bakthavatchala Reddy, G. V. Zyryanov, G. Mallikarjuna Reddy, A. Balakrishna,
A. Padmaja, V. Padmavathi, C. Suresh Reddy, J. R. Garcia, and G. Sravya
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SUPPORTING INFORMATION
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet