Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives

Article abstract of DOI:10.1002/jhet.3198

A series of 20 novel pyrazole derivatives were designed and prepared, characterized by ¹H-NMR, mass spectra (ES-MS), ¹³C-NMR, and elemental analysis. The synthesized compounds were then evaluated for their growth inhibitory activity

Full text of DOI:10.1002/jhet.3198

Month 2018
Antitubercular Activity and Synergistic Study of Novel
Pyrazole Derivatives
Sunil B. Jadhav,a,b Samreen Fatema,a,b Gajanan Sanap,c and Mazahar Farooquia,b
*
aPost Graduate and Research Centre, Maulana Azad College, Aurangabad 431001, India
bDr. Rafiq Zakaria College for Women, Navkhanda, Aurangabad 431001, India
cS.B. College of Science, Aurangabad 431001, India
*
E-mail: mazahar_64@rediffmail.com
Received July 30, 2017
DOI 10.1002/jhet.3198
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
1
A series of 20 novel pyrazole derivatives were designed and prepared, characterized by H-NMR, mass
spectra (ES-MS), 13C-NMR, and elemental analysis. The synthesized compounds were then evaluated for
their growth inhibitory activity against Mycobacterium smegmatis mc2 155 initially. Rifampicin was used
as standard reference. In this screening, derivatives 9, 10, and 11 presented superior inhibition compared
with standard. Later, these three compounds were exposed for their Mycobacterium tuberculosis H37Rv in-
hibitory assay using rifampicin as standard reference. Encouraging M. smegmatis mc2 155 inhibition (9 μg/
mL), M. tuberculosis H37Rv inhibition (1.9 μg/mL), and synergism with the first-line and second-line anti-
biotics made compound 10 as lead and safe antitubercular agent among the series.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
to synthesize and have low adverse effects. Therefore, it is
unavoidable to discover new drugs entities for treatment
of TB that has spread globally [2].
In the running clinical scenario, the universal
armamentarium of antitubercular drugs remains
inadequate to address the rising populations of patients
with multidrug-resistant and extensively drug-resistant
Mycobacterium tuberculosis. As per the World Health
Organization, tuberculosis (TB) is the second leading
reason for mortality from an infective disease. Current
documents record about 9 million new patients and 1.5
million deaths owing to this infection, including 360,000
deaths among HIV-positive people [1]. It is also specified
that one-third of the world’s people is infected with latent
TB and 10% of which is expected to develop active TB
at some point in their lives [1].
Electron-rich nitrogen heterocycles play vital role in
various pharmacological activities [3]. Pyrazole
derivatives have a long history of use in agrochemicals
as well as pharmaceutical industry such as herbicides
and active pharmaceuticals. The achievement of
pyrazole COX-2 inhibitor has further tinted the rank of
these heterocyclic rings in medicinal chemistry [4].
Also, the interest in another heterocycles, pyrrole and its
derivatives raises by the reason of their significant
pharmaceutical importance such as antimicrobial,
antiviral,
anti-inflammatory,
analgesic
antitumor,
and
antihyperlipidemic,
anticonvulsant,
The limit boundaries of the present anti-TB drugs are
numerous along with their drug resistance, the serious
adverse effects, lack of drug efficacy, and the treatment of
resistant strains that requires continuation treatments that
employ more toxic drugs, increasing the economic load,
which makes TB a vicious cycle. These factors necessitate
the hunt for new antimycobacterial agents whom are easy
antihyperglycemic agents [5]. The pyrrole derivative
BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)
methyl-pyrrole] is shown to have strong inhibitory
activity against both M. tuberculosis and some non-TB
mycobacteria. BM212 was inhibitory to drug-resistant
mycobacteria and also exerted bactericidal activity
against intracellular bacilli residing in the U937 human
© 2018 Wiley Periodicals, Inc.

S. B. Jadhav, S. Fatema, G. Sanap, and M. Farooqui
Vol 000
histiocytic lymphoma cell line [6]. The significant
importance of particular p-chlorophenyl substituent of
BM212 at N1 and C5 is also documented [7]. Lately,
these pyrrole derivatives were found more potent,
wherein the phenyl ring at N1 and C5 was substituted
by fluoro and chloro groups at para position, also less
toxic and more potent with respect to the lead
compound BM212 [8].
inhibition and synergistic studies for selected compounds
with the first-line and second-line antitubercular drugs.
RESULTS AND DISCUSSION
Chemistry. In continuation with our research activities
[12–15], we synthesized novel compounds (1–20) by
a synthetic route outlined in synthetic scheme. In
brief, the synthetic program started with preparation of
different pyrazole aldehydes D, one of the key precursors
according to the procedure reported in literature
[16]. Here, commercially available different substituted
acetophenones A were refluxed with commercially
available various phenylhydrazines B in acidic medium
in ethanol solvent to give corresponding imines C. These
imines C upon treatment with POCl3 in DMF underwent
cyclization to give different pyrazole aldehydes D in good
yield as key precursors via Vilsmeier–Haack reaction
conditions. Access to other important precursors 4-(7-
methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6-yl)-benzonitrile
I and 7-methyl-6-(4-trifluoromethoxy-phenyl)-thiazolo[3,2-
a]pyrimidin-5-one J was achieved by following the
process reported in literature [17]. Here, 2-aminothiazole
E was treated with ethyl acetoacetate F at reflux
temperature in acetic acid to yield 7-methyl-thiazolo[3,2-
a]pyrimidin-5-one G. This intermediate G when treated
with iodine and ceric ammonium nitrate in acetonitrile
at reflux temperature gave 6-iodo-7-methyl-thiazolo[3,2-
a]pyrimidin-5-one H in moderate to good yield. Finally,
the requisite key precursors 4-(7-methyl-5-oxo-5H-thiazolo
[3,2-a]pyrimidin-6-yl)-benzonitrile I and 7-methyl-6-(4-
trifluoromethoxy-phenyl)-thiazolo[3,2-a]pyrimidin-5-one J
were obtained by treating iodo intermediate H with
coupling partner 4-cyanophenylboronic acid and 4-
trifluoromethoxyphenylboronic acid using palladium (0)
catalyzed Suzuki cross-coupling reaction conditions.
The last step of this synthetic work was the preparation
of the novel targeted compounds 1–20, which involves
the condensation of different pyrazole aldehydes D
with 4-(7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6-yl)-
benzonitrile I and 7-methyl-6-(4-trifluoromethoxy-phenyl)-
thiazolo[3,2-a]pyrimidin-5-one J using sodium ethoxide at
reflux temperature in ethanol (synthetic Scheme 1 and
Table 1). Crude products obtained were stirred in diethyl
ether to get pure product. All the newly synthesized
compounds were isolated in moderate to good yield and
were characterized by ES-MS, 1H-NMR, 13C-NMR
spectral data, and elemental analysis.
A previous report of featured pharmacophoric model
describes the potent compounds for antimycobacterial
activity that includes (1) hydrophobic region, (2)
hydrogen bond acceptor, and (3) two aromatic rings [9];
BM212 skeleton bears all these features (Fig. 1). Taking
these hints, and in the absence of much literature
details, we synthesize the novel 20 substituted pyrazole
derivatives in which the phenyl ring (RA1) at N1 was
substituted by chloro (hydrophobic region, similar to
BM212) and methoxy groups; also in most of the
synthesized derivatives, N1 phenyl ring was kept as
unsubstituted. Another phenyl ring (RA2) was introduced
at C3 of pyrazole; it was substituted by bromo, methyl,
and methoxy groups at various positions. Additionally, a
biologically active fused thiazolo[3,2-a]pyrimidin-5-one
moiety was introduced at C4 position of pyrazole
along with trans-stilbene link to check the enhancement
of activity if any. Thiazolo[3,2-a]pyrimidin-5-one was
selected looking to its various biological importance
like anti-inflammatory, antihypertensive, antifungal,
antibiofilm, antibacterial, antiviral, antioxidant, antitumor,
anti-HIV, calcium channel blocking, antitubercular,
glutamate receptor antagonistic, 5-HT2a receptor
antagonistic, and group II metabotropic glutamate receptor
antagonist activities [3]. Moreover trans-stilbene
derivatives are reported for their antitubercular potential
[10,11].
Hence, the current article summarizes the synthesis of
novel pyrazole derivatives and their in vitro inhibitory
potentials against Mycobacterium smegmatis mc2 155
in preliminary level. M. tuberculosis H37Rv growth
Biology. M. smegmatis mc2 155 growth inhibitions.
The synthesized molecules (1–20) were examined
systematically to define the structure activity relationship
influencing potency; strategic modifications were followed
Figure 1. Pharmacological model.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives
Scheme 1. Reagents and conditions: (i) AcOH/EtOH, reflux, 30 min; (ii) DMF/POCl3, 0–30°C, 12–14 h; (iii) AcOH, 12–14 h reflux; (iv) iodine, CAN,
reflux, 2 h; (v) Pd (0), toluene, Na2CO3, phenylboronic acid, reflux, 12–14 h; (vi) NaOEt, EtOH, reflux, RT, 12–14 h.
Table 2
Antitubercular activity of 1–20 against M. smegmatis mc2 155 and their
Table 1
toxicity index towards human monocyte-derived macrophages.
Substitutional pattern for compounds 1–20.
M. smegmatis mc2 155
ID
R1
R2
R3
R4
R5
MIC (μg/
mL)
1
2
3
4
5
6
7
8
H
H
OMe
H
H
Br
F
H
Me
H
H
OMe
H
H
Me
H
H
Br
H
H
H
H
OMe
H
H
Br
F
H
Me
H
H
OMe
H
H
Me
H
H
H
H
H
H
OMe
H
H
Br
F
H
Me
H
H
OMe
H
H
Me
H
Cl
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
ID
REF SD
IC50 (μg/mL)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
21
620
58
31
78
55
49
74
17
9
15
71
47
62
71
56
87
72
57
69
29
1.3 0.09*
0.13 0.01
0.68 0.03
0.78 0.01
0.42 0.01
0.86 0.09
0.79 0.081
0.85 0.05
2.19 0.02
8.3 0.08*
1.9 0.03*
0.61 0.05
0.47 0.02
0.57 0.09
0.34 0.09
0.89 0.01
0.55 0.02
0.43 0.09
0.58 0.03
0.61 0.04
1.67 0.09*
172
ND
ND
189
ND
ND
ND
ND
381
421
367
ND
ND
ND
ND
ND
ND
ND
ND
ND
400
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
17
18
19
20
Br
H
H
Br
H
Rifampicin
wherein R1 to R5 were substituted by different groups
(Table 2 and Fig. 2). Rifampicin was used as standard
reference in this study.
MIC, minimum inhibitory concentration; REF, relative final fluorescence;
SD, standard deviation.
*Indicates probability value.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, G. Sanap, and M. Farooqui
Vol 000
Figure 2. Minimum inhibitory concentration (μg/mL) of compounds 1–20. [Color figure can be viewed at wileyonlinelibrary.com]
As per strategy, initially, compound 1 was synthesized
wherein, like BM212, chloro group was kept at R4 and
another substitution was introduced R5 (cyano). In the
assay, compound 1 demonstrated equal potency (21 μg/
mL) with rifampicin (29 μg/mL); this initial result gave
motivation to us for the further synthesis. Hence, cyano
group was fixed at R5, and smaller changes were brought
at R1 to R4 positions in the next level. Accordingly, a
novel derivative (compound 2) was synthesized, wherein
an additional methoxy group was employed at R4. In the
growth inhibition study, this compound 2 showed a
massive drop in inhibitory activity (620 μg/mL); we
thought that the substitutions at R4 may not be favorable
for the activity. Hence, other compounds were prepared
with the structural changes at R1–R3, and R4 was kept as
unsubstituted. Further, methoxy group was introduced
at R1–R3, and next set of compounds titled 3–5 was
prepared. This set demonstrated improvement in growth
inhibition compared with compound 2 although inhibition
activity was inferior to compound 1 and standard
rifampicin. Compound 4 displayed activity (31 μg/mL)
similar to rifampicin. Next set of compounds (6–8) was
prepared with bromo substitution at R1–R3; to our
disappointment, in this set, bromo substitution leads to
diminishing in growth inhibition; the inhibition profile
was poor among the compounds prepared till now.
Further modification leads us to another set of compounds
(9–11) wherein R1–R3 were substituted by methyl
group; to our surprise, a methyl modification at R1–R3
displayed favorable effect, and prominent improvement in
inhibition was noticed. Here, compounds 9 and 11 showed
superior growth inhibition profiles (17 and 15 μg/mL,
respectively), and compound 10 was the best (9 μg/mL)
among the compounds synthesized till now.
For cell cytotoxicity purpose, compounds 1, 4, 9, 10,
and 11 were emerged as active compounds from the
series. So these compounds were evaluated against human
monocyte-derived macrophages to check their ex vivo
cytotoxicity towards eukaryotic cells (Table 2). In this
assignment, compound 1 and compound 4 have proved
toxic (IC = 172 and 189 μg/mL, respectively) than
standard rifampicin. Compounds 9 (IC = 381 μg/mL), 10
(421 μg/mL), and 11 (367 μg/mL) were found to be safer
towards human macrophages compared with rifampicin
(400 μg/mL).
Evaluation of growth inhibition against M. tuberculosis
H37Rv.
Based on MIC and cell cytotoxicity results,
compounds 9, 10, and 11 were selected to establishing
their M. tuberculosis growth inhibition study. The results
are illustrated in Table 3. Here, compound 11 showed poor
result (MIC = 152 μg/mL), while compounds 9 and 10
displayed superior inhibitory activity (2.6 and 1.9 μg/mL,
respectively) when compared with standard rifampicin
(2.2 μg/mL).
Synergistic effect.
In the next level, according to
growth inhibition profile against M. tuberculosis H37Rv,
compounds 9 and 10 were taken ahead for synergistic
study with first-line rifampicin (RIF) and isoniazid (INH)
Table 3
Screening of antitubercular activity of selected compounds against M. tu-
berculosis H37Rv.
M. tuberculosis H37Rv
ID
MIC (μg/mL)
REF SD
9
10
11
2.6
1.9
152
2.2
2.13 0.10*
9.18 0.045*
0.29 0.021
1.35 0.04*
To explore our strategy, in the next level, cyano group at
R5 was replaced by trifluoromethyl, and the entire synthesis
was repeated (compounds 12–20). This modification
leads to diminishing effect on M. smegmatis mc2 155
growth inhibitions; none of the compound exhibited
improved inhibitory profile than either with compound 10
or with standard. Hence, compound 10 was the best
candidate in all.
Rifampicin
MIC, minimum inhibitory concentration; REF, relative final fluorescence;
SD, standard deviation.
MIC was determined by microdilution; REF was based on accumulation
of EtBr at 0.5 μg/mL; the results are presented as the average of three
independent assays plus SD.
*The results were considered significant when P < 0.05 and highly sig-
nificant when P < 0.01.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives
and second-line ofloxacin (OFX) and amikacin (AMK)
antitubercular drugs. The MICs of RIF, INH, OFX, and
AMK were calculated in the absence and in the presence
of various concentrations of each compound against
M. tuberculosis H37Rv (Table 4).
and m, multiple. The spectra of mass were recorded on Wa-
ters mass spectrometer (Acquity, Waters Corporation, Mil-
ford, MA). Microanalyses were carried out on elementar
(vario MICRO cube, Langenselbold, Germany). The
follow-up of reactions was monitored by thin-layer chro-
matography on silica gel-precoated aluminum sheets (type
60, F254, Merck, Darmstadt, Germany), and the spots were
detected by exposer to UV lamp at λ 254 nm for 20–30 s.
General procedure for synthesis of pyrazole aldehyde (D).
A mixture of acetophenone A (1.0 mol) and phenyl
hydrazine B (1.0 mol) was heated in ethanol (10 volumes)
in the presence of (1 mL) acetic acid at reflux temperature
for 30 min. Resulting yellow solid product was separated
by the filtration. This solid was washed by cold ethanol
(minimum) and was suck dried under vacuum to get
sufficient pure white product C in good yield.
A mixture of N,N-dimethylformamide (2.5 mol) and
POCl3 (2.5 mol) was stirred together at 0°C for 30 min.
To this reaction mixture, above solid (C) was added at
0°C with constant stirring. The reaction mixture was then
allowed to warm up to room temperature and stirred for
12–14 h. After completion, reaction mixture was poured
on crushed ice where upon the solid was separated. It
was filtered and washed by saturated aq. NaHCO3
solution followed by water. Solid was crystalized from
ethanol to get white crystalline product D in an average
70% yield.
Compounds 9 and 10 were tested at their ½ MIC followed
by two-dimensional broth microdilution checkerboard
assay, which is used to calculate magnitude of synergism.
Although compound 9 demonstrated M. tuberculosis
H37Rv growth inhibition superior than standard, in this
assay, it showed slight synergism with first-line antibiotics
INH only, while in case of RIF and in second-line
antibiotics, synergism was not reflected. While compound
10 created synergism everywhere, it imparted the
synergism even at 0.48 μg/mL in case of RIF and second-
line antibiotics, whereas in case of INH, the synergism
was displayed at 0.96 μg/mL. Hence, in general, we can
look at compound 10 as potent from the series of 20 novel
compounds.
EXPERIMENTAL
Chemistry.
All the reagents and solvents were
purchased from commercial sources and were dried and
purified when necessary by standard methods.
The melting points of the synthesized compound were
determined in open capillary tubes using VMP-D melting
point apparatus (Veego Instrument Corporation, Mumbai,
Synthesis of 7-methyl-thiazolo[3,2-a]pyrimidin-5-one (G).
Ethyl acetoacetate F (39 g, 0.3 mol) was added to a stirred
mixture of 2-aminothiazole E (20 g, 1.0 mol) and acetic
acid (200 mL). The mixture was refluxed for 15 h. The
reaction mixture was cooled to room temperature, and
acetic acid was removed to afford dark brown crude
solid. It was dissolved in ethyl acetate (250 mL) and
washed with saturated NaHCO3 solution (2 × 200 mL)
1
India) and are uncorrected. The H-NMR for the com-
pound synthesized was recorded on Varian Mercury Plus
400 (Varian, Zurich, Switzerland) using TMS as an internal
standard and DMSO-d6 solvent and chemical values are
given δ scales. The splitting patterns were assigned as fol-
lows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet;
Table 4
Synergistic effect and modulation factor for compounds 9 and 10 and with first-line and second-line drugs against M. tuberculosis H37Rv.
ID
Test conc.
INH
1.2
RIF
1.9
OFX
2.4
AMK
2.3
Standalone MIC (μg/mL)
9
64
32
16
0.013(92)
0.09(13.3)
0.21
0.08(21.2)
0.35
0.91
0.07(35)
0.19
1.32
0.25(11.6)
1.38
2.9
8
0.41
1.7
2.4
2.9
4
0.93
1.7
2.4
2.9
2
1.2
1.7
2.4
2.9
10
7.68
3.86
1.92
0.96
0.48
0.24
0.12
0.0092(130)
0.011(109)
0.09(13)
0.51
0.012(139)
0.021(81)
0.081(21)
0.19
0.019(122)
0.08(30)
0.21(12)
0.83
0.025(112)
0.030(95)
0.083(35)
0.13
1.2
1.2
1.2
0.38
0.81
1.9
1.3
2.4
2.4
1.11
2.3
2.3
Test conc., concentration at which the compound was tested (in μg/mL); INH, isoniazid; RIF, rifampin; OFX, ofloxacin; AMK, amikacin; modulation
factor = ratio of standalone minimum inhibitory concentration (MIC) of antibiotic to the MIC after combination.
Journal of Heterocyclic Chemistry
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S. B. Jadhav, S. Fatema, G. Sanap, and M. Farooqui
Vol 000
followed by sat. brine solution (200 mL). Organic layer
was dried over anhydrous Na2SO4, and solvent was
concentrated under vacuum to afford the crude product.
The crude was purified by column chromatography using
silica (60–120) to give white solid in 11.5 g (35%)
solution of 4-trifluoromethoxyphenyl boronic acid (11 g,
0.051 mol) in ethanol (100 mL) was added, and the
reaction was refluxed for overnight. Conversion was
monitored by mass analysis; after completion, reaction
mass was cooled, and then solvent was removed under
reduced pressure. Crude was added 200 mL water and
then was extracted by ethyl acetate (3 × 80 mL).
Organic layer was washed by saturated aq. solutions of
ammonium chloride, by sodium bicarbonate, and finally
by saturated aq. brine solution. Organic layer was dried
over anhydrous sodium sulfate, and solvent was
removed to afford crude product. It was purified by
column chromatography techniques to afford pure
1
quantity. H-NMR (400 MHz, DMSO-d6) δ ppm: 2.35 (s,
3H, pyrimidone ring CH3), 6.21 (s, 1H, pyrimidone ring
H), 6.91 (d, J = 5.4 Hz, thiazole ring H near to sulfur),
7.99 (d, J = 5.2 Hz, thiazole ring H near to nitrogen);
ES-MS m/z: 167.4 [M+1].
Synthesis of 6-iodo-7-methyl-thiazolo[3,2-a]pyrimidin-5-one
(H). A mixture of 7-methyl-thiazolo[3,2-a]pyrimidin-5-
one (8 g, 0.05 mol), ceric ammonium nitrate (13.20 g,
0.024 mol), and iodine (3.78 g, 0.03 mol) in acetonitrile
(100 mL) was stirred at 80°C for 2 h. Reaction mixture
was cooled to room temperature. Distilled water (80 mL)
was added to residue obtained after concentration of
reaction mixture and stirred it for 1 h at room temperature.
The reaction mixture was filtered and dried under vacuum
to yield 11 g of product as yellow solid. 1H-NMR
(400 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H, pyrimidone
ring H), 7.60 (d, J = 5.2 Hz, thiazole ring H near to
sulfur), 8.10 (d, J = 5.3 Hz, thiazole ring H near to
nitrogen); ES-MS m/z: 291.3 [MÀ1].
1
product (4.6 g). H-NMR (400 MHz, DMSO-d6) δ ppm:
2.31 (s, 3H, pyrimidinone CH3), 7.51–7.60 (m, 4H,
thiazole ring H near to sulfur and ArH), 7.56–7.81 (m,
1H, ArH), 8.00 (d, J = 5.12 Hz, thiazole ring H near to
nitrogen); ES-MS m/z: 311.3 [M+1].
General procedure for coupling of coupling of D with I
and J. Solid of I/J was suspended in ethanol at room
temperature, to that 1.3 eq. pyrazole aldehyde D was
added and the reaction was stirred for overnight at reflux
temperature. Clean transparent yellow solution was then
cooled, and final targeted compounds (1–20; Table 1)
were afforded as solid in an average yield after filtration.
Purification was done by stirring the crude solid in diethyl
ether. Structural identification was done by 1H-NMR,
Synthesis of 4-(7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-
6-yl)-benzonitrile (I). To a solution of 6-iodo-7-methyl-
thiazolo[3,2-a]pyrimidin-5-one H (10 g, 0.034 mol) and
Pd[(C6H5)3P]4 (19 g, 0.012 mol) in toluene (200 mL)
was added with sodium carbonate (22 g, 0.204 mol) in
90 mL water. After few minutes, a solution of 4-
cyanophenylboronic acid (7.5 g, 0.051 mol) in ethanol
(100 mL) was added, and the reaction was refluxed for
overnight. Conversion was monitored by mass analysis;
after completion, reaction mass was cooled, and then
solvent was removed under reduced pressure. Crude was
added 200 mL water and then was extracted by ethyl
acetate (3 × 80 mL). Organic layer was washed by
saturated aq. solutions of ammonium chloride, by sodium
bicarbonate, and finally by saturated aq. brine solution.
Organic layer was dried over anhydrous sodium sulfate,
and solvent was removed to afford crude product. It was
purified by column chromatography techniques to afford
mass spectroscopy, 13C-NMR, and elemental analysis.
4-{7-[2-(1-(4-Chloro-phenyl)-3-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(1). Yield 69%; mp 219–221°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 6.81 (d, 2H, J = 16 Hz, olefinic H
near to pyrazole ring), 7.01 (d, 2H, J = 8.0 Hz, ArH),
7.30–7.55 (m, 11H, ArH and H of thiazole ring near to
sulfur), 7.75 (d, 1H, J = 16 Hz, olefinic H near to
pyrimidone ring), 7.83 (d, 2H, J = 8 Hz, ArH), 7.93 (d,
1H, J = 4 Hz, thiazole ring H near to bridge head
nitrogen), 8.78 (s, 1H, pyrazole ring H); 13C-NMR
(100 MHz, DMSO-d6): 101.2 (thiazole ring C near to
sulfur), 107.8 (pyrazole ring C attached to olefin), 114
(phenyl C attached to cyano), 117.1 (CN), 119.4, 120.1,
120.9, 121.4, 121.9, 122.8, 123.6, 123.9, 126.7, 128.3,
132.3, 134.3, 138.4 (phenyl C attached to N), 144.2
(pyrimidinones ring C near to N), 148.7 (pyrazole ring C
attached to phenyl), 156.7 (phenyl C attached to OCH3),
160.2 (thiazole ring C near to sulfur and nitrogen). 162.8
(C═O); ES-MS m/z: 498.3 [M+1]. Anal. Calcd for
C30H18ClN5OS (497.3): C, 72.42; H, 3.85; N, 14.07.
1
pure product (3.5 g). H-NMR (400 MHz, DMSO-d6) δ
ppm: 2.21 (s, 3H, pyrimidinone ring CH3), 7.56 (d,
J = 4.99 Hz, thiazole ring H near to sulfur), 7.65 (d,
J = 7.81 Hz, 2H, ArH), 7.86 (d, J = 8.0 Hz, 2H, ArH),
8.01 (d, J = 5.10 Hz, thiazole ring H near to nitrogen);
ES-MS m/z: 268.3 [M+1].
Found: C, 72.41; H, 3.78; N, 13.99.
4-(7-{2-[1-(4-Methoxy-phenyl)-3-phenyl-1H-pyrazol-4-yl]-
Synthesis
of
7-methyl-6-(4-trifluoromethoxy-phenyl)-
thiazolo[3,2-a]pyrimidin-5-one (J).
To a solution of 6-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
iodo-7-methyl-thiazolo[3,2-a]pyrimidin-5-one H (10 g,
0.034 mol) and Pd[(C6H5)3P]4 (19 g, 0.012 mol) in
toluene (200 mL) was added with sodium carbonate
(22 g, 0.204 mol) in 90 mL water. After few minutes, a
(2).
Yield 66%; mp 224–226°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 3.82 (s, 3H, ArOCH3), 6.61 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.19 (d, 2H,
J = 8 Hz, ArH), 7.25–7.40 (m, 5H, ArH and thiazole ring
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives
H near to sulfur), 7.45–7.70 (m, 6H, ArH and olefinic H
near to pyrimidone ring), 7.78 (d, 2H, J = 8 Hz, ArH),
7.79 (d, 1H, thiazole ring H near to bridge head nitrogen),
8.99 (s, 1H, pyrazole ring H); 13C-NMR (100 MHz,
DMSO-d6): 102.5 (thiazole ring C near to sulfur), 106.9
(pyrazole ring C attached to olefin), 113.6 (phenyl C
attached to cyano), 116.2 (CN), 118.9, 119.2, 120.2,
120.9, 121.7, 122.1, 123.4, 129.3, 131.1 (olfine C near to
pyrazole), 135.3 (olefin C near to pyrimidinone), 138.4
(phenyl C attached to N), 142.2 (pyrimidinone ring C near
to N), 147.4 (pyrazole ring C attached to phenyl), 157.3
(phenyl C attached to OCH3), 161.2 (thiazole ring C near
to sulfur and nitrogen). 162.3 (C═O); ES-MS m/z: 528.3
[M+1]. Anal. Calcd for C31H21N5O2S (527.61): C, 72.78;
H, 4.14; N, 13.69. Found: C, 72.91; H, 3.98; N, 13.49.
ring C attached to phenyl), 158.7 (phenyl C attached to
OCH3), 161.2 (thiazole ring C near to sulfur and
nitrogen). 162.2 (C═O); ES-MS m/z: 528.4 [M+1]. Anal.
Calcd for C31H21N5O2S (527.61): C, 70.57; H, 4.01; N,
13.27. Found: C, 70.79; H, 3.54; N, 13.77.
4-(7-{2-[3-(4-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(5).
Yield 59%; mp 269–271°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 3.97 (s, 3H, ArOCH3), 6.68 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.11 (d, 2H,
J = 8.05 Hz, ArH), 7.34–739 (m, 3H, ArH), 7.43 (d, 1H,
ArH), 7.47–7.59 (m, 5H, ArH and olefinic H near to
pyrimidone ring), 7.81–7.86 (m, 4H, ArH), 8.01 (d, 1H,
thiazole ring H near to bridge head nitrogen), 8.99 (s, 1H,
pyrazol ring H); 13C-NMR (100 MHz, DMSO-d6): 103.9
(thiazole ring C near to sulfur), 107.6 (pyrazole ring C
attached to olefin), 114.7 (phenyl C attached to cyano),
116.9 (CN), 119.6, 120.4, 120.8, 121.1, 121.9, 123.6,
124.3, 126.3, 126.8, 130.1, 131.4, 133.6 (olfine C near to
pyrazole), 135.6 (olefin C near to pyrimidinone), 138.4
(phenyl C attached to N), 145.7 (pyrimidinone ring C near
to N), 149.2 (pyrazole ring C attached to phenyl), 157.8
(phenyl C attached to OCH3), 161.9 (thiazole ring C near
to sulfur and nitrogen). 162.9 (C═O); ES-MS m/z: 528.4
[M+1]. Anal. Calcd for C31H21N5O2S (527.61): C, 70.57;
4-(7-{2-[3-(2-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(3). Yield 72%; mp 266–268°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 3.98 (s, 3H, ArOCH3), 6.64 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.05 (d, 2H,
J = 8.00 Hz, ArH), 7.32–7.36 (m, 2H, ArH), 7.47–7.61
(m, 7H, ArH and thiazole ring H near to sulfur), 7.81–
7.88 (m, 5H, ArH and olefinic H near to pyrimidone
ring), 8.01 (d, 1H, J = 4.00 Hz, thiazole ring H near to
bridge head nitrogen), 8.99 (s, 1H, pyrazol ring H); 13C-
NMR (100 MHz, DMSO-d6): 102.8 (thiazole ring C near
to sulfur), 105.9 (pyrazole ring C attached to olefin),
113.1 (phenyl C attached to cyano), 115.1 (CN), 119.1,
120.9, 121.3, 121.7, 122.1, 122.9, 123.7, 124.3, 129.7,
132.4 (olfine C near to pyrazole), 135.8 (olefin C near to
pyrimidinone), 138.0 (phenyl C attached to N), 144
(pyrimidinone ring C near to N), 147.9 (pyrazole ring C
attached to phenyl), 158.1 (phenyl C attached to OCH3),
161.9 (thiazole ring C near to sulfur and nitrogen). 162.8
(C═O); ES-MS m/z: 528.4 [M+1]. Anal. Calcd for
C31H21N5O2S (527.61): C, 70.57; H, 4.01; N, 13.27.
Found: C, 70.49; H, 3.93; N, 13.98.
H, 4.01; N, 13.27. Found: C, 70.21; H, 3.27; N, 13.57.
4-(7-{2-[3-(2-Bromo-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(6). Yield 61%; mp 221–223°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 6.63 (d, 1H, J = 16 Hz, olefinic H
near to pyrazole ring), 7.00 (d, 2H, J = 8.00 Hz, ArH),
7.20–7.41 (m, 7H, ArH and thiazole ring H near to
sulfur), 7.56–7.61 (m, 4H, ArH), 7.79–7.95 (m, 3H,
ArH and olefinic H near to pyrimidone ring), 8.01 (d,
1H, thiazole ring H near to bridge head nitrogen), 8.91
(s, 1H, pyrazol ring H); 13C-NMR (100 MHz,
DMSO-d6): 103.2 (thiazole ring C near to sulfur), 106.4
(pyrazole ring C attached to olefin), 114.7 (phenyl C
attached to cyano), 117.6 (CN), 120.3, 120.8, 121.2,
121.7, 123.4, 126.8, 129.4, 132.8 (olfine C near to
pyrazole), 136.3 (olefin C near to pyrimidinone), 138.9
(phenyl C attached to N), 141.3 (phenyl C attached to
bromo), 145.7 (pyrimidinone ring C near to N), 149.9
(pyrazole ring C attached to phenyl), 161.7 (thiazole
ring C near to sulfur and nitrogen). 163.5 (C═O); ES-
MS m/z: 576.3 [M+], 578.5 [M+2]. Anal. Calcd for
C30H18BrN5OS (576.3): C, 62.51; H, 3.15; N, 12.15.
4-(7-{2-[3-(3-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(4).
Yield 67%; mp 261–263°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 3.95 (s, 3H, ArOCH3), 6.66 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.09 (d, 2H,
J = 7.55 Hz, ArH), 7.34–7.58 (m, 8H, ArH and thiazole H
near to sulfur), 7.71 (d, 1H, thiazole ring H near to bridge
head), 7.81–7.86 (m, 4H, ArH and olefinic H near to
pyrimidone), 8.01 (d, 1H, J = 4 Hz, thiazole ring H near
to bridge head nitrogen), 8.99 (s, 1H, pyrazol ring H);
13C-NMR (100 MHz, DMSO-d6): 103.0 (thiazole ring C
near to sulfur), 107.1 (pyrazole ring C attached to olefin),
114.1 (phenyl C attached to cyano), 116.4 (CN), 119.2,
120.2, 120.8, 121.3, 121.6, 121.9, 124.3, 126.1, 126.9,
129.4, 132.6 (olfine C near to pyrazole), 135.1 (olefin C
near to pyrimidinone), 138.4 (phenyl C attached to N),
145.1 (pyrimidinone ring C near to N), 148.2 (pyrazole
Found: C, 62.49; H, 3.53; N, 11.98.
4-(7-{2-[3-(3-Bromo-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(7).
Yield 67%; mp 210–212°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 6.62 (d, 1H, J = 15.2 Hz, olefinic H
near to pyrazole ring), 7.01 (d, 2H, J = 7.55 Hz, ArH),
7.20–7.42 (m, 5H, ArH and thiazole ring H near to sulfur),
7.54–7.58 (m, 4H, ArH), 7.72 (d, 1H, thiazole ring H near
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, G. Sanap, and M. Farooqui
Vol 000
to bridge head), 7.79–7.90 (m, 3H, ArH and olefinic H near
to pyrimidone ring), 8.00 (d, 1H, thiazole ring H near to
bridge head nitrogen), 9.00 (s, 1H, pyrazol ring H); 13C-
NMR (100 MHz, DMSO-d6): 103.9 (thiazole ring C near
to sulfur), 107.6 (pyrazole ring C attached to olefin), 114.7
(phenyl C attached to cyano), 116.9 (CN), 119.6, 120.4,
120.8, 121.1, 121.9, 123.6, 124.3, 126.3, 126.8, 130.1,
131.4, 133.6 (olfine C near to pyrazole), 135.6 (olefin C
near to pyrimidinone), 138.4 (phenyl C attached to N),
141.5 (phenyl C attached to bromo), 145.7 (pyrimidinone
ring C near to N), 149.2 (pyrazole ring C attached to
phenyl), 161.9 (thiazole ring C near to sulfur and
nitrogen). 162.9 (C═O); ES-MS m/z: 576.3 [M+], 578.3
[M+2]. Anal. Calcd for C30H18BrN5OS (576.3): C, 62.51;
H, 3.15; N, 12.15. Found: C, 63.09; H, 3.52; N, 12.61.
(C═O); ES-MS m/z: 512.2 [M+1]. Anal. Calcd for
C31H21N5OS (511.61): C, 72.78; H, 4.14; N, 13.69.
Found: C, 72.91; H, 3.98; N, 13.49.
4-{5-Oxo-7-[2-(1-phenyl-3-m-tolyl-1H-pyrazol-4-yl)-vinyl]-
5H-thiazolo[3,2-a]pyrimidin-6yl}-benzonitrile (10).
Yield
59%; mp 221–223°C; 1H-NMR (400 MHz, CDCl3) δ
ppm: 2.42 (s, 3H, ArCH3), 6.63 (d, 1H, J = 16 Hz, olefinic
H near to pyrazole), 6.98 (d, 1H, J = 8.05 Hz, ArH), 7.25–
7.37 (m, 4H, ArH),7.48–7.66 (m, 6H, ArH and thiazole
ring H near to sulfur), 7.74–7.80 (m, 4H, ArH and olefinic
H near to pyrimidone), 7.94 (d, 1H, thiazole ring H near
to nitrogen), 8.10 (s, 1H, pyrazol ring H); 13C-NMR
(100 MHz, DMSO-d6): 104.3 (thiazole ring C near to
sulfur), 107.2 (pyrazole ring C attached to olefin), 114.3
(phenyl C attached to cyano), 116.6 (CN), 119.3, 120.4,
120.9, 121.1, 121.8, 122.6, 122.9, 124.3, 129.7, 133.7
(olfine C near to pyrazole), 134.3 (olefin C near to
pyrimidinone), 139.2 (phenyl C attached to N), 145.5
(pyrimidinone ring C near to N), 149.7 (pyrazole ring C
attached to phenyl), 161.9 (thiazole ring C near to sulfur
and nitrogen). 163.5 (C═O); ES-MS m/z: 512.3 [M+1].
Anal. Calcd for C31H21N5OS (511.6): C, 72.78; H, 4.14;
4-(7-{2-[3-(4-Bromo-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-5-oxo-5H-thiazolo[3,2-a]pyrimidin-6yl)-benzonitrile
1
(8). Yield 59%; mp 214–216°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 6.80 (d, 1H, J = 16 Hz, olefinic H
near to pyrazole ring), 7.00 (d, 2H, J = 8 Hz, ArH),
7.20–7.40 (m, 5H, ArH and thiazole ring H near to
sulfur), 7.51–7.56 (m, 4H, ArH), 7.69 (d, 1H, ArH),
N, 13.69. Found: C, 72.43; H, 4.27; N, 13.20.
4-{5-Oxo-7-[2-(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-vinyl]-
7.81–7.90 (m, 3H, ArH and olefinic
H near to
pyrimidone ring), 8.01 (d, 1H, thiazole ring H near to
bridge head nitrogen), 8.95 (s, 1H, pyrazol ring H); 13C-
NMR (100 MHz, DMSO-d6): 103.8 (thiazole ring C near
to sulfur), 106.4 (pyrazole ring C attached to olefin),
114.9 (phenyl C attached to cyano), 116.9 (CN), 119.2,
120.3, 120.9, 121.1, 121.9, 122.3, 122.8, 124.3, 129.1,
132.9 (olfine C near to pyrazole), 135.9 (olefin C near to
pyrimidinone), 139.0 (phenyl C attached to N), 141.2
(phenyl C attached to bromo), 145.9 (pyrimidinone ring
C near to N), 149.7 (pyrazole ring C attached to phenyl),
162.9 (thiazole ring C near to sulfur and nitrogen). 162.5
(C═O); ES-MS m/z: 576.3 [M+], 578.4 [M+2]. Anal.
Calcd for C30H18BrN5OS (576.3): C, 62.51; H, 3.15; N,
12.15. Found: C, 63.00; H, 3.41; N, 12.82.
5H-thiazolo[3,2-a]pyrimidin-6yl}-benzonitrile (11).
Yield
65%; mp 224–226°C; 1H-NMR (400 MHz, CDCl3) δ
ppm: 2.41 (s, 3H, ArCH3), 6.67 (d, 1H, J = 16 Hz,
olefinic H near to pyrazole), 6.77 (d, 1H, J = 8.00 Hz,
ArH), 7.25–7.35 (m, 4H, ArH), 7.48–7.66 (m, 6H, ArH
and thiazole ring H near to sulfur), 7.70–7.78 (m, 3H,
ArH), 7.85 (d, 1H, J = 15.7 Hz, olefinic H near to
pyrimidone ring), 7.90 (d, 1H, J = 4 Hz, thiazole ring H
near to bridge head nitrogen), 8.12 (s, 1H, pyrazol ring
H); 13C-NMR (100 MHz, DMSO-d6): 103.9 (thiazole
ring C near to sulfur), 106.5 (pyrazole ring C attached to
olefin), 114.3 (phenyl C attached to cyano), 116.6 (CN),
119.3, 120.1, 120.5, 121.2, 121.7, 122.5, 122.9, 124.2,
129.2, 133.2 (olfine C near to pyrazole), 137.1 (olefin C
near to pyrimidinone), 139.0 (phenyl C attached to N),
145.9 (pyrimidinone ring C near to N), 149.7 (pyrazole
ring C attached to phenyl), 162.9 (thiazole ring C near to
sulfur and nitrogen). 162.5 (C═O); ES-MS m/z: 512.3 [M
+1]. Anal. Calcd for C31H21N5OS (511.6): C, 72.78; H,
4-{5-Oxo-7-[2-(1-phenyl-3-o-tolyl-1H-pyrazol-4-yl)-vinyl]-
5H-thiazolo[3,2-a]pyrimidin-6yl}-benzonitrile (9).
Yield
62%; mp 227–229°C; 1H-NMR (400 MHz, CDCl3) δ
ppm: 2.41 (s, 3H, ArCH3), 6.64 (d, 1H, J = 16 Hz,
olefinic
H near to pyrazole ring), 6.97 (d, 1H,
J = 8.00 Hz, ArH), 7.21–7.30 (m, 3H, ArH),7.45–7.59
(m, 6H, ArH and thiazole ring H near to sulfur), 7.65–
7.71 (d, 6H, ArH), 7.90 (d, 1H, thiazole ring H near to
nitrogen), 8.01 (s, 1H, pyrazol ring H); 13C-NMR
(100 MHz, DMSO-d6): 103.8 (thiazole ring C near to
sulfur), 106.4 (pyrazole ring C attached to olefin), 114.0
(phenyl C attached to cyano), 116.0 (CN), 120.1, 120.9,
121.4, 121.8, 122.6, 122.9, 124.5, 129.7, 133.2 (olfine C
near to pyrazole), 135.9 (olefin C near to pyrimidinone),
139.0 (phenyl C attached to N), 145.9 (pyrimidinone ring
C near to N), 149.7 (pyrazole ring C attached to phenyl),
162.9 (thiazole ring C near to sulfur and nitrogen). 163.5
4.14; N, 13.69. Found: C, 72.83; H, 4.09; N, 13.29.
7-{2-[3-(2-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-6(4-trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-
one (12).
Yield 73%; mp 248–250°C; 1H-NMR
(400 MHz, DMSO-d6) δ ppm: 3.87 (s, 3H, ArOCH3), 6.61
(d, 1H, J = 16 Hz, olefinic H near to pyrazole ring), 7.20–
7.40 (m, 7H, ArH), 7.55–7.60 (m, 5H, ArH and thiazole
ring H near to sulfur), 7.80 (d, 1H, J = 15.3 Hz, olefinic H
near to pyrimidone ring), 7.83–7.85 (d, 2H, J = 8 Hz),
8.01 (d, 1H, thiazole ring H near to bridge head nitrogen),
8.90 (s, 1H, pyrazol ring H); 13C-NMR (100 MHz,
DMSO-d6): 105.0 (thiazole ring C near to sulfur), 106.1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives
(pyrazole ring C attached to olefin), 119.1, 120.1, 120.4,
121.2, 121.7, 122.2, 122.9, 124.3, 129.5, 133.1 (olfine C
near to pyrazole), 134.1 (olefin C near to pyrimidinone),
139.1 (phenyl C attached to N), 145.0 (pyrimidinone ring
C near to N), 149.7 (pyrazole ring C attached to phenyl),
157.3 (phenyl C attached to OCH3), 161.9 (thiazole ring C
near to sulfur and nitrogen). 162.2 (C═O); ES-MS m/z:
571.4 [M+1]. Anal. Calcd for C31H21F3N4O2S (570.3): C,
J = 16 Hz, olefinic H near to pyrazole ring), 7.05 (d, 2H,
J = 7.8 Hz, ArH), 7.25–7.32 (m, 5H, ArH), 7.48–7.60 (m,
5H, ArH and thiazole ring H near to sulfur), 7.79 (d, 1H,
J = 15.8 Hz, olefinic H near to pyrimidone), 7.82–7.88 (d,
2H, J = 8 Hz, ArH), 8.00 (d, J = 4 Hz, thiazole ring H
near to bridgehead nitrogen), 8.90 (s, 1H, pyrazole ring
H); 13C-NMR (100 MHz, DMSO-d6): 105.2 (thiazole ring
C near to sulfur), 106.5 (pyrazole ring C attached to
olefin), 119.2, 120.3, 120.7, 121.1, 121.7, 122.3, 122.7,
124.1, 129.7, 133.9 (olefin C near to pyrazole), 134.1
(olefin C near to pyrimidinone), 139.3 (phenyl C attached
to N), 145.0 (pyrimidinone ring C near to N), 149.8
(pyrazole ring C attached to phenyl), 161.9 (thiazole ring
C near to sulfur and nitrogen). 163.2 (C═O); ES-MS m/z:
555.7 [M+1]. Anal. Calcd for C31H21F3N4OS (554): C,
67.25; H, 3.81; N, 10.10. Found: C, 67.61; H, 3.88; N, 9.91.
65.26; H, 3.71; N, 9.81. Found: C, 65.09; H, 3.47; N, 10.08.
7-{2-[3-(3-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-6(4-trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-
one (13).
Yield 77%; mp 243–245°C; 1H-NMR
(400 MHz, DMSO-d6) δ ppm: 3.87 (s, 3H, ArOCH3), 6.64
(d, 1H, J = 16 Hz, olefinic H near to pyrazole ring), 7.17
(d, 2H, J = 8 Hz, ArH), 7.20–7.38 (m, 6H, ArH), 7.47–
7.57 (m, 4H, ArH and thiazole ring H near to sulfur),
7.81–7.87 (m, 3H, ArH and olefinic H near to pyrimidone
ring), 8.09 (d, 1H, thiazole ring H near to bridge head
nitrogen), 9.00 (s, 1H, pyrazol ring H); 13C-NMR
(100 MHz, DMSO-d6): 105.3 (thiazole ring C near to
sulfur), 106.6 (pyrazole ring C attached to olefin), 119.3,
120.3, 120.7, 121.4, 121.7, 122.2, 122.9, 124.3, 129.5,
134.0 (olfine C near to pyrazole), 136.1 (olefin C near to
pyrimidinone), 141.3 (phenyl C attached to N), 145.5
(pyrimidinone ring C near to N), 149.6 (pyrazole ring C
attached to phenyl), 157.9 (phenyl C attached to OCH3),
162.9 (thiazole ring C near to sulfur and nitrogen). 163.8
(C═O); ES-MS m/z: 571.4 [M+1]. Anal. Calcd for
C31H21F3N4O2S (570.3): C, 65.26; H, 3.71; N, 9.81.
7-[2-(1-Phenyl-3-m-tolyl-1H-pyrazol-4-yl)-vinyl]-6(4-
trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-one (16).
Yield 67%; mp 238–240°C; 1H-NMR (400 MHz,
DMSO-d6) δ ppm: 3.34 (s, 3H, ArCH3), 6.69 (d, 1H,
J = 16 Hz, olefinic H near to pyrazole ring), 7.05 (d, 2H,
J = 7.8 Hz, ArH), 7.20–7.39 (m, 6H, ArH), 7.45–7.62
(m, 4H, ArH and thiazole ring H near to sulfur), 7.79–
7.84 (m, 3H, ArH and olefinic H near to pyrimidone),
8.05 (d, 1H, J = 4.3 Hz, thiazole ring H near to bridge
head nitrogen), 8.95 (s, 1H, pyrazole ring H); 13C-NMR
(100 MHz, DMSO-d6): 105.0 (thiazole ring C near to
sulfur), 106.1 (pyrazole ring C attached to olefin), 119.1,
120.1, 120.4, 121.2, 121.7, 122.2, 122.9, 124.3, 129.5,
133.1 (olfine C near to pyrazole), 134.1 (olefin C near to
pyrimidinone), 139.1 (phenyl C attached to N), 145.0
(pyrimidinone ring C near to N), 149.7 (pyrazole ring C
attached to phenyl), 161.9 (thiazole ring C near to sulfur
and nitrogen). 162.6 (C═O); ES-MS m/z: 555.7 [M+1].
Anal. Calcd for C31H21F3N4OS (554): C, 67.25; H, 3.81;
N, 10.10. Found: C, 67.72; H, 3.88; N, 9.88.
Found: C, 64.75; H, 3.78; N, 9.34.
7-{2-[3-(4-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-6(4-trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-
one (14).
Yield 71%; mp 241–243°C; 1H-NMR
(400 MHz, DMSO-d6) δ ppm: 3.81 (s, 3H, ArOCH3),
6.63 (d, 1H, J = 16 Hz, olefinic H near to pyrazole ring),
7.00 (d, 2H, J = 8 Hz, ArH), 7.25–7.40 (m, 5H, ArH),
7.42–7.58 (m, 5H, ArH and thiazole ring H near
to sulfur), 7.81–7.87 (m, 3H, ArH and olefinic H near to
pyrimidone ring), 8.00 (d, 1H, thiazole ring H near
to sulfur), 8.80 (s, 1H, pyrazol ring H); 13C-NMR
(100 MHz, DMSO-d6): 105.3 (thiazole ring C near to
sulfur), 106.4 (pyrazole ring C attached to olefin), 119.1,
119.8, 120.1, 120.7, 121.1, 121.7, 122.2, 122.9, 124.1,
129.3, 133.6 (olfine C near to pyrazole), 134.6 (olefin C
near to pyrimidinone), 139.2 (phenyl C attached to N),
145.5 (pyrimidinone ring C near to N), 149.9 (pyrazole
ring C attached to phenyl), 157.3 (phenyl C attached to
OCH3), 162.7 (thiazole ring C near to sulfur and
nitrogen). 163.5 (C═O); ES-MS m/z: 571.4 [M+1]. Anal.
Calcd for C31H21F3N4O2S (570.3): C, 65.26; H, 3.71; N,
7-[2-(1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)-vinyl]-6(4-
trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-one (17).
Yield 64%; mp 247–249°C; 1H-NMR (400 MHz,
DMSO-d6) δ ppm: 3.39 (s, 3H, ArCH3), 6.61 (d, 1H,
J = 16.2 Hz, olefinic H near to pyrazole ring), 7.09–
7.29 (m, 8H, ArH), 7.41–7.49 (m, 4H, ArH and thiazole
ring H near to sulfur), 7.81–7.89 (m, 3H, ArH and
olefinic
H
near to pyrimidone), 8.00 (d, 1H,
J = 3.99 Hz, thiazole ring H near to bridge head
nitrogen), 8.90 (s, 1H, pyrazole ring H);13C-NMR
(100 MHz, DMSO-d6): 105.1 (thiazole ring C near to
sulfur), 105.7 (pyrazole ring C attached to olefin),
119.3, 120.5, 120.9, 121.3, 121.9, 122.2, 122.9, 124.6,
129.5, 133.4 (olfine C near to pyrazole), 134.8 (olefin C
near to pyrimidinone), 139.1 (phenyl C attached to N),
145.7 (pyrimidinone ring C near to N), 149.7 (pyrazole
ring C attached to phenyl), 162.3 (thiazole ring C near
to sulfur and nitrogen). 163.7 (C═O); ES-MS m/z:
9.81. Found: C, 65.21; H, 3.48; N, 9.95.
7-[2-(1-Phenyl-3-o-tolyl-1H-pyrazol-4-yl)-vinyl]-6(4-
trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-one (15).
Yield 70%; mp 247–249°C; 1H-NMR (400 MHz,
DMSO-d6) δ ppm: 2.32 (s, 3H, ArCH3), 6.61 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, G. Sanap, and M. Farooqui
Vol 000
555.7 [M+1]. Anal. Calcd for C31H21F3N4OS (554): C,
67.25; H, 3.81; N, 10.10. Found: C, 67.13; H, 3.23; N,
9.41.
(s, 1H, pyrazol ring H); 13C-NMR (100 MHz,
DMSO-d6): 105.0 (thiazole ring C near to sulfur), 106.7
(pyrazole ring C attached to olefin), 120.4, 120.6, 121.5,
121.7, 122.6, 123.3, 124.3, 129.8, 133.8 (olfine C near
to pyrazole), 134.4 (olefin C near to pyrimidinone),
139.6 (phenyl C attached to N), 141.9 (phenyl C
attached to bromo), 145.6 (pyrimidinone ring C near to
N), 149.2 (pyrazole ring C attached to phenyl), 162.0
(thiazole ring C near to sulfur and nitrogen). 162.8
(C═O); ES-MS m/z: 619.1 [M+], 621.1 [M+2]. Anal.
Calcd for C30H18BrN4OS (619.1): C, 58.17; H, 2.93; N,
9.04. Found: C, 57.82; H, 2.77; N, 8.89.
7-{2-[3-(2-Bromo-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
6(4-trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-one
1
(18). Yield 74%; mp 231–233°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 6.59 (d, 1H, J = 16 Hz, olefinic H
near to pyrazole ring), 6.99 (d, 2H, J = 8 Hz, ArH),
7.20–7.37 (m, 4H, ArH), 7.43–7.60 (m, 6H, ArH and
thiazole ring H near to sulfur), 7.81 (d, 1H, J = 15.9 Hz,
olefinic H near to pyrimidone), 7.85 (d, 2H, J = 8 Hz,
ArH), 8.00 (d, 1H, J = 4 Hz, thiazole ring H near to
bridge head nitrogen), 8.86 (s, 1H, pyrazol ring H); 13C-
NMR (100 MHz, DMSO-d6): 105.1 (thiazole ring C near
to sulfur), 106.3 (pyrazole ring C attached to olefin),
119.2, 120.4, 120.4, 121.3, 121.7, 122.2, 122.9, 124.2,
129.6, 133.8 (olfine C near to pyrazole), 134.6 (olefin C
near to pyrimidinone), 139.5 (phenyl C attached to N),
145.6 (pyrimidinone ring C near to N), 149.2 (pyrazole
ring C attached to phenyl), 162.9 (thiazole ring C near to
sulfur and nitrogen). 163.6 (C═O); ES-MS m/z: 619.1
[M+], 621.1 [M+2]. Anal. Calcd for C30H18BrN4OS
(619.1): C, 58.17; H, 2.93; N, 9.04. Found: C, 58.88; H,
CONCLUSION
Present study reported design and synthesis of novel
pyrazole derivatives and their growth inhibition against
M. smegmatis mc2 155 as well as M. tuberculosis
H37Rv. Structures of the synthesized compounds were
confirmed by their 1H-NMR, mass spectra, and
elemental analysis. All the synthesized derivatives were
successively assayed for their M. smegmatis mc2 155
growth inhibitory potential and cytotoxicity towards
eukaryotic cells. Compounds 9, 10, and 11 (with
promising preliminary inhibitory activity) were evaluated
for their M. tuberculosis H37Rv growth inhibition
activity and synergistic performance with first-line and
second-line antitubercular drugs. Derivative 10 displayed
superior performance in growth inhibition for
M. tuberculosis H37Rv (1.9 μg/mL), and it also displayed
synergism everywhere in first-line and second-line drugs.
To summarize, compound 10 was identified as lead
candidate in this study.
3.00; N, 8.81.
7-{2-[3-(3-Bromo-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
6(4-trifluoromethyl-phenyl)-thiazolo[3,2-a]pyrimidin-5-one
1
(19). Yield 76%; mp 237–239°C; H-NMR (400 MHz,
DMSO-d6) δ ppm: 6.60 (d, 1H, J = 16 Hz, olefinic H
near to pyrazole ring), 7.00 (d, 2H, J = 8 Hz, ArH),
7.20–7.23 (m, 3H, ArH), 7.29–7.40 (m, 4H, ArH),
7.43–7.60 (m, 5H, ArH and thiazole ring H near to
sulfur), 7.81–7.83 (m, 3H, ArH and olefinic H near to
pyrimidone), 8.00 (d, 1H, thiazole ring H near to
sulfur), 8.80 (s, 1H, pyrazole ring H); 13C-NMR
(100 MHz, DMSO-d6): 105.4 (thiazole ring C near to
sulfur), 106.2 (pyrazole ring C attached to olefin),
120.4, 120.6, 121.5, 121.7, 122.2, 123.3, 124.5, 129.8,
133.3 (olfine C near to pyrazole), 134.4 (olefin C near
to pyrimidinone), 139.6 (phenyl C attached to N), 141.9
(phenyl C attached to bromo), 145.6 (pyrimidinone ring
C near to N), 149.2 (pyrazole ring C attached to
phenyl), 162.0 (thiazole ring C near to sulfur and
nitrogen). 162.6 (C═O); ES-MS m/z: 619.1 [M+], 621.1
[M+2]. Anal. Calcd for C30H18BrN4OS (619.1): C,
58.17; H, 2.93; N, 9.04. Found: C, 57.81; H, 3.02; N,
Acknowledgments. Authors are thankful to the managements of
Maulana Azad College and Dr. Rafiq Zakaria College for
Women for their constant encouragements.
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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