Thiazolo[3,2-a] Pyrimidones as a Novel Anti-TB Agents

Article abstract of DOI:10.1002/jhet.3362

A series of novel thiazolo pyrimidine derivatives were designed, synthesized, and assessed for their in vitro anti-mycobacterial activities. All hybrids displayed considerable antitubercular activities against primary Mycobacterium smegmatis mc² 155 screening and successive Mycobacterium tuberculosis H37Rv. In particular, the hybrid entities 13 and 14 (minimum inhibitory concentration: 47 and 39?μg/mL) were found to be equipotent candidates with first-line antitubercular agent rifampicin, which could act as a lead for further optimization.

Full text of DOI:10.1002/jhet.3362

Month 2018
Thiazolo[3,2-a] Pyrimidones as a Novel Anti-TB Agents
Sunil B. Jadhav, Samreen Fatema, Sunil S. Bhagat, and Mazahar Farooqui
a
a
b
a
*
aDr Rafiq Zakaria College for Womens, Jubliee Park, Navkhanda, Aurangabad, Maharashtra 431001, India
bR.B. Attal College, Ahilya Nagar, Georai, Beed, Maharashtra 431127, India
*E-mail: mazahar_64@rediffmail.com
Received June 30, 2018
DOI 10.1002/jhet.3362
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel thiazolo pyrimidine derivatives were designed, synthesized, and assessed for their
in vitro anti-mycobacterial activities. All hybrids displayed considerable antitubercular activities against pri-
mary Mycobacterium smegmatis mc2 155 screening and successive Mycobacterium tuberculosis H37Rv. In
particular, the hybrid entities 13 and 14 (minimum inhibitory concentration: 47 and 39 μg/mL) were found to
be equipotent candidates with first-line antitubercular agent rifampicin, which could act as a lead for further
optimization.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
market is lack of new anti-TB agent from the last 40 years
except Bedaquiline, which was approved in the year 2012
by USFDA [6]. Hence, advancement in anti-TB drugs is a
clinical need to reduce toxicity as well as treatment time.
It is a bigger global challenge to tackle the increasing
population of tuberculosis (TB) due to emergence
multidrug-resistant TB and extensively drug-resistant TB.
World Health Organization reports TB as a second
leading reason for mortality from an infective disease.
Current document records 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
mentioned 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]. The strategy of
vaccination and current antibiotic therapy to treat the
disease is not effective in current scenario due to
Pyrazole and its derivatives are considered
a
pharmacologically important active scaffold that
possesses almost all types of pharmacological activities.
Pyrazole in pharmacological agents of various therapeutic
areas, such as celecoxib, a potent anti-inflammatory; the
antipsychotic CDPPB; the anti-obesity drug rimonabant;
difenamizole, an analgesic; betazole, an H2-receptor
agonist; and the antidepressant agent fezolamide, has
proved the pharmacological potential of the pyrazole
nucleus [7]. Pyrazoles are also documented for their anti-
TB activity [8–10]. Our previous results showed that
hybrid pyrazole derivatives were endowed with potential
anti-TB property, wherein most active hybrid derivative
(compound 10) demonstrated minimum inhibitory
concentration (MIC) 1.9 μg/mL in M. tuberculosis
H37Rv screening [11] (Fig. 1). Further, compound 10
also showed very good synergism with the first-line and
second-line antibiotics used in the screening. Hence,
pyrazole derivatives are a reasonable choice to develop
new anti-TB agents.
multidrug resistance
strains
of Mycobacterium
tuberculosis [2]. In the early 1950s, there was a gradual
decline in the number of cases of TB, but there has been
resurgence since 1984 [3]. This growth of TB, all the way
through the recent years, was mainly due to HIV-1
infection, immigration, increased trade, and globalization
[4]. Due to multidrug-resistant and extensively drug-
resistant TB occurrence, in 1993, World Health
Organization declared TB a global emergency [5]. The
© 2018 Wiley Periodicals, Inc.

S. B. Jadhav, S. Fatema, S. S. Bhagat, and M. Farooqui
Vol 000
underwent cyclization to give different pyrazole
aldehydes D in good yield as key precursors. Another
important precursor F was prepared as outlined in
Scheme 1. 2-Amino thiazole E on treatment with ethyl
acetoacetate at reflux temperature in acetic acid affords 7-
methyl-thiazolo[3,2-a]pyrimidin-5-one F. Here, different
aldehydes D were condensed with 7-methyl-thiazolo[3,2-
a]pyrimidin-5-one F using sodium ethoxide at refluxed
temperature in ethanol to give targeted compounds 1–17
(Table 1).
Figure 1. Molecular designing for compounds 1–17. [Color figure can be
viewed at wileyonlinelibrary.com]
The progresses of all reactions were monitored by TLC.
All the newly synthesized compounds were isolated in
As an ongoing research program and to continue our
efforts to develop new anti-TB agents, a series of
pyrazole derivatives were designed, wherein our primary
objective was to remove benzene rings from our
previously synthesized series (Fig. 1) to bring down the
molecular bulk. Hence, novel derivatives 1–17 were
synthesized and were explored for their anti-TB potential.
Table 1
Substitution strategy for the compounds 1–17.
ID
R1
R2
R3
R4
1
2
3
H
H
H
H
H
H
H
H
H
H
Cl
F
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
OCH3
H
CH3
H
OCH3
CH3
CH3
H
H
H
H
H
H
H
H
OCH3
H
CH3
CH3
OCH3
CH3
H
Cl
F
OCH3
CF3
CH3
OCF3
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
RESULTS AND DISCUSSIONS
Chemistry.
The synthetic program starts with
preparation of different pyrazole aldehydes D as shown
in Scheme 1. Here, as per the literature [12],
commercially
acetophenones
available
different
substituted
A
when treated with commercially
available various phenylhydrazines B in acidic medium
in refluxing ethanol gave imine as an intermediate C.
This intermediate C upon reaction with POCl3 in DMF
Scheme 1. Reagents and conditions: (i) AcOH/EtOH, reflux, 30 min; (ii) DMF/POCl3, 0–30°C, 12–14 h; (iii) ethyl acetoacetate, AcOH, 12- to 14-h
reflux; and (iv) NaOEt, EtOH, reflux, room temperature, 12–14 h.
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Thiazolo[3,2-a] Pyrimidones as a Novel Anti-TB Agents
Table 2
moderate to good yields and were characterized by ES-MS,
1H NMR (400 MHz), 13C NMR spectral data, and
elemental analysis.
Figure 2 represents probable mechanistic pathway of
thiazo[3,2-a]pyrimidinone. Acetic acid provides initial
proton for triggering this reaction, wherein nitrogen and
oxygen uses their lone pair of electrons for bond
formations. The reaction completes when quenched with
proton donor producing ethanol and water as by product.
Antitubercular activity of 1–17 against Mycobacterium smegmatis mc2
155 and their toxicity index towards human monocyte derived
macrophages.
Mycobacterium smegmatis mc2 155
IC50
(μg/mL)
ID
MIC (μg/mL)
REF SD
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
85
110
121
139
201
367
87
151
69
191
342
312
47
1.1 0.03*
0.19 0.01
0.74 0.03
0.71 0.01
0.25 0.07
0.86 0.09
0.70 0.084
0.85 0.05
0.34 0.02
1.9 0.08*
1.7 0.03*
0.61 0.05
0.34 0.09
0.61 0.07
0.61 0.05
0.34 0.09
0.67 0.05
1.67 0.09*
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
377
369
ND
ND
ND
400
Biology. Growth
inhibitory
potential
against
Mycobacterium smegmatis mc2 155 stains and cell cytotoxicity
for compounds 1–17. Synthesized compounds from this
series were initially tested for their ability to inhibit the
growth of Mycobacterium smegmatis mc2 155 (Table 2).
In the beginning, compound 1 was synthesized and
tested. As a result, it was inferior (MIC = 85 μg/mL)
compared with standard. But, for the satisfaction, we
were happy with the result obtained. In the next step, H
at R4 position was replaced by chloro, fluoro, and methyl
groups (compounds 2–4). In screening, we found that
there is a massive drop in M. smegmatis mc2 155 growth
inhibition compared with compound 1. We concluded
that the substitution at R4 position may not be favorable
for the mentioned growth inhibition activity.
39
211
209
312
32
17
Rifampicin
MIC, minimum inhibitory concentration; ND, no data.
*P < 0.05.
In the next level, chloro, fluoro, methoxy,
trifluoromethyl, methyl, and trifluoromethoxy groups
were employed at R3 position (5–10). In the screening
results, no significant improvements have been noticed
except compounds 9 and 7. Compound 9 showed
MIC = 69 μg/mL; in addition, compound 7 displayed
MIC = 87 μg/mL. Based on these findings, we
synthesized 11 and 12, wherein methoxy group was
introduced at R1 and R2 positions, and activity was
screened. Both these compounds were inactive, hinted us
that methoxy group at these positions does not help.
Further, methyl group was introduced at R1 and R2.
Surprisingly, the resulted 13 and 14 were superior
compared with the compound prepared so far. Compound
13 displayed MIC = 42 μg/mL and that of 14 showed
MIC = 39 μg/mL. Further, 15–17 disubstitution by
methoxy and methyl groups was introduced at R1 and R2
positions. In the screening results, the growth inhibitory
potentials of all these compounds were poor, hinted us
that the disubstitutions at R1 and R2 positions are not
tolerated.
Cell cytotoxicity. Compounds 13 and 14 were taken for
cell cytotoxicity study. Here, 13 (IC50 = 377 μg/mL) and
14 (IC50 = 369 μg/mL) were found to be a safe
compound like rifampicin (400 μg/mL) (Table 2). Hence,
13 and 14 were taken ahead for growth inhibition study
against M. tuberculosis H37Rv.
Figure 2. Reaction mechanism of thiazo[3,2-a]pyrimidinone.
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S. B. Jadhav, S. Fatema, S. S. Bhagat, and M. Farooqui
Vol 000
Table 4
Growth inhibitory potential of compounds 13 and 14 against
Mycobacterium tuberculosis H37Rv.
Based on MIC and
Synergistic effect and modulation factor for compounds 13 and 14 with
first-line and second-line drugs against Mycobacterium tuberculosis
H37Rv.
cell cytotoxicity results obtained from the primary
screenings, compounds 13 and 14 were selected for
establishing their M. tuberculosis growth inhibition study
(Table 3). Herein, 13 and 14 were found equipotent
(MIC = 3.12 μg/mL and MIC = 3.05 μg/mL) when
compared with standard rifampicin (2.80 μg/mL).
Consequently, 13, 14, and rifampicin were found to be
almost similar in potency; therefore, these compounds
were taken ahead for further synergistic evaluation study
ID
Test conc.
INH
RIF
1.7
OFX
AMK
Standalone MIC
1.2
2.4
0.032
(35)
0.91
1.4
2.4
2.4
2.4
2.9
13
14
9.60
0.47
0.51
0.023
(127)
0.57
1.12
2.9
2.9
2.9
0.06
(49)
0.69
4.80
2.40
1.20
0.60
0.30
9.60
0.99
1.2
0.71
0.81
1.29
1.7
1.2
1.2
1.2
(Table 3).
1.7
0.029
(16)
0.071
(17)
1.2
0.021
(81)
0.19
(9)
0.04
(60)
0.29
Synergism. After screening growth inhibition against
M. tuberculosis H37Rv, in the next level, 13 and 14 were
taken ahead for synergistic study with first-line rifampicin
(RIF) and isoniazide (INH) 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 compounds 13 and 14 against M. tuberculosis H37Rv
(Table 4).
4.80
2.40
1.20
0.60
0.30
1.7
2.4
2.4
2.4
2.4
1.01
2.9
2.9
1.2
1.2
1.2
1.7
1.7
1.7
2.9
INH, isoniazid; RIF, rifampin; OFX, ofloxacin; AMK, amikacin; MIC,
minimum inhibitory concentration.
Compounds 13 and 14 were tested at their ½ MIC
followed by two-dimensional broth micro dilution
checkerboard assay, which is used to calculate the
magnitude of synergism. Compound 13 does not show
effective synergism with INH and RIF, whereas it
demonstrated good synergism with OFX and AMK. On
the other hand, 14 showed synergism everywhere. Hence,
14 was found to be a good potent compound among the
series.
the reaction was separated by the filtration. This product
C was washed by cold ethanol (7 mL) and was dried
under vacuum.
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 product C was
added at 0°C with constant stirring. The reaction mixture
was then slowly allowed to warm up to room temperature
and stirred for 12 h. After completion of reaction on TLC
and mass, the 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. The solid was crystallized from ethanol to get a
white crystalline product D in an average 70% yield. The
EXPERIMENTAL PROTOCOLS
Chemistry. Synthesis of 3-(substituted-phenyl)-1-(substi
tuted-phenyl)-1H-pyrazole-4-carbaldehyde (D).
Synthesis
of these aldehydes was carried using Vilsmeier–Haack
reaction condition. A mixture of substituted acetophenone
(A, 1 mol) and substituted phenyl hydrazine (B, 1 mol)
was heated in ethanol (20 mL) using AcOH as a catalyst
at reflux temperature for 30 min. Solid precipitated from
1
conversion was monitored by TLC only, so mass and H
NMR analysis was not performed at this stage of
chemistry.
Synthesis of 7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one
(F). Ethyl acetoacetate (39 g, 0.3 mol) was added to a
stirred mixture of 2-aminothiazole E (20 g, 0.2 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 then dissolved in ethyl acetate (250 mL) and
washed with saturated NaHCO3 solution (200 mL × 2)
followed by saturated brine (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 11.5 g (35%) of white solid of 7-
methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (F). 1H NMR
Table 3
Growth inhibitory potential of compounds 13 and 14 against Mycobacte-
rium tuberculosis H37Rv.
Mycobacterium tuberculosis H37Rv
ID
MIC (μg/mL)
REF SD
13
14
3.12
3.05
2.80
1.1 0.10*
2.3 0.03*
1.35 0.04*
Rifampicin
Results are presented as an average of three independent assays plus
standard deviation ( SD). MIC, minimum inhibitory concentration.
*P < 0.05.
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Thiazolo[3,2-a] Pyrimidones as a Novel Anti-TB Agents
(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].
Condensation of 3-(substituted-phenyl)-1-(substituted-
phenyl)-1H-pyrazole-4-carbaldehyde (D) and 7-methyl-5H-
thiazolo[3,2-a]pyrimidin-5-one (F) to yield compounds
and nitrogen), 162.5 (C═O); ES-MS (m/z) 431.1 (M + 1),
Anal. Calcd for C23H15ClN4OS (430.92): C, 64.11; H,
3.51; N, 13.00; found C, 64.23; H, 4.01; N, 13.41.
7-{2-[1-(4-Fluoro-phenyl)-3-phenyl-1H-pyrazol-4-yl}-
thiazolo[3,2-a]pyrimidin-5-one (3). Yield 61%, M.P. 227–
1
229°C, H NMR (400, DMSO-d6), δ ppm: 6.12 (s, 1H,
pyrimidinone ring H), 7.11 (d, 1H, J = 16 Hz, olefinic H
close to pyrazole ring), 7.31 (d, 1H, J = 4.0 Hz, thiazole
ring H near to sulfur), 7.45 (t, 2H, ArH), 7.41–7.77 (m,
8H, olefinic H near to pyrazole ring and ArH), 7.99 (d,
1H, J = 4.1 Hz, thiazole ring H near to bridge head
nitrogen), 9.21(s, 1H, pyrazole ring H); 13C NMR
(100 MHz, DMSO-d6): 103.6 (thiazole ring C near to
sulfur), 107.1 (pyrazole ring C attached to olefin), 119.6,
120.4, 121.1, 121.9, 123.6, 124.3, 126.8, 131.4, 133.6
(olfine C near to pyrazole), 135.1 (olefin C near to
pyrimidinone), 138.7 (phenyl C attached to N), 141.1
(phenyl C attached to fluoro), 145.8 (pyrimidinone ring C
near to N), 149.2 (pyrazole ring C attached to phenyl),
161.0 (thiazole ring C near to sulfur and nitrogen), 162.1
(C═O); ES-MS (m/z) 415.1 (M + 1), Anal. Calcd for
C23H15FN4OS (414.46): C, 66.65; H, 3.65; N, 13.52;
1–17.
A
mixture of 3-(substituted-phenyl)-1-
(substituted-phenyl)-1H-pyrazole-4-carbaldehyde (D)
(1.2 mol), 7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one
(F) (1.0 mol), and sodium ethoxide (2 mol) was refluxed
together in ethanol for 13 h (overnight). Heating was
ceased, and the reaction mixture was allowed to cool to
room temperature. On cooling, yellow solid was
separated. It was filtered and washed with cold ethanol.
The solid was then dissolved in ethyl acetate and
adsorbed on silica gel (60–120). Product was then
column purified, solvent was evaporated, and product
was then dried to obtain product (1–17) in 50–75% yield.
7-[2-(1,3-Diphenyl-1H-pyrazol-4-yl)-vinyl]-thiazolo[3,2-a]
pyrimidin-5-one (1).
Yield 59%, M.P. 211–213°C, 1H
NMR (400, DMSO-d6),
δ
ppm: 6.20 (s, 1H,
pyrimidinone ring H), 7.10 (d, 1H, J = 16 Hz, olefinic H
close to pyrazole ring), 7.38 (d, 1H, J = 4.3 Hz, thiazole
ring H near to sulfur), 7.40 (t, 2H, ArH), 7.50–7.70 (m,
7H, olefinic H near to pyrimidinone ring and ArH), 7.80
(t, 2H, ArH), 8.00 (d, 1H, J = 4 Hz, thiazole ring H near
to bridge head nitrogen), 9.20 (s, 1H, pyrazole ring H);
13C NMR (100 MHz, DMSO-d6): 102.8 (thiazole ring C
near to sulfur), 105.9 (pyrazole ring C attached to olefin),
118.2, 120.1, 121.4, 122.1, 122.4, 123.4, 124.3, 129.7,
132.3 (olfine C near to pyrazole), 135.1 (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), 161.9 (thiazole ring C near to sulfur
and nitrogen), 162.8 (C═O); ES-MS (m/z) 397.1 (M + 1),
Anal. Calcd for C23H16N4OS (396.47): C, 69.68; H,
found C, 66.89; H, 4.03; N, 13.21.
7-[2-[1-(3-Phenyl-1-p-tolyl-1H-pyrazol-4-yl}-thiazolo[3,2-a]
pyrimidin-5-one (4).
Yield 67%, M.P. 232–234°C, 1H
NMR (400, DMSO-d6), δ ppm: 2.38 (s, 3H, ArCH3),
6.22 (s, 1H, pyrimidinone ring H), 7.06 (d, 1H,
J = 16.2 Hz, olefinic H close to pyrazole ring), 7.21 (d,
1H, J = 4.3 Hz, thiazole ring H near to sulfur), 7.38 (d,
1H, J = 8.1 Hz, ArH), 7.41–7.67 (m, 6H, olefinic H near
to pyrimidinone ring and ArH), 7.78–7.80 (m, 3H, ArH),
8.07 (d, 1H, J = 4.1 Hz, thiazole ring H near to bridge
head nitrogen), 9.11 (s, 1H, pyrazole ring H); 13C NMR
(100 MHz, DMSO-d6): 103.1 (thiazole ring C near to
sulfur), 105.8 (pyrazole ring C attached to olefin), 120.3,
121.2, 121.9, 123.4, 129.4, 132.1 (olfine C near to
pyrazole), 136.1 (olefin C near to pyrimidinone), 138.4
(phenyl C attached to N), 145.2 (pyrimidinone ring C
near to N), 149.5 (pyrazole ring C attached to phenyl),
161.9 (thiazole ring C near to sulfur and nitrogen), 163.1
(C═O); ES-MS (m/z) 411.3 (M + 1), Anal. Calcd for
4.07; N, 14.23; found C, 68.99; H, 4.59; N, 13.91.
7-{2-[1-(4-Chloro-phenyl)-3-phenyl-1H-pyrazol-4-yl}-
thiazolo[3,2-a]pyrimidin-5-one (2). Yield 64%, M.P. 223–
1
225°C, H NMR (400, DMSO-d6), δ ppm: 6.19 (s, 1H,
pyrimidinone ring H), 7.05 (d, 1H, J = 16 Hz, olefinic H
close to pyrazole ring), 7.37 (d, 1H, J = 4.1 Hz, thiazole
ring H near to sulfur), 7.41 (t, 2H, ArH), 7.43–7.67 (m,
6H, olefinic H near to pyrazole ring and ArH), 7.88 (t,
2H, ArH), 8.01 (d, 1H, J = 4 Hz, thiazole ring H near to
bridge head nitrogen), 9.21 (s, 1H, pyrazole ring H); 13C
NMR (100 MHz, DMSO-d6): 103.2 (thiazole ring C near
to sulfur), 106.3 (pyrazole ring C attached to olefin),
119.2, 120.6, 121.5, 121.9, 124.3, 126.9, 129.4, 132.2
(olefinic C near to pyrazole), 135.8 (olefinic C near to
pyrimidinone), 138.2 (phenyl C attached to N), 145.3
(pyrimidinone ring C near to N), 148.1 (pyrazole ring C
attached to phenyl), 161.2 (thiazole ring C near to sulfur
C24H18N4OS (410.50): C, 70.22; H, 4.42; N, 13.62;
found C, 71.00; H, 4.32; N, 13.67.
7-{2-[3-(4-Chloro-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
thiazolo[3,2-a]pyrimidin-5-one (5).
227–229°C, H NMR (400, DMSO-d6), δ ppm: 6.17 (s,
1H, pyrimidinone ring H), 6.98 (d, 1H, J = 16.0 Hz,
Yield 63.5%, M.P.
1
olefinic
H close to pyrazole ring), 7.14 (d, 1H,
J = 4.3 Hz, thiazole ring H near to sulfur), 7.41 (t, 2H,
ArH), 7.45–7.70 (m, 6H, olefinic H near to pyrimidinone
ring and ArH), 7.89 (d, 2H, J = 8.2 Hz, ArH), 8.07 (d,
1H, J = 4.1 Hz, thiazole ring H near to bridge head
nitrogen), 9.18 (s, 1H, pyrazole ring H); 13C NMR
(100 MHz, DMSO-d6): 103.2 (thiazole ring C near to
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sulfur), 107.2 (pyrazole ring C attached to olefin), 114.7,
119.6, 120.4, 120.8, 121.9, 123.6, 126.3, 130.1, 131.4,
133.2 (olfine C near to pyrazole), 135.1 (olefin C near to
pyrimidinone), 137.2 (phenyl C attached to N), 144.3
(phenyl C attached to chloro), 145.1 (pyrimidinone ring
C near to N), 149.0 (pyrazole ring C attached to phenyl),
161.1 (thiazole ring C near to sulfur and nitrogen), 163.0
(C═O); ES-MS (m/z) 431.3 (M + 1), Anal. Calcd for
C23H15ClN4OS (430.92): C, 64.11; H, 3.51; N, 13.00;
1H, pyrimidinone ring H), 7.03 (d, 1H, J = 16.7 Hz,
olefinic close to pyrazole ring), 7.21 (d, 1H,
H
J = 4.8 Hz, thiazole ring H near to sulfur), 7.31 (d, 2H,
J = 8.2 Hz, ArH), 7.43–7.75 (m, 7H, olefinic H near to
pyrimidinone ring and ArH), 7.87 (d, 1H, J = 8.0 Hz,
ArH), 8.07 (d, 1H, J = 4.1 Hz, thiazole ring H near to
bridge head nitrogen), 9.09 (s, 1H, pyrazole ring H); 13C
NMR (100 MHz, DMSO-d6): 102.8 (thiazole ring C near
to sulfur), 105.1 (pyrazole ring C attached to olefin),
120.3, 121.1, 122.3, 122.8, 124.3, 129.1, 132.0 (olfine C
near to pyrazole), 135.1 (olefin C near to pyrimidinone),
139.2 (phenyl C attached to N), 141.2 (phenyl C attached
to trifluoro methyl), 145.2 (pyrimidinone ring C near to
N), 149.0 (pyrazole ring C attached to phenyl), 162.2
(thiazole ring C near to sulfur and nitrogen), 162.8
(C═O); E-MS (m/z) 465.3 (M + 1), Anal. Calcd for
C24H15F3N4OS (464.4): C, 62.05; H, 3.26; N, 12.06;
found C, 64.29; H, 3.89; N, 13.47.
7-{2-[3-(4-Fluoro-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
thiazolo[3,2-a]pyrimidin-5-one (6). Yield 59%, M.P. 209–
1
211°C, H NMR (400, DMSO-d6), δ ppm: 6.19 (s, 1H,
pyrimidinone ring H), 6.96 (d, 1H, J = 16.7 Hz, olefinic
H close to pyrazole ring), 7.20 (d, 1H, J = 4.1 Hz,
thiazole ring H near to sulfur), 7.35 (d, 1H, J = 8.3 Hz,
ArH), 7.39–7.65 (m, 7H, olefinic H near to pyrimidinone
ring and ArH), 7.80 (t, 2H, ArH), 8.07 (d, 1H,
J = 4.0 Hz, thiazole ring H near to bridge head nitrogen),
9.07 (s, 1H, pyrazole ring H); 13C NMR (100 MHz,
DMSO-d6): 103.2 (thiazole ring C near to sulfur), 106.1
(pyrazole ring C attached to olefin), 120.3, 121.2, 123.4,
126.8, 129.4, 132.8 (olfine C near to pyrazole), 136.1
(olefin C near to pyrimidinone), 138.3 (phenyl C attached
to N), 141.3 (phenyl C attached to fluoro), 145.7
(pyrimidinone ring C near to N), 149.2 (pyrazole ring C
attached to phenyl), 161.8 (thiazole ring C near to sulfur
and nitrogen), 163.5 (C═O); ES-MS (m/z) 415.1 (M + 1),
Anal. Calcd for C23H15FN4OS (414.16): C, 66.65; H,
found C, 61.98; H, 3.51; N, 12.10.
7-{2-[3-(4-Methyl-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
thiazolo[3,2-a]pyrimidin-5-one (9).
Yield 66.3%, M.P.
1
220–222°C, H NMR (400, DMSO-d6), δ ppm: 2.38 (s,
3H, Ar–CH3), 6.29 (s, 1H, pyrimidinone ring H), 7.09 (d,
1H, J = 16.0 Hz, olefinic H close to pyrazole ring), 7.23
(d, 1H, J = À4.1 Hz, thiazole ring H near to sulfur), 7.31
(d, 2H, J = 8.0 Hz, ArH), 7.43–7.79 (m, 6H, olefinic H
near to pyrimidinone ring and ArH), 7.84 (d, 1H,
J = 8.0 Hz, ArH), 8.07 (d, 1H, J = 4.1 Hz, thiazole ring
H near to bridge head nitrogen), 9.11 (s, 1H, pyrazole
ring H); 13C NMR (100 MHz, DMSO-d6): 101.9
(thiazole ring C near to sulfur), 106.0 (pyrazole ring C
attached to olefin), 120.9, 121.4, 122.6, 124.5, 129.7,
133.0 (olfine C near to pyrazole), 135.2 (olefin C near to
pyrimidinone), 138.0 (phenyl C attached to N), 145.0
(pyrimidinone ring C near to N), 149.2 (pyrazole ring C
attached to phenyl), 162.8 (thiazole ring C near to sulfur
and nitrogen), 163.1 (C═O); ES-MS (m/z) 411.3 (M + 1),
Anal. Calcd for C24H18F3N4OS (410.50): C, 70.22; H,
3.65; N, 13.52; found C, 66.98; H, 4.51; N, 13.04.
7-{2-[3-(4-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-thiazolo[3,2-a]pyrimidin-5-one (7). Yield 69.7%, M.
1
P. 229–231°C, H NMR (400, DMSO-d6), δ ppm: 3.89
(s, 3H, Ar–OCH3), 6.19 (s, 1H, pyrimidinone ring H),
7.01 (d, 1H, J = 16.7 Hz, olefinic H close to pyrimidone
ring), 7.19 (d, 2H, J = 4.0 Hz, thiazole ring H near to
sulfur and ArH), 7.39 (t, 1H, ArH), 7.51–7.68 (m, 6H,
olefinic H near to pyrazole ring and ArH), 7.91 (m, 2H,
ArH), 8.00 (d, 1H, J = 4.3 Hz, thiazole ring H near to
bridge head nitrogen), 9.07 (s, 1H, pyrazole ring H); 13C
NMR (100 MHz, DMSO-d6): 102.9 (thiazole ring C near
to sulfur), 107.1 (pyrazole ring C attached to olefin),
120.4, 121.1, 123.6, 124.3, 126.3, 126.8, 130.1, 131.4,
133.8 (olfine C near to pyrazole), 135.2 (olefin C near to
pyrimidinone), 138.5 (phenyl C attached to N), 141.8
4.42; N, 13.65; found C, 71.01; H, 4.21; N, 13.81.
7-{2-[3-(4-Trifluoromethoxy-phenyl)-1-phenyl-1H-pyrazol-4-
yl]-vinyl}-thiazolo[3,2-a]pyrimidin-5-one (10).
Yield 61%,
M.P. 226–228°C, 1H NMR (400, DMSO-d6), δ ppm: 6.37
(s, 1H, pyrimidinone ring H), 7.12 (d, 1H, J = 16.0 Hz,
olefinic H close to pyrazole ring), 7.29 (d, 1H, J = 4.0 Hz,
thiazole ring H near to sulfur), 7.38 (d, 2H, J = 8.0 Hz,
ArH), 7.46–7.68 (m, 7H, olefinic H near to pyrimidinone
ring and ArH), 7.90 (d, 1H, J = 8.0 Hz, ArH), 8.10 (d, 1H,
J = 4.1 Hz, thiazole ring H near to bridge head nitrogen),
9.13 (s, 1H, pyrazole ring H); 13C NMR (100 MHz,
DMSO-d6): 101.9 (thiazole ring C near to sulfur), 107.2
(pyrazole ring C attached to olefin), 120.4, 121.1, 121.8,
122.9, 124.3, 129.7, 133.1 (olfine C near to pyrazole),
134.1 (olefin C near to pyrimidinone), 139.7 (phenyl C
attached to N), 145.2 (pyrimidinone ring C near to N),
149.0 (pyrazole ring C attached to phenyl), 161.9 (thiazole
(phenyl
C
attached to methoxy group), 144.9
(pyrimidinone ring C near to N), 149.7 (pyrazole ring C
attached to phenyl), 161.7 (thiazole ring C near to sulfur
and nitrogen), 164.0 (C═O); ES-MS (m/z) 427.1 (M + 1),
Anal. Calcd for C24H18N4O2S (426.50): C, 67.60; H,
4.25; N, 13.14; found C, 66.94; H, 4.45; N, 13.47.
7-{2-[3-(4-Trifluoromethyl-phenyl)-1-phenyl-1H-pyrazol-4-
yl]-vinyl}-thiazolo[3,2-a]pyrimidin-5-one (8). Yield 64%, M.
P. 224–226°C, 1H NMR (400, DMSO-d6), δ ppm: 6.31 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Thiazolo[3,2-a] Pyrimidones as a Novel Anti-TB Agents
ring C near to sulfur and nitrogen), 163.1 (C═O); 13C NMR
(100 MHz, DMSO-d6): 103.1 (thiazole ring C near to
sulfur), 104.2 (pyrazole ring C attached to olefin), 120.1,
120.5, 121.2, 122.5, 124.2, 129.2, 133.5 (olfine C near to
pyrazole), 137.2 (olefin C near to pyrimidinone), 139.1
(phenyl C attached to N), 144.2 (pyrimidinone ring C near
to N), 147.3 (pyrazole ring C attached to phenyl), 162.4
(thiazole ring C near to sulfur and nitrogen), 162.8 (C═O);
7-{2-[3-(2-Methyl-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
thiazolo[3,2-a]pyrimidin-5-one (13).
Yield 66.3%, M.P.
1
220–222°C, H NMR (400, DMSO-d6), δ ppm: 2.39 (s,
3H, Ar–CH3), 6.60 (s, 1H, pyrimidinone ring H), 7.12 (d,
1H, J = 16.2 Hz, olefinic H close to pyrazole ring), 7.25
(d, 1H, J = 4.1 Hz, thiazole ring H near to sulfur), 7.38
(t, 2H, ArH), 7.44–7.46 (m, 3H, ArH), 7.48–7.71 (m, 4H,
olefinic H near to pyrimidinone ring and ArH), 7.94 (d,
1H, J = 8.2 Hz, ArH), 8.00 (d, 1H, J = 4.1 Hz, thiazole
ring H near to bridge head nitrogen), 9.08 (s, 1H,
pyrazole ring H); 13C NMR (100 MHz, DMSO-d6):
103.3 (thiazole ring C near to sulfur), 104.6 (pyrazole
ring C attached to olefin), 119.9, 121.4, 121.7, 122.2,
122.9, 129.5, 134.4 (olfine C near to pyrazole), 136.3
(olefin C near to pyrimidinone), 141.4 (phenyl C attached
to N), 145.5 (pyrimidinone ring C near to N), 149.0
(pyrazole ring C attached to phenyl), 162.5 (thiazole ring
C near to sulfur and nitrogen), 163.1 (C═O); ES-MS (m/
z) 411.3 (M + 1), Anal. Calcd for C24H18N4OS (410.50):
C, 70.22; H, 4.42; N, 13.65; found C, 71.11; H, 4.49; N,
13.81.
ES-MS (m/z) 481.4 (M
+ 1), Anal. Calcd for
C24H15F3N4O2S (480.47): calculated C, 60.00; H, 3.15;
N, 11.66; observed C, 60.89; H, 3.27; N, 12.00.
7-{2-[3-(2-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-thiazolo[3,2-a]pyrimidin-5-one (11).
Yield 67.88%,
M.P. 221–223°C, 1H NMR (400, DMSO-d6), δ ppm:
3.79 (s, 3H, Ar–OCH3), 6.37 (s, 1H, pyrimidinone ring
H), 7.19 (d, 1H, J = 16.1 Hz, olefinic H close to
pyrazole ring), 7.20 (d, 1H, J = 4.0 Hz, thiazole ring H
near to sulfur), 7.40 (d, 1H, J = 7.90 Hz, ArH), 7.43–
7.76 (m, 8H, olefinic H near to pyrimidinone ring and
ArH), 7.84 (d, 1H, J = 8.0 Hz, ArH), 8.01 (d, 1H,
J = 4.7 Hz, thiazole ring H near to bridge head
nitrogen), 9.09 (s, 1H, pyrazole ring H); 13C NMR
(100 MHz, DMSO-d6): 102.8 (thiazole ring C near to
sulfur), 103.8 (pyrazole ring C attached to olefin), 119.9,
121.2, 122.3, 122.9, 124.9, 129.5, 133.1 (olfine C near
to pyrazole), 134.2 (olefin C near to pyrimidinone),
139.5 (phenyl C attached to N), 145.2 (pyrimidinone
ring C near to N), 149.0 (pyrazole ring C attached to
phenyl), 157.0 (phenyl C attached to OCH3), 161.9
(thiazole ring C near to sulfur and nitrogen), 162.2
(C═O); ES-MS (m/z) 427.3 (M + 1), Anal. Calcd for
C24H18N4O2S (426.50): found C, 67.60; H, 4.25; N,
7-{2-[3-(3-Methyl-phenyl)-1-phenyl-1H-pyrazol-4-yl]-vinyl}-
thiazolo[3,2-a]pyrimidin-5-one (14).
Yield 63.2%, M.P.
1
219À221°C, H NMR (400, DMSO-d6), δ ppm: 2.41 (s,
3H, Ar–CH3), 6.68 (s, 1H, pyrimidinone ring H), 7.22 (d,
1H, J = 16.2 Hz, olefinic H close to pyrazole ring), 7.27
(d, 1H, J = 4.1 Hz, thiazole ring H near to sulfur), 7.40–
7.44 (m, 3H, ArH), 7.50–7.57 (m, 2H, ArH), 7.48–7.71
(m, 4H, olefinic H near to pyrimidinone ring and ArH),
7.90 (d, 1H, J = 8.2 Hz, ArH), 8.05 (d, 1H, J = 4.1 Hz,
thiazole ring H near to bridge head nitrogen), 9.12 (s, 1H,
pyrazole ring H); 13C NMR (100 MHz, DMSO-d6):
102.3 (thiazole ring C near to sulfur), 104.4 (pyrazole
ring C attached to olefin), 119.1, 120.7, 121.1, 122.2,
124.1, 129.3, 133.6 (olfine C near to pyrazole), 134.8
(olefin C near to pyrimidinone), 139.2 (phenyl C attached
to N), 145.1 (pyrimidinone ring C near to N), 149.2
(pyrazole ring C attached to phenyl), 162.8 (thiazole ring
C near to sulfur and nitrogen), 163.7 (C═O); ES-MS (m/
z) 411.3 (M + 1), Anal. Calcd for C24H18N4OS (410.50):
C, 70.22; H, 4.42; N, 13.65; found C, 71.11; H, 4.49; N,
13.14; observed C, 66.84; H, 4.41; N, 13.40.
7-{2-[3-(3-Methoxy-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-thiazolo[3,2-a]pyrimidin-5-one (12). Yield 58%, M.
1
P. 224–226°C, H NMR (400, DMSO-d6), δ ppm: 3.84
(s, 3H, Ar–OCH3), 6.40 (s, 1H, pyrimidinone ring H),
7.20 (d, 1H, J = 16.0 Hz, olefinic H close to pyrazole
ring), 7.21 (d, 1H, J = 4.0 Hz, thiazole ring H near to
sulfur), 7.42–7.46 (m, 5H,, ArH), 7.51–7.67 (m, 4H,
olefinic H near to pyrimidinone ring and ArH), 7.80 (d,
1H, J = 8.29 Hz, ArH), 8.00 (d, 1H, J = 4.0 Hz, thiazole
ring H near to bridge head nitrogen), 9.10 (s, 1H,
pyrazole ring H); 13C NMR (100 MHz, DMSO-d6):
102.0 (thiazole ring C near to sulfur), 103.1 (pyrazole
ring C attached to olefin), 119.1, 120.1, 121.7, 122.2,
124.3, 129.5, 133.3 (olfine C near to pyrazole), 134.4
(olefin C near to pyrimidinone), 139.2 (phenyl C attached
to N), 143.2 (pyrimidinone ring C near to N), 149.6
(pyrazole ring C attached to phenyl), 157.6 (phenyl C
attached to OCH3), 161.9 (thiazole ring C near to sulfur
and nitrogen), 162.9 (C═O); ES-MS (m/z) 427.3 (M + 1),
Anal. Calcd for C24H18N4O2S (426.50): C, 67.60; H,
4.25; N, 13.14; found C, 67.04; H, 4.91; N, 13.42.
13.88.
7-{2-[3-(2-Methoxy-3-methyl-phenyl)-1-phenyl-1H-pyrazol-
4-yl]-vinyl}-thiazolo[3,2-a]pyrimidin-5-one (15). Yield 51%,
M.P. 212–214°C, 1H NMR (400, DMSO-d6), δ ppm: 2.31
(s, 3H, Ar–CH3), 3.49 (s, 3H, Ar–OCH3), 6.79 (s, 1H,
pyrimidinone ring H), 7.10 (d, 1H, J = 16.0 Hz, olefinic
H close to pyrazole ring), 7.19 (d, 1H, J = 4.1 Hz,
thiazole ring H near to sulfur), 7.38–7.49 (m, 4H, ArH),
7.51–7.75 (m, 4H, olefinic H near to pyrimidinone ring
and ArH), 7.91 (d, 1H, J = 8.0 Hz, ArH), 8.07 (d, 1H,
J = 4.1 Hz, thiazole ring H near to bridge head nitrogen),
9.00 (s, 1H, pyrazole ring H); 13C NMR (100 MHz,
DMSO-d6): 102.2 (thiazole ring C near to sulfur), 104.5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. B. Jadhav, S. Fatema, S. S. Bhagat, and M. Farooqui
(pyrazole ring C attached to olefin), 120.3, 121.2, 121.7, CONCLUSION
Vol 000
122.7, 124.1, 129.7, 133.9 (olefin C near to pyrazole),
134.8 (olefin C near to pyrimidinone), 139.3 (phenyl C
attached to N), 145.1 (pyrimidinone ring C near to N),
149.0 (pyrazole ring C attached to phenyl), 161.6
(thiazole ring C near to sulfur and nitrogen), 163.8
(C═O); ES-MS (m/z) 441.4 (M + 1), Anal. Calcd for
C25H20N4O2S (440.53): C, 68.16; H, 4.58; N, 12.72;
Present communication reports novel pyrazole
analogues and their growth inhibition study against
M. smegmatis mc2 155 strain. The design of these novel
derivatives was based on our previous report. Selected
compounds from preliminary screening (M. smegmatis
mc2 155 strain) were exposed for M. tuberculosis H37Rv
growth inhibition studies as well as synergistic studies
with first-line and second-line antibiotics. Compounds 13
and 14 (MIC: 47 and 39 μg/mL) were found to be
equipotent candidates with first-line antitubercular agent
rifampicin, which could act as a lead for further
optimization.
found C, 68.11; H, 4.41; N, 12.67.
7-{2-[3-(2-Methyl-3-methoxy-phenyl)-1-phenyl-1H-pyrazol-
4-yl]-vinyl}-thiazolo[3,2-a]pyrimidin-5-one (16). Yield 57%,
M.P. 217–219°C, 1H NMR (400, DMSO-d6), δ ppm: 2.33
(s, 3H, Ar–CH3), 3.59 (s, 3H, Ar–OCH3), 6.82 (s, 1H,
pyrimidinone ring H), 7.17 (d, 1H, J = 16.1 Hz, olefinic
H close to pyrazole ring), 7.21 (d, 1H, J = 4.1 Hz,
thiazole ring H near to sulfur), 7.40 (t, 1H, ArH), 7.42–
7.49 (m, 3H, ArH), 7.51–7.71 (m, 4H, olefinic H near to
pyrimidinone ring and ArH), 7.82 (d, 1H, J = 8.0 Hz,
ArH), 8.11 (d, 1H, J = 4.1 Hz, thiazole ring H near to
bridge head nitrogen), 9.03 (s, 1H, pyrazole ring H); 13C
NMR (100 MHz, DMSO-d6): 103.0 (thiazole ring C near
to sulfur), 104.1 (pyrazole ring C attached to olefin),
120.4, 121.2, 121.7, 122.2, 122.9, 124.3, 129.5, 133.2
(olfine C near to pyrazole), 133.9 (olefin C near to
pyrimidinone), 139.7 (phenyl C attached to N), 144.9
(pyrimidinone ring C near to N), 149.7 (pyrazole ring C
attached to phenyl), 162.2 (thiazole ring C near to sulfur
and nitrogen), 163.6 (C═O); ES-MS (m/z) 441.38
(M + 1), Anal. Calcd for C25H20N4O2S (440.53): C,
68.16; H, 4.58; N, 12.72; found C, 68.77; H, 4.55; N,
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12.98.
7-{2-[3-(2,3-Dimethyl-phenyl)-1-phenyl-1H-pyrazol-4-yl]-
vinyl}-thiazolo[3,2-a]pyrimidin-5-one (17). Yield 57%, M.
P. 217–219°C, H NMR (400, DMSO-d6), δ ppm: 2.33
1
(s, 3H, Ar–CH3), 2.34 (s, 3H, CH3), 6.80 (s, 1H,
pyrimidinone ring H), 7.20 (d, 1H, J = 16.1 Hz, olefinic
H close to pyrazole ring), 7.29 (d, 1H, J = 4.1 Hz,
thiazole ring H near to sulfur), 7.42 (t, 1H, ArH), 7.42–
7.48 (d, 1H, J = 8.23 Hz, ArH), 7.51–7.71 (m, 6H,
olefinic H near to pyrimidinone ring and ArH), 7.84 (d,
1H, J = 8.0 Hz, ArH), 8.11 (d, 1H, J = 4.1 Hz, thiazole
ring H near to bridge head nitrogen), 9.09 (s, 1H,
pyrazole ring H); ES-MS (m/z) 425.4 (M + 1), Anal.
Calcd for C25H20N4OS (424.53): C, 70.73; H, 4.74; N,
13.20; found C, 69.79; H, 4.65; N, 12.92.
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SUPPORTING INFORMATION
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