Facile one-pot synthesis and antimycobacterial evaluation of pyrazolo[3,4-d]pyrimidines

Article abstract of DOI:10.1002/ardp.200800027

The present article describes a facile one-pot synthesis of a series of eight pyrazolo[3,4-d]pyrimidines 4a-h which were evaluated for their in-vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar-Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. The compounds 4b, 4c, 4d, and 4g exhibited the best results (1.2 μg/mL) when compared with first-line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore, this class of compounds could be a good starting point to develop new lead compounds in the treatment of multidrug-resistant tuberculosis.

Full text of DOI:10.1002/ardp.200800027

Arch. Pharm. Chem. Life Sci. 2008, 341, 435–439
A. Trivedi et al.
435
Full Paper
Facile One-Pot Synthesis and Antimycobacterial Evaluation of
Pyrazolo[3,4-d]pyrimidines
Amit Trivedi, Dipti Dodiya, Janak Surani, Samir Jarsania, Hitesh Mathukiya, Naresh Ravat, and
Viresh Shah
Chemical Research Laboratory, Department of Chemistry, Saurashtra University, Rajkot, India
The present article describes a facile one-pot synthesis of a series of eight pyrazolo[3,4-d]pyrimi-
dines 4a–h which were evaluated for their in-vitro antibacterial activity against Mycobacterium
tuberculosis H37Rv using the Alamar-Blue susceptibility test and the activity expressed as the
minimum inhibitory concentration (MIC) in mg/mL. The compounds 4b, 4c, 4d, and 4g exhibited
the best results (1.2 lg/mL) when compared with first-line drugs such as isoniazid (INH) and
rifampicin (RIP). Therefore, this class of compounds could be a good starting point to develop
new lead compounds in the treatment of multidrug-resistant tuberculosis.
Keywords: Antimycobacterial activity / Antitubercular activity / Mycobacterium tuberculosis H37Rv / One-pot synthe-
sis / Pyrazolo[3,4-d]pyrimidines /
Received: February 19, 2008; accepted: March 27, 2008
DOI 10.1002/ardp.200800027
Due to the increase of MDR-TB and AIDS cases worldwide
and the lack of new drugs nowadays, there is an urgent
need for new drugs to fight against this disease.
Introduction
Nowadays, microorganisms resistant to multiple antimi-
crobial agents are a serious problem worldwide in the
fight against infectious diseases, increasing morbidity
and mortality with an overall increase in healthcare
costs. In this context, tuberculosis (TB) has become again
an important public health problem worldwide since the
mid-1980s, due to two major factors, the AIDS epidemic
and the advent of multidrug-resistant strains (MDR). TB is
responsible for 20% of all deaths in adults, and, each
year, there are about 8.9 to 9 millions of new cases, of
which 15% are children, and 1.7 to 2 millions of deaths,
of which 450,000 are children. Globally, the number of
TB cases is currently rising at 2% per year with the estima-
tive of 32% of the world population, about two billion
people, being infected by latent TB. In the case of patients
with AIDS, TB is the most common opportunistic infec-
tion and cause of death killing one of every three patients
In this context, pyrazole and pyrimidine derivatives
attracted organic chemists very much due to their biolog-
ical and chemotherapeutic importance. Pyrazolopyrimi-
dines and related fused heterocycles are of interest as
potential bioactive molecules. They are known to exhibit
pharmacological activities such as CNS depressant [1],
neuroleptic [2], and tuberculostatic [3]. Pyrazolo[3,4-
d]pyrimidines were identified as a general class of adeno-
sine receptors [3, 4]. There is not much difference in the
basic structures of pyrazolopyrimidines and purines.
Purine-containing molecules are ubiquitous in nature
and are found as components of nucleosides, nucleoti-
des, co-factors, and signaling molecules. A significant
proportion of any genome codes for proteins that recog-
nize purine-containing ligands (e.g., kinases, DNA and
RNA polymerases, ATPases, GTPases, purine receptors).
Unsurprisingly, structural analogues of purines have
proved attractive templates for drug discovery programs,
leading to a number of significant synthetic drugs (e.g., 6-
thiopurine for leukaemia [5], acyclovir as an antiviral [6]
and allopurinol for treatment of gout [7]). Recently, the
purine core has been exploited in the synthesis of protein
kinase inhibitors [8, 9, 10, 11] inhibitors of carbohydrate
[see:
http://www.who.int/tdr/diseases/tb/default.htm.].
Correspondence: Dr. Viresh Shah, Chemical Research Laboratory, De-
partment of Chemistry, Saurashtra University, Kalawad Road, 360005
Rajkot, India.
E-mail: drvireshshah@gmail.com
Fax: +91 281-2576802
Abbreviations: tuberculosis (TB); multidrug-resistant strains (MDR)
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A. Trivedi et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 435–439
cycloaddition of azahexatrienes obtained from reaction
of an arylaldehyde and a 6-uracil hydrazone. One disad-
vantage of this approach is the concomitant arylation of
the pyrazole moiety. Earlier, this class of compounds was
synthesized by fusion of 6-uracil hydrazones at 3008C
[28]. Another synthesis reported by Maki et al. [28]
required the cycloaddition of an arylhydrazone to 6-
chloro-5-nitrouracil, which involved several steps. Fur-
ther, Kanazawa et al. [29] synthesized pyrazolo[3,4-d]pyri-
midines by the reaction of 6-benzylidenehydrazonoura-
cils with N-bromosuccinimide (NBS) in acetic acid under
reflux conditions, which yielded triazino- and pyrida-
zino-uracils in addition to the pyrazolo[3,4-d]pyrimi-
dines. However, literature survey revealed only a few
reports on the synthesis of the parent pyrazolo[3,4-d]pyri-
midine moiety, which usually requires drastic condi-
tions, long reaction times, and complex pathways.
Therefore, we developed an interest in pyrazolopyrimi-
dines and herein present a simple one-pot synthetic strat-
egy toward their synthesis with complete regiocontrol
using readily available starting materials and reagents.
Thus, the synthesis of 6-amino-4-(5-chloro-3-methyl-1-phe-
nyl-1H-pyrazol-4-yl)-1-(aryl)-4,5-dihydro-3-methyl-1H-pyra-
zolo[3,4-d]pyrimidine derivatives 4a–h involved a one-
pot reaction between 5-chloro-3-methyl-1-phenyl-1H-pyra-
zole-4-carbaldehyde 1 [30], 3-methyl-1-(4-aryl)-5-pyrazo-
lone 2a–h [31], and guanidine hydrochloride 3 as
described in the general procedure; (see Section 4 Experi-
mental), leading to the desired compounds 4a–h in 68–
100% yields (Scheme 1). All the compounds were identi-
fied by spectral data. In general, IR spectra showed confir-
matory absence of C=O peak around 1650 cm– 1. The 1H-
NMR spectrum showed the amine protons as singlet
around d = 8.912–8.996 ppm. Further, the 13C-NMR spec-
trum showed the C-NH2 signals at d = 163–164.9 ppm.
This confirmed the formation of the desired compounds.
Figure 1. Purine-related anti-mycobacterials: (1) [15], (2) [16],
(3) [17], (4) [18], (5) [19].
[12] and estrogen [13] sulfotransferases, as well as in com-
pounds displaying osteogenesis-inducing activity in stem
cells [14]. Compounds of this generic nature 1–5 have
also been reported to display anti-mycobacterial activity
(Fig. 1) [15, 16, 17, 18, and 19].
The isomeric pyrazolo[3,4-d]pyrimidine nucleus has
attracted comparatively little attention, though it has
been exploited in inhibitors of Src protein kinases [20],
EGF receptor tyrosine kinases [21], cyclic AMP phospho-
diesterases [22], and Staphylococcus aureus DNA polymer-
ase III [23]. Interestingly, such a compound reported as an
intermediate in the synthesis of prospective HIV replica-
tion inhibitors showed modest anti-mycobacterial activ-
ity (compound 5; MIC 12.5 lg/mL) [19]. In addition, few
other pyrazolo[3,4-d]pyrimidine nucleus has been previ-
ously reported to demonstrate anti-mycobacterial activ-
ity [24, 25, 26]. These diverse bioactivity results prompted
us to explore the pyrazolo[3,4-d]pyrimidine template in
our search for new antimycobacterial agents, given an
encouraging level of potency and straightforward one-
pot synthesis of pyrazolo[3,4-d]pyrimidines.
Biological screening
The antimycobacterial activities of compounds 4a–h
were assessed against M. tuberculosis ATTC 2729415 using
the microplate Alamar Blue assay (MABA) [32] (Table 1).
This method is nontoxic, uses a thermally-stable reagent,
and shows good correlation with proportional and BAC-
TEC radiometric methods [33, 34]. Briefly, 200 lL of ster-
ile deionized water was added to all outer-perimeter
wells of sterile 96-well plates (falcon, 3072: Becton Dickin-
son, Lincoln Park, NJ, USA) to minimize evaporation of
the medium in the test wells during incubation. The 96-
well plates received 100 lL of the Middlebrook 7H9 broth
(Difco laboratories, Detroit, MI, USA) and a serial dilution
of the compounds 4a–h were made directly on the plate.
The final drug concentrations tested were 0.01 to 20.0 lL/
Results and discussion
Chemistry
To date, several methods have been developed to synthe-
size pyrazolo[3,4-d]pyrimidine, Yoneda et al. [27] used the
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Arch. Pharm. Chem. Life Sci. 2008, 341, 435–439
Pyrazolo[3,4-d]pyrimidines as Antimycobacterial Agents
437
A blue color in the well was interpreted as no bacterial
growth, and a pink color was scored as growth. The MIC
(minimal inhibition concentration) was defined as the
lowest drug concentration, which prevented a color
change from blue to pink.
It was clearly evident from the antitubercular activity
data that all the compounds displayed significant activ-
ity. But, compounds 4b, 4c, 4d, and 4g were found to be
particularly active against Mycobacterium tuberculosis H37
Rv strain. These results led us to the SAR conclusion that
the presence of 2-chloro-, 3-chloro-, 4-methyl- and 2-
chloro-5-sulfonyl substituents markedly enhances the
biological activity.
Conclusions
In summary, 6-amino-4-(5-chloro-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-(aryl)-4,5-dihydro-3-methyl-1H-pyra-
zolo[3,4-d]pyrimidines have been investigated as anti-
mycobacterial agents. In the case of all the evaluated
compounds, the best result was the compound 4b, 4c, 4d,
and 4g (1.2 lg/mL) when compared with first line drugs
as isoniazid (INH) and rifampin (RIP). It suggests that this
class of compounds may be selectively targeted to M.
tuberculosis growth and could be a good starting point to
find new lead compounds.
Scheme 1. Synthesis of 6-amino-4-(5-chloro-3-methyl-1-phenyl-
1H-pyrazol-4-yl)-1-(aryl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-
d]pyrimidine derivatives 4a–h.
The authors have declared no conflict of interest.
Table 1. Antimycobacterial activities and log P measurements of
6-amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-
(aryl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-d]pyrimidines 4a–
h.
Experimental
Melting points were determined on a Bꢀchi apparatus (Bꢀchi
Labortechnik, Flawil, Switzerland) and are uncorrected. Infrared
spectra were recorded on a Thermo Nicolet Nexus 670 spectrom-
eter (Nicolet, Madison, WI, USA) as potassium bromide pellets
and frequencies are expressed in cm– 1. Mass spectra (CG/MS)
were recorded on a Agilent Tecnologies 6890/5972A mass spec-
Compound R
MIC
Log Pa)
(lg/mL)
4a
4b
4c
4d
4e
4f
Phenyl
3.25
1.20
1.20
1.20
3.25
3.25
1.20
4.91
5.47
5.47
5.40
4.07
4.07
4.63
5.15
2.78
–0.96
trometer (Agilent, Palo Alto, CA, USA). H- and 13C-NMR spectra
1
2-chlorophenyl
3-chlorophenyl
4-methylphenyl
3-sulfophenyl
4-sulfophenyl
2-chloro-4-sulfophenyl
were taken on Varian Mercury VX-BB 300 at 300 and 75 MHz,
respectively (Varian, Palo Alto, CA, USA). TMS was used as an
inner standard. Microanalyses were recorded on Fisons Instru-
ments EA1110CE CHN analyst (Fisons Instruments, Mainz, Ger-
many). For TLC, plates coated with silica gel were run in chloro-
form/methanol mixture and spots were developed in ultraviolet.
4g
4h
RIP
INH
2,5-dichloro-4-sulfophenyl 3.25
1.0
0.2
General procedure for 6-amino-4-(5-chloro-3-methyl-
1-phenyl-1H-pyrazol-4-yl)-1-(aryl)-4,5-dihydro-3-
a)
Calculated by http://www.molinspiration.com/
methyl-1H-pyrazolo[3,4-d]pyrimidines 4a–h
An equimolar mixture of 5-chloro-3-methyl-1-phenyl-1H-pyra-
zole-4-carbaldehyde 1, 3-methyl-1-(4-aryl)-5-pyrazolone 2a–h and
guanidine hydrochloride was heated under reflux condition for
5 h using ethanol as a solvent. The reaction mixture was kept at
room temperature for 3 h. The product was filtered, dried, and
recrystallized from ethanol.
mL. Plates were covered and sealed with parafilm and
incubated at 378C for five days. After this time, 25 lL of a
freshly prepared 1 : 1 mixture of Alamar Blue (Accumed
International, Westlake, OH, USA) reagent and 10%
Tween 80 was added to the plate and incubated for 24 h.
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A. Trivedi et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 435–439
N, 19.77; O, 9.68; S, 6.47. Found (%): C, 53.17; H, 3.54; Cl, 7.02; N,
19.66; O, 9.56; S, 6.33.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
4,5-dihydro-3-methyl-1-phenyl-1H-pyrazolo[3,4-
d]pyrimidine 4a
Mp. 223–2258C; Yield 71%; IR (cm– 1): 3421, 1610, 1599, 1546,
1294, 1066, 756. 1H-NMR ([d6] DMSO): d (ppm) = 2.518–2.60 (26s,
6H, 26CH3), 7.49–8.18 (m, 10H, Harom), 8.97 (s, 2H, NH2); 13C-NMR
(CDCl3): d (ppm) = 11.2, 16.2, 109.2, 116.2, 121.4, 126.8, 129.2,
129.9, 140.2, 144.9, 151.2, 163.9, 166.1; MS (m/z) 415. Anal. calcd.
for C22H18ClN7 (%): C, 63.54; H, 4.36; Cl, 8.52; N, 23.58. Found (%):
C, 63.42; H, 4.25; Cl, 8.41; N, 23.54.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(4-sulfophenyl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-
d]pyrimidine 4f
Mp. 229–2318C; Yield 63%; IR (cm– 1): 3425, 1612, 1602, 1541,
1368, 1299, 1113, 1061, 752; 1H-NMR ([d6] DMSO): d (ppm) =
2.53–2.65 (26s, 6H, 26CH3), 5.12 (s, 1H, CH), 7.50–8.25 (m, 9H,
Harom), 8.99 (s, 2H, NH2), 12.39 (s, 1H, OH); 13C-NMR (CDCl3): d
(ppm) = 11.4, 16.3, 109.4, 116, 121.2, 121.9, 126.6, 129.2, 129.8,
130.2, 140.2, 143.9, 144.9, 147.8, 151.2, 163.6, 165.9; MS (m/z)
495. Anal. calcd. for C22H18ClN7O3S (%): C, 53.28; H, 3.66; Cl, 7.15;
N, 19.77; O, 9.68; S, 6.47. Found (%): C, 53.16; H, 3.55; Cl, 7.04; N,
19.63; O, 9.54; S, 6.37.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(2-chlorophenyl)-4,5-dihydro-3-methyl-1H-
pyrazolo[3,4-d]pyrimidine 4b
Mp. 239–2418C; Yield 66%; IR (cm– 1): 3415, 1616, 1603, 1545,
1289, 1069, 750; 1H-NMR ([d6] DMSO): d (ppm) = 2.51–2.59 (26s,
6H, 26CH3), 7.47–8.10 (m, 9H, Harom), 8.95 (s, 2H, NH2); 13C-NMR
(CDCl3): d (ppm) = 11.4, 16.4, 109.6, 115.8, 120.8, 122.1, 126.6,
127.4, 127.9, 128.9, 129.7, 129.9, 130.1, 133.9, 140.2, 143.6,
144.9, 151.2, 164.2, 166.9; MS (m/z) 450. Anal. calcd. for
C22H17Cl2N7 (%): C, 58.68; H, 3.81; Cl, 15.75; N, 21.77. Found (%): C,
58.55; H, 3.70; Cl, 15.61; N, 21.65.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(2-chloro-5-sulfophenyl)-4,5-dihydro-3-methyl-1H-
pyrazolo[3,4-d]pyrimidine 4g
Mp. 215–2178C; Yield 58%; IR (cm– 1): 3419, 1623, 1591, 1562,
1362, 1290, 1104, 1060, 762; 1H-NMR ([d6] DMSO): d (ppm) =
2.56–2.89 (26s, 6H, 26CH3), 7.51–8.32 (m, 8H, Harom), 8.99 (s,
2H, NH2), 12.39 (s, 1H, OH); 13C-NMR (CDCl3): d (ppm) = 11.4, 16.6,
108.8, 116.4, 118.4, 120.6, 126.8, 127.4, 129.2, 129.8, 131.2,
139.2, 140.2, 144.4, 144.9, 149.6, 150.8, 164.8, 166.4; MS (m/z)
530. Anal. calcd. for C22H17Cl2N7O3S (%): C, 49.82; H, 3.23; Cl,
13.37; N, 18.49; O, 9.05; S, 6.05. Found (%): C, 49.71; H, 3.11; Cl,
13.25; N, 18.35; O, 8.94; S, 5.93.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(3-chlorophenyl)-4,5-dihydro-3-methyl-1H-
pyrazolo[3,4-d]pyrimidine 4c
Mp. 207–2098C; Yield 68%; IR (cm– 1): 3419, 1614, 1596, 1549,
1299, 1061, 753; 1H-NMR ([d6] DMSO): d (ppm) = 2.51–2.57 (26s,
6H, 26CH3), 7.46–8.10 (m, 9H, Harom), 8.94 (s, 2H, NH2); 13C-NMR
(CDCl3): d (ppm) = 11.4, 16.4, 109.2, 115.8, 116.4, 119.4, 120.8,
126.7, 126.8, 129.2, 129.6, 131.2, 135.2, 139.9, 141.7, 144.8, 11.2,
164.4, 166.2; MS (m/z) 450. Anal. calcd. for C22H17Cl2N7 (%): C,
58.68; H, 3.81; Cl, 15.75; N, 21.77. Found (%): C, 58.56; H, 3.68; Cl,
15.63; N, 21.64.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(2,5-dichloro-4-sulfophenyl)-4,5-dihydro-3-methyl-1H-
pyrazolo[3,4-d]pyrimidine 4h
Mp. 246–2488C; Yield 56%; IR (cm– 1): 3409, 1610, 1595, 1556,
1367, 1289, 1113, 1058, 759; 1H-NMR ([d6] DMSO): d (ppm) =
2.57–2.99 (26s, 6H, 26CH3), 7.59–8.44 (m, 7H, Harom), 8.99 (s,
2H, NH2), 12.38 (s, 1H, OH); 13C-NMR (CDCl3): d (ppm) = 11.5, 16.9,
109.1, 116.4, 120.9, 126.4, 126.8, 129.2, 130.1, 136.9, 140.2,
143.1, 144.2, 150.6, 150.9, 164.9, 166.2; MS (m/z) 564. Anal. calcd.
for C22H16Cl6N7O3S (%): C, 49.82; H, 3.23; Cl, 13.37; N, 18.49; O,
9.05; S, 6.05. Found (%): C, 49.70; H, 3.10; Cl, 13.25; N, 18.34; O,
8.94; S, 5.91.
6-Amino-4-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(4-methylphenyl)-4,5-dihydro-3-methyl-1H-
pyrazolo[3,4-d]pyrimidine 4d
Mp. 219–2218C; Yield 65%; IR (cm– 1): 3422, 1616, 1589, 1555,
1368, 1292, 1063, 1112, 750; 1H-NMR ([d6] DMSO): d (ppm) =
2.53–2.99 (36s, 6H, 36CH3), 7.46–8.11 (m, 10H, Harom), 8.91 (s,
2H, NH2); 13C-NMR (CDCl3): d (ppm) = 11.4, 15.9, 24.8, 109.2, 116.4,
120.6, 120.8, 126.6, 129.2, 129.6, 129.9, 136.4, 137.2, 140.2,
145.1, 150.9, 164.1; MS (m/z) 429. Anal. calcd. for C23H20ClN7 (%):
C, 64.26; H, 4.69; Cl, 8.25; N, 22.81. Found (%): C, 64.22; H, 4.66;
Cl, 8.23; N, 22.69.
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