Synthesis, characterization and biological screening of novel 5-imidazopyrazole incorporated fused pyran motifs under microwave irradiation

Article abstract of DOI:10.1039/c3nj01327h

A novel combinatorial library of fused pyran derivatives has been designed and synthesized under microwave irradiation by one-pot three-component cyclocondensation reaction of 5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H- pyrazole-4-carbaldehyde with two active methylene compounds and enolizable ketones/phenols in the presence of piperidine as a basic catalyst. All the newly synthesized compounds have been characterized by elemental analysis and various spectroscopic methods. All the final motifs have been screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, preliminary in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv and also for their antimalarial activity against Plasmodium falciparum.

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ARTICLE TYPE
Synthesis, characterization and biological screening of novel 5-
imidazopyrazole incorporated fused pyran motifs under microwave
irradiation
Piyush N. Kalaria, Shailesh P. Satasia, Dipak K. Raval*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Abstract
A novel combinatorial library of fused pyran derivatives has been designed and synthesized under
microwave irradiation by oneꢀpot threeꢀcomponent cyclocondensation reaction of 5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ
10 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde with two active methylene compounds and enolizable
ketones / phenols in presence of piperidine as a basic catalyst. All the newly synthesized compounds
have been characterized by elemental analysis and various spectroscopic methods. All the final motifs
have been screened for their preliminary in vitro antibacterial activity against a panel of pathogenic
strains of bacteria and fungi, preliminary in vitro antituberculosis activity against Mycobacterium
15 tuberculosis H37Rv and also for their antimalarial activity against Plasmodium falciparum.
Meanwhile, imidazole derivatives are known to be associated
with various biological properties, such as antiꢀinflammatory,13
analgesic, antiꢀconvulsant,14 antitubercular,15 antimicrobial,16
anticancer and antiꢀParkinson17 activities. The fused pyran ring is
50 an important heterocyclic core constitution and prominent
structural motif found in numerous pharmaceutically active
compounds. Among the significant pharmacophores responsible
for antimicrobial and antituberculosis activity, the fused pyran
scaffold is still considered a viable lead structure for the synthesis
55 of more efficacious and broad spectrum antimicrobial and
antituberculosis agents. Fused pyran derivatives represent an
important class of compounds which hold high activity profile
due to their wide range of biological activities such as
1. Introduction
Malaria is a mosquitoꢀborne infectious disease of humans and
other animals caused by protists of the genus Plasmodium. The
WHO estimates that the mortality rate due to malaria is
20 comparable to roughly 2000 deaths every day.1, Plasmodium
2
falciparum is the parasite responsible for most malaria cases
(80%), which often prove harmless. The malaria burden is
concentrated in 14 endemic countries, which account for an
estimated 80% of malaria deaths.3 Likewise, the occurrence of
25 multidrugꢀresistant M. tuberculosis strains is one of the chief
causes of the revival of tuberculosis observed during the world
since the midꢀ1980s.4 Multidrugꢀresistant TB and extensively
drugꢀresistant TB are inflexible to handle with any of the usually
accessible drugs. This warrants the need for latest component of
30 drugs to counter successfully the danger posed by these strains.5
It is a disgusting revelation that MDRꢀTB is present in almost all
countries as per the recent survey by the WHO.6 The WHO has
declared tuberculosis to be a ‘global emergency’ and estimates
that about 30 million people will be infected by mycobacteria
35 tuberculosis within the next 20 years.7 All the above facts
disclose that there is an urgent need for expansion of new drugs
with divergent and unique structure and with a mechanism of
action possibly different from that of existing drugs. In this
regard, it was thought worth to synthesize various novel
40 compounds which may have combined applications as
antimalarial, antituberculosis and antimicrobial agents.
spasmolytic,
diuretic,
anticoagulant,
anticancer,
60 antianaphylactic,18 antimicrobial,19 antiviral,20 anticancer,21
antimalarial,22 antiꢀHIV, antiꢀtuberculosis, antiꢀinflammatory and
antiꢀfungal agents.23
In modern era, the multiꢀcomponent reactions are extremely
significant because of their broad range of applications in
65 pharmaceutical chemistry for manufacture of the diversified
structural scaffolds and combinatorial libraries for drug
discovery.24 Multi component reactions (MCRs) are enormously
convergent, producing a remarkably high increase of molecular
complexity in just one step.25 Moreover, microwave irradiation
70 has also become a useful tool in the synthesis of organic
molecules. The conventional procedures do not give satisfactory
result with regard to operational simplicity, effectiveness and
yield.26 In recent years, microwave irradiation has been reputable
not only to considerably accelerate many organic reactions, but
75 also to improve yields and selectivity. In context of the above
biological consequences, we thought of to synthesize some fused
Pyrazole and its derivatives are an important class of
heterocycles. Pyrazole derivatives possess a broad spectrum of
pharmacological activities such as, anticancer,8 antibacterial,9
45 antiviral,10 analgesic11 and antiꢀinflammatory12 activities.
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pyran scaffold by taking various heterocyclic intermediates and to
study their antimalarial, antitubercular and antimicrobial activity.
We construct to pyrazole and imidazole motifs in one molecule
which may play an essential role as a significant building block in
the final synthesized compounds (6a-x). In continuation of our
research work,27 we report herein on the utility of 5ꢀ(1Hꢀ
imidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde
as the building block for the synthesis of functionalized fused
pyran scaffold. The disparity in the nature and size of substituent
5
10 in the structures was thought to be of interest representing
variable electronic, lipophilic, and steric surroundings that would
influence the anticipated pharmacological activities.
2. Results and discussion
2.1 Chemistry
15 The synthetic approach adopted to obtain the targeted 5ꢀ
imidazopyrazole incorporated fused pyran derivatives is
summarized in Scheme 2. The starting material 5ꢀchloroꢀ3ꢀ
methylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde
1 was prepared
according to Vilsmeier–Haack reaction of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ
20 pyrazolꢀ5(4H)ꢀone.28 The final aldehyde 5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀ
methylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde 3 was prepared by
nucleophilic displacement of chloro group at C5 in 5ꢀchloroꢀ3ꢀ
methylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde 1 with secondary
amine of imidazole 2 in refluxing DMF using anhydrous
25 potassium carbonate as base (Scheme 1).
Scheme 2. Synthesis of the substituted 4ꢀ(5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ
1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)ꢀ4Hꢀpyranꢀ2ꢀamine
Piperidine, MW, 2ꢀ4 min, 80 °C.
6a-x.
(ii)
Ethanol,
55
30
Scheme 1. Synthesis of 5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1H
pyrazoleꢀ4ꢀcarbaldehyde 3 (i) DMF, K2CO3, Reflux 2 h.
Subsequently, 4ꢀ(5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ
35 pyrazolꢀ4ꢀyl)ꢀ4Hꢀpyranꢀ2ꢀamine derivatives 6a-x have been
synthesized. Thus oneꢀpot threeꢀcomponent cyclocondensation
Figure 1. Plausible mechanistic pathway for the synthesis of fused pyran
derivatives (6a-x).
reaction
of
5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀ
2.2. Pharmacology
pyrazoleꢀ4ꢀcarbaldehyde 3, malononitrile 4a or ethylcayno
acetate 4b and compounds 5a-k was performed in microwave
40 oven in the presence of piperidine as catalyst to give moderate to
good yield (66–86%) (Scheme 2, Table 1). The reaction
mechanism (Figure 1) occured via an in situ initial formation of
the heterylidenenitrile, containing the electronꢀpoor C=C double
bond, from the Knoevenagel condensation between 5ꢀ(1Hꢀ
45 imidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde 3
and malononitrile 4a or ethylcayno acetate 4b by loss of water
molecules. Finally, Michael addition of 5a-k to the initially
formed unsaturated nitrile, i.e. nucleophilic attack of hydroxyl
moiety to the cyano moiety afforded cyclized pyran derivatives
50 6a-x.
2.2.1. In vitro antimicrobial activity
60 The antibacterial activity of all synthesized compounds 6a-x was
screened against three Gram positive bacteria (Bacillus subtilis
MTCC 441, Clostridium tetani MTCC 449, Streptococcus
pneumoniae MTCC 1936) and three Gram negative bacteria
(Escherichia coli MTCC 443, Salmonella typhi MTCC 98, Vibrio
65 cholerae MTCC 3906) by using ampicillin, norfloxacin and
ciprofloxacin as the standard antibacterial drugs. Antifungal
activity was screened against two fungal species (Candida
albicans MTCC 3008 and Aspergillus fumigatus MTCC 227)
where nystatin and griseofulvin were used as the standard
70 antifungal drugs. The minimal inhibitory concentration (MIC) of
all compounds 6a-x was determined by broth microdilution
method according to National Committee for Clinical Laboratory
Standards (NCCLS).29 The inoculums concentration of the test
strain was adjusted to 108 CFU (colonyꢀforming units) per mL by
2
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Table 2. In vitro antimicrobial activity (MIC, ꢁg/mL) of compounds 6a-
x.
comparing the sample turbidity. Mueller Hinton broth was used
as nutrient medium to grow and dilute the drug suspension for the
test. DMSO was used as the diluent to get the desired
concentration of compounds to test upon the standard bacterial
strains. The obtained results are presented in Table 2.
Gram positive bacteria Gram negative bacteria
S.P. B.S. C.T. S.P. B.S. C.T.
MTCC MTCC MTCC MTCC MTCC MTCC MTCC MTCC
Fungi
C.A. A.F.
Comp.
5
1936
200
125
200
100
200
100
100
100
250
250
500
250
200
100
125
200
125
100
100
250
500
100
100
250
100
10
441
250
200
200
200
250
100
250
250
200
250
500
500
250
100
200
250
125
200
250
200
500
500
125
100
250
100
50
449
200
250
250
250
500
200
100
125
250
200
100
200
250
200
200
500
250
125
100
250
500
500
125
200
250
50
1936
250
200
100
200
250
250
200
250
100
100
200
125
200
62.5
200
100
200
125
62.5
200
100
250
250
250
100
10
441
250
250
250
100
100
100
250
200
125
250
200
250
100
100
200
250
250
250
100
100
250
500
250
125
100
10
449
200
200
250
100
250
200
200
200
62.5
200
250
200
200
200
227 3008
>1000 200
>1000 250
1000 500
1000 500
6a
6b
6c
6d
6e
6f
6g
6h
6i
2.2.2. In vitro antituberculosis activity
All the synthesized compounds 6a-x were evaluated for their in
vitro
antituberculosis
activity
against
Mycobacterium
500
500
250
200
10 tuberculosis H37Rv strain. Primary screening of all the newly
synthesized compounds was conducted at 250 ꢁg/mL and 100
ꢁg/mL by using LowensteineꢀJensen medium as described by
Rattan.30 Rifampicin and Isoniazid were used as the standard
drugs. The results of antituberculosis screening data are shown in
15 Table 3.
>1000 >1000
250
500
500 1000
6j
6k
6l
1000 500
500
1000 200
500
500
1000 500
500
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
6x
A
2.2.3. In vitro antimalarial activity
All new fused pyran derivatives 6a-x were evaluated for their
antimalarial activity against P. falciparum strain. Chloroquine
20 and quinine were used as the reference drugs. The results of the
pharmacological screening are expressed as the drug
concentration resulting in 50% inhibition (IC50) of parasite
growth. The obtained results are presented in Table 4.
62.5 >1000 200
100
100
125
200
200
250
500
250
200
100
10
>1000 250
200 1000
1000 500
500 1000
1000 500
>1000 1000
500 1000
250 >1000
500 1000
n. t.a n. t.
2.3. Analytical results
25 The structures of all the newly synthesized compounds were
1
confirmed by H NMR, FTꢀIR, 13C NMR, mass and elemental
B
C
D
E
n. t.
n. t.
100
500
n. t.
n. t.
100
100
1
25
n. t.
n. t.
100
n. t.
n. t.
25
n. t.
n. t.
25
n. t.
n. t.
25
n. t.
n. t.
analysis. The H NMR spectra of compounds 6a-x exhibited the
n. t.
n. t.
presence of the –CH (C4 proton of pyran ring) as a sharp singlet
around δ 4.25 – 5.14 ppm and one more singlet arising at δ 2.15
30 – 2.80 ppm due to methyl proton (–CH3) present in pyrazole ring.
The aromatic protons resonate as multiplets at around δ 6.31 –
7.93 ppm. The IR spectrum of compounds 6a-x exhibited
characteristic absorption bands around 2185 – 2191 cmꢀ1 and
1680 – 1729 cmꢀ1 which may be attributed to the presence of
35 nitrile C≡N stretching and ester carbonyl (odd and even number
of compounds at C3 position in pyran ring respectively). The
strong absorptions band was observed in the range of 1365 –
1382 cmꢀ1 due to the CH3 stretching. While the characteristic
absorption band in the range 3478 – 3301 cmꢀ1 may be attributed
40 to asymmetric & symmetric stretching of NH2. The characteristic
absorption band of C–O–C ether linkage is found around 1214 –
1250 cmꢀ1 supports the formation of pyran derivatives. Similarly
in 13C NMR spectra, the signals at around δ 55.1 – 59.4 ppm and
74.3 – 76.6 ppm are assigned to carbon attached to carbonitrile
45 and ester group respectively. One more signal arising at δ 12.5 –
13.3 ppm may be due to methyl proton (–CH3) present in
pyrazole ring. The mass spectrum of all the compounds showed
molecular ion peak at M+ corresponding to its molecular weight,
which confirmed its chemical structure.
60 S.P.: Streptococcus pneumoniae, B.S.: Bacillus subtilis, C.T.: Clostridium
tetani, E.C.: Escherichia coli S.T.: Salmonella typhi, V.C.: Vibrio
cholerae, C.A.: Candida albicans, A.F.: Aspergillus fumigatus, MTCC:
Microbial Type Culture Collection. A: Ampicillin, B: Norfloxacin, C:
Ciprofloxacin, D: Nystatin, E: Griseofulvin, a n.t.: not tested.
65 pyrazolꢀ5ꢀone, X = CN), 6h (R = 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ5ꢀ
one, X = COOEt), 6n (R = Nꢀmethyl barbituric acid, X =
COOEt), 6r (Ar1 = βꢀnapthol, X = COOEt), 6s (Ar1 = resorcinol,
X = CN), 6v (Ar1 = 2ꢀmethyl resorcinol, X = COOEt) and Ar1
(Ar = αꢀnapthol, X = CN) against S. pneumoniae showed same
70 potency as compared to ampicillin (MIC = 250 ꢁg/mL). Whereas
compounds 6f (R = 4ꢀhydroxy coumarin, X = COOEt), 6n (R =
Nꢀmethyl barbituric acid, X = COOEt) and 6x (Ar1 = αꢀnapthol,
X = COOEt) illustrated equal activity against B. subtilis as
compared to norfloxacin (MIC = 100 ꢁg/mL). The compounds 6g
75 (R = 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ5ꢀone, X = CN), 6k (R =
thiobarbituric acid, X = CN) and 6s (Ar1 = resorcinol, X = CN)
showed same potency against C. tetani as compared to
ciprofloxacin (MIC = 100 ꢁg/mL). Whereas in inhibiting gram
negative bacteria, the compounds 6i (R = 3ꢀmethylꢀ1Hꢀpyrazolꢀ
80 5(4H)ꢀone, X = CN), 6o (R = barbituric acid, X = CN) and 6n (R
= Nꢀmethyl barbituric acid, X = COOEt), 6s (Ar1 = resorcinol, X
= CN) showed brilliant activity i.e. 62.5 ꢁg/mL against V.
cholera and E. coli as compared to ampicillin (MIC = 100
ꢁg/mL). Compounds 6c (R = cyclohexaneꢀ1, 3ꢀdione, X = CN),
85 6i (R = 3ꢀmethylꢀ1Hꢀpyrazolꢀ5(4H)ꢀone, X = CN), 6j (R = 3ꢀ
methylꢀ1Hꢀpyrazolꢀ5(4H)ꢀone, X = COOEt) and 6u (Ar1 = 2ꢀ
methyl resorcinol, X = CN) against E. coli showed equal activity
as compared to ampicillin (MIC = 100 ꢁg/mL), while compounds
6d (R = cyclohexaneꢀ1, 3ꢀdione, X = COOEt), 6e (R = 4ꢀhydroxy
50 2.4 Biological results
2.4.1. Antibacterial activity
Upon investigation of antimicrobial screening data (Table 2), it
has been observed that majority of the compounds showed
excellent activity against gram positive bacteria B. subtilis and C.
55 tetani as compared to ampicillin (MIC
Compounds 6d (R = cyclohexaneꢀ1, 3ꢀdione, X = COOEt), 6f (R
= 4ꢀhydrohxy coumarin, X = COOEt), 6g (R = 3ꢀmethylꢀ1ꢀphenyl
= 250 ꢁg/mL).
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coumarin, X = CN), 6f (R = 4ꢀhydroxy coumarin, X = COOEt),
6m (R = Nꢀmethyl barbituric acid, X = CN), 6n (R = Nꢀmethyl
barbituric acid, X = COOEt), 6s (Ar1 = resorcinol, X = CN) and
activity against P. falciparum strain as compared to quinine IC50
0.268. Whereas compound 6g (R = 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ5ꢀ
one, X = CN) was found to possess moderate activity i.e. IC50
6t (Ar1 = resorcinol, X = COOEt) against S. typhi as well as 50 0.034 aligned with chloroquine. All other compounds were found
5
compounds 6d (R = cyclohexaneꢀ1, 3ꢀdione, X = COOEt), 6p (R
= barbituric acid, X = COOEt) and 6q (Ar1 = βꢀnapthol, X = CN)
against V. cholerae showed same potency as compared to
ampicillin (MIC = 250 ꢁg/mL).
to be not as much active as chloroquine and quinine against P.
falciparum strain.
Table 4. In vitro antimalarial activity of compounds 6a-x.
Comp.
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
IC50 (ꢁg/mL)
1.55
Comp.
6n
6o
6p
6q
6r
6s
6t
IC50 (ꢁg/mL)
0.049
1.54
10 2.4.2. Antituberculosis activity
0.067
0.088
1.47
0.42
0.78
0.034
0.062
0.57
0.82
1.36
The cheering results from the antibacterial activity encouraged us
to go for preliminary screening of the all synthesized compounds
for their in vitro antituberculosis activity. Antituberculosis
screening of all fused pyran derivatives 6a-x was conducted at
15 two concentrations i.e. 250 ꢁg/mL and 100 ꢁg/mL against M.
tuberculosis H37Rv strain (Table 3). At the commencement of
this study in the preliminary screening, compound 6o (R =
barbituric acid, X = CN) displayed better activity and showed
95% inhibition at 250 ꢁg/mL concentration and 92% inhibition at
20 100 ꢁg/mL concentration. Compound 6h (R = 3ꢀmethylꢀ1ꢀphenyl
pyrazolꢀ5ꢀone, X = COOEt) was found to possess excellent
activity at both the concentrations i.e. 92% at 250 ꢁg/mL and 100
ꢁg/mL. While compounds 6n (R = Nꢀmethyl barbituric acid, X =
COOEt) and 6t (Ar = resorcinol, X = COOEt) are moderately
25 active against M. tuberculosis H37Rv. All other compounds
showed poor inhibition of M. tuberculosis growth. From the
above results, it can be concluded that, compounds 6o (R =
barbituric acid, X = CN) and 6h (R = 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ
5ꢀone, X = COOEt) may become new class of antitubercular
30 agents in future.
0.97
0.32
1.69
0.38
0.089
0.52
0.061
0.54
1.040
0.020
0.268
6u
6v
6w
6x
1.88
0.082
Chloroquine
Quinine
6m
55 2.4.4. Structure-activity relationship (SAR)
The structure activity relationships study (Figure 2) revealed that
various heterocyclic motifs fused at 5, 6 positions in pyran were
responsible for broad range of antimicrobial, antituberculosis and
antimalarial activities. The different natures of the fused motifs
60 have led to significant variations in all three activities. The
compound 6i made up from 3ꢀmethylꢀ1Hꢀpyrazolꢀ5ꢀone showed
maximum activity against V. cholerae and B. subtilis while
compound 6n containing Nꢀmethyl barbituric acid showed
highest activity against E. coli, B. subtilis and C. tetani and also
65 increased antimalarial activity against P. falciparum. Compound
6o bearing barbituric acid illustrated maximum antibacterial
activity against V. cholera, B. subtilis and C. tetani as well as
increased antituberculosis activity against M. tuberculosis H37Rv
strain. Compound 6s containing resorcinol showed highest
70 inhibition against bacterial strain E. coli and C. tetani and also
showed highest inhibition against fungal strain C. albicans. The
compounds 6h and 6g containing 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ5ꢀ
one showed excellent antimalarial activity against P. falciparum
and only 6h showed good antituberculosis activity against M.
75 tuberculosis H37Rv strain. It can be concluded that carbonitrile
and ester groups present at third position in pyran ring may be
considered responsible for variation in activity. Both the groups
are electron withdrawing by resonance effect even though they
showed different activity. Compounds 6n and 6m contain Nꢀ
80 methyl barbituric acid. Among them compound 6n containing
carbonitrile group showed superior antibacterial activity against
E. coli and increased antimalarial activity against P. falciparum.
The compound 6m having an ester group showed poor activity
against E. coli and P. falciparum. The compounds 6g and 6h
85 bearing 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ5ꢀone, among them
compound 6h containing ester group showed good
antituberculosis activity. On the other hand, both compounds
possess better antimalarial activity. This may be attributed to the
hydrophobicity and size of the group. Pyrazolone and barbituric
90 acid are found as the intermediates in many standard drugs
because of their wide range of biological activity.
Table 3. In vitro antituberculosis activity (% inhibition) of compounds
6a-x against M. tuberculosis H37Rv (at concentration 250 ꢁg/mL and 100
ꢁg/mL).
Comp.
% Inhibition
Comp.
% Inhibition
250 ꢁg/mL 100 ꢁg/mL
250 ꢁg/mL 100 ꢁg/mL
6a
6b
6c
6d
6e
6f
6g
6h
6i
6n
6o
6p
6q
6r
6s
6t
6u
6v
16
24
11
75
48
20
36
92
74
32
51
77
37
14
17
5
84
95
42
71
36
78
84
33
12
8
71
92
31
61
25
68
77
29
7
47
37
17
24
92
45
28
47
61
30
6j
6k
6l
6w
6x
4
71
98
99
66
98
99
Rifampicin
Isoniazid
6m
35 2.4.3. Antimalarial activity
All the compounds 6a-x were evaluated for their antimalarial
activity against P. falciparum strain. All experiments were
performed in duplicate and a mean value of IC50 is mentioned in
Table 4. The compounds 6b (R = dimedone, X = COOEt), 6c (R
40 = cyclohexaneꢀ1, 3ꢀdione, X = CN), 6g (R = 3ꢀmethylꢀ1ꢀphenyl
pyrazolꢀ5ꢀone, X = CN), 6h (R = 3ꢀmethylꢀ1ꢀphenyl pyrazolꢀ5ꢀ
one, X = COOEt), 6m (R = Nꢀmethyl barbituric acid, X = CN),
6n (R= Nꢀmethyl barbituric acid, X = COOEt), 6t (Ar1
=
resorcinol, X = COOEt) and 6v (Ar1 = 2ꢀmethyl resorcinol, X =
45 COOEt) were found to have IC50 in the range of 0.034 to 0.089
upon P. falciparum strain. These compounds showed principal
4
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Figure 2. Structureꢀactivity relationship for antimicrobial, antituberculosis and antimalarial activity of the synthesized compound 6a-x.
Majority of our active compounds are either pyrazolone or 25 antituberculosis activities. While in antimalarial activity, one
barbituric acid derivatives. These two biological active
intermediate could be considered responsible for the observed
activity. The strongly active compounds of the series with
reference to the standard drugs are shown in Figure 3.
third of the compounds have shown excellent activity against
strains of P. falciparum as compared to quinine. Imidazole and
pyrazole nucleus which are present in the synthesized compounds
are expected to be responsible for the biological activity.
5
30 4. Experimental section
4.1 Chemistry
All the reagents were obtained commercially and used without
further purification. Solvents used were of analytical grade.
Melting points were taken in melting point apparatus
35 ꢁThermoCal10 (Analab Scientific Pvt. Ltd, India) and are
uncorrected. Thinꢀlayer chromatography (TLC, on aluminum
plates coated with silica gel 60 F254, 0.25 mm thickness, Merck)
was used for monitoring the progress of all reactions. Mass
spectra were recorded on Shimadzu LCMS 2010 spectrometer
40 (Shimadzu, Tokyo, Japan) purchased under PURSE programme
of DST at Sardar Patel University, Vallabh Vidyanagar. The IR
10 Figure 3. Strong antibacterial, antifungal, antitubercular and antimalarial
compounds from the series.
3. Conclusion
spectra
were
recorded
on
Shimadzu
FTIR
8401
Novel fused pyran derivatives bearing 5ꢀimidazopyrazole nucleus
have been synthesized by oneꢀpot multicomponent reaction under
15 microwave irradiation. All the new compounds were examined
for their antimicrobial, antimalarial and antituberculosis activities
with the hope of discovering new structure leads helping as
potent antimicrobial, antimalarial and antituberculosis agents. It
can be concluded that the compounds 6i, 6n, 6o and 6s were
20 found to be most proficient members of the series. Majority of the
compounds were found to be active against C. tetani and B.
subtilis. In antifungal activity, compounds 6h, 6q and 6w have
shown excellent activity against C. albicans as compared to
griseofulvin. The compounds 6h, 6n, 6o and 6t exhibited good
spectrophotometer using potassium bromide pellets in the range
4000 ꢀ 400 cmꢀ1 and frequencies of only characteristic peaks are
45 expressed in cmꢀ1. The elemental analysis was carried out by
using PerkinꢀElmer 2400 seriesꢀII elemental analyzer (Perkinꢀ
Elmer, USA) at Sophisticated Instrumentation Centre for Applied
Research & Training (SICART), Vallabh Vidyanagar and all
compounds are within ± 0.4% of the theoretical compositions. All
50 the reactions were carried out at atmospheric pressure using a
multimode microwave reactor (Microwave Synthesis System,
Model: CataꢀR, CatalystTM Systems, Puneꢀ India). Microwaves
are generated by magnetron at a frequency of 2450 MHz having
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an adjustable output power levels (i.e. 1 to 10 levels from 140 to 60 126.9, 129.8, 129.9, 130.0, 132.4, 134.3, 134.5, 137.9, 148.1,
700 Watts) and with an individual sensor for temperature control
through attachment of reflux condenser with constant stirring.
The temperature was monitored with an external flexible probe.
1H NMR and 13C NMR spectra were recorded in DMSOꢀd6 on a
Bruker Avance 400F (MHz) spectrometer using solvent peak as
internal standard at 400 and 100 MHz, respectively. Chemical
shifts are reported in parts per million (ppm).
(14C, Ar–C), 195.7 (C=O); ESIꢀMS (m/z): 441.0 (M+); Anal.
Calcd. (%) for C25H24N6O2 : C, 68.17; H, 5.49; N, 19.08. Found:
C, 67.12; H, 5.42; N, 19.20.
4.1.2.2. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
65 pyrazol-4-yl)-2-amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carboxylate (6b)
5
Yield 76 %; m.p. 222ꢀ224 °C; IR (KBr, νmax, cmꢀ1): 3470 & 3350
(asym. & sym. str. of –NH2), 1721 (C=O, ester str.), 1375 (–CH3
str.), 1230 (C–O–C ether streching); 1H NMR (400 MHz, DMSOꢀ
70 d6): δ 0.81 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.95 (t, J=7.2, 3H,
CH3), 1.70 (d, J=17.6 Hz, 1H, CH2), 1.94 (d, J=17.2 Hz, 1H,
CH2), 2.14 (s, 2H, CH2), 2.41 (s, 3H, CH3) 3.44 (q, J=7.2, 2H,
CH2), 4.30 (s, 1H, CH), 4.97 (s, 2H, NH2) 7.44ꢀ7.73 (m, 7H, Arꢀ
H), 7.85 (s, 1H, imidazole); 13C NMR (100 MHz, DMSOꢀd6) δ:
75 13.1 (CH3), 27.9, 28.4, 15.6 (3C, CH3), 28.6 (C4), 32.6 (C(CH3)2),
40.6, 48.6 (2(CH2)2), 58.5 (C, OCH2), 76.1 (C–COOEt), 108.5,
120.5, 122.5, 123.0, 123.2, 127.2, 129.5, 129.9, 130.2, 132.9,
134.1, 134.5, 138.2, 147.6 (14C, Ar–C), 160.5, 195.9 (2C, C=O);
ESIꢀMS (m/z): 488.1 (M+); Anal. Calcd. (%) for C27H29N5O4: C,
80 66.51; H, 6.00; N, 14.36. Found: C, 66.40; H, 6.08; N, 14.35.
10 4.1.1. General procedure for the synthesis of 5-(1H-imidazol-
1-yl)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3)
5ꢀchloroꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde 1 (1.1
gm, 5 mmol), appropriate imidazole 2 (0.51 gm, 7.5 mmol) and
anhydrous potassium carbonate (0.6 gm, 10 mmol) in
15 dimethylformamide (5 mL) were charged in a 50 mL round
bottom flask equipped with a mechanical stirrer and a condenser.
The reaction mixture was refluxed for 2 h and the progress of the
reaction was monitored by TLC. After the completion of reaction
(as evidenced by TLC), the reaction mixture was cooled to room
20 temperature and then poured into ice cold water (50 mL) with
continuous stirring followed by neutralization with 1 N HCl until
pH 7. The separated precipitates of 5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀ
4.1.2.3.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6c)
methylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde
3 were filtered,
thoroughly washed with water, dried, and recrystallized from
25 ethanol.
Yield 81 %; m.p. 217ꢀ219 °C; IR (KBr, νmax, cmꢀ1): 3429 & 3335
85 (asym. & sym. str. of –NH2), 2189 (C≡N str.), 1370 (–CH3 str.),
1225 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ 1.84
(s, 3H, CH3), 2.00ꢀ2.39 (m, 6H, 3CH2), 4.35 (s, 1H, CH), 5.39 (s,
2H, NH2), 7.34ꢀ7.73 (m, 7H, ArꢀH), 7.92 (s, 1H, imidazole); 13C
NMR (100 MHz, DMSOꢀd6) δ: 13.3 (CH3), 21.3 (CH2), 28.5
90 (C4), 30.4, 38.2 (2(CH2)2), 59.2 (C–CN), 108.3, 120.3, 122.4,
122.9, 123.5, 127.6, 129.5, 130.0, 130.7, 132.4, 134.4, 134.6,
138.4, 147.9 (14C, Ar–C), 195.7 (C=O); ESIꢀMS (m/z): 413.1
(M+); Anal. Calcd. (%) for C23H20N6O2: C, C, 66.98; H, 4.89; N,
Yield 79 %; m.p. 203ꢀ205 °C; 1H NMR (400 MHz, DMSOꢀd6): δ
2.59 (s, 3H, CH3), 7.07ꢀ7.46 (m, 7H, Ar–H), 7.94 (s, 1H,
imidazole), 9.74 (s, 1H, CHO); ESIꢀMS (m/z): = 252.0 (M+).
30 4.1.2. General procedure for the synthesis of 4-(5-(1H-
imidazol-1-yl)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-4H-pyran-
2-amine derivatives (6a-x)
5ꢀ(1Hꢀimidazolꢀ1ꢀyl)ꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4 carbald
ehyde 3 (10 mmol), malononitrile 4a or ethylcaynoacetate 4b (10
35 mmol) and phenol 5i-k/enolizable ketone 5a-h (10 mmol) were
thoroughly mixed in ethanol (10 mL) with catalytic amount of
piperidine (2ꢀ3 drops). The reaction mixture was irradiated in
microwave oven at 350 W (50% of output power) for 2ꢀ4 min.
The reaction mixture attained 80° C temperature at this power
40 level. After the completion of reaction, monitored by TLC (ethyl
acetate:hexane = 1:1) the reaction mixture was cooled to room
temperature. The solid separated was filtered, washed with
ethanol (10 ml), dried and recrystallized from chloroform to get
the pure solid sample 6a-x. The physicochemical and
45 spectroscopic characterization data of the prepared compounds
are given below.
20.38. Found: C, 67.13; H, 4.72; N, 20.47.
95 4.1.2.4. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carboxylate (6d)
Yield 75 %; m.p. 220ꢀ222 °C; IR (KBr, νmax, cmꢀ1): 3430 & 3321
(asym. & sym. str. of –NH2), 1700 (C=O, ester str.), 1369 (–CH3
100 str.), 1219 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): ):
δ 1.08 (t, J=17.2, 3H, CH3), 2.08 (s, 3H, CH3), 2.31ꢀ2.48 (m, 6H,
3CH2), 3.87 (q, J=13.2, 2H, CH2), 4.58 (s, 1H, CH), 5.59 (s, 2H,
NH2), 6.94ꢀ7.42 (m, 8H, ArꢀH); 13C NMR (100 MHz, DMSOꢀd6)
δ: 13.2 (CH3), 21.4 (CH2), 28.8 (C4), 30.6, 38.0 (2(CH2)2), 58.7
105 (C, OCH2), 75.9 (C–COOEt), 108.4, 120.4, 122.2, 122.7, 123.7,
126.5, 128.9, 130.1, 131.5, 132.3, 134.3, 134.5, 138.3, 147.2
(14C, Ar–C), 160.4, 195.8 (2C, C=O); ESIꢀMS (m/z): 460.0
(M+); Anal. Calcd. (%) for C25H25N5O4: C, 65.35; H, 5.48; N,
15.24. Found: C, 65.32; H, 5.48; N, 15.29.
4.1.2.1.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
50 4H-chromene-3-carbonitrile (6a)
Yield 84 %; m.p. 228ꢀ230 °C; IR (KBr, νmax, cmꢀ1): 3476 & 3362
110 4.1.2.5.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-5-oxo-4,5-dihydropyrano[3,2-
c]chromene-3-carbonitrile (6e)
(asym. & sym. stretching of –NH2), 2188 (C≡N stretching), 1365
(–CH3 stretching), 1250 (C–O–C ether str.); 1H NMR (400 MHz,
DMSOꢀd6): δ 1.09 (s, 3H, CH3), 1.10 (s, 3H, CH3), 2.22 (d,
55 J=17.6 Hz, 2H, CH2), 2.31 (s, 3H, CH3), 2.40 (d, J=18 Hz, 1H,
CH2), 4.25 (s, 1H, CH), 4.84 (s, 2H, NH2), 7.09ꢀ7.32 (m, 7H, Arꢀ
H), 7.75 (s, 1H, imidazole); 13C NMR (100 MHz, DMSOꢀd6) δ:
13.3 (CH3), 27.8, 28.4 (2C, CH3), 28.9 (C4), 32.4 (C(CH3)2), 40.6,
48.8 (2(CH2)2), 59.4 (C–CN), 108.2, 120.0, 122.1, 122.5, 122.9,
Yield 86 %; m.p. 266ꢀ268 °C; IR (KBr, νmax, cmꢀ1): 3410 & 3360
(asym. & sym. str. of –NH2), 2185 (C≡N str.), 1375 (–CH3 str.),
115 1236 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ 2.26
(s, 3H, CH3), 4.39 (s, 1H, CH), 6.92ꢀ7.78 (m, 14H, ArꢀH + NH2);
13C NMR (100 MHz, DMSOꢀd6) δ: 12.6 (CH3), 26.8 (C4), 55.9
(C–CN), 95.8 (C5), 101.4, 101.9, 103.4, 111.1, 113.1, 117.1,
117.9, 119.8, 123.0, 125.1, 128.1, 129.6, 133.4, 137.9, 147.7,
6
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4.1.3.0. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-6-amino-3-methyl-1,4-dihydropyrano[2,3-c]
pyrazole-5-carboxylate (6j)
152.6, 154.0, 157.6, 158.5 (20C, Ar–C), 160.2 (C=O); ESIꢀMS
(m/z): 463.0 (M+); Anal. Calcd. (%) for C26H18N6O3: C, 67.53; H,
3.92; N, 18.17. Found: C, 67.58; H, 3.99; N, 18.12.
4.1.2.6. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-5-oxo-4,5-dihydropyrano[3,2-c]
chromene-3-carboxylate (6f)
Yield 69 %; m.p. 224ꢀ226 °C; IR (KBr, νmax, cmꢀ1): 3420 & 3351
65 (asym. & sym. str. of –NH2), 1699 (C=O, ester str.), 1371 (–CH3
str.), 1229 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ
1.05 (t, J=8, 3H, CH3), 1.92 (s, 3H, CH3), 2.19 (s, 3H, CH3), 4.09
(q, J=6.8, 2H, CH2), 4.71 (s, 1H, CH), 6.96ꢀ7.70 (m, 10H, ArꢀH +
NH2), 12.0 (s, 1H, NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 10.4,
5
Yield 78 %; m.p. 257ꢀ259 °C; IR (KBr, νmax, cmꢀ1): 3422 & 3352
(asym. & sym. str. of –NH2), 1694 (C=O, ester str.), 1372 (–CH3
str.), 1232 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ
10 1.03 (t, J=7.6, 3H, CH3), 2.65 (s, 3H, CH3), 3.92 (q, J=7.2, 2H, 70 12.8, 15.0 (3C, CH3), 24.3 (C4), 59.0 (C, OCH2), 74.3 (C–
CH2), 4.38 (s, 1H, CH), 6.93ꢀ7.81 (m, 14H, ArꢀH + NH2); 13C
NMR (100 MHz, DMSOꢀd6) δ: 12.5, 15.5 (2C, CH3), 26.8 (C4),
58.5 (C, OCH2), 75.2 (C–COOEt), 94.8 (C5), 101.9, 102.2, 102.9,
111.5, 113.1, 117.4, 118.4, 119.7, 122.7, 124.7, 128.2, 129.6,
COOEt), 98.3 (C5), 121.1, 121.6, 122.8, 127.7, 129.6, 129.9,
132.0, 133.8, 135.6, 138.3, 145.2, 147.2, 152.7, 154.9, 162.4
(15C, Ar–C), 169.1 (C=O); ESIꢀMS (m/z): 446.3 (M+); Anal.
Calcd. (%) for C21H18N7O3: C, 62.01; H, 5.20; N, 22.01. Found:
15 133.4, 137.8, 146.2, 152.0, 153.4, 157.8, 158.7 (20C, Ar–C), 75 C, 61.89; H, 5.26; N, 21.96.
160.2, 176.1 (2C, C=O); ESIꢀMS (m/z): 510.0 (M+); Anal. Calcd.
(%) for C28H23N5O5: C, 66.00; H, 4.55; N, 13.75. Found: C,
66.18; H, 4.69; N, 13.62.
4.1.3.1.
5-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-7-amino-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]pyrimidine-6-carbonitrile (6k).
Yield 81 %; m.p. 242ꢀ244 °C; IR (KBr, νmax, cmꢀ1): 3478 & 3370
4.1.2.7.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
80 (asym. & sym. str. of –NH2), 2188 (C≡N str.), 1382 (–CH3 str.),
1216 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ 2.31
(s, 3H, CH3), 4.26 (s, 1H, CH), 6.95ꢀ7.40 (m, 9H, ArꢀH + NH2),
20 pyrazol-4-yl)-6-amino-3-methyl-1-phenyl-1,4-dihydropyrano
[2,3-c]pyrazole-5-carbonitrile (6g)
Yield 76 %; m.p. 278ꢀ280 °C; IR (KBr, νmax, cmꢀ1): 3450 & 3322
(asym. & sym. str. of –NH2), 2190 (C≡N str.), 1379 (–CH3 str.),
1221 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ 1.94
7.86 (s, 1H, imidazole), 9.50 (s, 1H, NH), 11.88 (s, 1H, NH); 13
C
NMR (100 MHz, DMSOꢀd6) δ: 12.5 (CH3), 28.5 (C4), 56.6 (C–
25 (s, 3H, CH3), 2.23 (s, 3H, CH3), 4.58 (s, 1H, CH), 6.96ꢀ7.67 (m, 85 CN), 87.1 (C5), 119.4, 119.9, 122.3, 123.0, 127.9, 130.0, 133.1,
15H, ArꢀH + NH2); 13C NMR (100 MHz, DMSOꢀd6) δ: 12.6, 12.9
(2C, CH3), 26.4 (C4), 56.6 (C–CN), 96.2 (C5), 120.7, 120.8,
121.7, 123.0, 123.2, 126.8, 128.1, 129.6, 129.7, 133.2, 137.8,
138.0, 138.9, 144.3, 145.4, 147.4, 159.8 (17C, Ar–C); ESIꢀMS
30 (m/z): 475.0 (M+); Anal. Calcd. (%) for C27H22N8O: C, 68.34; H,
138.2, 147.4, 150.3, 151.5 (11C, Ar–C), 158.4 (C, C=O); ESIꢀMS
(m/z): 445.0 (M+); Anal. Calcd. (%) for C21H16N8O2S: C, 56.75;
H, 3.63; N, 25.21. Found: C, 56.76; H, 3.72; N, 25.04.
4.1.3.2. ethyl 5-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
90 pyrazol-4-yl)-7-amino-4-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-
pyrano[2,3-d]pyrimidine-6-carboxylate (6l).
4.67; N, 23.61. Found: C, 68.30; H, 4.57; N, 23.54.
4.1.2.8. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-6-amino-3-methyl-1-phenyl-1,4-dihydropyrano
[2,3-c]pyrazole-5-carboxylate (6h)
Yield 74 %; m.p. 250ꢀ252 °C; IR (KBr, νmax, cmꢀ1): 3449 & 3310
(asym. & sym. str. of –NH2), 1706 (C=O, ester str.), 1375 (–CH3
str.), 1232 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ
35 Yield 72 %; m.p. 262ꢀ264 °C; IR (KBr, νmax, cmꢀ1): 3452 & 3310 95 1.11 (t, J=13.2, 3H, CH3), 2.35 (s, 3H, CH3), 3.84 (q, J=13.2, 2H,
(asym. & sym. str. of –NH2), 1710 (C=O, ester str.), 1374 (–CH3
str.), 1225 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ
1.06 (t, J=6.8, 3H, CH3), 1.92 (s, 3H, CH3), 2.19 (s, 3H, CH3),
4.09 (q, J=13.6, 2H, CH2), 4.71 (s, 1H, CH), 6.96ꢀ7.88 (m, 15H,
CH2), 4.58 (s, 1H, CH), 6.13 (s, 2H, NH2), 6.89ꢀ7.67 (m, 7H, Arꢀ
H), 7.78 (s, 1H, imidazole), 9.51 (s, 1H, NH), 11.98 (s, 1H, NH);
13C NMR (100 MHz, DMSOꢀd6) δ: 12.5, 16.6 (2C, CH3), 28.8
(C4), 58.5 (C, OCH2), 77.3 (C–COOEt), 110.8, 122.3, 122.5,
40 ArꢀH + NH2); 13C NMR (100 MHz, DMSOꢀd6) δ: 12.6, 12.9, 15.9 100 127.6, 129.5, 131.7, 132.7, 138.2, 141.0, 145.9, 147.0, 157.9
(3C, CH3), 26.5 (C4), 58.9 (C, OCH2), 75.8 (C–COOEt), 95.8
(C5), 120.9, 121.4, 121.6, 123.2, 124.0, 126.5, 128.2, 129.4,
130.2, 133.3, 138.0, 138.6, 139.4, 143.9, 145.5, 147.1 (16C, Ar–
C), 160.1 (C, C=O); ESIꢀMS (m/z): 522.2 (M+); Anal. Calcd. (%)
45 for C29H27N7O3: C, 66.78; H, 5.22; N, 18.80. Found: C, 66.81; H,
5.29; N, 18.62.
(12C, Ar–C), 159.7, 161.5, 170.0 (3C, C=O); ESIꢀMS (m/z):
491.9 (M+); Anal. Calcd. (%) for C23H21N7O4S: C, 56.20; H,
4.31; N, 19.95. Found: C, 56.06; H, 4.21; N, 20.10.
4.1.3.3.
5-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
105 pyrazol-4-yl)-7-amino-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahy
dro-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile (6m).
Yield 78 %; m.p. 224ꢀ226 °C; IR (KBr, νmax, cmꢀ1): 3461 & 3351
4.1.2.9.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
(asym. & sym. str. of –NH2), 2186 (C≡N str.), 1369 (–CH3 str.),
1228 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ 2.29
pyrazol-4-yl)-6-amino-3-methyl-1,4-dihydropyrano[2,3-
c]pyrazole-5-carbonitrile (6i)
50 Yield 73 %; m.p. 218ꢀ220 °C; IR (KBr, νmax, cmꢀ1): 3402 & 3336 110 (s, 3H, CH3), 3.13 (s, 3H, CH3), 3.22 (s, 3H, CH3), 4.28 (s, 1H,
(asym. & sym. str. of –NH2), 2191 (C≡N str.), 1376 (–CH3 str.),
1235 (C–O–C ether str.); 1H NMR (400 MHz, DMSOꢀd6): δ 1.94
(s, 3H, CH3), 2.17 (s, 3H, CH3), 4.67 (s, 1H, CH), 6.76ꢀ7.43 (m,
CH), 7.06ꢀ7.37 (m, 9H, ArꢀH + NH2), 7.70 (s, 1H, imidazole);
13C NMR (100 MHz, DMSOꢀd6) δ: 12.6 (CH3), 26.4, 26.6 (2C,
2N–CH3), 28.3 (C4), 56.6 (C–CN), 86.7 (C5), 119.0, 119.6, 122.3,
122.8, 128.0, 129.7, 132.9, 137.9, 147.5, 150.2, 151.2 (11C, Ar–
9H, ArꢀH + NH2), 7.82 (s, 1H, imidazole), 11.96 (s, 1H, NH); 13
C
55 NMR (100 MHz, DMSOꢀd6) δ: 10.3, 12.8 (2C, CH3), 24.5 (C4), 115 C), 158.1, 161.0 (2C, C=O) ESIꢀMS (m/z): 456.8 (M+); Anal.
55.6 (C–CN), 98.1 (C5), 120.8, 121.3, 123.2, 127.8, 129.6, 130.1,
132.5, 134.1, 135.6, 137.6, 145.1, 147.2, 153.0, 155.0, 161.9
(15C, Ar–C); ESIꢀMS (m/z): 398.9 (M+); Anal. Calcd. (%) for
C21H18N8O: C, 63.31; H, 4.55; N, 28.12. Found: C, 63.29; H,
60 4.43; N, 27.95.
Calcd. (%) for C23H20N8O3: C, 60.52; H, 4.42; N, 24.55. Found:
C, 60.43; H, 4.41; N, 24.41.
4.1.3.4. ethyl 5-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-7-amino-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahy
120 dro-1H-pyrano[2,3-d]pyrimidine-6-carboxylate (6n).
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Yield 88 %; m.p. 219ꢀ221 °C; IR (KBr, νmax, cmꢀ1): 3470 & 3353
(asym. & sym. stretching of –NH2), 1722 (C=O, ester stretching),
1381 (–CH3 stretching), 1240 (C–O–C ether stretching); 1H NMR
(400 MHz, DMSOꢀd6): δ 1.00 (t, J=6.8, 3H, CH3), 2.80ꢀ2.90 (m,
(400 MHz, DMSOꢀd6): δ 1.00 (t, J=8, 3H, CH3), 2.18 (s, 3H,
CH3), 4.10 (q, J=7.6, 2H, CH2), 5.11 (s, 1H, CH), 7.06ꢀ7.46 (m,
15H, ArꢀH + NH2), 7.96 (s, 1H, imidazole); 13C NMR (100 MHz,
DMSOꢀd6) δ: 12.8, 17.2 (2C, CH3), 28.3 (C4), 59.0 (C, OCH2),
5
9H, (CH3)3), 3.87 (q, J=8.4, 2H, CH2), 4.41 (s, 1H, CH), 6.23 (s, 65 75.4 (C–COOEt), 111.9, 117.0, 117.5, 120.1, 121.9, 122.4, 123.1,
2H, NH2) 7.06ꢀ7.60 (m, 7H, ArꢀH), 7.72 (s, 1H, imidazole); 13C
NMR (100 MHz, DMSOꢀd6) δ: 12.4, 16.6 (2C, CH3), 26.9, 27.5
(2C, (N–CH3)2) 29.0 (C4), 58.4 (C, OCH2), 77.6 (C–COOEt),
111.1, 122.2, 122.5, 127.4, 129.3, 132.1, 132.5, 137.9, 140.7,
123.9, 124.4, 125.4, 127.9, 128.5, 128.9, 129.7, 130.2, 130.3,
131.3, 131.8, 132.0, 138.2, 146.9, 159.9 (22C, Ar–C), 169.0
(C=O); ESIꢀMS (m/z): 492.0 (M+); Anal. Calcd. (%) for
C29H25N5O3: C, 70.83; H, 5.13; N, 14.25. Found: C, 70.70; H,
10 145.7, 148.2, 158.3 (12C, Ar–C), 160.0, 161.6, 169.7 (3C, C=O); 70 4.99; N, 14.22.
ESIꢀMS (m/z): 504.2 (M+); Anal. Calcd. (%) for C25H25N7O5: C,
59.63; H, 5.00; N, 19.47. Found: C, 59.55; H, 4.86; N, 19.55.
4.1.3.5. 5-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
4.1.3.9.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-7-hydroxy-4H-chromene-3-carbonitrile
(6s).
Yield 79 %; m.p. 230ꢀ232 °C; IR (KBr, νmax, cmꢀ1): 3413 & 3301
pyrazol-4-yl)-7-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyra
15 no[2,3-d]pyrimidine-6-carbonitrile (6o).
75 (asym. & sym. stretching of –NH2), 2190 (C≡N stretching), 1375
(–CH3 stretching), 1229 (C–O–C ether stretching); H NMR (400
Yield 80 %; m.p. 263ꢀ265 °C; IR (KBr, νmax, cmꢀ1): 3480 & 3369
1
(asym. & sym. stretching of –NH2), 2191 (C≡N stretching), 1369
(–CH3 stretching), 1214 (C–O–C ether stretching); H NMR (400
MHz, DMSOꢀd6): δ 2.16 (s, 3H, CH3), 4.66 (s, 1H, CH), 6.34ꢀ
7.58 (m, 13H, ArꢀH + NH2), 9.64 (s, b, 1H, OH); 13C NMR (100
MHz, DMSOꢀd6) δ: 12.7 (CH3), 28.4 (C4), 59.0 (C–CN), 102.2,
1
MHz, DMSOꢀd6): δ 2.16 (s, 3H, CH3), 4.31 (s, 1H, CH), 6.98ꢀ
20 7.94 (m, 12H, ArꢀH + NH2 + 2NH); 13C NMR (100 MHz, 80 112.9, 114.0, 122.0, 122.7, 123.1, 127.7, 129.6, 129.9, 130.4,
DMSOꢀd6) δ: 12.4 (CH3), 28.4 (C4), 56.9 (C–CN), 86.8 (C5),
119.2, 119.8, 122.3, 123.2, 128.3, 129.8, 133.3, 138.0, 147.2,
150.0, 151.3 (11C, Ar–C), 158.2 (C, C=O); ESIꢀMS (m/z): 428.9
(M+); Anal. Calcd. (%) for C21H16N8O3: C, 58.88; H, 3.76; N,
132.1, 138.2, 147.0, 149.3, 157.4, 161.2, 168.6 (17C, Ar–C); ESIꢀ
MS (m/z): 410.9 (M+); Anal. Calcd. (%) for C23H18N6O2: C,
67.31; H, 4.42; N, 20.48. Found: C, 67.22; H, 4.29; N, 20.31.
4.1.4.0. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
85 pyrazol-4-yl)-2-amino-7-hydroxy-4H-chromene-3-carboxylate
(6t).
25 26.16. Found: C, 58.76; H, 3.59; N, 25.95.
4.1.3.6. ethyl 5-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-7-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyra
no[2,3-d]pyrimidine-6-carboxylate (6p).
Yield 74 %; m.p. 246ꢀ248 °C; IR (KBr, νmax, cmꢀ1): 3422 & 3306
(asym. & sym. stretching of –NH2), 1680 (C=O, ester stretching),
1382 (–CH3 stretching), 1217 (C–O–C ether stretching); 1H NMR
Yield 73 %; m.p. 270ꢀ272 °C; IR (KBr, νmax, cmꢀ1): 3399 & 3339
30 (asym. & sym. stretching of –NH2), 1729 (C=O, ester stretching), 90 (400 MHz, DMSOꢀd6): δ 1.01 (t, J=6.8, 3H, CH3), 2.17 (s, 3H,
1369 (–CH3 stretching), 1226 (C–O–C ether stretching); 1H NMR
(400 MHz, DMSOꢀd6): δ 1.02 (t, J=6.8, 3H, CH3), 2.25 (s, 3H,
CH3), 3.85 (q, J=8.4, 2H, CH2), 4.34 (s, 1H, CH), 6.86ꢀ7.89 (m,
12H, ArꢀH + NH2 + 2NH); 13C NMR (100 MHz, DMSOꢀd6) δ:
CH3), 4.00 (q, J=8, 2H, CH2), 4.69 (s, 1H, CH), 7.14ꢀ7.72 (m,
13H, ArꢀH + NH2), 9.64 (s, b, 1H, OH); 13C NMR (100 MHz,
DMSOꢀd6) δ: 12.7, 15.6 (2C, CH3), 28.2 (C4), 58.5 (C, OCH2),
75.5 (C–COOEt), 102.3, 113.2, 114.2, 122.1, 123.1, 123.8, 127.8,
35 12.3, 16.8 (2C, CH3), 28.6 (C4), 58.8 (C, OCH2), 77.3 (C– 95 129.6, 130.2, 130.5, 131.9, 138.6, 147.1, 149.0, 157.8, 161.5,
COOEt), 111.3, 122.5, 123.0, 127.1, 129.5, 132.0, 132.4, 138.2,
141.7, 146.3, 147.0, 157.9 (12C, Ar–C), 159.6, 161.4, 169.7 (3C,
C=O); ESIꢀMS (m/z): 475.8 (M+); Anal. Calcd. (%) for
C23H21N7O5: C, 58.10; H, 4.45; N, 20.62. Found: C, 58.01; H,
40 4.29; N, 20.49.
168.8 (17C, Ar–C), 169.5 (C=O); ESIꢀMS (m/z): 458.0 (M+);
Anal. Calcd. (%) for C25H23N5O4: C, 65.63; H, 5.07; N, 15.31.
Found: C, 65.49; H, 4.89; N, 15.12.
4.1.4.1.
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
100 pyrazol-4-yl)-2-amino-7-hydroxy-8-methyl-4H-chromene-3-
carbonitrile (6u).
4.1.3.7.
1-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
Yield 78 %; m.p. 241ꢀ243 °C; IR (KBr, νmax, cmꢀ1): 3400 & 3321
pyrazol-4-yl)-3-amino-1H-benzo [f]chromene-2-carbonitrile
(6q).
(asym. & sym. stretching of –NH2), 2189 (C≡N stretching), 1381
Yield 81 %; m.p. 238ꢀ240 °C; IR (KBr, νmax, cmꢀ1): 3389 & 3328
(–CH3 stretching), 1232 (C–O–C ether stretching); H NMR (400
1
45 (asym. & sym. stretching of –NH2), 2190 (C≡N stretching), 1382 105 MHz, DMSOꢀd6): δ 1.98 (s, 3H, CH3), 2.05 (s, 3H, CH3), 4.31 (s,
1
(–CH3 stretching), 1238 (C–O–C ether stretching); H NMR (400
MHz, DMSOꢀd6): δ 2.16 (s, 3H, CH3), 5.14 (s, 1H, CH), 6.98ꢀ
7.93 (m, 16H, ArꢀH + NH2); 13C NMR (100 MHz, DMSOꢀd6) δ:
12.6 (CH3), 28.2 (C4), 55.5 (C–CN), 112.6, 116.9, 117.0, 120.0,
1H, CH), 6.57ꢀ7.38 (m, 11H, ArꢀH + NH2), 7.69 (1H, imidazole),
9.57 (s, b, 1H, OH); 13C NMR (100 MHz, DMSOꢀd6) δ: 8.0, 12.6
(2C, CH3), 28.3 (C4), 59.2 (C–CN), 102.1, 113.0, 114.1, 122.3,
122.9, 123.1, 127.7, 129.6, 129.9, 130.1, 132.0, 138.5, 147.3,
50 121.5, 121.7, 122.9, 123.0, 123.4, 125.4, 127.8, 128.1, 129.1, 110 149.4, 157.6, 161.4, 168.7 (17C, Ar–C); ESIꢀMS (m/z): 424.8
129.2, 129.6, 130.2, 130.3, 131.1, 132.4, 137.8, 147.1, 160.2
(22C, Ar–C); ESIꢀMS (m/z): 445.0 (M+); Anal. Calcd. (%) for
C27H20N6O: C, 72.96; H, 4.54; N, 18.91. Found: C, 73.12; H,
(M+); Anal. Calcd. (%) for C24H20N6O2: C, 67.91; H, 4.75; N,
19.80. Found: C, 68.12; H, 4.63; N, 19.59.
4.1.4.2. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-7-hydroxy-8-methyl-4H-chromene-3-
115 carboxylate (6v).
4.63; N, 18.77.
55 4.1.3.8. ethyl 1-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-3-amino-1H-benzo [f]chromene-2-carboxylate
(6r).
Yield 68 %; m.p. 226ꢀ228 °C; IR (KBr, νmax, cmꢀ1): 3391 & 3330
(asym. & sym. stretching of –NH2), 1721 (C=O, ester stretching),
1382 (–CH3 stretching), 1222 (C–O–C ether stretching); 1H NMR
(400 MHz, DMSOꢀd6): δ 1.07 (t, J=6.8, 3H, CH3), 2.06 (s, 3H,
Yield 71 %; m.p. 227ꢀ229 °C; IR (KBr, νmax, cmꢀ1): 3395 & 3331
(asym. & sym. stretching of –NH2), 1712 (C=O, ester stretching),
60 1382 (–CH3 stretching), 1225 (C–O–C ether stretching); 1H NMR 120 CH3), 2.14 (s, 3H, CH3), 4.14 (q, J=10.8, 2H, CH2), 4.64 (s, 1H,
8
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DOI: 10.1039/C3NJ01327H
CH), 6.55ꢀ7.82 (m, 12H, ArꢀH + NH2), 9.48 (s, b, 1H, OH); 13C
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NMR (100 MHz, DMSOꢀd6) δ: 8.3, 12.5, 15.6 (3C, CH3), 28.5
(C4), 58.4 (C, OCH2), 75.5 (C–COOEt), 102.0, 113.1, 113.9,
122.2, 123.2, 123.7, 128.8, 129.9, 130.4, 130.8, 132.4, 138.5,
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66.23; H, 5.34; N, 14.85. Found: C, 66.09; H, 5.19; N, 14.73.
60
65
70
75
5
4.1.4.3.
pyrazol-4-yl)-2-amino-4H-benzo[h]chromene-3-carbonitrile
10 (6w).
Yield 74 %; m.p. 244ꢀ246 °C; IR (KBr, νmax, cmꢀ1): 3451 & 3327
4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
5
6
(asym. & sym. stretching of –NH2), 2188 (C≡N stretching), 1374
7
8
1
(–CH3 stretching), 1225 (C–O–C ether stretching); H NMR (400
MHz, DMSOꢀd6): δ 1.97 (s, 3H, CH3), 4.62 (s, 1H, CH), 7.05ꢀ
15 8.20 (m, 14H, ArꢀH + NH2); 13C NMR (100 MHz, DMSOꢀd6) δ:
12.8 (CH3), 28.5 (C4), 55.1 (C–CN), 112.3, 116.4, 117.2, 120.0,
121.4, 121.9, 123.2, 123.4, 123.5, 125.0, 128.0, 128.1, 128.9,
129.6, 130.0, 130.2, 130.7, 131.1, 132.4, 138.0, 147.3, 159.9
(22C, Ar–C); ESIꢀMS (m/z): 445.2 (M+); Anal. Calcd. (%) for
20 C27H20N6O: C, 72.96; H, 4.54; N, 18.91. Found: C, 73.12; H,
9
80 10 G.P. Ouyang, X.J. Cai, Z. Chen, B.A. Song, P.S. Bhadury, S. Yang,
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4.1.4.4. ethyl 4-(5-(1H-imidazol-1-yl)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-2-amino-4H-benzo[h]chromene-3-carboxylate
(6x).
25 Yield 66 %; m.p. 230ꢀ232 °C; IR (KBr, νmax, cmꢀ1): 3441 & 3312
85
A. Naylor, B. Passingham, L. Winyard, Bioorg. Med. Chem. Lett.,
2008 18, 3392ꢀ3399.
(asym. & sym. stretching of –NH2), 1701 (C=O, ester stretching),
1380 (–CH3 stretching), 1234 (C–O–C ether stretching); 1H NMR
(400 MHz, DMSOꢀd6): δ 1.07 (t, J=6.8, 3H, CH3), 2.06 (s, 3H,
CH3), 4.07 (q, J=12.8, 2H, CH2), 4.83 (s, 1H, CH), 7.28ꢀ8.26 (m,
30 16H, ArꢀH + NH2); 13C NMR (100 MHz, DMSOꢀd6) δ: 12.6, 17.2
(2C, CH3), 28.1 (C4), 59.3 (C, OCH2), 75.0 (C–COOEt), 112.0,
117.3, 117.9, 119.9, 122.0, 122.9, 123.1, 123.9, 124.0, 125.8,
128.1, 128.5, 129.2, 129.7, 130.0, 130.9, 131.4, 131.6, 132.1,
137.9, 147.2, 159.4 (22C, Ar–C), 169.5 (C=O); ESIꢀMS (m/z):
35 491.9 (M+); Anal. Calcd. (%) for C29H25N5O3: C, 70.83; H, 5.13;
N, 14.25. Found: C, 70.63; H, 5.02; N, 14.11.
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Acknowledgment
The authors are thankful to Head, Department of Chemistry,
Sardar Patel University for providing 1H NMR and 13C NMR
40 spectroscopy and research facilities. We are also thankful to
Sophisticated Instrumentation Centre for Applied Research and
Training (SICART), Vallabh Vidyanagar for FTꢀIR analysis at
concessional rate and Dhanji P. Rajani, Microcare Laboratory,
Surat for antimicrobial, antimalarial and antituberculosis
45 screening of the compounds reported herein. PNK and SPS are
grateful to University Grants Commission – New Delhi, India for
Meritorious Fellowships in Sciences for Meritorious Students.
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Notes and References
Department of Chemistry, Sardar Patel University, Vallabh
50 Vidyanagarꢀ 388 120, Gujarat, India
*Corresponding author. Tel.: +91ꢀ02692ꢀ226856 ꢀ Ext. ꢀ 211;
Fax: +91ꢀ02692 236475.
Eꢀmail: dipanalka@yahoo.com
The spectral data of synthesized compound are shown in
55 supplementary data.
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