Green synthesis and pharmacological screening of polyhydroquinoline derivatives bearing a fluorinated 5-aryloxypyrazole nucleus

Article abstract of DOI:10.1039/c5ra00388a

A novel series of polyhydroquinoline scaffolds 8a-p has been designed and synthesized under ultrasonic irradiation by a one-pot three-component cyclocondensation reaction of 3-methyl-5-substituted aryloxy-1-phenyl-1H-pyrazole-4-carbaldehydes 3a-d with malononitrile 7 and various enhydrazinoketones 6a-e in the presence of piperidine as basic catalyst. All the synthesized compounds have been characterized by various spectroscopic techniques and elemental analysis. All the synthesized compounds were evaluated for their in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and also for their in vitro antimalarial activity against Plasmodium falciparum. Compounds 8c, 8i, 8j, 8l and 8m exhibited excellent antimalarial potency. The cytotoxicity of the synthesized compounds was tested using a bioassay of S. pombe cells at the cellular level. Compounds 8i, 8j, 8k and 8l were found to have maximum toxicity, while compounds 8e, 8m, 8c were found to be less cytotoxic. Some of them displayed luminous antibacterial activity and reasonable antituberculosis activity as compared with the first line drugs.

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Journal Name
RSCPublishing
ARTICLE
Green synthesis and pharmacological screening
of polyhydroquinoline derivatives bearing
fluorinated 5-aryloxypyrazole nucleus
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Sharad C. Karad*a, Vishal B. Purohita, Dipak K. Ravala, Piyush N. Kalariaa,
Jemin R. Avalania, Parth Thakorb, Vasudev R. Thakkarb
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel series of polyhydroquinoline scaffold 8a-p has been designed and synthesized under
ultrasonic irradiation by one-pot three-component cyclocondensation reaction of 3-methyl-5-
substituted aryloxy-1-phenyl-1H-pyrazole-4-carbaldehydes 3a-d with malononitrile
7 and various
enhydrazinoketones 6a-e in presence of piperidine as basic catalyst. All the synthesized
compounds have been characterized by various spectroscopic techniques and elemental
analysis. All the synthesized compounds were evaluated for their in vitro antibacterial activity
against a panel of pathogenic strains of bacteria and fungi, in vitro antitubercular activity against
Mycobacterium tuberculosis H37Rv strain and also for their in vitro antimalarial activity against
Plasmodium falciparum. Compounds 8c
potency. Cytotoxicity of synthesized compounds was tested using bioassay of S. pombe cells at
the cellular level. Compounds 8i 8j 8k and 8l were found to have maximum toxicity, while
compounds 8e 8m 8c were found to be less cytotoxic. Some of them displayed luminous
, 8i, 8j, 8l and 8m were exhibited excellent antimalarial
,
,
,
,
antibacterial activity and reasonable antituberculosis activity as compared with the first line
drugs.
Multiꢀcomponent reactions (MCRs) are the most efficient and
powerful methods in the context of modern drug discovery for
1. Introduction
Malaria and tuberculosis (TB) are the most disturbing
infectious diseases in the world, due to their high mortality and
morbidity. The protozoan parasite Plasmodium falciparum and
the pathogen Mycobacterium tuberculosis (MTB) are
respectively responsible for their occurrence. It has been
estimated that around 500 million people get infected in
subtropical and tropical countries by malaria and 2.5 million
deaths occur annually1ꢀ3. The World Health Organization has
declared TB to be a ‘global emergency’ and a recent estimation
by WHO showed that within next 20 years around 30 million
people will be infected by M. tuberculosis4, 5. The recurrence of
TB infection has been connected to coꢀinfection with the
human immunodeficiency virus (HIV)6. The appearance of
multidrugꢀresistant (MDR) and extensively drugꢀresistant
(XDR) M. tuberculosis strains are resistant to the existing
therapies7. Thus to overcome the threat of MDRꢀTB and XDRꢀ
TB, there is an imperative need for development of new drugs
with divergent and unique structures and possibly with a
different mechanism of action from that of the existing drugs8.
the preparation of bioactive heterocyclic compounds because of
their atom economy, high yields of the products and simple
experimentation9, 10. Ultrasound irradiation is also a superior
technique in green synthetic approach, which is being used to
accelerate organic reactions. It is considered as a processing aid
in terms of energy conservation compared with conventional
12
methods as it provides uniform and noncontact heating11,
.
The significant features of the ultrasound approach are
improved rate of reaction, easier handling and formation of
pure products in prominent yields.
Fluorine substituted quinolones (Figure 1) such as norfloxacin,
ofloxacin,
ciprofloxacin,
temafloxacin,
defloxacin,
sparfloxacin, delafloxacin, lomefloxacin etc. are used clinically
as they possess effective antibacterial potency13. The
substitution of fluorine in to a potential drug molecule can
extend not only pharmacokinetic properties but also enhances
the properties of pharmacodynamics, toxicology and efficacy of
drugs14.
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synthesizing the target molecules (c) biological evaluation
including antibacterial, antimalarial and antituberculosis studies
and cytotoxicity.
In continuation of our efforts to synthesize some novel
heterocyclic motifs with biological interest30ꢀ37, herein we
report for the synthesis and biological screening of novel
polyhydroquinoline derivatives bearing
a fluorinated 5ꢀ
aryloxypyrazole nucleus using ultrasonic irradiation. In the
context of biological importance, we intended to develop novel
approach for structural diversity of heterocycles incorporating
polyhydroquinoline scaffold. The modifications made on
quinolone core for probing antibacterial, antimalarial and
antitubercular activity includes; (A) fluorinated 5ꢀsubstituted
aryloxypyrazole at Cꢀ4 position (B) 4ꢀsubstituted phenylamino
nucleus at Nꢀ1 position and (C) methyl group on Cꢀ7 position
to validate lipophilicity of the target molecules.
Pyrazole and its derivatives are the key structural motifs in
heterocyclic chemistry and occupy a significant position in
biological and medicinal chemistry. They exhibited a broad
spectrum of pharmacological activities such as such as
anticancer15, antibacterial16, antiviral17, analgesic18, antiꢀ
inflammatory19, antimalarial, antituberculosis and antifungal
activities20. Polyhydroquinoline derivatives have experienced
tremendous upsurge in the modern era. They exhibited diverse
therapeutic and pharmacological importance, such as calcium
channel blockers, hepatoprotective agents, vasodilators,
antiatherosclerotic agents, bronchodilators, geroprotective
2. Chemistry
The synthesis of targeted 5ꢀ(variously fluorinated aryloxy)ꢀ
pyrazole incorporated polyhydroquinoline derivatives are
summarized in Scheme 1. The starting material 5ꢀchloroꢀ3ꢀ
methylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde
1 was prepared
agents, antitumor agents, antidiabetic agents, etc21ꢀ25
.
according to Vilsmeier–Haack reaction of 3ꢀmethylꢀ1ꢀphenylꢀ
1Hꢀpyrazolꢀ5(4H)ꢀone38. 3ꢀmethylꢀ5ꢀsubstituted aryloxyꢀ1ꢀ
phenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehydes 3a-d were prepared by
Substituted 1,4ꢀdihydropyridines are also well known as
calcium channel blockers (CCB) which are often used to treat
orderly cardiovascular diseases including hypertension26ꢀ28
.
refluxing compound
1 and substituted phenols 2a-d in presence
of anhydrous K2CO3 as basic catalyst in DMF as solvent. The
required enhydrazinoketones 6a-e were prepared by the
Lichitsky and coꢀworkers reported the conventional synthesis
of fused Nꢀsubstituted 1,4ꢀdihydropyridines by reacting cyclic
enhydrazinoketones and arylidene derivatives of malononitrile
in two step without biological evaluation. They employed
simple aromatic aldehydes and only two substituted phenyl
hydrazine hydrochlorides for the synthesis29. In the context of
our interest we designed and synthesized fluorinated 5ꢀ
reaction of βꢀdiketone dimedone
4 with 4ꢀsubstituted phenyl
hydrazine hydrochlorides 5a-e under aqueous condition. The
targeted compounds fluorinated pyrazole incorporated
polyhydroquinoline derivatives 8a-p were synthesized by
cyclocondensation reaction of 3ꢀmethylꢀ5ꢀsubstituted aryloxyꢀ
1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehydes
enhydrazinoketones 6a-e and malononitrile
3a-d
,
substituted
in absolute
7
(substituted
aryloxy)ꢀpyrazole
nucleus
based
on
ethanol using piperidine as the basic catalyst by conventional
and ultrasonic irradiation methods (Scheme 1, Table 1)
polyhydroquinoline scaffold Figure 2. In current work, we
have concentrated on following points: (a) Synthesis of target
compounds by single step oneꢀpot threeꢀcomponent
cyclocondensation reaction employing conventional as well as
ultrasonic irradiation method (b) Use of heteroaromatic
.
A plausible mechanism for the reaction is outlined in Scheme
. The reaction occurs via in situ initial formation of the
2
heterylidenenitrile, containing the electronꢀpoor C=C double
bond, from the Knoevenagel condensation between 3ꢀmethylꢀ5ꢀ
substituted aryloxyꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehydes 3a-
aldehydes
(3ꢀmethylꢀ5ꢀsubstituted
aryloxyꢀ1ꢀphenylꢀ1Hꢀ
pyrazoleꢀ4ꢀcarbaldehydes) and variously substituted phenyl
hydrazine hydrochlorides
(4ꢀF, 4ꢀBr, 4ꢀCl, 4ꢀOMe) in
d
and malononitrile 7 by loss of water molecule, Michael
addition of enhydrazinoketones 6a-e to the ylidenic bond to
form an acyclic intermediate which undergoes cyclization by
nucleophilic attack of the ꢀNH group on the electron deficient
cyano carbon, followed by tautomerisation to the final products
8a-p.
3. Pharmacology
3.1. In vitro antimicrobial activity
The antimicrobial activity of the newly synthesized compounds
8a-p was carried out by broth micro dilution method according
2 | J. Name., 2012, 00, 1-3
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to National Committee for Clinical Laboratory Standards 3.2. In vitro antituberculosis activity
(NCCLS)39. Antibacterial activity was screened against three
A primary in vitro antituberculosis activity of the newly
synthesized compounds 8aꢀp was conducted at 250 ꢁg/mL
against Mycobacterium tuberculosis H37Rv strain by using
LowensteineꢀJensen medium as described by Rattan40. The
obtained results are presented in Table 3 in form of %
inhibition. Isoniazid and Rifampicin were used as the standard
drugs.
Gram positive (Bacillus subtilis MTCC 441, Clostridium tetani
MTCC 449, and Streptococcus pneumoniae MTCC 1936) and
three Gram negative (Salmonella typhi MTCC 98, Escherichia
coli MTCC 443, and Vibrio cholerae MTCC 3906) bacteria by
using
ampicillin,
ciprofloxacin,
norfloxacin
and
chloramphenicol as the standard antibacterial drugs. Antifungal
activity was screened against two fungal species (Aspergillus
fumigats MTCC 3008 and Candida albicans MTCC 227) where
griseofulvin and nystatin were used as the standard antifungal
drugs. The strains employed for the activity were procured from
the Institute of Microbial Technology, Chandigarh (MTCCꢀ
Micro Type Culture Collection). 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 result of antimicrobial screening data is shown in
Table 1. Reaction parameters under conventional method and sonication (8a-
p).
Conventional
method
Ultrasonic
method
Time
Entry
R
R1
Time
(h)
Yielda
Yielda
(%)
88
(%)
79
78
64
76
73
76
65
73
76
75
61
71
77
79
62
68
(min)
25
20
30
20
15
15
15
20
15
25
20
20
20
25
30
20
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
2ꢀF
2ꢀF
2ꢀF
2ꢀF
4ꢀF
4ꢀBr
4ꢀF
4ꢀCl
ꢀH
ꢀH
4ꢀOMe
ꢀH
2.5
2.0
2.5
2.5
1.5
1.5
2.0
2.5
2.0
2.5
2.0
1.5
91
79
87
84
88
76
85
83
87
74
81
86
89
78
80
Table 2
.
2ꢀF
3ꢀF
3ꢀCF3
3ꢀCF3 4ꢀOMe
3ꢀCF3
3ꢀCF3
3ꢀF
3ꢀF
3ꢀF
4ꢀF
4ꢀF
ꢀH
4ꢀBr
4ꢀF
4ꢀOMe
4ꢀBr
4ꢀF
2.0
2.5
2.0
1.5
4ꢀBr
4ꢀF
a Isolated
3.3. In vitro antimalarial activity
In vitro antimalarial activity of the newly synthesized
compounds 8a-p against P. falciparum strain was performed
using quinine and chloroquine as the reference compounds. The
consequences of the antimalarial screening are expressed as the
drug concentration resulting in 50% inhibition (IC50) of parasite
growth and are listed in Table 4.
Scheme 1. synthesis of 2-amino-7, 7-dimethyl-4-(3-methyl-5-substituted aryloxy-
1-phenyl-1H-pyrazol-4-yl)-5-oxo-1-(phenylamino)-1,4,5,6,7,8-hexahydro
quinoline-3-carbonitrile 8a-p (i) DMF, K2CO3, Reflux 2 h. (ii) H2O stirring RT, 6 h.
(iii) (A) Ethanol, Piperidine, Reflux 1.5-2.5 h (iii) (B) Ethanol, Piperidine, ))) RT 15-
30 min.
4. Results and discussion
4.1. Optimization of reaction conditions for the target
compounds
The reactions leading to the desired products were performed
using conventional method (Path A in Scheme 1) as well as
ultrasonic irradiation (Path B in Scheme 1). It was observed
that, all the reactions by conventional route consumed very long
time (1.5ꢀ2.5 h) for completion with relatively lower yields (61ꢀ
79%). The same transformations could be successfully
accomplished under ultrasound irradiation in comparatively
shorter duration (15ꢀ30 min.) with moderate to excellent yields
(
Table 1). The differences in yield and reaction time as
compared to conventional method may be ascribed to cavitation
in irradiated reaction mixture enhancing the mass transfer
which allows chemical reactions to occur at the faster rate41.
Thus ultrasonic irradiation method was found to be more
advantageous for the synthesis of novel polyhydroquinoline
Scheme
polyhydroquinoline.
2
.
Plausible mechanistic pathway for the synthesis of
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VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5RA00388A
derivatives bearing a fluorinated 5ꢀ substituted aryloxypyrazole spectra of compounds 8a-p exhibited the presence of the ꢀCH
nucleus.
proton (C4ꢀH of polyhydroquinoline ring) as a sharp singlet
around δ 4.56ꢀ4.53 ppm and a broad singlet at δ 8.70ꢀ8.22 ppm
arising due to ꢀNH proton. Multiplets in the range between δ
7.53ꢀ5.78 ppm appeared for amine and aromatic protons. The
mass spectrum of all the compounds showed molecular ion
peak at (M+) corresponding to their respective molecular
weights, which confirmed the chemical structures.
Table 2. In vitro antimicrobial activity of polyhydroquinoline derivatives 8a-
p (MICs, µg/mL)
Gram positive
bacteria
Gram negative
bacteria
Fungi
Comp.
S.P. B.S. C.T. E.C. S.T. V.C. C.A. A.F.
MTCCMTCCMTCCMTCCMTCCMTCCMTCCMTCC
1936 441 449 443
98 3906 227 3008
Table 4. In vitro antimalarial activity of polyhydroquinoline derivatives 8a-p
8a
8b
8c
8d
8e
8f
8g
8h
8i
200 500 250 200 250 500 1000 500
500 500 125 125 500 250 1000 1000
100 250 125 250 100 250 1000 500
125 62.5 500 100 250 200 500 500
500 200 200 250 250 250 500 1000
125 250 250 250 200 100 >1000 500
200 100 250 250 200 250 1000 500
250 200 100 500 250 125 1000 1000
62.5 250 125 200 100 100 250 100
100 62.5 100 62.5 200 250 250 500
125 100 500 250 250 250 1000 1000
500 200 500 100 200 62.5 1000 100
Comp.
8a
8b
IC50 (µg/mL)
0.58
Comp.
8j
8k
IC50 (µg/mL)
0.073
1.54
0.95
8c
8d
8e
8f
0.090
1.45
1.24
8l
8m
8n
8o
0.067
0.088
1.47
1.56
0.42
8g
8p
2.10
0.78
8j
8k
8l
8h
8i
Chloroquine
Quinine
0.020
0.268
0.59
0.042
8m 500 500 250 200 500 200 500 1000
8n
8o
8p
A
B
C
D
E
125 100 200 250 500 250 200 500
200 200 250 200 100 250 1000 >1000
250 500 250 100 500 200 1000 >1000
100 250 250 100 100 100 n. t.a n. t.
4.3. Biological section
4.3.1. In vitro antibacterial activity
10
50
25
100
50
50
50
50
100
10
50
25
10
50
25
10
50
25
n. t. n. t.
n. t. n. t.
n. t. n. t.
The antibacterial screening of the tested compounds 8a-p
showed moderate to excellent inhibitory activity (Table 2). It
has been observed that against S. pneumonia, compound 8i (R=
3ꢀCF3, R1= 4ꢀOCH3) was found to be more potent i.e. 62.5
ꢁg/mL as compared to ampicillin i.e. 100 ꢁg/mL. While
compounds 8c (R= 2ꢀF, R1= 4ꢀCl) and 8j (R= 3ꢀCF3, R1= 4ꢀBr)
showed comparable activity to that of ampicillin. Against B.
subtillis, compounds 8d (R= 2ꢀF, R1= 4ꢀH) and 8j (R= 3ꢀCF3,
R1= 4ꢀBr) showed maximum potency i.e. 62.5 ꢁg/mL as
compared to ampicillin i.e. 250 ꢁg/mL as well as norfloxacin
i.e. 100 ꢁg/mL. Compounds 8c (R= 2F, R1= 4ꢀCl), 8f (R= 2ꢀF,
R1= 4ꢀOCH3), 8i (R= 3ꢀCF3, R1= 4ꢀOCH3) MIC = 250 ꢁg/mL
showed equivalent potency to that of ampicillin. Compounds 8e
(R= 4ꢀF, R1= 4ꢀH), 8h (R= 3ꢀCF3, R1= 4ꢀH), 8l (R= 3ꢀF, R1= 4ꢀ
OCH3) and 8o (R= 4ꢀF, R1= 4ꢀBr) i.e. 200 ꢁg/mL were found to
be more effective as compared to ampicillin MIC = 250 ꢁg/mL.
Against C. tetani, compounds 8a (R= 2ꢀF, R1= 4ꢀBr), 8f (R= 2ꢀ
F, R1= 4ꢀOCH3), 8m (R= 3ꢀF, R1= 4ꢀBr), 8o (R= 4ꢀF, R1= 4ꢀ
Br), 8p (R= 4ꢀF, R1= 4ꢀF), and 8g (R= 3ꢀF, R1= 4ꢀH), MIC =
250 ꢁg/mL showed same influence as that of ampicillin.
Compounds 8h (R= 3ꢀCF3, R1= 4ꢀH), 8j (R= 3ꢀCF3, R1= 4ꢀBr)
MIC = 100 ꢁg/mL and compound 8b (R= 2ꢀF, R1= 4ꢀF), 8c (R=
2ꢀF, R1= 4ꢀCl), 8i (R= 3ꢀCF3, R1= 4ꢀOCH3) MIC = 125 ꢁg/mL
were found to more active than ampicillin MIC = 250 ꢁg/mL.
n. t. n. t. n. t. n. t. n. t. n. t. 100 100
n. t. n. t. n. t. n. t. n. t. n. t. 500 100
F
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: Chloramphenicol, D:
Ciprofloxacin
Table 3. In vitro antituberculosis activity (% inhibition) of
polyhydroquinoline derivatives 8a-p against M. tuberculosis H37Rv (at
concentration 250 µg/mL).
Comp.
8a
8b
8c
8d
8e
8f
8g
8h
% Inhibition
Comp.
% Inhibition
26
16
52
48
94
63
14
25
30
8j
8k
8l
8m
8n
21
95
88
91
20
36
89
98
99
8o
8p
Rifampicin
Isoniazid
8i
4.2. Analytical results
The structures of the newly synthesized compounds were
confirmed by 1H NMR, FTꢀIR, mass spectrometry and
elemental analysis. The IR spectrum of compounds 8a-p
exhibited characteristic absorption band in the range 1263ꢀ1224
cmꢀ1. This can be attributed to the presence of ether linkage. The
carbonyl group stretching frequency was observed at 1665ꢀ
1645 cmꢀ1. The absorption band in the range of 2188ꢀ2210 cmꢀ1
observed for all the compounds are due to ꢀC≡N stretching. The
strong absorption band was also observed in the range of 1375ꢀ
1364 cmꢀ1 due to ꢀCH3 rocking. The characteristic absorption
band in the range 3486ꢀ3321 cmꢀ1 may be attributed to
asymmetric & symmetric stretching of ꢀNH2. The 1H NMR
In case of inhibiting gram negative bacteria, compounds 8j (R=
3ꢀCF3, R1= 4ꢀBr) and 8l (R= 3ꢀF, R1= 4ꢀOCH3) MIC = 62.5
ꢁg/mL were found to have higher potency against E. coli and V.
cholera respectively as compared to ampicillin. Compounds 8c
(R= 2ꢀF, R1= 4ꢀCl), 8i (R= 3ꢀCF3, R1= 4ꢀOCH3), 8o (R= 4ꢀF,
R1= 4ꢀBr) and compounds 8f (R= 2ꢀF, R1= 4ꢀOCH3), 8i (R= 3ꢀ
CF3, R1= 4ꢀOCH3) also exhibited the similar activity as that of
ampicillin i.e. 100 ꢁg/mL respectively against S. typhi and V.
cholera
.
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4.3.5. Cytotoxicity
Table 5. The percentage viability of different chemically synthesized
compounds was listed in table.
Cytotoxicity of synthesized compounds was tested using
bioassay of S. pombe cells at the cellular level. From the result,
cell death caused by toxicity of the synthesized compounds
could be easily monitored by vital staining. The toxicity was
found to vary with the type of substituent present and
concentrations of the synthesized compounds. It has been
observed that cytotoxicity was found to increase with
Conc. 8C 8M 8K 8L 8I 8J 8E DMSO
Untreated
cell
ꢀ
2.5
5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
97
98
94
90
84
78
75
95
91
90
88
85
76
74
72
63
57
78 82 66 85
74 80 62 76
64 76 60 73
51 71 58 70
55 64 56 63
7.5
10
12.5
concentration of drugs. Compounds 8i
,
8j
,
8k and 8l were
8m 8c
found to have maximum toxicity, while compounds 8e
,
,
were found to be less cytotoxic (Figure 1). After 17 hrs of the
treatment, many of the S. pombe cells were killed due to toxic
nature of the compound.
4.4 Structure-activity relationship (SAR)
The results of the biological screening showed that the activity
was significantly affected by introducing fluorinated 5ꢀ
substituted aryloxypyrazole at Cꢀ4 position and phenylamino
nucleus at Nꢀ1 position on polyhydroquinoline scaffold
Figure 3. Effect of synthesized compounds on viability of S. Pombe at different
(
Figure-4).
concentrations
4.3.2. In vitro antifungal activity
The antifungal screening data from Table 2 revealed that
Against C. albicans, compound 8n (R= 3ꢀF, R1= 4ꢀF) i.e. 200
ꢁg/mL, compounds 8i (R= 3ꢀCF3, R1= 4ꢀOCH3) and 8j (R= 3ꢀ
CF3, R1= 4ꢀBr) i.e. 250 ꢁg/mL were found to have significant
activity as compared to griseofulvin. Compounds 8i (R= 3ꢀCF3,
R1= 4ꢀOCH3) and 8l (R= 3ꢀF, R1= 4ꢀOCH3) exhibited
equivalent potency i.e. 100 ꢁg/mL against A. fumigates. From
the above results, it can be concluded that compound 8j showed
the potential to become new class of antimicrobial agent in
future.
4.3.3. In vitro antituberculosis activity
Antituberculosis screening of the novel compounds 8a-p was
conducted at 250ꢁg/mL concentrations against Mycobacterium
tuberculosis H37Rv strain. Compounds 8e (R= 4ꢀF, R1= 4ꢀH),
8k (R= 3ꢀCF3, R1= 4ꢀF) and 8m (R= 3ꢀF, R1= 4ꢀBr) were found
to possess brilliant activity (i.e. 94%, 95% and 91% at 250
ꢁg/mL) against M. tuberculosis H37Rv. The compounds 8l (R=
3ꢀF, R1= 4ꢀOCH3) and 8p (R= 4ꢀF, R1= 4ꢀF) are moderately
active and remaining all other compounds showed poor
Figure 4. Structureꢀactivity relationships for antimicrobial, antituberculosis,
antimalarial and cytotoxicity activity of the synthesized compounds 8a-p.
We perceived that the methoxy group existing at R1 position in
Nꢀphenyl moiety at Nꢀ1 in polyhydroquinoline and ꢀCF3 group
at meta position of aryloxy ring in pyrazole nucleus exhibited
excellent antimalarial activity against P. falciparum strain as
compared to quinine as well as improved antibacterial activity
against S. pneumonia. Without any substitution at R1 position
and fluoro group at ortho potion of aryloxy ring revealed
highest activity against B. subtilis. The fluoro group prevailing
at R1 positions and ꢀCF3 group at meta potion of aryloxy ring
displayed superior antituberculosis activity against M.
tuberculosis H37Rv. The replacement of electron donating
methoxy group with electron withdrawing chloro groups at R1
position increased antimalarial activity. The bromo group
present at R1 position and ꢀCF3 group at meta position in
aryloxy ring exhibited brilliant activity against B. subtilis and
inhibition against M. tuberculosis H37Rv growth (Table 3)
.
4.3.4. In vitro antimalarial activity
The newly synthesized compounds 8a-p were evaluated for
their antimalarial screening against chloroquine and quinine
sensitive strain of P. falciparum. All the experiments were
performed in duplicate and a mean value of IC50 is mentioned
in Table 4. The compounds 8c (R= 2ꢀF, R1= 4ꢀCl), 8i (R= 3ꢀ
CF3, R1= 4ꢀOCH3), 8j (R= 3ꢀCF3, R1= 4ꢀBr) 8l (R= 3ꢀF, R1= 4ꢀ
OCH3) and 8m (R= 3ꢀF, R1= 4ꢀBr) were found to have IC50 in
the range of 0.042 to 0.090 upon P. falciparum strain. Above
compounds displayed fabulous activity against P. falciparum
strain as compared to quinine IC50 0.268.
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DOI: 10.1039/C5RA00388A
improved antimalarial activity. The bromo, fluoro and methoxy Research & Training (SICART), Vallabh Vidyanagar, India.
groups present at R1 position and ꢀCF3 and –F groups at meta All the compounds were found to be within ±0.4% of their
position in aryloxy ring demonstrate higher cytotoxicity against theoretical values. The reaction mixtures were irradiated by
S. pombe cells at a cellular level. But the chloro and bromo ultrasound at room temperature in a Dꢀcompact ultrasonic
groups existing at R1 positions and ꢀF group at ortho and meta cleaner with a frequency of 30 kHz and an output power of 250
potions of aryloxy ring displayed inferior cytotoxicity against S. W. The reaction flask was kept at the maximum energy area in
pombe cells at a cellular level. It can be concluded that electron the cleaner and the level of the reactants was kept slightly lower
donating and withdrawing groups at R1 position and ꢀCF3 group than the level of water in the bath. 1H NMR spectra (in DMSOꢀ
at meta position of aryloxy ring are observed to be chiefly d6) were recorded on Bruker Avance 400F (MHz) NMR
responsible for deviation in biological potency.
Spectrometer at 400 MHz using TMS as the internal standard.
5. Conclusion
6.1.1. General procedure for the synthesis of 3-methyl-5-
We designed and synthesized some novel polyhydroquinoline
derivatives bearing a fluorinated 5ꢀsubstituted aryloxypyrazole
nucleus advantageously using ultrasonic irradiation and
examined their antimicrobial, antimalarial and antituberculosis
activities. The results indicated that majority of the compounds
substituted aryloxy-1-phenyl-1H-pyrazole-4-carbaldehydes (3a-
d)
5ꢀchloroꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehyde 1 (1
mmol), substituted phenols 2aꢀd (1 mmol) and anhydrous
potassium carbonate (2 mmol) in dimethylformamide (10 mL)
were charged in a 100 mL round bottom flask equipped with a
mechanical stirrer and a condenser. The reaction mixture was
heated at 90°C for 2 h and the progress of the reaction was
monitored by TLC. After the completion of reaction confirmed
by the TLC, the reaction mixture was poured in to 100 mL iceꢀ
water and filtered, washed thoroughly with water, dried and
recrystallized from hot ethanol (10 mL) to obtain a white solid.
were found to be most active against B. subtilis and C. tetani
Amongst the tested compounds, 8e 8k, and 8m showed
prominent antituberculosis activities. The Compounds 8c 8i 8l
.
,
,
,
and 8m displayed superior antimalarial activity. Finally
compound 8i could be recognized as the most biologically
active member within the synthesized series showing an
interesting dual antimalarial and antibacterial profile. The SAR
results revealed that the presence of electron donating and
withdrawing groups at R1 position and ꢀCF3 group at meta
position of aryloxy ring played effective role in boasting the
prepared
polyhydroquinoline
derivatives
as
potent
6.1.1.1 5-(2-Fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazole-4-
antimicrobial, antimalarial and antitubercular agents. The
chloro and bromo groups existing at R1 positions and ꢀF group carbaldehyde (3a)
at ortho and meta potions of aryloxy ring displayed inferior
Yield 85 %; m.p. 225ꢀ227 °C; 1H NMR (400 MHz, DMSOꢀd6):
δ 2.46 (s, 3H, ꢀCH3), 7.13ꢀ7.64 (m, 9H, Ar–H), 9.56 (s, 1H, ꢀ
CHO)
cytotoxicity against S. pombe cells at a cellular level.
Consequently, polyhydroquinoline scaffold represents a class
that needs further investigation with the hope of discovering
new antimicrobial and antimalarial agents.
6.1.1.2 5-(3-Fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazole-
4-carbaldehyde (3b)
Yield 78 %; m.p. 210ꢀ212 °C; 1H NMR (400 MHz, DMSOꢀd6):
δ 2.47 (s, 3H, ꢀCH3), 6.92ꢀ7.63 (m, 9H, Ar–H), 9.61 (s, 1H, ꢀ
CHO)
6. Experimental section
6.1. Chemistry
All the reagents were obtained commercially and used without
further purification. Solvents used were of analytical grade.
Melting points (°C, uncorrected) were determined in open
capillaries on µThermoCal10 melting point apparatus (Analab
Scientific Pvt. Ltd, India). Precoated silica gel plates (silica gel
0.25 mm, 60 G F 254; Merck, Germany) were used for thin
layer chromatography. Electron impact Mass Spectra were
recorded on Shimadzu LCMS 2010 spectrometer (Shimadzu,
Tokyo, Japan) purchased under PURSE programme of DST at
Sardar Patel University, Vallabh Vidyanagar, India. The IR
spectra were recorded on Shimadzu FTIR 8401
spectrophotometer using potassium bromide pellets in the range
4000–400 cmꢀ1and frequencies of only characteristic peaks are
expressed in cmꢀ1. The elemental analysis was performed on
PerkinꢀElmer 2400 seriesꢀII elemental analyzer (PerkinꢀElmer,
USA) at Sophisticated Instrumentation Centre for Applied
6.1.1.3 5-(4-Fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazole-
4-carbaldehyde (3c)
Yield 82 %; m.p. 245ꢀ247 °C; 1H NMR (400 MHz, DMSOꢀd6):
δ 2.46 (s, 3H, ꢀCH3), 7.17ꢀ7.64 (m, 9H, Ar–H), 9.54 (s, 1H, ꢀ
CHO)
6.1.2. General procedure for the synthesis of substituted 5,5-
dimethyl-3-(2-phenylhydrazinyl) cyclohex-2-enones (6a-e)
1, 3ꢀdimedone
4 (10 mmol), substituted phenyl hydrazine
hydrochlorides 5a-e (10 mmol) and water (10 mL) were
charged in a 100mL round bottom flask equipped with a
mechanical stirrer. The reaction mixture was stirred at room
temperature for 6 h. After the completion of reaction (checked
by TLC), the separated substituted enhydrazinoketones 6a-e
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA00388A
were filtered and washed with water to obtain the pure solid 135.07, 138.15, 142.86, 144.08, 152.97, 154.16, 161.18 (25C,
product.
ArꢀC), 195.07 (C=O); ESIꢀMS (m/z): 653.1 (M+), 655.1 (M+2);
Anal. Calcd (%) for C34H30BrFN6O2: C, 62.48; H, 4.63; N,
12.86. Found: C, 62.24; H, 4.40; N, 12.63.
6.1.3 (A). General procedure for the conventional synthesis of 2-
amino-7,7-dimethyl-4-(3-methyl-5-substituted aryloxy-1-phenyl-
1H-pyrazol-4-yl)-5-oxo-1-(phenylamino)-1,4,5,6,7,8-hexahydro
quinoline-3-carbonitriles (8a-p).
6.1.3.2. 2-Amino-4-(5-(2-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-((4-fluorophenyl)amino)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8b)
A 100 mL round bottomed flask was charged with a mixture of
3ꢀmethylꢀ5ꢀsubstituted
carbaldehydes 3a-d (1 mmol), malononitrile
aryloxyꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀ Yield 91 %; m.p. 202ꢀ204 °C; IR (KBr, νmax, cmꢀ1): 3472 &
7
(1 mmol), 3340 (asym. & sym. str. of –NH2), 2198 (C≡N str.), 1645 (C=O
1
substituted enhydrazinoketones 6a-e (1 mmol), and catalytic str.), 1375 (–CH3 rocking), 1231 (C–O–C ether str.); H NMR
amount of piperidine (2ꢀ3 drops) in ethanol (10 mL). The (400 MHz, DMSOꢀd6): δ 0.83 (s, 3H, ꢀCH3 ), 0.89 (s, 3H, ꢀ
reaction mixture was refluxed for an appropriate time period till CH3), 1.69ꢀ2.02 (m, 4H, 2 × ꢀCH2 ), 2.31 (s, 3H, ꢀCH3 ), 4.56 (s,
the completion of the reaction as indicated by TLC (Table 1). 1H, ꢀCH ), 597ꢀ7.50 (m, 15H, Ar–H And ꢀNH2 ), 8.46 (s, 1H, ꢀ
After the completion of reaction, the reaction mixture was NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.57 (pyrazoleꢀCH3),
stirred magnetically for further 10 min. After cooling the 26.35, 28.03 (C(CH3)2), 31.92 (C4), 37.65 (CH2), 49.35 (CH2ꢀ
separated solid mass was collected by filtration, washed well CO), 56.67 (CꢀCN), 109.75, 109.93, 113.93, 114.38, 121.54,
with ethanol (10 mL) and crystallized from hot ethanol (10 121.88, 122.22, 129.65, 137.99, 138.17, 142.05, 143.51,
mL).
143.90, 144.03, 144.34, 144.61, 147.76, 150.16, 151.20,
152.59, 152.72, 152.88, 152.24, 154.18, 161.25 (25C, ArꢀC),
195.04 (C=O); ESIꢀMS (m/z): 593.2 (M+); Anal. Calcd (%) for
C34H30F2N6O2: C, 68.91; H, 5.10; N, 14.18. Found: C, 68.68; H,
4.83; N, 13.97.
6.1.3 (B). General procedure for the synthesis of 2-amino-7,7-
dimethyl-4-(3-methyl-5-
pyrazol-4-yl)-5-oxo-1-(phenylamino)-1,4,5,6,7,8-hexahydro
quinoline-3-carbonitriles (8a-p) using sonochemical method.
substituted
aryloxy-1-phenyl-1H-
6.1.3.3.
2-Amino-1-((4-chlorophenyl)amino)-4-(5-(2-
A 100 mL round bottomed flask was charged with a mixture of
3ꢀmethylꢀ5ꢀaryloxyꢀ1ꢀphenylꢀ1Hꢀpyrazoleꢀ4ꢀcarbaldehydes 3a-
fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-7,7-
dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(8c)
d
(1 mmol), malononitrile
7
(1 mmol),
substituted
enhydrazinoketones 6a-e (1 mmol) and catalytic amount of
piperidine (2ꢀ3 drops) in ethanol (10 mL). The reaction flask Yield 79 %; m.p. 218ꢀ220 °C; IR (KBr, νmax, cmꢀ1): 3439 &
was located in the ultrasonic bath so as to keep the level of 3334 (asym. & sym. str. of –NH2), 2210 (C≡N str.), 1660 (C=O
reactants slightly lower than the level of water in bath. The str.), 1371 (–CH3 rocking), 1224 (C–O–C ether str.); 760 (CꢀCl
reaction mixture was sonicated at room temperature for an stretching );1H NMR (400 MHz, DMSOꢀd6): H NMR (400
1
appropriate time period till the completion of the reaction as MHz, DMSOꢀd6): δ 0.85 (s, 3H, ꢀCH3 ), 0.91(s, 3H, ꢀCH3),
indicated by TLC (Table 1). After the completion of reaction, 1.68ꢀ2.20 (m, 4H, 2 × ꢀCH2 ), 2.31 (s, 3H, ꢀCH3 ), 4.56 (s, 1H, ꢀ
the reaction mixture was stirred magnetically for further 10 CH ), 5.99ꢀ7.50 (m, 15H, Ar–H And ꢀNH2 ), 8.61 (s, 1H, ꢀNH);
min. The separated solid mass was collected by filtration, 13C NMR (100 MHz, DMSOꢀd6) δ: 13.54 (pyrazoleꢀCH3),
washed well with cold ethanol (10 mL) and crystallized from 28.08, 28.55 (C(CH3)2), 31.96 (C4), 37.72 (CH2), 49.82 (CH2ꢀ
hot ethanol (10 mL). The physicochemical and spectroscopic CO), 56.74 (CꢀCN), 109.95, 109.97, 113.86, 114.26, 121.57,
characterization data of the synthesized compounds 8a-p are 121.85, 122.19, 124.14, 129.71, 138.01, 138.26, 143.93,
given below.
144.49, 145.15, 146.10, 147.77, 147.82, 147.93, 150.18,
152.25, 152.48, 152.79, 153.10, 154.15, 161.22 (25C, ArꢀC),
195.07 (C=O); ESIꢀMS (m/z): 610.1 (M+); Anal. Calcd (%) for
C34H30ClFN6O2: C, 67.04; H, 4.96; N, 13.80. Found: C, 66.79;
H, 4.75; N, 13.53.
6.1.3.1.
2-Amino-1-((4-bromophenyl)amino)-4-(5-(2-
fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-7,7-
dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(8a)
6.1.3.4. 2-Amino-4-(5-(2-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-7,7-dimethyl-5-oxo-1-(phenylamino)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile.(8d)
Yield 88 %; m.p. 215ꢀ217 °C; IR (KBr, νmax, cmꢀ1): 3478 &
3336 (asym. & sym. str. of –NH2), 2188 (C≡N str.), 1650 (C=O
1
str.), 1368 (–CH3 rocking), 1260 (C–O–C ether str.); H NMR
(400 MHz, DMSOꢀd6): δ 0.85 (s, 3H, ꢀCH3 ), 0.91 (s, 3H, ꢀ Yield 87 %; m.p. 196ꢀ198 °C; IR (KBr, νmax, cmꢀ1): 3431 &
CH3), 1.68ꢀ2.20 (m, 4H, 2 × ꢀCH2 ), 2.31 (s, 3H, ꢀ CH3 ), 4.56 3321 (asym. & sym. str. of –NH2), 2188 (C≡N str.), 1658 (C=O
1
(s, 1H, ꢀCH ), 5.98ꢀ7.50 (m, 15H, Ar–H And ꢀNH2 ), 8.62 (s, str.), 1369 (–CH3 rocking), 1232 (C–O–C ether str.); H NMR
1H, ꢀNH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.93 (pyrazoleꢀ (400 MHz, DMSOꢀd6): δ 0.83 (s, 3H, ꢀCH3 ), 0.90 (s, 3H, ꢀ
CH3), 26.68, 28.46 (C(CH3)2), 32.31 (C4), 37.65 (CH2), 49.21 CH3), 1.74ꢀ2.20 (m, 4H, 2 × ꢀCH2 ), 2.31 (s, 3H, ꢀCH3 ), 4.56 (s,
(CH2ꢀCO), 56.33 (CꢀCN), 109.98, 110.84, 111.47, 114.13, 1H, ꢀCH ), 5.95ꢀ7.51 (m, 16H, Ar–H And ꢀNH2 ), 8.49 (s, 1H, ꢀ
117.40, 120.69, 120.77, 121.86, 122.14, 123.59, 125.10, NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.62 (pyrazoleꢀCH3),
126.90, 127.15, 130.78, 131.85, 132.81, 134.55, 134.70, 28.28, 28.49 (C(CH3)2), 31.95 (C4), 38.01 (CH2), 49.64 (CH2ꢀ
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CO), 56.74 (CꢀCN), 109.78, 111.73, 112.13, 116.45, 117.58, 28.44, 29.08 (C(CH3)2), 32.11 (C4), 37.80 (CH2), 49.48 (CH2ꢀ
120.37, 120.73, 121.56, 121.86, 122.05, 122.17, 124.34, CO), 56.80 (CꢀCN), 109.42, 109.75, 110.48, 111.46, 114.14,
125.32, 127.04, 129.55, 129.70, 129.85, 130.32, 144.39, 120.67, 121.52, 121.91, 126.99, 129.62, 129.73, 129.89,
144.73, 147.05, 147.88, 152.74, 153.36, 154.09 (25C, ArꢀC), 131.57, 138.15, 139.27, 144.31, 144.66, 147.03, 147.79,
195.07 (C=O); ESIꢀMS (m/z): 575.2 (M+); Anal. Calcd (%) for 152.60, 153.44, 154.27, 154.72, 157.64, 161.89 (25C, ArꢀC),
C34H31FN6O2: C, 71.06; H, 5.44; N, 14.62. Found: C, 70.78; H, 194.92 (C=O); ESIꢀMS (m/z): 575.2 (M+); Anal. Calcd (%) for
5.21; N, 14.36.
C34H31FN6O2: C, 71.06; H, 5.44; N, 14.62. Found: C, 70.81; H,
5.21; N, 14.33.
6.1.3.5. 2-Amino-4-(5-(4-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-7,7-dimethyl-5-oxo-1-(phenylamino)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (8e).
Yield 84 %; m.p. 192ꢀ194 °C; IR (KBr, νmax, cmꢀ1): 3452 &
3332(asym. & sym. str. of –NH2), 2210 (C≡N str.), 1646(C=O
str.), 1350(–CH3 rocking), 1232 (C–O–C ether str.); H NMR Yield 85 %; m.p. 201ꢀ203 °C; IR (KBr, νmax, cmꢀ1): 3481 &
6.1.3.8. 2-Amino-7,7-dimethyl-4-(3-methyl-1-phenyl-5-(3-
(trifluoromethyl )phenoxy)-1H-pyrazol-4-yl)-5-oxo-1-
(phenylamino)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(8h)
1
(400 MHz, DMSOꢀd6): δ 0.83 (s, 3H, ꢀCH3 ), 0.88 (s, 3H, ꢀ 3333 (asym. & sym. str. of –NH2), 2197 (C≡N str.), 1665 (C=O
1
CH3), 1.73ꢀ2.19 (m, 4H, 2 × ꢀCH2 ), 2.40 (s, 3H, ꢀCH3 ), 4.55 (s, str.), 1371(–CH3 rocking), 1259 (C–O–C ether str.); H NMR
1H, ꢀCH ), 5.84ꢀ7.53 (m, 16H, Ar–H And ꢀNH2 ), 8.55 (s, 1H, ꢀ (400 MHz, DMSOꢀd6): δ 0.80 (s, 3H, ꢀCH3 ), 0.86 (s, 3H, ꢀ
NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.62 (pyrazoleꢀCH3), CH3), 1.62ꢀ2.21 (m, 4H, 2 × ꢀCH2 ), 2.34 (s, 3H,ꢀCH3 ), 4.56 (s,
28.13, 28.37 (C(CH3)2), 32.11 (C4), 37.79 (CH2), 49.52 (CH2ꢀ 1H, ꢀCH ), 5.84ꢀ7.52 (m, 16H, Ar–H And ꢀNH2 ), 8.56 (s, 1H, ꢀ
CO), 56.33 (CꢀCN), 109.55, 111.99, 112.14, 113.93, 116.91, NH ); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.58 (pyrazoleꢀ
117.10, 120.51, 121.42, 121.93, 122.08, 126.83, 126.95, CH3), 27.97, 28.25 (C(CH3)2), 32.10 (C4), 37.78 (CH2), 49.48
129.57, 129.68, 129.91, 138.08, 145.08, 145.40, 147.06, (CH2ꢀCO), 56.79 (CꢀCN), 109.37, 111.95, 112.77, 113.85,
147.81, 152.57, 152.77, 153.32, 154.21, 159.55 (25C, ArꢀC), 114.06, 119.38, 120.70, 121.73, 122.23, 127.17, 129.62,
195.07 (C=O); ESIꢀMS (m/z): 575.1 (M+); Anal. Calcd (%) for 129.92, 131.51, 131.69, 137.91, 138.05, 144.11, 146.99,
C34H31FN6O2: C, 71.06; H, 5.44; N, 14.62. Found: C, 70.85; H, 147.89, 152.60, 152.72, 152.95, 153.42, 154.32, 156.69, 156.77
5.15; N, 14.36.
(26C, ArꢀC), 194.84 (C=O); ESIꢀMS (m/z): 625.1 (M+); Anal.
Calcd (%) for C35H31F3N6O2: C, 67.30; H, 5.00; N, 13.45.
Found: C, 67.06; H, 4.73; N, 13.18.
6.1.3.6. 2-Amino-4-(5-(2-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-((4-methoxyphenyl)amino)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8f)
Yield 88 %; m.p. 240ꢀ242 °C; IR (KBr, νmax, cmꢀ1): 3470 &
3339 (asym. & sym. str. of –NH2), 2192 (C≡N str.), 1655 (C=O
str.), 1362 (–CH3 rocking), 1262 (C–O–C ether str.); H NMR Yield 83 %; m.p. 245ꢀ247 °C; IR (KBr, νmax, cmꢀ1): 3472 &
6.1.3.9. 2-Amino-1-((4-methoxyphenyl)amino)-7,7-dimethyl-4-(3-
methyl-1-phenyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazol-4-
yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8i)
1
(400 MHz, DMSOꢀd6): δ 0.84 (s, 3H, ꢀCH3 ), 0.91(s, 3H, ꢀCH3), 3338 (asym. & sym. str. of –NH2), 2197 (C≡N str.), 1664 (C=O
1
1.76ꢀ2.20 (m, 4H, 2 × ꢀCH2 ), 2.38 (s, 3H, ꢀCH3 ), 3.69 (s, 3H, ꢀ str.), 1367(–CH3 rocking), 1254 (C–O–C ether str.); H NMR
OCH3 ), 4.55 (s, 1H, ꢀCH ), 5.91ꢀ7.51 (m, 15H, Ar–H And ꢀ (400 MHz, DMSOꢀd6): δ 0.80 (s, 3H, ꢀCH3 ), 0.86 (s, 3H, ꢀ
NH2 ), 8.22 (s, 1H, ꢀNH); 13C NMR (100 MHz, DMSOꢀd6) δ: CH3), 1.63ꢀ2.23 (m, 4H, 2 × ꢀCH2 ), 2.41 (s, 3H, ꢀCH3 ), 3.73 (s,
13.94 (pyrazoleꢀCH3), 28.19, 28.48 (C(CH3)2), 32.57 (C4), 3H, ꢀOCH3 ), 4.53 (s, 1H, ꢀCH ), 5.78ꢀ7.52 (m, 15H, Ar–H And
36.31 (CH2), 49.20 (CH2ꢀCO), 51.04 (ArꢀCꢀOCH3), 55.97 (Cꢀ ꢀNH2 ), 8.28 (s, 1H, ꢀNH); 13C NMR (100 MHz, DMSOꢀd6) δ:
CN), 104.97, 106.41, 110.22, 111.14, 114.19, 117.20, 117.86, 13.60 (pyrazoleꢀCH3), 28.06, 28.25 (C(CH3)2), 32.17 (C4),
121.71, 124.76, 125.53, 125.92, 126.85, 127.53, 129.80, 37.79 (CH2), 49.51 (CH2ꢀCO), 55.79 (ArꢀCꢀOCH3), 56.73 (Cꢀ
131.89, 137.89, 143.76, 145.68, 147.70, 148.46, 149.77, CN), 109.27, 109.66, 113.17, 113.93, 114.16, 115.00, 115.24,
152.22, 155.71, 157.23, 161.20 (25C, ArꢀC), 195.05 (C=O); 119.60, 121.72, 122.30, 127.16, 129.62, 129.91, 131.71,
ESIꢀMS (m/z): 605.1(M+); Anal. Calcd (%) for C35H33FN6O3: 137.91, 138.07, 140.50, 140.63, 144.50, 147.59, 153.11,
C, 69.52; H, 5.50; N, 13.90. Found: C, 69.29; H, 5.26; N, 13.62. 153.55, 153.05, 154.28, 154.47, 156.72 (26C, ArꢀC), 195.11
(C=O); ESIꢀMS (m/z): 655.1 (M+); Anal. Calcd (%) for
6.1.3.7. 2-Amino-4-(5-(3-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-7,7-dimethyl-5-oxo-1-(phenylamino)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile (8g)
C36H33F3N6O3: C, 66.05; H, 5.08; N, 12.84. Found: C, 65.82; H,
4.81; N, 12.63.
6.1.3.10. 2-Amino-1-((4-bromophenyl)amino)-7,7-dimethyl-4-(3-
methyl-1-phenyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazol-4-
yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8j)
Yield 76 %; m.p. 195ꢀ197 °C; IR (KBr, νmax, cmꢀ1): 3471&
3340 (asym. & sym. str. of –NH2), 2191 (C≡N str.), 1656 (C=O
1
str.), 1372 (–CH3 rocking), 1263 (C–O–C ether str.); H NMR
(400 MHz, DMSOꢀd6): δ 0.82 (s, 3H, ꢀCH3 ), 0.88 (s, 3H, ꢀ Yield 87 %; m.p. 232ꢀ234 °C; IR (KBr, νmax, cmꢀ1): 3482&
CH3), 1.68ꢀ2.18 (m, 4H, 2 × ꢀCH2 ), 2.28 (s, 3H, ꢀCH3 ), 4.55 (s, 3338 (asym. & sym. str. of –NH2), 2196 (C≡N str.), 1663 (C=O
1
1H, ꢀCH ), 5.87ꢀ7.53 (m, 16H, Ar–H And ꢀNH2 ), 8.56 (s, 1H, ꢀ str.), 1366 (–CH3 rocking), 1257 (C–O–C ether str.); H NMR
NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.58 (pyrazoleꢀCH3), (400 MHz, DMSOꢀd6): δ 0.81 (s, 3H, ꢀCH3 ), 0.87 (s, 3H, ꢀ
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DOI: 10.1039/C5RA00388A
1
CH3), 1.58ꢀ1.99 (m, 4H, 2 × ꢀCH2 ), 2.33 (s, 3H, ꢀCH3 ), 4.55 (s, str.), 1371 (–CH3 rocking), 1258 (C–O–C ether str.); H NMR
1H, ꢀCH ), 5.90ꢀ7.54 (m, 15H, Ar–H And ꢀNH2 ), 8.70 (s, 1H, ꢀ (400 MHz, DMSOꢀd6): δ 0.83 (s, 3H, CH3 ), 0.89 (s, 3H, CH3),
NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.52 (pyrazoleꢀCH3), 1.40ꢀ2.18 (m, 4H, 2 × CH2 ), 2.33 (s, 3H, CH3 ), 4.54 (s, 1H,
27.20, 28.13 (C(CH3)2), 32.12 (C4), 37.74 (CH2), 49.44 (CH2ꢀ CH ), 6.45ꢀ7.72 (m, 15H, Ar–H And NH2 ), 8.70 (s, 1H, NH);
CO), 56.82 (CꢀCN), 109.57, 109.84, 111.71, 113.85, 113.95, 13C NMR (100 MHz, DMSOꢀd6) δ: 13.58 (pyrazoleꢀCH3),
114.46, 119.70, 121.75, 122.28, 127.13, 129.59, 131.70, 28.40, 28.29, (C(CH3)2), 32.80 (C4), 37.95 (CH2), 49.51 (CH2ꢀ
132.38, 132.52, 137.88, 138.03, 144.26, 146.39, 147.87, CO), 56.33 (CꢀCN), 109.88, 110.28, 111.45, 111.76, 114.13,
152.38, 152.71, 153.08, 153.45, 154.96, 156.64, 156.74 (26C, 117.40, 120.75, 121.76, 122.24, 123.49, 125.19, 126.93,
ArꢀC), 194.87 (C=O); ESIꢀMS (m/z): 703.1 (M+), 705.1 (M+2); 127.17, 130.88, 131.75, 132.71, 134.65, 134.79, 135.17,
Anal. Calcd (%) for: C35H30BrF3N6O2: C, 59.75; H, 4.30; N, 138.35, 142.76, 144.88, 152.87, 154.26, 161.38 (25C, ArꢀC),
11.95. Found: C, 59.49; H, 4.05; N, 11.67.
195.07 (C=O); ESIꢀMS (m/z): 653.1 (M+), 655.1 (M+2); Anal.
Calcd (%) for: C34H30BrFN6O2: C, 62.48; H, 4.63; N, 12.86.
Found: C, 62.24; H, 4.36; N, 12.63.
6.1.3.11. 2-Amino-1-((4-fluorophenyl)amino)-7,7-dimethyl-4-(3-
methyl-1-phenyl-5-(3-(trifluoromethyl)phenoxy)-1H-pyrazol-4-
yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8k)
Yield 74 %; m.p. 224ꢀ226 °C; IR (KBr, νmax, cmꢀ1): 3486 &
3338 (asym. & sym. str. of –NH2), 2193 (C≡N str.), 1662 (C=O
str.), 1370 (–CH3 rocking), 1263 (C–O–C ether str.); H NMR Yield 89 %; m.p. 204ꢀ206 °C; IR (KBr, νmax, cmꢀ1): 3483 &
6.1.3.14. 2-Amino-4-(5-(3-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-((4-fluorophenyl)amino)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8n)
1
(400 MHz, DMSOꢀd6): δ 0.83 (s, 3H, ꢀCH3 ), 0.89 (s, 3H, ꢀ 3340 (asym. & sym. str. of –NH2), 2195(C≡N str.), 1662 (C=O
1
CH3), 1.61ꢀ2.21 (m, 4H, 2 × ꢀCH2 ), 2.33 (s, 3H, ꢀCH3 ), 4.54 (s, str.), 1364 (–CH3 rocking), 1257 (C–O–C ether str.); H NMR
1H, ꢀCH ), 5.87ꢀ7.53 (m, 15H, Ar–H And ꢀNH2 ), 8.54 (s, 1H, ꢀ (400 MHz, DMSOꢀd6): δ 0.83 (s, 3H, ꢀCH3 ), 0.90 (s, 3H, ꢀ
NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.63 (pyrazoleꢀCH3), CH3), 1.36ꢀ2.19 (m, 4H, 2 × ꢀCH2 ), 2.33 (s, 3H, ꢀCH3 ), 4.54 (s,
28.08, 28.23 (C(CH3)2), 32.09 (C4), 37.88 (CH2), 49.48 (CH2ꢀ 1H, ꢀCH ), 5.90ꢀ7.53 (m, 15H, Ar–H And ꢀNH2 ), 8.53 (s, 1H, ꢀ
CO), 56.75 (CꢀCN), 109.50, 109.88, 114.04, 116.43, 119.26, NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.55 (pyrazoleꢀCH3),
121.71, 122.21, 127.16, 129.58, 129.73, 131.47, 131.71, 28.01, 28.36, (C(CH3)2), 32.13 (C4), 37.80 (CH2), 49.48 (CH2ꢀ
138.08, 143.51, 144.10, 144.48, 147.96, 152.50, 152.88, CO), 56.83 (CꢀCN), 109.55, 109.91, 111.44, 113.37, 113.67,
153.27, 153.71, 153.89, 156.12, 156.38, 156.47, 156.81 (26C, 113.92, 114.13, 116.34, 116.56, 121.53, 121.87, 122.06,
ArꢀC), 195.07 (C=O); ESIꢀMS (m/z): 643.1 (M+); Anal. Calcd 126.98, 129.60, 129.72, 131.56, 138.15, 143.51, 147.59,
(%) for: C35H30F4N6O2: C, 65.41; H, 4.71; N, 13.08. Found: C, 152.65, 153.64, 154.77, 154.82, 157.54, 161.79 (25C, ArꢀC),
65.17; H, 4.42; N, 12.85.
194.92 (C=O); ESIꢀMS (m/z): 593.2 (M+); Anal. Calcd (%) for:
C34H30F2N6O2: C, 68.91; H, 5.10; N, 14.18. Found: C, 68.63; H,
4.86; N, 13.97.
6.1.3.12. 2-Amino-4-(5-(3-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-((4-methoxyphenyl)amino)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile(8l)
6.1.3.15.
2-Amino-1-((4-bromophenyl)amino)-4-(5-(4-
fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-7,7-
dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(8o)
Yield 81 %; m.p. 248ꢀ250 °C; IR (KBr, νmax, cmꢀ1): 3477 &
3334 (asym. & sym. str. of –NH2), 2185 (C≡N str.), 1658 (C=O
1
str.), 1365 (–CH3 rocking), 1259 (C–O–C ether str.); H NMR
(400 MHz, DMSOꢀd6): δ 0.81 (s, 3H, ꢀCH3 ), 0.86(s, 3H, ꢀCH3), Yield 78 %; m.p. 238ꢀ240 °C; IR (KBr, νmax, cmꢀ1): 3473 &
1.63ꢀ2.22 (m, 4H, 2 × ꢀCH2 ), 2.33 (s, 3H, ꢀCH3 ), 3.74 (s, 3H, ꢀ 3338 (asym. & sym. str. of –NH2), 2197 (C≡N str.), 1664 (C=O
1
OCH3 ), 4.54 (s, 1H, ꢀCH ), 5.79ꢀ7.52 (m, 15H, Ar–H And ꢀ str.), 1372 (–CH3 rocking), 1261 (C–O–C ether str.); H NMR
NH2 ), 8.37 (s, 1H, ꢀNH); 13C NMR (100 MHz, DMSOꢀd6) δ: (400 MHz, DMSOꢀd6): δ 0.85 (s, 3H, ꢀCH3 ), 0.89 (s, 3H, ꢀ
13.82 (pyrazoleꢀCH3), 26.78, 28.41 (C(CH3)2), 32.45 (C4), CH3), 1.70ꢀ2.19 (m, 4H, 2 × ꢀCH2 ), 2.32 (s, 3H, ꢀCH3 ), 4.53 (s,
36.24 (CH2), 49.43 (CH2ꢀCO), 51.52 (ArꢀCꢀOCH3), 56.39 (Cꢀ 1H, ꢀCH ), 5.89ꢀ7.52 (m, 15H, Ar–H And ꢀNH2 ), 8.68 (s, 1H, ꢀ
CN), 105.13, 106.18, 111.67, 114.53, 116.73, 117.97, 120.78, NH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.55 (pyrazoleꢀCH3),
121.86, 122.74, 123.89, 125.50, 126.70, 127.75, 130.88, 27.68, 28.23, (C(CH3)2), 32.14 (C4), 37.74 (CH2), 49.52 (CH2ꢀ
131.89, 132.71, 134.85, 134.95, 135.15, 138.75, 142.96, CO), 56.50 (CꢀCN), 109.75, 110.00, 111.67, 113.80, 114.13,
144.58, 157.77, 160.93, 164.37 (25C, ArꢀC), 194.47 (C=O); 116.67, 116.90, 121.47, 122.15, 123.75, 125.18, 126.85,
ESIꢀMS (m/z): 605.2 (M+); Anal. Calcd (%) for: C35H33FN6O3: 129.53, 129.68, 129.96, 138.27, 145.28, 145.50, 147.46,
C, 69.52; H, 5.50; N, 13.90. Found: C, 69.29; H, 5.23; N, 13.62. 147.71, 152.47, 152.67, 153.38, 154.48, 159.59 (25C, ArꢀC),
194.95 (C=O); ESIꢀMS (m/z): 653.1(M+), 655.1 (M+2); Anal.
6.1.3.13.
2-Amino-1-((4-bromophenyl)amino)-4-(5-(3-
Calcd (%) for: C34H30BrFN6O2: C, 62.48; H, 4.63; N, 12.86.
Found: C, 62.22; H, 4.40; N, 12.58.
fluorophenoxy)-3-methyl-1-phenyl-1H-pyrazol-4-yl)-7,7-
dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(8m)
Yield 86 %; m.p. 228ꢀ230 °C; IR (KBr, νmax, cmꢀ1): 3475 &
6.1.3.16. 2-Amino-4-(5-(4-fluorophenoxy)-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-((4-fluorophenyl)amino)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (8p)
3339 (asym. & sym. str. of –NH2), 2190 (C≡N str.), 1665 (C=O
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

RSC Advances
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VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5RA00388A
Yield 80 %; m.p. 226ꢀ228 °C; IR (KBr, νmax, cmꢀ1): 3483 & 4. WHO Weekly epidemiological record No. 15, 2003, 78
3342 (asym. & sym. str. of –NH2), 2198 (C≡N str.), 1662 (C=O 121ꢀ128.
str.), 1367(–CH3 rocking), 1262 (C–O–C ether str.); H NMR 5. G. T. Controlesurveillance, Planning, Financing. WHO
(400 MHz, DMSOꢀd6): δ 0.84 (s, 3H, ꢀCH3 ), 0.89 (s, 3H, ꢀ Report
CH3), 1.70ꢀ2.19 (m, 4H, 2 × ꢀCH2 ), 2.32 (s, 3H, ꢀCH3 ), 4.54 (2006).http://www.who.int/tb/publications/global_report/2
,
1
(s, 1H, ꢀCH ), 5.87ꢀ7.53 (m, 15H, Ar–H And ꢀNH2 ), 8.52 (s,
006/pdf/fullꢀreport_
1H, ꢀNH); 13C NMR (100 MHz, DMSOꢀd6) δ: 13.55 (pyrazoleꢀ correctedversion.pdf.
CH3), 28.15, 28.27, (C(CH3)2), 32.13 (C4), 37.79 (CH2), 49.54 6. A. Goldfeld and J. J. Ellner, Tuberculosis, 2007, 87
,
(CH2ꢀCO), 56.87 (CꢀCN), 109.70, 110.00, 113.36, 113.79,
S26ꢀS30.
113.88, 116.32, 116.59, 116.89, 117.22, 121.46, 121.87, 7. WHO Report
122.15, 126.85, 129.53, 129.68, 138.08, 143.50, 145.08, (2007).http://www.stoptb.org/wg/advocacyꢀ
145.38, 147.79, 152.48, 153.10, 154.50, 156.90, 159.27 (25C,
ArꢀC), 194.93 (C=O); ESIꢀMS (m/z): 593.2 (M+); Anal. Calcd documents/Global%20MDR.XDR.response.plan.pdf.
(%) for: C34H30F2N6O2: C, 68.91; H, 5.10; N, 14.18. Found: C, 8. H. Tomioka, Y. Tatano, K. Yasumoto and T. Shimizu,
communication/acsmcl/assets/
68.69; H, 4.84; N, 13.91.
Expert Review of Respiratory Medicine, 2008, 2,
455ꢀ471.
9. V. A. Chebanov, E. A. Muravyova, S. M. Desenko, V.
I. Musatov, I. V. Knyazeva, S. V. Shishkina, O. V.
Shishkin and C. O. Kappe, J. Comb. Chem., 2006,
Acknowledgment
The authors wish to express thanks to Head, Department of
Chemistry, Sardar Patel University for providing research
facilities. We are also thankful to Dhanji P. Rajani, Microcare
Laboratory, Surat for antimicrobial, antituberculosis and
antimalarial screening of the compounds reported herein and
Sophisticated Instrumentation Centre for Applied Research and
Training (SICART), Vallabh Vidyanagar for FTꢀIR analysis at
concessional rate. SCK and VBP wish to acknowledge the
University Grants Commission – New Delhi, India for
meritorious fellowships awarded to them during 2013ꢀ2015
8
, 427ꢀ434.
10.A. Dondoni, A. Massi, E. Minghini and V. Bertolasi,
Helv. Chim. Acta, 2002, 85, 3331ꢀ3348.
11.A. Bazgir, S. Ahadi, R. Ghahremanzadeh, H. R.
Khavasi and P. Mirzaei, Ultrason. Sonochem.
2010, 17, 447ꢀ452.
,
12.J.ꢀT. Li, M.ꢀX. Sun and Y. Yin, Ultrason. Sonochem.
2010, 17, 359ꢀ362.
,
13.C. Zhi, Z.ꢀy. Long, A. Manikowski, J. Comstock, W.ꢀ
C. Xu, N. C. Brown, P. M. Tarantino, K. A. Holm,
E. J. Dix, G. E. Wright, M. H. Barnes, M. M.
Butler, K. A. Foster, W. A. LaMarr, B. Bachand,
R. Bethell, C. Cadilhac, S. Charron, S. Lamothe, I.
Notes
*aDepartment of Chemistry, Sardar Patel University, Vallabh
Vidyanagarꢀ 388 120, Gujarat, India,
bB. R. Doshi School of Biosciences, Sardar Patel Maidan,
BakrolꢀVadtal road, Satellite campus, Sardar Patel University,
Motorina and R. Storer, J. Med. Chem., 2006, 49
1455ꢀ1465.
,
Vallabh Vidyanagarꢀ388120, Gujarat, India
14.B. E. Smart, J. Fluorine Chem., 2001, 109, 3ꢀ11.
15.S. Fletcher, E. P. Keaney, C. G. Cummings, M. A.
Blaskovich, M. A. Hast, M. P. Glenn, S.ꢀY.
Chang, C. J. Bucher, R. J. Floyd, W. P. Katt, M.
H. Gelb, W. C. Van Voorhis, L. S. Beese, S. M.
Sebti and A. D. Hamilton, J. Med. Chem., 2010,
53, 6867ꢀ6888.
Eꢀmail: krdsharad1126@gmail.com
The spectral data of synthesized compound are shown in
supplementary data.
16.A. Tanitame, Y. Oyamada, K. Ofuji, M. Fujimoto, N.
Iwai, Y. Hiyama, K. Suzuki, H. Ito, H. Terauchi,
M. Kawasaki, K. Nagai, M. Wachi and J.ꢀi.
Yamagishi, J. Med. Chem., 2004, 47, 3693ꢀ3696.
17.G. Ouyang, X.ꢀJ. Cai, Z. Chen, B.ꢀA. Song, P. S.
Bhadury, S. Yang, L.ꢀH. Jin, W. Xue, D.ꢀY. Hu
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Antimicrobial Susceptibility Testing: Twelfth
Informational Supplement (2002), ISBN 1ꢀ56238ꢀ
454ꢀ6 M100ꢀS12 (M7).
40.A. Rattan, Antimicrobials in Laboratory Medicine.
Churchill B. I., Livingstone, New Delhi,, 2000, 85ꢀ
108.
41.T. J. Mason, Chem. Soc. Rev., 1997, 26, 443ꢀ451.
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