Synthesis and antimicrobial activity of some new N-substituted quinoline derivatives of 1H-pyrazole

Article abstract of DOI:10.1002/ardp.201000010

A new series of 32 derivatives of 4-pyrazolyl-N-(hetero)arylquinoline 5a-p and 6a-p were synthesized by a one-pot base-catalyzed cyclocondensation reaction of 1-phenyl-3-(hetero)aryl-pyrazole-4-carbaldehyde 1a-h, malononitrile 2, and 3-(hetero)aryl-5,5-disubstitutedcyclohex-2-enone 3a-b or 4a-b, respectively. All the synthesized compounds were characterized by elemental analysis, FT-IR, ¹H-NMR, and ¹³C-NMR spectral data. All the synthesized compounds were screened, against six bacterial pathogens, namely Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae, Salmonella typhi, Vibrio cholerae, Escherichia coli, and antifungal activity, against two fungal pathogens Aspergillus fumigatus and Candida albicans, using broth microdilution MIC method. Some of the compounds were found to be more or equipotent against most of the employed strains than commercially available drugs as evident from the screening data. Quinoline derivatives are known to exhibit a wide range of biological activities. Therefore, a series of some new 1,4-di(hetero)aryl quinoline derivatives bearing a 1H-pyrazole nucleus have been synthesized and were evaluated for their antimicrobial activities against a panel of human pathogens. Copyright

Full text of DOI:10.1002/ardp.201000010

Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
91
Full Paper
Synthesis and Antimicrobial Activity of Some
New N-Substituted Quinoline Derivatives of 1H-Pyrazole
Nilesh J. Thumar and Manish P. Patel
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
A new series of 32 derivatives of 4-pyrazolyl-N-(hetero)arylquinoline 5a–p and 6a–p were synthesized
by
a one-pot base-catalyzed cyclocondensation reaction of 1-phenyl-3-(hetero)aryl-pyrazole-4-
carbaldehyde 1a–h, malononitrile 2, and 3-(hetero)aryl-5,5-disubstitutedcyclohex-2-enone 3a–b or
4a–b, respectively. All the synthesized compounds were characterized by elemental analysis, FT-IR,
1H-NMR, and 13C-NMR spectral data. All the synthesized compounds were screened, against six
bacterial pathogens, namely Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae, Salmonella
typhi, Vibrio cholerae, Escherichia coli, and antifungal activity, against two fungal pathogens Aspergillus
fumigatus and Candida albicans, using broth microdilution MIC method. Some of the compounds were
found to be more or equipotent against most of the employed strains than commercially available
drugs as evident from the screening data.
Keywords: Antimicrobial activity / MCR / MIC / Pyrazole-4-carbaldehyde / Quinoline
Received: January 8, 2010; Accepted: March 3, 2010
DOI 10.1002/ardp.201000010
Introduction
a single reference has been found where 1,3-diaryl pyrazole-4-
carbaldehydes and thiazole were used and evaluated for their
biological profile. Several pyrazolylquinoline skeleton sys-
tems have been found to exhibit multiple pharmacological
activities such as antibacterial, antimalarial, antifungal, and
anticancer activity [18].
Quinoline derivatives are known to exhibit a wide range of
biological activities such as antibacterial, anticancer, anti-
malarial, and antiproliferative properties [1–8]. Recently,
4-functionally substituted 1,3-diaryl pyrazole derivatives
have received considerable attention due to their wide range
of useful biological properties [9–16].
Thus, by considering that a modification at the 1- and
4-position of the quinoline nucleus could bring significant
changes of the pharmacological activities and could provide
new classes of therapeutically active compounds for bio-
medical screening, and as part of our ongoing approach in
developing new antimicrobial agents containing quinoline
[19, 20], thiazole [22], and pyrazole-4-carbaldehyde [20, 21]
derivatives, herein, we report the synthesis of some new
derivatives of 4-pyrazolyl-N-(hetero)arylquinoline 5a–p and
6a–p via a multi component reaction (MCR) approach. The
constitution of all the products was characterized using
elemental analysis, FT-IR, 1H-NMR, 13C-NMR; some selected
compounds were also confirmed by mass spectrometry.
All synthesized compounds were screened for their in-vitro
antimicrobial activity against eight human pathogens, of
which three were Gram-positive bacterial strains, namely
Streptococcus pneumoniae, Clostridium tetani, and Bacillus subtilis,
three Gram-negative bacterial strains Salmonella typhi, Vibrio
cholerae, and Escherichia coli, and two fungal pathogens
Aspergillus fumigatus and Candida albicans, using the broth
Various routes for the synthesis of N-arylquinoline deriva-
tives have been reported using two-component as well as
three-component reactions. Yao and coworkers have reported
fluoride-ion-catalyzed multicomponent reactions for the
synthesis of N-arylquinoline derivatives in aqueous media.
Tu and coworkers have carried out a clean synthesis of 1,4-
diarylquinoline derivatives catalyzed by benzyl-triethyl
ammonium chloride (TEBAC) in aqueous media. They have
also reported a three-component green synthesis in ionic
liquid [Bmimþ][BF4ꢀ] and under microwave irradiation.
A literature survey [17] reveals studies concerning N-sub-
stituted quinoline derivatives of aromatic aldehydes, but not
Correspondence: Dr. Manish P. Patel, Department of Chemistry, Sardar
Patel University, Vallabh Vidyanagar – 388120, Gujarat, India.
E-mail: patelmanish1069@yahoo.com
Fax: þ91-2692-237258
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

92
N. J. Thumar and M. P. Patel
Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
microdilution MIC (minimum inhibitory concentration)
method [23].
under basic condition requiring prolonged refluxing and
still resulted in a poor yield. The most optimal condition
for the title derivatives is refluxing the mixture in aceto-
nitrile for 3–4 h in the presence of piperidine as basic cata-
lyst; this will lead to moderate to good yields (57–79%)
(Scheme 2). A mechanism for the formation of the quinoline
derivatives 5a–p and 6a–p is outlined in Scheme 3. The
reaction occurs via an in-situ initial formation of the heter-
Results and discussion
Chemistry
In continuation of our interest on synthesizing biologically
potent antimicrobials [19–22], herein, we report a new series
of 4-pyrazolyl-N-(4-fluorophenyl)-quinoline 5a–p and 4-pyra-
zolyl-N-(4-(4-fluorophenyl)thiazol-2-yl)-quinoline 6a–p deriva-
tives, via an one-pot three-component cyclocondensation
reaction of 1-phenyl-3-(hetero)aryl-pyrazole-4-carbaldehyde
1a–h, malononitrile 2, and 3-(4-fluorophenylamino)-5,5-di-
substituted cyclohex-2-enone 3a–b or 3-(4-(4-fluorophenyl)-
thiazol-2-ylamino)-5,5-disubstituted cyclohex-2-enone 4a–b,
respectively. The required 1-phenyl-3-(hetero)aryl-pyrazole-4-
carbaldehyde 1a–h were synthesized by the Vilsmeier–Haack
reaction of respective (hetero)arylhydrazone at 908C for 4 h
[24] (Scheme 1). The solid-phase reaction of 4-fluoroacetophe-
none, thiourea, and iodine (4 h at 1208C) afforded 2-amino-4-
(4-fluorophenyl)thiazole [25]. The required b-enaminones
were prepared by reacting b-diketone with 4-fluoroaniline
under microwave irradiation [26] resulting in 3a–b or with 2-
amino-4-(4-fluorophenyl)thiazole in refluxing methanol in
the presence of acetic acid to give 4a–b. To obtain the title
N-arylquinoline derivatives, we have tried to carry out the
reaction in aqueous medium and under neutral conditions
but failed to proceed even under prolonged refluxing.
Similarly, microwave irradiation was unsuccessful. The reac-
tion proceeded in ethanol, methanol, benzene, or DMF,
–
ylidenenitrile, containing the electron-poor C C double
–
bond, from the Knoevenagel condensation between pyra-
zole-4-carbaldehyde and malononitrile by loss of water mol-
ecules. Finally, a Michael addition of 3 or 4 to the initially
formed unsaturated nitrile, i. e. a nucleophilic attack of the
enaminone at the cyano olefins affords the cyclized quinoline
derivatives 5a–p and 6a–p. The structures of all new synthe-
sized compounds were well supported by 1H-NMR, 13C-NMR,
and FT-IR spectral data and the molecular weight of some
selected compounds was confirmed by mass spectrometry.
All spectroscopic data are provided in the Experimental sec-
tion. In addition, all compounds were screened for their
antibacterial and antifungal activity.
Antimicrobial screening
The examination of the data (Table 1) reveals that most of the
compounds showed excellent antibacterial and antifungal
activity when compared with the standard drugs ampicillin
and griseofulvin. Against the Gram-positive pathogen
S. pneumoniae, compounds 5i and 6e (MIC ¼ 100 mg/mL) were
found to exhibit comparable activity to that of ampicillin
(MIC ¼ 100 mg/mL). The compounds 5k, 6a, 6c, 6l, and 6n
(MIC < 250 mg/mL) were found to be more efficient, whereas,
5a, 5d–e, 5g–h, 5l–o, 6b, 6d, 6g, 6i, 6k, 6m, and 6p
(MIC ¼ 250 mg/mL) were found equally potent to ampicillin
(MIC ¼ 250 mg/mL) towards C. tetani. Compounds 5f, 5h, 5i,
5k, 6a, 6e, 6g, 6h, 6i, and 6l (MIC < 250 mg/mL) show better
activity, whereas 5b, 5g, 5j, 5l, 5o, 6b, 6f, 6j, and 6k
(MIC ¼ 250 mg/mL) found equally potent to ampicillin
(MIC ¼ 250 mg/mL) against B. subtilis. Towards the Gram-nega-
tive strain S. typhi, compounds 5b, 5f, and 6l (MIC ¼
100 mg/mL) were equally active compared to ampicillin
(MIC ¼ 100 mg/mL). Compounds 5m and 6i (MIC ¼ 100 mg/mL)
found to be equipotent towards ampicillin (MIC ¼ 100 mg/mL)
against V. cholerae. Compounds 5f and 6a (MIC < 100 mg/mL)
show
a better and 5k, 5o, 6c, 6e, 6g, 6j, and 6m
(MIC ¼ 100 mg/mL) were found to exhibit a comparable
activity compared to that of ampicillin (MIC ¼ 100 mg/mL)
towards E. coli. Against the fungal pathogen C. albicans, com-
pounds 5g–h, 5p, 6a–b, 6d, and 6n (MIC < 500 mg/mL) exhib-
ited a better activity whereas, 5a, 5c–f, 5i–k, 5m–n, 6c, 6g, 6i,
6k, and 6o (MIC ¼ 500 mg/mL) were found to be equipotent
compared to griseofulvin (MIC ¼ 500 mg/mL). Only one of the
tested compounds, 6a (MIC ¼ 100 mg/mL), was found to be
Scheme 1. Synthetic pathway for the intermediates 1a–h, 3a–b,
and 4a–b.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
New N-(Hetero)Arylquinoline Derivatives of 1H-Pyrazole
93
Scheme 2. Synthetic pathway for the compounds 5a–p and 6–p.
Scheme 3. Plausible mechanistic pathway of the synthesis of quinoline derivatives.
potent against the fungal strains C. albicans and A. fumigatus,
compared to the standard drug nystatin (MIC ¼ 100 mg/mL).
The remaining compounds showed moderate to good activity
inhibiting the growth of bacterial pathogens but are all less
effective than the standard drugs.
whereas the unsubstituted phenyl-ring-containing com-
pound was found to be the most potent among all against
both fungal species C. albicans and A. fumigatus. From the SAR
study of the title derivatives, it is interesting to note that a
minor alteration in the molecular configuration of the inves-
tigated compounds may have a pronounced effect on the
antimicrobial activity.
The investigation of the structure-activity relationships
(SAR) of antibacterial screening revealed that the compounds
with p-methoxy or unsubstituted phenyl at the 3-position of
the pyrazole nucleus gave better results against V. cholerae and Conclusion
S. pneumoniae. Similarly, towards C. tetani compounds with
phenyl, thienyl, or p-chloro or fluorophenyl substituents at
the 3-position of the pyrazole were found to be highly active.
Against B. subtilis, thienyl, p-chloro, methyl, methoxy, nitro,
fluoro, or unsubstituted phenyl-containing compounds were
found to be more potent. Compounds containing p-bromo,
fluoro, or methyl substituents exhibited a comparable
activity against S. typhi. The antifungal evaluation showed
that thienyl-, p-bromo-, fluoro-, methyl-, or nitrophenyl-con-
taining compounds were found to be active against C. albicans,
Two new series of substituted 4-pyrazolyl-N-(4-fluorophenyl)-
quinoline 5a–p and 4-pyrazolyl-N-(4-(4-fluorophenyl)thiazol-2-
yl)-quinoline 6a–p derivatives have been synthesized via MCR
approach; the compounds were characterized by elemental
and spectral analysis. This synthetic strategy allows the con-
struction of relatively complicated nitrogen-containing fused
heterocyclic system as well as the introduction of various
(hetero)aromatic substitutions into the 1- and 4-position of
the quinoline system. It can be concluded from the
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

94
N. J. Thumar and M. P. Patel
Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
Table 1. Antimicrobial activity of compounds 5a–p and 6a–p.
Compound
Minimum Inhibitory Concentration (MIC, mg/mL)
Gram-positive bacteria Gram-negative bacteria
Fungi
Aspergillus
Streptococcus
pneumoniae
Clostridium
tetani
Bacillus
subtilis
Salmonella
typhi
Vibrio
cholerae
Escherichia
coli
Candida
albicans
fumigatus
MTCC 1936
MTCC 449
MTCC 441
MTCC 98
MTCC 3906
MTCC 443
MTCC 3008
MTCC 227
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
500
250
1000
500
500
150
200
150
100
250
200
250
500
500
250
500
150
250
250
500
100
500
250
200
200
250
250
200
500
1000
1000
500
100
50
250
1000
1000
250
250
500
250
250
1000
500
200
250
250
250
250
500
200
250
150
250
500
500
250
500
250
500
250
125
250
150
500
250
250
50
500
250
1000
500
500
150
250
150
100
250
200
250
500
500
250
500
200
250
500
500
100
250
200
200
200
250
250
200
500
1000
1000
1000
250
50
250
100
250
250
1000
100
200
250
250
250
150
500
200
250
150
250
150
500
250
500
250
500
250
125
250
150
250
100
500
500
500
500
100
50
250
1000
1000
500
500
250
1000
500
500
150
200
150
100
250
200
250
500
500
250
500
150
250
250
500
100
500
250
200
200
250
500
500
100
50
250
150
200
200
500
62.5
125
250
250
150
100
500
150
250
100
500
62.5
500
100
500
100
500
100
250
250
100
200
150
100
500
250
500
100
50
1000
1000
500
1000
1000
>1000
200
500
1000
500
500
500
500
100
200
500
500
500
>1000
500
500
1000
250
100
250
500
250
1000
1000
500
1000
500
1000
500
1000
1000
250
500
1000
–
500
>1000
1000
500
>1000
>1000
1000
500
>1000
100
500
250
1000
500
500
1000
1000
500
1000
1000
>1000
>1000
>1000
500
>1000
–
–
–
–
100
6m
6n
6o
6p
Ampi.
Chlorm.
Cipro.
Genta.
Grise.
Nyst.
–
–
–
500
100
50
0.5
–
100
5
–
50
1
–
25
5
–
25
5
–
25
0.05
–
–
–
–
–
–
–
100
Ampi.: Ampicillin; Chlorm.: Chloramphenicol; Cipro.: Ciprofloxacin; Genta.: Gentamicin; Grise.: Griseofulvin; Nyst.: Nystatin.
antimicrobial screening (Table 1), against a panel of human
pathogens that most of the synthesized quinoline derivatives
were found to be highly active, compared to standard drugs
against bacterial pathogens. Among them, many compounds
were found to be most active against Clostridium tetani and
Bacillus subtilis compared to the rest of the investigated
species. The antifungal activity of the new compounds shows
that most of the compounds active against C. albicans
compared to A. fumigatus. It is worth mentioning that a minor
change in the molecular configuration of these compounds
profoundly influences the activity.
Experimental
General procedures
Phenyl hydrazine was distilled before use; all other reagents are
commercially available and were used without further purifi-
cation. The solvents used were of analytical grade. All melting
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
New N-(Hetero)Arylquinoline Derivatives of 1H-Pyrazole
95
points were taken in open capillaries and are uncorrected. Thin-
layer chromatography (TLC, on aluminum plates precoated with
13C-NMR (100 MHz, DMSO-d6) dC (ppm): 20.37 (CH2), 27.60 (CH2),
36.79 (CH2–CO), 105.35, 106.78, 113.04, 127.93, 131.82, 148.63,
60
–
silica gel,
F
,
0.25 mm thickness; Merck, Darmstadt,
154.41, 159.30, 162.11 (9C, Ar–C), 197.49 (C O). Anal. calcd.
–
for C15H13FN2OS (288.34 g/mol): C, 62.48; H, 4.54; N, 9.72.
254
Germany) was used for monitoring the progress of all reactions,
purity, and homogeneity of the synthesized compounds; eluent:
toluene/ethyl acetate, 7:3. UV radiation and / or iodine were used
as visualizing agents. Elemental analysis (% C, H, N) was carried
out with a Perkin-Elmer 2400 series-II elemental analyzer (Perkin-
Elmer, USA) and all compounds are within ꢁ0.4% of theoretical
value. The IR spectra were recorded in KBr on a Perkin-Elmer
Spectrum GX FT-IR spectrophotometer (Perkin-Elmer, USA) and
only the characteristic peaks are reported in cmꢀ1. 1H-NMR and
13C-NMR spectra were recorded in DMSO-d6 on a Bruker Avance
400F (MHz) spectrometer (Bruker Scientific Corporation Ltd.,
Switzerland) using the solvent peak as internal standard at
400 and 100 MHz, respectively. Chemical shifts are reported
in parts per million (ppm). Mass spectra were scanned on a
Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan).
Found: C, 62.63; H, 4.27; N, 9.87.
3-(4-(4-Fluorophenyl)thiazol-2-ylamino)-5,
5-dimethylcyclohex-2-enone 4b
Yield: 72%; m. p.: 218–2208C; IR (KBr, n, cmꢀ1): 3385 (NH str.),
1
–
1670 (–C O str.); H-NMR (400 MHz, DMSO-d ) d (ppm): 1.04 (s,
–
6
H
6H, CH3), 2.14–2.43 (4H, m, 2 CH2), 6.80–7.81 (m, 6H, Ar–H), 10.34
(s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6) dC (ppm): 28.33 (CH3),
32.82 (C(CH3)2), 42.17 (CH2), 50.65 (CH2–CO), 104.78, 104.94,
114.65, 127.51, 130.73, 150.85, 155.37, 159.59, 161.29 (9C,
–
Ar–C), 197.98 (C O). Anal. calcd. for C17H17FN2OS (316.39 g/mol):
–
C, 64.53; H, 5.42; N, 8.85. Found: C, 64.75; H, 5.27; N, 8.69.
General procedure for the synthesis of 2-amino-4-(3-aryl-
1-phenyl-1H-pyrazol-4-yl)-1-(hetero)aryl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 5a–p and
6a–p
Chemistry
General procedure for the synthesis of 3-aryl-1-
phenylpyrazole-4-carbaldehyde 1a–h
A
mixture of 3-aryl-1-phenylpyrazole-4-carbaldehyde 1a–h
3-Aryl-1-phenylpyrazole-4-carbaldehydes 1a–h were prepared
according to the literature procedure [24] by Vilsmeier–Haack
reaction of acetophenone (hetero)arylhydrazones (Scheme 1).
(30 mmol), malononitrile 2 (30 mmol), and appropriate b-enam-
inone 3a–b or 4a–b (30 mmol) in acetonitrile (20 mL) containing
three drops of piperidine was slowly heated and refluxed for 3–
4 h. On completion of the reaction, monitored by TLC (ethyl
acetate/toluene, 3:7), the reaction mixture was cooled to room
temperature and the solid separated was filtered and washed
with a mixture of chloroform and methanol (1:1) to obtain the
pure compounds 5a–p and 6a–p. Analytical and spectroscopic
characterization data of the synthesized compounds 5a–p and
6a–p are given below.
General procedure for the synthesis of 2-amino-4-
(4-fluorophenyl)thiazole
2-(4-Fluorophenyl)thiazol-4-amine was synthesized according to
the literature procedure [25] by the solid-phase reaction of
thiourea, 1-(4-fluorophenyl)ethanone, and iodine (Scheme 1).
General procedure for the synthesis of 3-
(4-fluorophenylamino)- 5,5-(un)substituted cyclohex-2-
enones 3a–b
2-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-1-
(4-fluorophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
3-(4-Fluorophenylamino)-5,5-(un)substituted cyclohex-2-enones
were synthesized according to the literature procedure [26] by
the solid-phase reaction of the 1,3-dicarbonyl compound and 4-
fluoroaniline under microwave irradiation (Scheme 1).
carbonitrile 5a
Yield: 76%; m. p.: 244–2468C; IR (KBr, n, cmꢀ1): 3400 asym. & sym.
str. of –NH ), 2200 (–CꢀN str.), 1675 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.81–2.34 (6H, m, 3 CH2), 4.54
(s, 1H, quinoline H-4), 5.28 (s, 2H, NH2), 7.06–7.97 (m, 14H,
Ar–H), 8.28 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6)
dC (ppm): 26.41 (C4), 20.87, 28.56 (2C, CH2), 36.16 (CH2–CO), 62.91
(C–CN), 112.55, 113.31, 114.22, 118.92, 121.39, 124.01, 126.09,
126.13, 127.87, 128.16, 131.72, 134.29, 135.77, 137.00, 145.63,
General procedure for the synthesis of 3-(4-(4-
fluorophenyl)- thiazol-2-ylamino)-5,5-(un)substituted
cyclohex-2-enones 4a–b
The 1,3-dicarbonyl compound (30 mmol), 2-amino-4-(4-fluoro-
phenyl)thiazole (30 mmol), methanol (15 mL) and two drops
of acetic acid were charged in a 100 mL round-bottom flask
equipped with a refluxing condenser. The reaction mixture
was slowly heated and refluxed for 1 h. On completion of reac-
tion, monitored by TLC using 30% EtOAc in toluene as eluent, the
reaction mixture was cooled to room temperature and the solid
which separated was filtered and washed with methanol to
obtain the pure compounds 4a–b. Analytical and spectroscopic
characterization data of the synthesized compounds 4a–b are
given below.
–
150.11, 152.67, 157.07, 159.86 (19C, Ar–C), 194.87 (C O). Anal.
–
calcd. for C31H24FN5O (501.55 g/mol): C, 74.24; H, 4.82; N, 13.96.
Found: C, 74.09; H, 5.09; N, 14.15.
2-Amino-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-fluorophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-
3-carbonitrile 5b
Yield: 62%; m. p.: 236–2388C; IR (KBr, n, cmꢀ1): 3395 & 3360 (asym.
1
ꢀ
–
–
& sym. str. of –NH ), 2185 (–CꢀN str.), 1680 (–C O str.); H-NMR
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.97–2.41 (6H, m, 3 CH2), 4.69 (s,
1H, quinoline H-4), 5.25 (s, 2H, NH2), 7.01–8.07 (m, 13H, Ar–H),
8.36 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm):
25.81 (C4), 21.45, 29.17 (2C, CH2), 37.12 (CH2–CO), 62.35 (C–CN),
111.08, 112.24, 112.32, 115.40, 120.84, 126.43, 127.71, 128.47,
128.52, 129.79, 131.30, 133.76, 135.27, 136.75, 147.04, 151.96,
3-(4-(4-Fluorophenyl)thiazol-2-ylamino)cyclohex-2-enone 4a
Yield: 70%; m. p.: 199–2018C; IR (KBr, n, cmꢀ1): 3430 (NH str.),
1655 (–C O str.); 1H-NMR (400 MHz, DMSO-d6) dH (ppm): 1.92–
2.33 (6H, m, 3 CH2), 6.87–7.94 (m, 6H, Ar–H), 10.55 (s, 1H, NH);
–
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

96
N. J. Thumar and M. P. Patel
Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
–
154.36, 159.12, 161.50 (19C, Ar–C), 196.10 (C O). Anal. calcd.
–
for C31H23BrFN5O (580.45 g/mol): C, 64.15; H, 3.99; N, 12.07.
Found: C, 63.91; H, 4.17; N, 11.88.
CH2), 36.85 (CH2–CO), 62.29 (C–CN), 113.49, 114.33, 114.85,
115.19, 118.15, 120.26, 124.06, 126.48, 126.59, 127.17, 130.70,
134.81, 137.66, 138.99, 145.02, 152.38, 153.20, 157.80, 158.82
–
(19C, Ar–C), 196.35 (C O). Anal. calcd. for C H FN O (515.58 g/mol):
32 26
–
5
C, 74.55; H, 5.08; N, 13.58. Found: C, 74.78; H, 4.81; N,
13.39.
2-Amino-4-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-fluorophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-
3-carbonitrile 5c
2-Amino-1-(4-fluorophenyl)-4-(3-(4-nitrophenyl)-1-phenyl-
1H-pyrazol-4-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile 5g
Yield: 75%; m. p.: 277–2808C; IR (KBr, n, cmꢀ1): 3450 asym. & sym.
str. of –NH ), 2210 (–CꢀN str.), 1685 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.80–2.32 (6H, m, 3 CH2), 4.68
(s, 1H, quinoline H-4), 5.38 (s, 2H, NH2), 7.09–7.85 (m, 13H,
Ar–H), 8.49 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6)
dC (ppm): 26.52 (C4), 20.90, 28.24 (2C, CH2), 36.78 (CH2–CO), 59.08
(C–CN), 113.20, 113.97, 114.14, 115.18, 120.42, 125.34, 126.63,
127.21, 127.37, 128.58, 132.56, 134.90, 136.57, 138.65, 149.54,
–
Yield: 74%; m. p.: 281–2838C; IR (KBr, n, cmꢀ1): 3420 asym. & sym.
str. of –NH ), 2200 (–CꢀN str.), 1685 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.89–2.31 (6H, m, 3 CH2), 4.53
(s, 1H, quinoline H-4), 5.36 (s, 2H, NH2), 7.13–8.14 (m, 13H,
Ar–H), 8.25 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6)
dC (ppm): 25.79 (C4), 21.54, 28.12 (2C, CH2), 36.56 (CH2–CO), 60.17
(C–CN), 112.64, 112.95, 114.98, 115.23, 118.60, 120.46, 123.35,
126.04, 127.74, 127.94, 131.51, 135.28, 137.68, 139.78, 144.61,
151.69, 153.88, 156.43, 159.68 (19C, Ar–C), 195.02 (C O). Anal.
–
calcd. for C31H23ClFN5O (536.00 g/mol): C, 69.47; H, 4.33; N,
13.07. Found: C, 69.31; H, 4.17; N, 12.85.
–
151.05, 152.41, 155.89, 161.25 (19C, Ar–C), 194.92 (C O). Anal.
–
calcd. for C31H23FN6O3 (546.55 g/mol): C, 68.12; H, 4.24; N, 15.38.
Found: C, 67.91; H, 3.98; N, 15.63.
2-Amino-1-(4-fluorophenyl)-4-(3-(4-fluorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5d
2-Amino-1-(4-fluorophenyl)-5-oxo-4-(1-phenyl-3-
(thiophen-2-yl)-1H-pyrazol-4-yl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5h
Yield: 60%; m. p.: 190–1918C; IR (KBr, n, cmꢀ1): 3455 & 3370 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2190 (–CꢀN str.), 1675 (–C O str.); H-NMR
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.76–2.20 (6H, m, 3 CH2), 4.73 (s,
1H, quinoline H-4), 5.27 (s, 2H, NH2), 6.96–7.92 (m, 13H, Ar–H),
8.43 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm):
26.73 (C4), 20.97, 29.33 (2C, CH2), 35.88 (CH2–CO), 61.56 (C–CN),
112.79, 113.05, 114.54, 116.00, 118.86, 120.45, 125.97, 126.03,
128.30, 128.73, 130.91, 135.53, 137.17, 139.37, 146.75, 153.44,
Yield: 69%; m. p.: 225–2278C; IR (KBr, n, cmꢀ1): 3440 asym. & sym.
str. of –NH ), 2180 (–CꢀN str.), 1650 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.73–2.22 (6H, m, 3 CH2), 4.49
(s, 1H, quinoline H-4), 5.31 (s, 2H, NH2), 7.20–7.90 (m, 12H,
Ar–H), 8.32 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6)
dC (ppm): 26.73 (C4), 20.99, 28.50 (2C, CH2), 36.45 (CH2–CO), 60.92
(C–CN), 112.87, 117.07, 117.29, 118.77, 126.64, 127.93, 128.26,
129.10, 129.89, 133.13, 133.23, 135.73, 139.77, 144.94, 151.17,
–
155.93, 156.62, 160.83 (19C, Ar–C), 195.19 (C O). Anal. calcd.
–
for C31H23F2N5O (519.54 g/mol): C, 71.67; H, 4.46; N, 13.48.
Found: C, 71.49; H, 4.27; N, 13.72.
–
152.63, 161.58, 164.03 (19C, Ar–C), 195.57 (C O). Anal. calcd. for
–
C29H22FN5OS (507.58 g/mol): C, 68.62; H, 4.37; N, 13.80. Found: C,
68.79; H, 4.28; N, 14.07.
2-Amino-1-(4-fluorophenyl)-4-(3-(4-methoxyphenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5e
2-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-1-
(4-fluorophenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5i
Yield: 66%; m. p.: 267–2708C; IR (KBr, n, cmꢀ1): 3460 asym. & sym.
str. of –NH ), 2175 (–CꢀN str.), 1650 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.71–2.17 (6H, m, 3 CH2), 3.84
(s, 3H, OCH3), 4.76 (s, 1H, quinoline H-4), 5.25 (s, 2H, NH2),
7.04–7.90 (m, 13H, Ar–H), 8.27 (s, 1H, pyrazole H-5); 13C-NMR
(100 MHz, DMSO-d6) dC (ppm): 26.88 (C4), 21.00, 28.50 (2C, CH2),
36.50 (CH2–CO), 55.60 (OCH3), 61.77 (C–CN), 113.13, 114.09,
118.60, 121.79, 123.45, 126.28, 126.78, 127.47, 128.90, 129.82,
130.35, 133.06, 133.25, 136.04, 140.11, 150.67, 150.88, þ152.16,
Yield: 79%; m. p.: 239–2418C; IR (KBr, n, cmꢀ1): 3430 asym. & sym.
str. of –NH ), 2190 (–CꢀN str.), 1685 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 0.80 (s, 3H, CH3), 0.95 (s, 3H,
CH3), 2.19–2.47 (4H, m, 2 CH2), 4.66 (s, 1H, quinoline H-4), 5.38
(s, 2H, NH2), 7.14–7.90 (m, 14H, Ar–H), 8.32 (s, 1H, pyrazole H-5);
13C-NMR (100 MHz, DMSO-d6) dC (ppm): 26.21, 27.87 (2C, CH3),
28.39 (C4), 33.36 (C(CH3)2), 40.14 (CH2), 51.05 (CH2–CO), 63.61
(C–CN), 112.85, 114.52, 115.11, 116.60, 118.24, 120.38, 122.94,
126.21, 126.38, 127.93, 132.30, 134.20, 135.02, 137.79, 146.12,
–
–
159.46 (19C, Ar–C), 195.71 (C O); MS m/z: 532.2 [M þ 1] . Anal.
calcd. for C32H26FN5O2 (531.58 g/mol): C, 72.30; H, 4.93; N, 13.17.
Found: C, 71.99; H, 5.14; N, 12.88.
–
152.38, 155.67, 160.32, 163.44 (19C, Ar–C), 196.48 (C O). Anal.
–
calcd. for C33H28FN5O (529.61 g/mol): C, 74.84; H, 5.33; N, 13.22.
Found: C, 75.05; H, 5.56; N, 12.98.
2-Amino-1-(4-fluorophenyl)-5-oxo-4-(1-phenyl-3-p-tolyl-
1H-pyrazol-4-yl)-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile 5f
2-Amino-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-fluorophenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5j
Yield: 68%; m. p.: 237–2398C; IR (KBr, n, cmꢀ1): 3395 & 3335 (asym.
1
ꢀ
–
–
& sym. str. of –NH ), 2195 (–CꢀN str.), 1675 (–C O str.); H-NMR
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.86–2.25 (6H, m, 3 CH2), 2.34 (s,
3H, tolyl-CH3), 4.65 (s, 1H, quinoline H-4), 5.49 (s, 2H, NH2), 6.88–
7.95 (m, 13H, Ar–H), 8.39 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz,
DMSO-d6) dC (ppm): 21.29 (tolyl-CH3), 25.92 (C4), 21.73, 29.20 (2C,
Yield: 74%; m. p.: 260–2628C; IR (KBr, n, cmꢀ1): 3435 & 3360 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2205 (–CꢀN str.), 1680 (–C O str.); H-NMR
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 0.88 (s, 3H, CH3), 0.96 (s, 3H, CH3),
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
New N-(Hetero)Arylquinoline Derivatives of 1H-Pyrazole
97
2.12–2.40 (4H, m, 2 CH2), 4.69 (s, 1H, quinoline H-4), 5.22 (s, 2H,
NH2), 6.92–7.99 (m, 13H, Ar–H), 8.24 (s, 1H, pyrazole H-5);
13C-NMR (100 MHz, DMSO-d6) dC (ppm): 25.37, 26.05 (2C, CH3),
29.16 (C4), 32.09 (C(CH3)2), 39.97 (CH2), 52.20 (CH2–CO), 64.29
(C–CN), 111.85, 114.50, 115.49, 117.23, 121.19, 122.04, 126.35,
127.51, 128.48, 128.59, 133.28, 133.68, 136.66, 138.70, 147.17,
2-Amino-1-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4-
(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5n
Yield: 75%; m. p.: 272–2748C; IR (KBr, n, cmꢀ1): 3400 asym. & sym.
str. of –NH ), 2200 (–CꢀN str.), 1660 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 0.94 (s, 3H, CH3), 1.03 (s, 3H,
CH3), 2.13–2.37 (4H, m, 2 CH2), 2.40 (s, 3H, tolyl-CH3), 4.76 (s,
1H, quinoline H-4), 5.24 (s, 2H, NH2), 6.81–7.84 (m, 13H, Ar–H),
8.32 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm):
21.38 (tolyl-CH3), 25.09, 26.45 (2C, CH3), 28.87 (C4), 32.68
(C(CH3)2), 40.75 (CH2), 50.67 (CH2–CO), 60.72 (C–CN), 111.63,
113.84, 114.14, 116.97, 118.18, 121.34, 125.56, 125.69, 126.24,
127.87, 132.47, 133.36, 133.90, 136.00, 147.96, 153.22, 158.50,
–
154.81, 157.99, 160.25, 162.51 (19C, Ar–C), 196.91 (C O). Anal.
–
calcd. for C33H27BrFN5O (608.50 g/mol): C, 65.14; H, 4.47; N,
11.51. Found: C, 64.97; H, 4.26; N, 11.69.
2-Amino-4-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-fluorophenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5k
–
Yield: 71%; m. p.: 243–2458C; IR (KBr, n, cmꢀ1): 3430 asym. & sym.
160.62, 163.83 (19C, Ar–C), 194.90 (C O). Anal. calcd.
–
for C34H30FN5O (543.63 g/mol): C, 75.12; H, 5.56; N, 12.88.
str. of –NH ), 2205 (–CꢀN str.), 1690 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
Found: C, 74.90; H, 5.39; N, 13.15.
(400 MHz, DMSO-d6) dH (ppm): 0.84 (s, 3H, CH3), 0.89 (s, 3H,
CH3), 1.80–2.16 (4H, m, 2 CH2), 4.75 (s, 1H, quinoline H-4), 5.29
(s, 2H, NH2), 7.30–7.94 (m, 13H, Ar–H), 8.29 (s, 1H, pyrazole H-5);
13C-NMR (100 MHz, DMSO-d6) dC (ppm): 27.05, 27.45 (2C, CH3),
29.12 (C4), 32.44 (C(CH3)2), 41.58 (CH2), 49.82 (CH2–CO), 61.23
(C–CN), 111.78, 117.23, 117.46, 118.81, 121.83, 126.68, 127.73,
128.78, 129.28, 129.94, 130.82, 132.77, 133.21, 139.92, 149.86,
2-Amino-1-(4-fluorophenyl)-7,7-dimethyl-4-(3-
(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 5o
Yield: 70%; m. p.: 210–2128C; IR (KBr, n, cmꢀ1): 3430 asym. & sym.
1
ꢀ
–
str. of –NH ), 2175 (–CꢀN str.), 1660 (–C O str.); H-NMR (400 MHz,
–
2
ꢀ
–
150.40, 150.92, 161.58, 164.03 (19C, Ar–C), 195.65 (C O). Anal.
–
calcd. for C33H27ClFN5O (564.05 g/mol): C, 70.27; H, 4.82; N,
DMSO-d6) dH (ppm): 1.02 (s, 3H, CH3), 1.09 (s, 3H, CH3), 2.05–2.35
(4H, m, 2 CH2), 4.70 (s, 1H, quinoline H-4), 5.42 (s, 2H, NH2), 7.27–
8.26 (m, 13H, Ar–H), 8.34 (s, 1H, pyrazole H-5); 13C-NMR (100 MHz,
DMSO-d6) dC (ppm): 25.65, 26.76 (2C, CH3), 28.20 (C4), 32.05
(C(CH3)2), 40.01 (CH2), 51.68 (CH2–CO), 63.43 (C–CN), 111.46,
112.95, 114.21, 115.73, 118.55, 120.71, 124.45, 125.30, 127.53,
132.37, 133.32, 134.72, 134.87, 136.91, 148.86, 156.39, 158.62,
12.42. Found: C, 69.96; H, 5.11; N, 12.63.
2-Amino-1-(4-fluorophenyl)-4-(3-(4-fluorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5l
–
159.07, 163.09 (19C, Ar–C), 195.83 (C O). Anal. calcd. for
–
C33H27FN6O3 (574.60 g/mol): C, 68.98; H, 4.74; N, 14.63. Found:
Yield: 69%; m. p.: 210–2118C; IR (KBr, n, cmꢀ1): 3390 asym. & sym.
str. of –NH ), 2180 (–CꢀN str.), 1670 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
C, 69.21; H, 4.88; N, 14.46.
(400 MHz, DMSO-d6) dH (ppm): 1.03 (s, 3H, CH3), 1.09 (s, 3H,
CH3), 2.02–2.36 (4H, m, 2 CH2), 4.71 (s, 1H, quinoline H-4), 5.40
(s, 2H, NH2), 7.12–8.16 (m, 13H, Ar–H), 8.40 (s, 1H, pyrazole H-5);
13C-NMR (100 MHz, DMSO-d6) dC (ppm): 26.62, 27.42 (2C, CH3),
28.74 (C4), 33.21 (C(CH3)2), 41.88 (CH2), 50.01 (CH2–CO), 62.32
(C–CN), 113.88, 114.26, 115.64, 117.00, 119.15, 120.98, 124.46,
126.33, 126.74, 128.06, 131.39, 133.77, 134.89, 138.57, 148.78,
2-Amino-1-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4-
(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5p
Yield: 67%; m. p.: 231–2348C; IR (KBr, n, cmꢀ1): 3395 & 3320 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2190 (–CꢀN str.), 1690 (–C O str.); H-NMR
–
2
ꢀ
–
151.41, 156.05, 159.61, 162.82 (19C, Ar–C), 195.87 (C O). Anal.
–
calcd. for C33H27F2N5O (547.60 g/mol): C, 72.38; H, 4.97; N, 12.79.
(400 MHz, DMSO-d6) dH (ppm): 0.90 (s, 3H, CH3), 1.03 (s, 3H, CH3),
2.18–2.44 (4H, m, 2 CH2), 4.61 (s, 1H, quinoline H-4), 5.36 (s, 2H,
NH2), 6.80–7.89 (m, 12H, Ar–H), 8.26 (s, 1H, pyrazole H-5); 13C-
NMR (100 MHz, DMSO-d6) dC (ppm): 26.33, 26.48 (2C, CH3), 28.82
(C4), 32.74 (C(CH3)2), 39.68 (CH2), 50.94 (CH2–CO), 64.57 (C–CN),
112.13, 114.07, 115.25, 116.11, 119.64, 120.89, 123.92, 126.77,
127.11, 130.08, 132.31, 133.93, 135.44, 137.57, 149.34, 153.12,
Found: C, 72.55; H, 5.20; N, 12.54.
2-Amino-1-(4-fluorophenyl)-4-(3-(4-methoxyphenyl)-1-
phenyl-1H-pyrazol-4-yl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 5m
–
157.41, 160.48, 162.28 (19C, Ar–C), 196.31 (C O); MS m/z: 536.1
–
Yield: 78%; m. p.: 255–2588C; IR (KBr, n, cmꢀ1): 3380 asym. & sym.
[M þ 1]þ. Anal. calcd. for C31H26FN5OS (535.63 g/mol): C, 69.51;
1
ꢀ
–
str. of –NH ), 2210 (–CꢀN str.), 1680 (–C O str.); H-NMR (400 MHz,
–
2
ꢀ
H, 4.89; N, 13.07. Found: C, 69.36; H, 5.14; N, 12.88.
DMSO-d6) dH (ppm): 0.89 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.06–2.39
(4H, m, 2 CH2), 3.81 (s, 3H, OCH3), 4.67 (s, 1H, quinoline H-4), 5.35 (s,
2H, NH2), 7.00–7.90 (m, 13H, Ar–H), 8.28 (s, 1H, pyrazole H-5); 13C-
NMR (100 MHz, DMSO-d6) dC (ppm): 25.13, 26.25 (2C, CH3), 29.94
(C4), 32.97 (C(CH3)2), 42.20 (CH2), 50.33 (CH2–CO), 54.83 (OCH3),
62.11 (C–CN), 112.73, 114.42, 115.54, 116.71, 119.01, 120.03,
124.40, 126.58, 127.76, 131.80, 135.27, 135.65, 136.16, 139.75,
2-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-1-(4-
(4-fluorophenyl)thiazol-2-yl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6a
Yield: 67%; m. p.: 228–2298C; IR (KBr, n, cmꢀ1): 3430 asym. & sym.
1
ꢀ
–
str. of –NH ), 2210 (–CꢀN str.), 1695 (–C O str.); H-NMR (400 MHz,
–
2
ꢀ
–
149.09, 154.13, 155.32, 160.29, 164.56 (19C, Ar–C), 195.69 (C O).
–
Anal. calcd. for C34H30FN5O2 (559.63 g/mol): C, 72.97; H, 5.40; N,
DMSO-d6) dH (ppm): 1.82–2.34 (6H, m, 3 CH2), 4.84 (s, 1H, quinoline
H-4), 6.11 (s, 2H, NH2), 7.11–7.98 (m, 14H, Ar–H), 8.32 (s, 1H, pyrazole
H-5), 8.39 (s, 1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC
12.51. Found: C, 73.19; H, 5.24; N, 12.73.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

98
N. J. Thumar and M. P. Patel
Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
(ppm): 26.88 (C4), 21.34, 28.48 (2C, CH2), 36.44 (CH2–CO), 62.53
(C–CN), 112.91, 116.58, 117.47, 118.40, 120.01, 122.55, 124.70,
125.71, 126.11, 126.85, 128.78, 132.87, 139.13, 142.92, 144.07,
151.31, 153.69, 155.32, 156.08, 160.29, 162.00, 164.60 (22C, Ar-C),
(400 MHz, DMSO-d6) dH (ppm): 1.93–2.37 (6H, m, 3 CH2), 3.78
(s, 3H, OCH3), 4.81 (s, 1H, quinoline H-4), 6.16 (s, 2H, NH2),
7.21–8.08 (m, 13H, Ar–H), 8.25 (s, 1H, pyrazole H-5), 8.31 (s,
1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm): 25.84
(C4), 21.22, 28.76 (2C, CH2), 36.56 (CH2–CO), 54.04 (OCH3), 59.75
(C–CN), 112.85, 117.98, 118.06, 118.74, 120.59, 124.35, 126.24,
126.95, 128.28, 129.15, 135.04, 136.48, 140.89, 143.78, 147.17,
152.81, 155.02, 155.41, 156.82, 158.36, 161.62, 163.30 (22C, Ar–C),
–
196.07 (C O). Anal. calcd. for C34H25FN6OS (584.67 g/mol): C, 69.85;
–
H, 4.31; N, 14.37. Found: C, 70.03; H, 4.45; N, 14.22.
2-Amino-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-(4-fluorophenyl)thiazol-2-yl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6b
–
194.94 (C O). Anal. calcd. for C35H27FN6O2S (614.69 g/mol):
–
C, 68.39; H, 4.43; N, 13.67. Found: C, 68.52; H, 4.59; N, 13.52.
Yield: 62%; m. p.: 245–2488C; IR (KBr, n, cmꢀ1): 3450 asym. & sym.
1
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-5-oxo-4-
(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6f
ꢀ
–
str. of –NH ), 2170 (–CꢀN str.), 1670 (–C O str.); H-NMR (400 MHz,
–
2
ꢀ
DMSO-d6) dH (ppm): 1.77–2.26 (6H, m, 3 CH2), 4.98 (s, 1H, quinoline
H-4), 6.04 (s, 2H, NH2), 7.12–8.09 (m, 13H, Ar–H), 8.28 (s, 1H, pyrazole
H-5), 8.33 (s, 1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC
(ppm): 25.93 (C4), 22.03, 28.59 (2C, CH2), 36.90 (CH2–CO), 59.24
(C–CN), 111.19, 113.84, 115.42, 118.54, 119.97, 121.73, 123.76,
124.34, 124.58, 126.56, 131.91, 137.03, 140.65, 146.53, 147.29,
152.90, 153.22, 154.09, 155.16, 158.36, 163.83, 166.74 (22C,
Yield: 57%; m. p.: 234–2378C; IR (KBr, n, cmꢀ1): 3440 asym. & sym.
str. of –NH ), 2180 (–CꢀN str.), 1660 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.95–2.33 (6H, m, 3 CH2), 2.38
(s, 3H, tolyl-CH3), 4.98 (s, 1H, quinoline H-4), 6.13 (s, 2H, NH2),
7.03–7.96 (m, 13H, Ar–H), 8.34 (s, 1H, pyrazole H-5), 8.39 (s, 1H,
thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm): 20.96 (tolyl-
CH3), 26.95 (C4), 20.82, 29.17 (2C, CH2), 37.26 (CH2–CO), 60.64
(C–CN), 112.07, 116.50, 118.32, 119.19, 121.60, 122.12, 123.79,
124.29, 126.11, 126.23, 129.66, 137.32, 139.53, 146.38, 148.27,
–
Ar–C), 195.22 (C O). Anal. calcd. for C H BrFN OS (663.56 g/mol):
–
C, 61.54; H, 3.65; N, 12.67. Found: C, 61.42; H, 3.78; N, 12.48.
34 24
6
2-Amino-4-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-(4-fluorophenyl)thiazol-2-yl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6c
150.05, 151.67, 154.08, 155.61, 157.45, 161.67, 164.92 (22C,
þ
–
Ar–C), 195.43 (C O); MS m/z: 599.2 [M þ 1] . Anal. calcd.
–
for C35H27FN6OS (598.69 g/mol): C, 70.22; H, 4.55; N, 14.04.
Found: C, 69.97; H, 4.72; N, 13.90.
Yield: 64%; m. p.: 208–2108C; IR (KBr, n, cmꢀ1): 3440 asym. & sym.
str. of –NH ), 2185 (–CꢀN str.), 1685 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.70–2.12 (6H, m, 3 CH2), 4.72
(s, 1H, quinoline H-4), 6.09 (s, 2H, NH2), 7.29–7.92 (m, 13H,
Ar–H), 8.41 (s, 1H, pyrazole H-5), 8.46 (s, 1H, thiazole H-5); 13C-
NMR (100 MHz, DMSO-d6) dC (ppm): 26.34 (C4), 21.69, 28.90 (2C,
CH2), 35.94 (CH2–CO), 61.66 (C–CN), 112.83, 115.63, 118.14,
118.95, 120.21, 123.40, 125.45, 128.27, 128.47, 129.12, 134.37,
136.75, 140.72, 142.43, 145.50, 150.00, 151.08, 152.30, 156.07,
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-4-(3-
(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6g
Yield: 59%; m. p.: 260–2628C; IR (KBr, n, cmꢀ1): 3435 & 3375 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2210 (–CꢀN str.), 1665 (–C O str.); H-NMR
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.86–2.38 (6H, m, 3 CH2), 4.86 (s,
1H, quinoline H-4), 5.97 (s, 2H, NH2), 7.32–8.35 (m, 13H, Ar–H),
8.40 (s, 1H, pyrazole H-5), 8.42 (s, 1H, thiazole H-5); 13C-NMR
(100 MHz, DMSO-d6) dC (ppm): 27.24 (C4), 21.09, 27.44 (2C,
CH2), 36.43 (CH2–CO), 63.09 (C–CN), 115.35, 116.07, 116.29,
118.80, 120.84, 124.14, 127.10, 128.25, 128.42, 128.77, 129.86,
130.68, 139.71, 140.92, 147.37, 148.78, 150.62, 151.30, 152.18,
–
159.16, 161.55, 163.23 (22C, Ar–C), 195.40 (C O). Anal. calcd.
–
for C34H24ClFN6OS (619.11 g/mol): C, 65.96; H, 3.91; N, 13.57.
Found: C, 66.13; H, 4.09; N, 13.30.
2-Amino-4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-(4-fluorophenyl)thiazol-2-yl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6d
–
157.23, 161.44, 163.88 (22C, Ar–C), 196.01 (C O). Anal. calcd.
–
for C34H24FN7O3S (629.66 g/mol): C, 64.85; H, 3.84; N, 15.57.
Yield: 65%; m. p.: 200–2018C; IR (KBr, n, cmꢀ1): 3385 & 3340 (asym.
1
Found: C, 65.01; H, 3.69; N, 15.69.
ꢀ
–
& sym. str. of –NH ), 2205 (–CꢀN str.), 1680 (–C O str.); H-NMR
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.84–2.25 (6H, m, 3 CH2), 4.77 (s,
1H, quinoline H-4), 5.94 (s, 2H, NH2), 7.19–8.10 (m, 13H, Ar–H),
8.36 (s, 1H, pyrazole H-5), 8.39 (s, 1H, thiazole H-5); 13C-NMR
(100 MHz, DMSO-d6) dC (ppm): 26.27 (C4), 20.85, 29.15 (2C,
CH2), 36.23 (CH2–CO), 62.82 (C–CN), 113.59, 114.18, 116.63,
118.79, 120.66, 124.39, 126.46, 126.52, 128.00, 128.69, 129.57,
133.80, 134.76, 144.50, 145.44, 153.96, 155.86, 157.90, 158.62,
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-5-oxo-4-
(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6h
Yield: 65%; m. p.: 255–2568C; IR (KBr, n, cmꢀ1): 3390 asym. & sym.
str. of –NH ), 2205 (–CꢀN str.), 1680 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.72–2.31 (6H, m, 3 CH2), 4.72
(s, 1H, quinoline H-4), 5.98 (s, 2H, NH2), 7.15–7.84 (m, 12H,
Ar–H), 8.27 (s, 1H, pyrazole H-5), 8.34 (s, 1H, thiazole H-5);
13C-NMR (100 MHz, DMSO-d6) dC (ppm): 25.88 (C4), 21.19, 28.68
(2C, CH2), 36.10 (CH2–CO), 61.85 (C–CN), 112.49, 115.64, 116.51,
118.00, 118.33, 120.29, 122.46, 124.26, 124.93, 127.12, 128.68,
134.20, 138.77, 142.25, 146.47, 152.99, 153.88, 154.70, 154.96,
–
–
158.84, 160.53, 164.80 (22C, Ar–C), 194.82 (C O). Anal. calcd.
–
for C34H24F2N6OS (602.66 g/mol): C, 67.76; H, 4.01; N, 13.94.
Found: C, 67.92; H, 3.87; N, 14.13.
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-4-(3-
(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-
5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6e
Yield: 63%; m. p.: 211–2138C; IR (KBr, n, cmꢀ1): 3430 asym. & sym.
157.02, 162.13, 163.54 (22C, Ar–C), 195.47 (C O). Anal. calcd.
–
for C32H23FN6OS2 (590.69 g/mol): C, 65.07; H, 3.92; N, 14.23.
Found: C, 65.22; H, 4.11; N, 14.02.
str. of –NH ), 2200 (–CꢀN str.), 1670 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
New N-(Hetero)Arylquinoline Derivatives of 1H-Pyrazole
99
8.31 (s, 1H, thiazole H-5); 13C NMR (100 MHz, DMSO-d6) dC (ppm):
26.42, 27.75 (2C, CH3), 29.49 (C4), 32.02 (C(CH3)2), 41.10 (CH2),
51.56 (CH2–CO), 64.90 (C–CN), 112.26, 113.90, 116.96, 117.03,
121.42, 125.95, 126.57, 127.15, 127.83, 128.99, 129.89, 130.68,
131.94, 134.80, 137.31, 138.05, 149.88, 152.30, 159.51, 158.61,
2-Amino-4-(1,3-diphenyl-1H-pyrazol-4-yl)-1-(4-
(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6i
Yield: 70%; m. p.: 241–2428C; IR (KBr, n, cmꢀ1): 3395 & 3320 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2195 (–CꢀN str.), 1665 (–C O str.); H-NMR
–
2
ꢀ
–
160.49, 162.98 (22C, Ar–C), 197.02 (C O). Anal. calcd.
–
for C36H28F2N6OS (630.71 g/mol): C, 68.56; H, 4.47; N, 13.32.
(400 MHz, DMSO-d6) dH (ppm): 0.96 (s, 3H, CH3), 1.03 (s, 3H, CH3),
2.01–2.38 (4H, m, 2 CH2), 4.83 (s, 1H, quinoline H-4), 6.02 (s, 2H,
NH2), 7.16–8.03 (m, 14H, Ar–H), 8.35 (s, 1H, pyrazole H-5), 8.39 (s,
1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm): 26.57,
27.42 (2C, CH3), 29.46 (C4), 33.59 (C(CH3)2), 41.29 (CH2), 51.83
(CH2–CO), 60.93 (C–CN), 112.04, 114.12, 116.32, 117.81, 120.72,
125.95, 126.17, 126.28, 127.14, 127.35, 128.79, 129.33, 130.82,
132.65, 136.49, 139.61, 149.38, 151.15, 157.99, 159.01, 161.72,
Found: C, 68.39; H, 4.33; N, 13.48.
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-4-(3-
(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-7,7-
dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile 6m
Yield: 72%; m. p.: 265–2688C; IR (KBr, n, cmꢀ1): 3390 asym. & sym.
–
162.06 (22C, Ar–C), 195.56 (C O). Anal. calcd. for C36H29FN6OS
–
(612.72 g/mol): C, 70.57; H, 4.77; N, 13.72. Found: C, 70.29; H,
str. of –NH ), 2200 (–CꢀN str.), 1665 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
4.56; N, 13.89.
(400 MHz, DMSO-d6) dH (ppm): 0.97 (s, 3H, CH3), 1.05 (s, 3H,
CH3), 2.10–2.49 (4H, m, 2 CH2), 3.90 (s, 3H, OCH3), 4.79 (s, 1H,
quinoline H-4), 6.06 (s, 2H, NH2), 7.11–8.17 (m, 13H, Ar–H), 8.37 (s,
1H, pyrazole H-5), 8.45 (s, 1H, thiazole H-5); 13C-NMR (100 MHz,
DMSO-d6) dC (ppm): 25.69, 26.88 (2C, CH3), 28.02 (C4), 33.21
(C(CH3)2), 40.79 (CH2), 50.72 (CH2–CO), 56.67 (OCH3), 63.09
(C–CN), 112.84, 113.73, 115.39, 116.79, 117.27, 120.34, 126.18,
126.58, 127.03, 127.47, 128.65, 128.72, 128.87, 131.75, 134.09,
139.31, 148.22, 151.71, 157.53, 158.69, 160.32, 161.29 (22C, Ar–C),
2-Amino-4-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6j
Yield: 77%; m. p.: 216–2188C; IR (KBr, n, cmꢀ1): 3425 & 3355 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2180 (–CꢀN str.), 1685 (–C O str.); H-NMR
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 1.04 (s, 3H, CH3), 1.11 (s, 3H, CH3),
2.18–2.41 (4H, m, 2 CH2), 4.73 (s, 1H, quinoline H-4), 6.15 (s, 2H,
NH2), 7.25–8.17 (m, 13H, Ar–H), 8.37 (s, 1H, pyrazole H-5), 8.44 (s,
1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm): 25.32,
26.17 (2C, CH3), 28.93 (C4), 31.17 (C(CH3)2), 40.49 (CH2), 52.24
(CH2–CO), 62.78 (C–CN), 111.31, 112.85, 115.98, 116.74, 118.49,
121.94, 125.35, 126.28, 126.59, 127.51, 128.04, 128.66, 128.81,
131.29, 136.20, 137.02, 148.52, 152.25, 158.06, 158.35, 162.73,
–
195.91 (C O). Anal. calcd. for C37H31FN6O2S (642.74 g/mol):
–
C, 69.14; H, 4.86; N, 13.08. Found: C, 68.97; H, 5.03; N, 12.89.
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-
5-oxo-4-(1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 6n
–
163.88 (22C, Ar–C), 196.29 (C O). Anal. calcd. for C36H28BrFN6OS
–
(691.61 g/mol): C, 62.52; H, 4.08; N, 12.15. Found: C, 62.70; H,
Yield: 76%; m. p.: 292–2938C; IR (KBr, n, cmꢀ1): 3420 asym. & sym.
str. of –NH ), 2185 (–CꢀN str.), 1685 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
3.94; N, 12.31.
(400 MHz, DMSO-d6) dH (ppm): 0.89 (s, 3H, CH3), 0.94 (s, 3H,
CH3), 2.08–2.31 (4H, m, 2 CH2), 2.40 (s, 3H, tolyl-CH3), 4.76 (s,
1H, quinoline H-4), 5.99 (s, 2H, NH2), 7.33–8.05 (m, 13H, Ar–H),
8.25 (s, 1H, pyrazole H-5), 8.34 (s, 1H, thiazole H-5); 13C-NMR
(100 MHz, DMSO-d6) dC (ppm): 21.44 (tolyl-CH3), 26.94, 27.71
(2C, CH3), 28.49 (C4), 32.90 (C(CH3)2), 40.41 (CH2), 49.99
(CH2–CO), 64.43 (C–CN), 116.07, 116.15, 116.36, 118.51, 120.85,
126.62, 127.22, 128.68, 128.81, 129.42, 130.00, 130.63, 130.69,
131.07, 137.55, 139.89, 149.80, 150.91, 151.22, 157.93, 161.47,
2-Amino-4-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6k
Yield: 75%; m. p.: 273–2748C; IR (KBr, n, cmꢀ1): 3390 asym. & sym.
str. of –NH ), 2195 (–CꢀN str.), 1670 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 0.97 (s, 3H, CH3), 1.05 (s, 3H,
CH3), 2.15–2.36 (4H, m, 2 CH2), 4.99 (s, 1H, quinoline H-4), 5.99
(s, 2H, NH2), 7.17–7.94 (m, 13H, Ar–H), 8.42 (s, 1H, pyrazole H-5),
8.47 (s, 1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm):
26.06, 26.84 (2C, CH3), 29.52 (C4), 32.73 (C(CH3)2), 40.67 (CH2),
51.01 (CH2–CO), 59.46 (C–CN), 113.27, 114.18, 115.49, 118.33,
120.64, 122.24, 126.06, 126.22, 127.23, 128.48, 129.50, 130.93,
131.78, 135.32, 136.17, 136.67, 147.70, 151.50, 156.82, 159.52,
–
163.90 (22C, Ar–C), 195.74 (C O). Anal. calcd. for C37H31FN6OS
–
(626.75 g/mol): C, 70.91; H, 4.99; N, 13.41. Found: C, 71.10; H,
5.23; N, 13.25.
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-
4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6o
–
161.02, 163.36 (22C, Ar–C), 196.78 (C O). Anal. calcd.
–
for C36H28ClFN6OS (647.16 g/mol): C, 66.81; H, 4.36; N, 12.99.
Yield: 74%; m. p.: 287–2898C; IR (KBr, n, cmꢀ1): 3385 & 3325 (asym.
Found: C, 67.02; H, 4.61; N, 12.76.
1
ꢀ
–
& sym. str. of –NH ), 2200 (–CꢀN str.), 1685 (–C O str.); H-NMR
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 0.91 (s, 3H, CH3), 1.00 (s, 3H, CH3),
2.12–2.40 (4H, m, 2 CH2), 4.85 (s, 1H, quinoline H-4), 6.19 (s, 2H,
NH2), 7.13–8.24 (m, 13H, Ar–H), 8.33 (s, 1H, pyrazole H-5), 8.37 (s,
1H, thiazole H-5); 13C NMR (100 MHz, DMSO-d6) dC (ppm): 26.21,
27.39 (2C, CH3), 29.51 (C4), 31.72 (C(CH3)2), 39.31 (CH2), 52.08
(CH2–CO), 63.80 (C–CN), 114.63, 115.40, 117.42, 118.00, 120.92,
122.56, 126.01, 126.76, 127.37, 127.90, 128.96, 130.77, 131.16,
133.45, 136.91, 139.83, 149.13, 152.00, 158.86, 159.54, 162.62,
2-Amino-4-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
1-(4-(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6l
Yield: 69%; m. p.: 182–1848C; IR (KBr, n, cmꢀ1): 3400 asym. & sym.
str. of –NH ), 2170 (–CꢀN str.), 1650 (–C O str.); 1H-NMR
ꢀ
–
–
2
ꢀ
(400 MHz, DMSO-d6) dH (ppm): 0.85 (s, 3H, CH3), 0.98 (s, 3H,
CH3), 2.04–2.32 (4H, m, 2 CH2), 4.88 (s, 1H, quinoline H-4), 6.04
(s, 2H, NH2), 7.28–8.26 (m, 13H, Ar–H), 8.24 (s, 1H, pyrazole H-5),
–
163.43 (22C, Ar–C), 195.25 (C O). Anal. calcd. for C36H28FN7O3S
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

100
N. J. Thumar and M. P. Patel
Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
(657.72 g/mol): C, 65.74; H, 4.29; N, 14.91. Found: C, 65.88; H,
4.42; N, 14.76.
compared. A set of tubes containing only seeded broth and
the solvent controls were maintained under identical conditions
so as to make sure that the solvent had no influence on strain
growth. The result of this is much affected by the size of the
inoculum. The test mixture should contain 108 CFU mLꢀ1 organ-
isms. The protocols are summarized in Table 1 as the minimal
inhibitory concentration (MIC, mg mLꢀ1).
2-Amino-1-(4-(4-fluorophenyl)thiazol-2-yl)-7,7-dimethyl-5-
oxo-4-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)-
1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile 6p
Yield: 72%; m. p.: 227–2298C; IR (KBr, n, cmꢀ1): 3435 & 3340 (asym.
1
ꢀ
–
& sym. str. of –NH ), 2190 (–CꢀN str.), 1650 (–C O str.); H-NMR
–
2
ꢀ
The authors are thankful to the Head of the Department of Chemistry,
Sardar Patel University, for providing 1H-NMR, 13C-NMR spectroscopy, and
research facilities. We are also thankful to Oxygen Healthcare Research Pvt.
Ltd., Ahmedabad, for providing mass spectroscopy facilities; to SICART,
Vallabh Vidyanagar, for the FT-IR and elemental analyses, and Dhanji
P. Rajani, Microcare Laboratory, Surat, for the antimicrobial screening
of the compounds reported herein. One of the authors is grateful to UGC,
New Delhi, for a Research Fellowship in Sciences for Meritorious
Students.
(400 MHz, DMSO-d6) dH (ppm): 0.89 (s, 3H, CH3), 0.95 (s, 3H, CH3),
2.14–2.33 (4H, m, 2 CH2), 4.88 (s, 1H, quinoline H-4), 6.03 (s, 2H,
NH2), 7.22–8.06 (m, 12H, Ar–H), 8.27 (s, 1H, pyrazole H-5), 8.33 (s,
1H, thiazole H-5); 13C-NMR (100 MHz, DMSO-d6) dC (ppm): 26.99,
27.64 (2C, CH3), 28.58 (C4), 32.89 (C(CH3)2), 40.07 (CH2), 50.01
(CH2–CO), 64.10 (C–CN), 115.91, 116.13, 116.34, 118.44, 118.63,
120.95, 126.41, 126.56, 126.88, 127.02, 127.91, 128.08, 128.79,
130.04, 130.65, 135.39, 139.63, 145.15, 149.88, 151.10, þ151.30,
–
–
157.92 (22C, Ar–C), 195.57 (C O); MS m/z: 619.2 [M þ 1] . Anal.
calcd. for C34H27FN6OS2 (618.75 g/mol): C, 66.00; H, 4.40; N,
13.58. Found: C, 65.83; H, 4.23; N, 13.67.
The authors have declared no conflict of interest.
Methodology for in-vitro antimicrobial screening or
Minimal Inhibitory Concentration (MIC) measurement
The in-vitro antimicrobial activities of all the synthesized com- References
pounds and the standard drugs were assessed against three
representatives of Gram-positive bacteria viz. Streptococcus pneumo-
niae (MTCC 1936), Clostridium tetani (MTCC 449), Bacillus subtilis
(MTCC 441), three Gram-negative bacteria viz. Salmonella typhi
(MTCC 98), Vibrio cholerae (MTCC 3906), Escherichia coli (MTCC
443), and two fungi viz. Aspergillus fumigatus (MTCC 3008) and
Candida albicans (MTCC 227) by the Broth Microdilution MIC
method recommended by the National Committee for Clinical
Laboratory Standards (NCCLS) [23]. The strains employed for the
activity were procured from the Institute of Microbial
Technology, Chandigarh (MTCC – micro type culture collection).
The inoculum size for the test strain was adjusted to 108 CFU
mLꢀ1 (colony forming unit per milliliter) by comparing the
turbidity (turbidimetric method). Mueller–Hinton broth was
used as nutrient medium to grow and dilute the compound
suspensions for the test bacteria and Sabouraud Dextrose broth
was used as fungal nutrition. Ampicillin, chloramphenicol,
ciprofloxacin, gentamicin, and norfloxacin were used as stan-
dard antibacterial drugs, whereas griseofulvin and nystatin were
used as standard antifungal drugs. DMSO was used as diluent/
vehicle to get the desired concentrations of the synthesized
compounds and standard drugs for testing the standard
microbial strains. Serial dilutions were prepared for primary
and secondary screening. Each synthesized compound and the
standard drugs were diluted ob mg mLꢀ1 concentrations of the
synthesized drugs were taken. The active synthesized com-
pounds found in this primary screening were further diluted
to obtain 200, 100, 62.5, 50, 25, 12.5, and 6.25 mg mLꢀ1 concen-
trations for a secondary screening to test all microorganisms.
The control tube containing no antibiotic was immediately
subcultured (before inoculation) by spreading a loopful evenly
over a quarter of a plate of medium suitable for the growth of the
test organism. The tubes were then incubated at 378C for 24 h for
bacteria and 48 h for fungi. The highest dilution (lowest con-
centration) preventing the appearance of turbidity was con-
sidered as minimal inhibitory concentration (MIC, in mg
mLꢀ1), i. e. the amount of growth from the control tube before
incubation (which represents the original inoculum) is
[1] N. Fokialakis, P. Magiatis, L. Chinou, S. Mitaku, F. Tillequin,
Chem. Pharm. Bull. 2002, 50, 413–414.
[2] L. R. Morgan, B. S. Jursic, C. L. Hooper, D. M. Neumann, et al.,
Bioorg. Med. Chem. Lett. 2002, 12, 3407–3411.
[3] A. Ryckebusch, R. Derprez-Poulain, L. Maes, M. A. Debreu-
Fontaine, et al., J. Med. Chem. 2003, 46, 542–557.
[4] P. Beagley, M. A. L. Blackie, K. Chibale, C. Clarkson, et al.,
Dalton Trans. 2003, 3046–3051.
[5] P. Fossa, L. Mosti, G. Menozzi, C. Marzano, et al., Bioorg. Med.
Chem. 2002, 10, 743–751.
[6] A. Bolognese, G. Correale, M. Manfra, A. Lavecchia, et al.,
J. Med. Chem. 2004, 47, 849–858.
[7] Z. Ma, Y. Hano, T. Nomura, Y. Chen, Bioorg. Med. Chem. Lett.
2004, 14, 1193–1196.
[8] Y. Sawada, H. Kayakiri, Y. Abe, T. Mizutani, et al., J. Med. Chem.
2004, 47, 2853–2863.
[9] I. Damljanovic, M. Colovic, M. Vukicevic, D. Manojlovic,
et al., J. Organomet. Chem. 2009, 694, 1575–1580; I.
Damljanovic, M. Vukicevic, N. Radulovic, R. Palic, et al.,
Bioorg. Med. Chem. Lett. 2009, 19, 1093–1096; O. Prakash, R.
Kumar, V. Parkash, Eur. J. Med. Chem. 2008, 43, 435–440; O.
Prakash, R. Kumar, R. Sehrawat, Eur. J. Med. Chem. 2009, 44,
1763–1767; M. K. Bratenko, V. A. Chornous, O. I.
Panimarchuk, M. V. Vovk, I. P. Burdenyuk, Pharm. Chem. J.
2006, 40, 498–500; R. Sridhar, P. T. Perumal, S. Etti, G.
Shanmugam, et al., Bioorg. Med. Chem. Lett. 2004, 14, 6035–
6040.
[10] A. A. Bekhit, H. M. A. Ashour, Y. S. A. Ghany, A. E. A. Bekhit,
A. M. Baraka, Eur. J. Med. Chem. 2008, 43, 456–463; A. A.
Bekhit, T. Abdel-Aziem, Bioorg. Med. Chem. 2004, 12, 1935–
1945; A. A. Bekhit, H. T. Y. Fahmy, S. A. F. Rostom, A. M.
Baraka, Eur. J. Med. Chem. 2003, 38, 27–36; A. A. Bekhit, H. T. Y.
Fahmy, Arch. Pharm. Pharm. Med. Chem. 2003, 336, 111–118;
A. A. Bekhit, H. T. Y. Fahmy, Arch. Pharm. Pharm. Med. Chem.
2000, 333, 53–57.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 2, 91–101
New N-(Hetero)Arylquinoline Derivatives of 1H-Pyrazole
101
[11] P. T. Chovatia, J. D. Akabari, P. K. Kachhadia, P. D. Zalawadia,
H. S. Joshi, J. Serb. Chem. Soc. 2007, 71, 713–720.
Enein, Arch. Pharm. 2001, 334, 117–120; R. G. Stein, J. H. Biel,
T. Singh, J. Med. Chem. 1970, 13, 153–155; W. Cunico, C. A.
Cechinel, H. G. Bonacorso, M. A. P. Martins, et al., Bioorg. Med.
Chem. Lett. 2006, 16, 649–653; B. S. Holla, M. Mahalinga, M. S.
Karthikeyan, P. M. Akberali, N. S. Shetty, Bioorg. Med. Chem.
2006, 14, 2040–2047; M. P. Wentland, S. C. Aldous, M. D.
Gruett, R. B. Perni, et al., Bioorg. Med. Chem. Lett. 1995, 5, 405–
410.
[12] M. D. Joksovic, V. Markovic, Z. D. Juranic, T. Stanojkovic,
et al., J. Organomet. Chem. 2009, 694, 3935–3942; H. T. Y.
Fahmy, S. A. F. Rostom, A. A. Bekhit, Arch. Pharm. Pharm.
Med. Chem. 2002, 335, 213–222.
[13] A. H. Abadi, A. A. H. Eissa, G. S. Hassan, Chem. Pharm. Bull.
2003, 51, 838–844.
[19] N. K. Ladani, M. P. Patel, R. G. Patel, Phosphorus, Sulfur, Silicon
2010, 185, 658–662; D. C. Mungra, M. P. Patel, R. G. Patel,
ARKIVOC 2009, (xiv), 64–74; J. P. Nirmal, M. P. Patel, R. G.
Patel, Indian J. Chem. 2009, 48B, 712–717; N. K. Shah, M. P.
Patel, R. G. Patel, Phosphorus, Sulfur Silicon Relat. Elem. 2009,
184, 2704–2719; N. K. Ladani, M. P. Patel, R. G. Patel, ARKIVOC
2009, (vii), 292–302; N. K. Ladani, M. P. Patel, R. G. Patel,
Indian J. Chem. 2009, 48B, 261–266; N. A. Patel, M. P. Patel, R.
G. Patel, J. Environ. Res. Dev. 2009, 3, 851–858; S. F. Thakor, P.
V. Parmar, M. P. Patel, R. G. Patel, Saudi Pharma. J. 2008, 16,
64–68; S. F. Thakor, D. M. Patel, M. P. Patel, R. G. Patel, Saudi
Pharma. J. 2007, 15, 48–54.
[14] P. Rathelot, N. Azas, H. El-Kashef, F. Delmas, et al., Eur. J. Med.
Chem. 2002, 37, 671–679.
[15] A. I. Hashem, A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-
Elmagd, Eur. J. Med. Chem. 2007, 42, 934–939; A. Farghaly,
H. El-Kashef, ARKIVOC 2006 (xi), 76–90; A. Farghaly, E. De
Clercq, H. El-Kashef, ARKIVOC 2006, (x), 137–151.
[16] S. C. Shetty, V. C. Bhagat, Asian J. Chem. 2008, 20, 5037–5045.
[17] S. I. Alqasoumi, A. M. A. Taweel, A. M. Alafeefy, M. M. Hamed,
et al., Bioorg. Med. Chem. Lett. 2009, 19, 6939–6942; S. Gao, C. H.
Tsai, C. Tseng, C. F. Yao, Tetrahedron 2008, 64, 9143–9149; C.
Shi, H. Chen, Y. Li, D. Shi, M. Ji, J. Chem. Res. 2008, 534–537;
X. S. Wang, M. M. Zhang, H. Jiang, C. S. Yao, S. J. Tu,
Tetrahedron 2007, 63, 4439–4449; X. S. Wang, M. M. Zhang,
H. Jiang, D. Q. Shi, S. J. Tu, J. Chin. Chem. Soc. 2007, 54, 1033–
1039; S. J. Tu, B. Jiang, R. H. Jia, J. Y. Zhang, et al., Org. Biomol.
Chem. 2006, 4, 3664–3668; S. J. Tu, Y. Zhang, R. Jia, Jiang. Bo,
et al., Tetrahedron Lett. 2006, 47, 6521–6525; S. M. Abdel-
Gawad, M. S. A. El-Gaby, H. I. Heiba, H. M. Aly, M. M.
Ghorab, J. Chin. Chem. Soc. 2005, 52, 1227–1236; B. V.
Lichitsky, A. A. Dudinov, M. M. Krayushkin, ARKIVOC
2001, (ix), 73–79; B. V. Lichitsky, V. N. Yarovenko, I. V.
Zavarzin, M. M. Krayushkin, Russ. Chem. Bull. 2000, 49,
1251–1254; V. K. Ahuwalia, P. Sharma, B. Goyal, Indian J.
Chem. 1997, 36B, 169–171; M. G. Assy, R. M. Fikry, N. H. Aouf,
J. Indian Chem. Soc. 1997, 74, 152–153; M. G. Assy, F. M. A. E.
Motti, Egypt. J. Chem. 1996, 39, 581–586; M. G. Assy, F. M. A. E.
Motti, Indian J. Chem. 1996, 35B, 608–610; M. Hammouda,
M. M. Mashaly, E. M. Afsah, Pharmazie 1994, 49, 365–366.
[20] N. K. Shah, M. P. Patel, R. G. Patel, Indian J. Chem. 2009, 48B,
1170–1173.
[21] N. J. Thumar, M. P. Patel, ARKIVOC 2009, (xiii), 363–380.
[22] N. J. Thumar, M. P. Patel, Phosphorus, Sulfur Silicon Relat. Elem.
2009, 184, 2720–2732; N. A. Patel, M. P. Patel, R. G. Patel,
Phosphorus, Sulfur Silicon Relat. Elem. 2008, 183, 2191–2203; R.
D. Patel, M. P. Patel, R. G. Patel, Indian J. Chem. 2005, 44B,
1944–1946.
[23] National Committee for Clinical Laboratory Standards
(NCCLS), Performance Standards for Antimicrobial Susceptibility
Testing, Twelfth Informational Supplement, Wayne, PA, USA
2002, M100-S12 (M7).
[24] M. A. Kira, M. O. Abdel-Rahman, K. Z. Gadalla, Tetrahedron
Lett. 1969, 10, 109–110.
[25] R. M. Dodson, L. C. King, J. Am. Chem. Soc. 1945, 67, 2242–2243.
[26] K. Chanda, M. C. Dutta, J. N. Vishwakarma, Indian J. Chem.
2004, 43B, 2475–2477.
[18] S. T. Selvi, V. Nadaraj, M. Sellappan, R. Sasi, M. Hema, Biorg.
Med. Chem. 2006, 14, 3896–3903; O. A. El-Sayed, Y. Aboul-
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com