New N-arylamino biquinoline derivatives: Microwave-assisted synthesis and their antimicrobial activities

Article abstract of DOI:10.1007/s00044-012-0031-0

A new series of N-arylamino biquinoline derivatives 5a-x were synthesized under microwave irradiation technique in good yields compared with conventional method and screened for their antimicrobial activity. All the synthesized compounds have been established by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectral data. In vitro antimicrobial activity was carried out against three Gram-positive bacteria (Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae), three Gram-negative bacteria (Escherichia coli, Salmonella typhi, Vibrio cholerae) and two fungal species (Aspergillus fumigatus, Candida albicans) using broth microdilution method. Of the compounds studied, compound 5u exhibited promising antimicrobial activity against Streptococcus pneumoniae and Salmonella typhi.

Full text of DOI:10.1007/s00044-012-0031-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0031-0
ORIGINAL RESEARCH
New N-arylamino biquinoline derivatives: microwave-assisted
synthesis and their antimicrobial activities
•
Nimesh M. Shah Manish P. Patel
•
Ranjan G. Patel
Received: 21 October 2011 / Accepted: 10 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A new series of N-arylamino biquinoline
derivatives 5a–x were synthesized under microwave irra-
diation technique in good yields compared with conven-
tional method and screened for their antimicrobial activity.
All the synthesized compounds have been established by
elemental analysis, IR, 1H NMR, 13C NMR and mass
spectral data. In vitro antimicrobial activity was carried out
against three Gram-positive bacteria (Bacillus subtilis,
Clostridium tetani, Streptococcus pneumoniae), three
Gram-negative bacteria (Escherichia coli, Salmonella
typhi, Vibrio cholerae) and two fungal species (Aspergillus
fumigatus, Candida albicans) using broth microdilution
method. Of the compounds studied, compound 5u exhib-
ited promising antimicrobial activity against Streptococcus
pneumoniae and Salmonella typhi.
processes, and numerous derivatives of quinolines have been
reported to have wide biological activities (Charris et al.,
2005; Bava and Kumar 2009; Shi et al., 2008; Naik et al.,
2009), including the antimycobacterial (De Souza et al.,
2009) and antimicrobial (Eswaran et al., 2009) activity.
Because of the biological activities they exhibit, these
compounds have distinguished themselves as heterocycles
of profound chemical and biological significance. Thus, the
synthesis of these molecules has attracted considerable
attention.
Various routes for the synthesis of N-substituted quino-
line derivatives have been reported using two-component as
well as three-component reactions. Gao et al. (2008) have
reported fluoride ion catalyzed multicomponent reactions
for synthesis of N-substituted quinoline derivatives in
aqueous media. Wang et al. (2007) have carried out clean
synthesis of 1,4-diarylquinoline derivatives catalyzed by
Keywords Quinoline Á Microwave irradiation Á
MIC Á Antimicrobial activity
TEBAC in aqueous media. They have also reported a three-
-
component green synthesis in ionic liquid [Bmim?][BF4
]
and under microwave irradiation. However, the synthesis of
new heterocyclic compounds containing the N-substituted
quinoline scaffold and the development of more rapid and
efficient entry to these heterocycles are strongly desired.
Literature survey reveals studies concerning N-substi-
tuted quinoline, e.g., Alqasoumi et al. (2009) have reported
synthesis of some novel quinoline derivatives bearing a
trimethoxyphenyl moiety. Ghorab et al. (2010) have
reported anticancer activity of some new quinoline deriv-
atives bearing a free sulfonamide moiety. Heravi et al.
(2010) have carried out synthesis of indeno[1,2-b]-quino-
line catalyzed by heteropolyacid. However, after extensive
literature search, it was observed that till date enough
efforts have not been made to synthesize N-arylamino
biquinoline scaffold and to study its antimicrobial activity.
Consequently, prompted from the findings described
Introduction
Emerging infectious diseases and the increasing number of
multi-drug resistant microbial pathogens still make the
treatment of infectious diseases an important and pressing
global problem. Therefore, a substantial research for the
discovery and synthesis of new classes of antimicrobial
agents is needed (Kaplancıklı et al., 2008).
Quinoline derivatives have received considerable atten-
tion because of their pivotal role in various biological
N. M. Shah Á M. P. Patel Á R. G. Patel (&)
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Gujarat, India
e-mail: patelranjanben@yahoo.com
123

Med Chem Res
above, and as a part of our ongoing approach in developing
new biologically active heterocycles containing quinoline
(Shah et al., 2011; Ladani et al. 2009a, b, 2010; Mungra
et al. 2009, 2011; Nirmal et al., 2009; Shah et al. 2009a, b;
Makawana et al., 2011; Thakor et al., 2007; Thumar and
Patel 2010), we here report synthesis and antimicrobial
evaluation of some new N-arylamino biquinoline deriva-
tives 5a–x under microwave irradiation via Multi Com-
ponent Reaction (MCR) approach.
probable antimicrobial effects. The required 2-chloro-3-
formyl quinoline 2a–d was prepared by Vilsmeier-Haack
reaction of acetanilide 1a–d according to literature proce-
dure (Meth-Cohn and Bramha 1978). The required
enhydrazinoketones 4a–f were prepared by the reaction of
b-diketone with phenyl hydrazine according to literature
procedure (Lichitsky et al. 2000).
In this work, a new series of N-arylamino biquinoline
derivatives have been synthesized by one-pot three-
component condensation reaction of 2-chloro-3-formyl
quinolines 2a–d with ethyl cyanoacetate and enhydrazi-
noketones 4a–f in ethanol in the presence of piperidine as
a catalyst both under conventional heating and microwave
irradiation method. The N-arylamino quinoline 5a–x were
synthesized in ethanol as a solvent in conventional
method, which took longer period for completion of
reaction (3–3.5 h) with yields (60–78 %). The reactions
Results and discussion
Chemistry
This study was undertaken to synthesize some new
N-arylamino biquinoline derivatives and investigate their
Scheme 1 General synthetic
route for the title compounds
5a–x VHR: Vilsmeier-Haack
Reaction
123

Med Chem Res
To explore conditions of the reaction of 2-chloro-
3-formyl quinolines 2a–d with ethyl cyanoacetate and
enhydrazinoketones 4a–f in ethanol (Scheme 1) under
MW, various reaction conditions were investigated,
including solvent and base. To search for the optimal
reaction solvent, the reaction was examined in ethylene
glycol, DMF, glacial acetic acid and ethanol, respectively
under MW at the maximum power of 350 Watt. The
reaction in ethanol resulted in higher yields and shorter
reaction time than others. So ethanol was chosen as the
appropriate solvent. Furthermore, to further improve the
reaction yields, different bases were examined for their
ability to promote this reaction. The base piperidine
afforded the target product 5a in 86 % yield. Therefore,
piperidine was chosen as the most suitable base for all
further microwave-assisted reactions. A comparative study
of all the compounds synthesized by conventional method
and microwave method are provided in a Table 1.
Table 1 Comparative study between microwave-assisted and con-
ventional method for the synthesis of N-arylamino biquinoline
derivatives 5a–x in terms of yield and time
Compd.
Microwave
Time (min)
Conventional
Time (min)
Yielda %
Yielda %
5a
5b
5c
5d
5e
5f
3
86
81
78
83
81
77
80
78
73
72
76
81
79
77
71
73
72
74
79
83
81
84
81
87
180
190
220
180
185
200
210
190
210
200
240
200
195
200
185
215
200
190
200
185
180
185
220
180
74
67
71
75
78
70
78
62
65
69
71
73
78
73
60
62
71
70
63
79
68
77
75
71
3.5
3.5
3
3
4
5g
5h
5i
5
3
4.5
5
5j
5k
5l
6
3.5
4
A possible mechanism for the reaction is outlined in
Scheme 2. The reaction occurs via an in situ initial forma-
tion of the heterylidenenitrile, containing the electron-poor
C=C double bond, from the Knoevenagel condensation
between 2-chloro-3-formyl quinolines 2a–d and ethyl cya-
noacetate by loss of water molecules. Michael addition of
enhydrazinoketones 4a–f to the ylidenic bond is forming an
acyclic intermediate that cyclizes by nucleophilic attack of
the NH group on the cyano carbon, followed by tautomeri-
sation to the final products 5a–x.
5m
5n
5o
5p
5q
5r
5s
5t
4.5
5
4
3.5
3
4
4 5
3
5u
5v
5w
5x
a
3.5
3.5
3
The structures of the obtained compounds were fully
1
characterized by H NMR, 13C NMR and FT-IR spectral
data and molecular weight of some selected compounds
confirmed by mass spectrometry. 1H NMR (DMSO-d6)
spectrum of N-arylamino biquinoline derivatives 5a–
x exhibited a singlet around d 5.22–5.28 for methine (H4)
and 8.91–9.20 ppm for –NH– proton, respectively. The
Isolated yield
when carried out under microwave irradiation were
completed within 3–6 min with substantial increase in
yield of products (86 %).
Scheme 2 Plausible
mechanistic pathway of the
synthesis of N-arylamino
biquinoline derivatives
123

Med Chem Res
13C NMR spectrum of 5a is in good agreement with the
structure assigned. The peaks at d 14.78, 26.80 and
29.52 ppm are assigned to three methyl carbons, the peaks
at d 38.09 and 49.73 ppm are assigned to two methylene
carbons. The peak at d 77.29 ppm is assigned to carbon of
carboxylate, peaks at d 169.02 and 195.05 ppm are
assigned to two carbonyl carbons. All compounds gave
satisfactory elemental analyses. Mass spectra of the com-
pound 5a and 5h showed [M ? H]? peaks in agreement
with their exact mass or molecular weight. All spectro-
scopic data have been given in experimental section.
microorganisms. The compounds found active in primary
screening were similarly diluted to obtain 200, 100, 50, 25,
12.5, 6.250, 3.125 and 1.5625 lg/mL concentrations. The
highest dilution showing at least 99 % inhibition is taken as
MIC. The protocols were summarized in Table 2.
Screening results displayed that compounds 5a–x
exhibited good-to-moderate activity for all the bacterial
strains, compared with other standard drugs. An examina-
tion of the data (Table 1) reveals that against Gram-posi-
tive pathogen Streptococcus pneumoniae, compounds 5d
and 5k–l (MIC 100 lg/ml) were found to exhibit compa-
rable activity to ampicillin (MIC 100 lg/ml). Compound
5u (MIC 25 lg/ml) possessed pronounced activity against
S. pneumoniae compared with ampicillin (MIC 100 lg/
ml), chloramphenicol (MIC 50 lg/ml) and ciprofloxacin
(MIC 50 lg/ml). Compounds 5a, 5c–e, 5k, 5m–o and 5x
(MIC 200 lg/ml) show good activity compared with
ampicillin (MIC 250 lg/ml) towards Bacillus subtilis. The
compound 5v (MIC 100 lg/ml) found equally potent, to
norfloxacin (MIC 100 lg/ml) against B. subtilis. The
compounds 5d–f, 5k, 5m–n, 5q and 5w (MIC \ 250 lg/
ml) found to be more efficient against Clostridium tetani
compared with ampicillin (MIC 250 lg/ml). The com-
pounds 5n and 5q (MIC 100 lg/ml) were found to exhibit
comparable activity to ciprofloxacin (MIC 100 lg/ml)
towards C. tetani. Towards Gram-negative strain, Salmo-
nella typhi, compounds 5g, 5m, 5r and 5x (MIC 100 lg/
ml) were found equally active to ampicillin (MIC 100 lg/
ml), whereas compounds 5k (MIC 62.5 lg/ml) and 5u
(MIC 50 lg/ml) were found more potent to ampicillin
(MIC 100 lg/ml). Compound 5u (MIC 50 lg/ml) was also
found equally active to chloramphenicol (MIC 50 lg/ml)
towards S. typhi. The compounds 5b, 5d and 5n (MIC
100 lg/ml) were found equipotent than ampicillin (MIC
100 lg/ml) against Vibrio cholerae. The compounds 5a
(MIC 50 lg/ml), 5f (MIC 62.5 lg/ml) and 5q (MIC 50 lg/
ml) show better and 5b, 5g, 5m–n and 5u (MIC 100 lg/ml)
were equally active to ampicillin (MIC 100 lg/ml) towards
E. coli. Against fungal pathogen C. albicans, compounds
5a, 5l–m, 5n and 5q–r were found to have better activity,
whereas 5b, 5f–g, 5k, 5v and 5x were found to be equi-
potent compared with Griseofulvin. Rest of the compounds
showed less activity against all the microorganisms tested.
A close examination of the structures of the active
compounds in Table 2 revealed that, substituents at the
quinoline-C6, together with the substituent linked to the
arylamino part of the structure influence the antimicrobial
activities. Thus, in the case of C. tetani, compounds with
R1 = H/CH3/OCH3/Cl and R2 = Cl/F/CH3 showed good
activity, whereas analogs with R1 = H/CH3 and R2 = H/
CH3/Br lacked any activity against the same organism.
However, the same trend is not observed for the other
bacterial strains. Compound 5u without a substituent in the
Antimicrobial activity
All the glass apparatus used were sterilized before use. The
MICs of all the synthesized compounds was carried out by
broth microdilution method (NCCLS 2002). Mueller–
Hinton broth was used as nutrient medium to grow and
dilute the compound suspension for the test bacteria, and
Sabouraud Dextrose broth was used for fungal nutrition.
Inoculum size for test strain was adjusted to 108 colony
forming unit (CFU) per milliliter by comparing the tur-
bidity. The strains used for the activity were procured from
(MTCC—microbial type culture collection) Institute of
Microbial Technology, Chandigarh. DMSO was used as
diluent to get desired concentration of compounds to test
on standard bacterial strains. Serial dilutions were prepared
in primary and secondary screening. The control tube
containing no antibiotic was immediately subcultured
(before inoculation) by spreading a loopful evenly over a
quarter of plate of medium suitable for the growth of the
test organism and put for incubation at 37 °C overnight.
The tubes were then incubated overnight. The MIC of the
control organism was read to check the accuracy of the
compound concentrations. The lowest concentration
inhibiting growth of the organism was recorded as the
MIC. All the tubes not showing visible growth (in the same
manner as control tube described above) was subcultured
and incubated overnight at 37 °C. The amount of growth
from the control tube before incubation (which represents
the original inoculum) was compared. Subcultures might
show similar number of colonies indicating bacteriostatic;
a reduced number of colonies indicating a partial or slow
bactericidal activity and no growth if the whole inoculum
has been killed. The test must include a second set of the
same dilutions inoculated with an organism of known
sensitivity. Each synthesized compound was diluted to
2,000 lg/mL concentration, as a stock solution. In primary
screening, 500, 250 and 125 lg/mL concentrations of
the synthesized compounds were taken. The active syn-
thesized compounds found in this primary screening were
further tested in a second set of dilution against all
123

Med Chem Res
Table 2 Antimicrobial activity of the compounds 5a–x
Compounds
Minimum inhibitory concentration (MIC, lg/mL)
Gram-positive bacteria
Gram-negative bacteria
Fungi
S.P.
MTCC
1936
C.T.
MTCC
449
B.S.
MTCC
441
S.T.
MTCC
98
V.C.
MTCC
3906
E.C.
MTCC
443
A.F.
MTCC
3008
C.A.
MTCC
227
5a
200
250
200
100
200
500
250
500
250
250
100
100
200
200
250
500
200
125
250
500
25
500
500
250
200
125
200
250
250
500
500
125
500
200
100
250
250
100
250
250
250
500
500
200
250
250
50
200
500
200
200
200
500
250
500
500
250
200
250
200
200
200
500
250
250
250
500
250
100
250
200
250
50
200
250
250
250
250
200
100
250
250
500
62.5
500
100
200
200
250
200
100
200
250
50
500
100
250
100
250
250
250
250
125
500
500
500
200
100
250
500
200
250
250
250
500
500
200
250
100
50
50
[1000
[1000
[1000
250
250
500
[1000
1000
1000
500
500
1000
[1000
1000
500
250
250
100
1000
1000
250
250
1000
1000
[1000
500
[1000
500
–
5b
100
250
125
200
62.5
100
250
250
250
125
500
100
100
125
200
50
5c
5d
5e
250
5f
[1000
[1000
500
5g
5h
5i
[1000
[1000
[1000
[1000
500
5j
5k
5l
5m
5n
[1000
[1000
[1000
500
5o
5p
5q
5r
250
200
250
100
500
200
200
100
50
500
5s
500
5t
[1000
[1000
1000
500
5u
5v
250
250
200
100
50
500
200
100
100
50
5w
5x
1000
–
Ampicillin
Chloramphencol
Ciprofloxacin
Gentamicin
Norfloxacin
Griseofulvin
Nystatin
–
–
50
100
5
50
25
25
25
–
–
0.5
10
1
5
5
0.05
10
–
–
50
100
–
10
10
–
–
–
–
–
–
–
100
500
100
–
–
–
–
–
–
100
E.C. Escherichia coli, S.T. Salmonella typhi, V.C. Vibrio cholerae, A.F. Aspergillus fumigatus, C.A. Candida albicans
Bold entries indicate that the compounds are found equipotent or more potent compared to the standard drugs used
quinoline-C6 and arylamino ring containing a bromo sub-
stituent shows greater activity against S. pneumonia and
S. typhi compared with the other compounds studied.
Introduction of a methyl/methoxy/chlorine atom to the
structure as in compounds 5v, 5w and 5x resulted in
reduction in the antibacterial activity against both the
organism. Replacement of the bromo substituent on
arylamino ring with H/Cl/CH3/F/OCH3 (compounds 5a, 5e,
5i, 5m and 5q) also decreased antibacterial potency against
both the organism. On the same grounds, the analogs
5a without a substituent in the quinoline-C6 and aryla-
mino ring and compound 5q without a substituent in the
quinoline-C6 and arylamino ring containing a methoxy
substituent are the most active compounds against E. coli.
It is worthy to mention that the biological activity of the
target compounds depends not only on the bicyclic het-
eroaromatic pharmacophore but also on the nature of the
substituents and may also on their spatial relationships.
Experimental
All the reagents were obtained commercially and used with
further purification. Solvents used were of analytical grade.
123

Med Chem Res
All melting points were taken in open capillaries and are
uncorrected. Thin-layer chromatography (TLC, on alu-
minium plates coated with silica gel 60 F254, 0.25-mm
thickness, Merck) was used for monitoring the progress of
all reactions, purity and homogeneity of the synthesized
compounds. Elemental analysis (% C, H, N) was carried
out by Perkin-Elmer 2400 series-II elemental analyzer and
all compounds are within 0.4 % of theory specified. The
IR spectra were recorded on a Shimadzu FTIR 8401
spectrophotometer using KBr discs and only the charac-
teristic peaks are reported in cm-1. 1H NMR and 13C NMR
spectra were recorded in DMSO-d6 on a Bruker Avance
400F (MHz) spectrometer using solvent peak as internal
standard at 400 and 100 MHz, respectively. Chemical
shifts are reported in parts per million (ppm). Mass spectra
were scanned on a Shimadzu LCMS 2010 spectrometer.
Mode of ionization employed was ESI (electrospray ioni-
zation). The microwave oven used was specially modified
by RAGA’s Electromagnetic systems.
for C29H29ClN4O3 (517.02 g/mol): C 67.37, H 5.65, N
10.84 % Found: C 67.51, H 5.47, N 10.76 %. IR (KBr,
cm-1): 3360 and 3250 (asym. and sym. stretching of
1
–NH2), 1660 (C=O), 1640 (C=O), 750 (C–Cl). H NMR
(400 MHz, DMSO-d6): d 0.82 (s, 3H, CH3), 0.96 (t, 3H,
CH3), 0.99 (s, 3H, CH3), 1.87–2.75 (m, 4H, 2 9 CH2), 3.90
(q, 2H, OCH2), 5.26 (s, 1H, quinoline H4), 6.87–8.25
(m, 12H, Ar–H and NH2), 8.97 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.78 (CH3), 26.80, 29.52 (2C,
CH3), 32.01 (C(CH3)2), 34.22 (C4), 38.09 (CH2), 49.73
(CH2–CO), 58.75 (OCH2), 77.29 (C–COOEt), 112.67,
113.65, 120.51, 127.72, 127.90, 130.02, 130.11, 130.30,
138.57, 145.78, 147.11, 147.50, 150.61, 151.22, 153.70,
154.24 (16C, Ar–C), 169.02 (C=OOC2H5), 195.05 (C=O),
MS: 517.2 [M ? H]?, 519.2 [M ? 2?H]?.
Ethyl 2-amino-4-(2-chloro-6-methyl(3-quinolyl))-7,7-
dimethyl-5-oxo-1-phenylamino-1,4,6,7,8-pentahydro quin-
oline-3-carboxylate (5b): yield 81 %, m.p. 241–243 °C,
Anal. Calcd. for C30H31ClN4O3 (531.05 g/mol): C 67.85,
H 5.88, N 10.55 % Found: C 68.03, H 5.63, N 10.41 %. IR
(KBr, cm-1): 3400 and 3355 (asym. and sym. str. of
General procedure for the synthesis of ethyl 2-amino-4-
(2-chloro-6-(un)substituted (3-quinolyl))-7,7-dimehyl-
5-oxo-1-arylamino-1,4,6,7,8,-pentahydro quinoline-3-
carboxylate
1
–NH2), 1665 (C=O), 1640 (C=O), 750 (C–Cl). H NMR
(400 MHz, DMSO-d6): d 0.84 (s, 3H, CH3), 0.97 (t, 3H,
CH3), 0.99 (s, 3H, CH3), 1.83–2.73 (m, 4H, 2 9 CH2), 2.46
(s, 3H, Ar–CH3), 3.93 (q, 2H, OCH2), 5.28 (s, 1H, quino-
line H4), 6.96–8.29 (m, 11H, Ar–H and NH2), 8.99 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6) d: 14.76 (CH3),
21.58 (Ar–CH3), 26.84, 29.25 (2C, CH3), 32.12 (C(CH3)2),
34.68 (C4), 38.05 (CH2), 49.84 (CH2–CO), 58.91 (OCH2),
77.57 (C–COOEt), 112.27, 113.81, 120.12, 126.42, 126.95,
127.32, 130.02, 131.36, 132.55, 134.72, 138.26. 142.46,
144.26, 148.73, 150.38, 154.31 (16C, Ar–C), 168.94
(C=OOC2H5), 195.08 (C=O), MS: 531.2 [M ? H]?, 533.2
[M ? 2?H]?.
Conventional synthesis
2-Chloro-3-formyl quinoline 2a–d (1 mmol), ethyl cya-
noacetate (1 mmol) and enhydrazinoketones 4a–f (1 mmol)
in absolute ethanol containing catalytic amount of piperi-
dine were charged in round bottom flask. Then, the reac-
tion mixture was refluxed for 3–3.5 h. The completion of
reaction was monitored by the TLC. The solid product
5a–x separated was filtered off and purified using chloro-
form–methanol.
Ethyl 2-amino-4-(2-chloro-6-methoxy(3-quinolyl))-7,7-
dimethyl-5-oxo-1-phenylamino-1,4,6,7,8,-pentahydro quin-
oline-3-carboxylate (5c): yield 78 %, m.p. 257–259 °C,
Anal. Calcd. for C30H31ClN4O4 (547.04 g/mol): C 65.87,
H 5.71, N 10.24 % Found: C 65.73, H 5.82, N 10.38 %. IR
(KBr, cm-1): 3395 and 3360 (asym. and sym. str. of
Microwave-induced synthesis
2-Chloro-3-formyl quinoline 2a–d (1 mmol), ethyl cya-
noacetate (1 mmol) and enhydrazinoketones 4a–f (1 mmol)
in absolute ethanol containing catalytic amount of piperidine
were charged in round bottom flask. The mixture was irra-
diated for 3–6 min at power of 350 W. On completion of the
reaction as indicated by TLC monitoring, the reaction mix-
ture was cooled to room temperature. The solid product 5a–
x was filtered and washed with EtOH (95 %), and subse-
quently dried and purified using chloroform–methanol. The
physicochemical and spectral properties of all the newly
synthesized compounds 5a–x are presented below.
1
–NH2), 1665 (C=O), 1645 (C=O), 745 (C–Cl). H NMR
(400 MHz, DMSO-d6): d 0.82 (s, 3H, CH3), 0.98 (t, 3H,
CH3), 1.01 (s, 3H, CH3), 1.87–2.77 (m, 4H, 2 9 CH2), 3.86
(s, 3H, Ar–OCH3), 3.92 (q, 2H, OCH2), 5.22 (s, 1H,
quinoline H4), 6.71–8.14 (m, 11H, Ar–H and NH2), 8.95
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 14.80
(CH3), 27.01, 29.45 (2C, CH3), 32.01 (C(CH3)2), 34.12
(C4), 38.10 (CH2), 49.77 (CH2–CO), 55.95 (OCH3), 58.72
(OCH2), 77.35 (C–COOEt), 105.63, 112.87, 113.54,
120.52, 122.69, 128.48, 129.71, 130.01, 141.75, 147.14,
147.48, 148.02, 153.67, 154.10, 154.50, 157.92 (16C,
Ar–C), 169.04 (C=OOC2H5), 194.99 (C=O), MS: 547.2
[M ? H]?, 549.2 [M ? 2?H]?.
Ethyl 2-amino-4-(2-chloro(3-quinolyl))-7,7-dimethyl-5-
oxo-1-phenylamino-1,4,6,7,8-pentahydro quinoline 3-car-
boxylate (5a): yield 86 %, m.p. 269–271 °C, Anal. Calcd.
123

Med Chem Res
Ethyl 2-amino-4-(2,6-dichloro(3-quinolyl))-7,7-dimethyl-
5-oxo-1-phenylamino-1,4,6,7,8,-pentahydro quinoline-3-
carboxylate (5d): yield 83 %, m.p. 219–221 °C, Anal.
Calcd. for C29H28Cl2N4O3 (551.46 g/mole): C 63.16, H
5.12, N 10.16 % Found: C 63.29, H 4.94, N 10.30 %. IR
(KBr, cm-1): 3410 and 3350 (asym. and sym. str. of
120.33, 126.07, 126.47, 127.46, 131.77, 132.46, 134.43,
138.02, 141.63, 144.42, 149.03, 150.14, 153.31, 154.18
(16C, Ar–C), 169.03 (C=OOC2H5), 194.98 (C=O),
MS: 565.2 [M ? H]?, 567.2 [M ? 2?H]?, 569.2
[M ? 4?H]?.
Ethyl 2-amino-4-(2-chloro-6-methoxy(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-chlorophenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5g): yield 80 %, m.p.
263–265 °C, Anal. Calcd. for C30H30Cl2N4O4 (581.49 g/
mole): C 61.97, H 5.20, N 9.64 % Found: C 62.09, H 5.29,
N 9.49 %. IR (KBr, cm-1): 3395 and 3335 (asym. and sym.
1
–NH2), 1660 (C=O), 1645 (C=O), 755 (C–Cl). H NMR
(400 MHz, DMSO-d6): d 0.83 (s, 3H, CH3), 0.95 (t, 3H,
CH3), 0.99 (s, 3H, CH3), 1.88–2.73 (m, 4H, m, 2 9 CH2),
3.92 (q, 2H, OCH2), 5.25 (s, 1H, quinoline H4), 6.93–8.24
(m, 11H, Ar–H and NH2), 8.94 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.76 (CH3), 27.03, 29.46 (2C,
CH3), 32.03 (C(CH3)2), 34.12 (C4), 38.02 (CH2), 49.72
(CH2–CO), 58.74 (OCH2), 77.23 (C–COOEt), 112.14,
113.41, 120.26, 126.48, 128.20, 129.78, 130.52, 131.23,
134.06, 144.42, 147.23, 147.66, 151.39, 153.62, 154.11,
154.56 (16C, Ar–C), 168.98 (C=OOC2H5), 195.52 (C=O),
MS: 551.2 [M ? H]?, 553.2 [M ? 2?H]?, 555.2
[M ? 4?H]?.
1
str. of –NH2), 1665 (C=O), 1640 (C=O), 750 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.84 (s, 3H, CH3), 0.97
(t, 3H, CH3), 1.00 (s, 3H, CH3), 1.86–2.75 (m, 4H,
2 9 CH2), 3.87 (s, 3H, Ar–OCH3), 3.92 (q, 2H, OCH2),
5.26 (s, 1H, quinoline H4), 6.69–8.16 (m, 10H, Ar–H and
NH2), 8.95 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6)
d: 14.78 (CH3), 27.01, 29.42 (2C, CH3), 32.04 (C(CH3)2),
34.48 (C4), 38.06 (CH2), 49.83 (CH2–CO), 55.59 (Ar–
OCH3), 58.79 (OCH2), 77.59 (C–COOEt), 105.27, 112.16,
113.63, 122.31, 128.72, 129.40, 130.51, 134.19, 138.88,
141.02, 145.36, 149.20, 150.42, 154.25, 154.73, 157.69
(16C, Ar–C), 169.07 (C=OOC2H5), 194.68 (C=O), MS:
Ethyl 2-amino-4-(2-chloro-(3-quinolyl))-7,7-dimethyl-
5-oxo-1-(4-chlorophenylamino)-1,4,6,7,8-pentahydro quin-
oline-3-carboxylate (5e): yield 81 %, m.p. 233–235 °C,
Anal. Calcd. for C29H28Cl2N4O3 (551.46 g/mole): C 63.16,
H 5.12, N 10.16 % Found: C 63.03, H 5.01, N 10.33 %. IR
(KBr, cm-1): 3455 and 3370 (asym. and sym. str. of
581.1
[M ? 4?H]?.
[M ? H]?,
583.2
[M ? 2?H]?,
585.2
1
–NH2), 1665 (C=O), 1640 (C=O), 740 (C–Cl). H NMR
Ethyl 2-amino-4-(2,6-dichloro(3-quinolyl))-7,7-dime-
thyl-5-oxo-1-(4-chlorophenylamino)-1,4,6,7,8-pentahydro
quinoline-3-carboxylate (5h): yield 78 %, m.p. 250–
252 °C, Anal. Calcd. for C29H27Cl3N4O3 (585.91 g/mole):
C 59.45, H 4.64, N 9.56 % Found: C 59.57, H 4.53, N
9.71 %. IR (KBr, cm-1): 3450 and 3250 (asym. and sym.
stretching of –NH2), 1660 (C=O), 1630 (C=O), 740 (C–Cl).
1H NMR (400 MHz, DMSO-d6): d 0.83 (s, 3H, CH3), 0.96
(t, 3H, CH3), 0.99 (s, 3H, CH3), 1.88–2.71 (m, 4H,
2 9 CH2), 3.89 (q, 2H, OCH2), 5.24 (s, 1H, quinoline H4),
(400 MHz, DMSO-d6): d 0.84 (s, 3H, CH3), 0.96 (t, 3H,
CH3), 1.02 (s, 3H, CH3), 1.88–2.76 (m, 4H, 2 9 CH2), 3.89
(q, 2H, q, OCH2), 5.24 (s, 1H, quinoline H4), 6.84–8.22 (m,
11H, Ar–H and NH2), 9.00 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.79 (CH3), 26.95, 29.42 (2C,
CH3), 32.02 (C(CH3)2), 34.16 (C4), 37.98 (CH2), 49.74
(CH2–CO), 58.77 (OCH2), 77.32 (C–COOEt), 111.32,
113.47, 120.44, 126.14, 127.69, 128.28, 129.46, 130.78,
131.70, 134.28, 144.34, 147.16, 151.61, 153.36, 154.08,
154.54 (16C, Ar–C), 168.78 (C=OOC2H5), 195.24 (C=O),
MS: 551.2 [M ? H]?, 553.2 [M ? 2?H]?, 555.2
[M ? 4?H]?.
6.91–8.29 (m, 10H, Ar–H and NH2), 9.18 (s, 1H, NH). 13
C
NMR (100 MHz, DMSO-d6) d: 14.77 (CH3), 27.05, 29.40
(2C, CH3), 32.05 (C(CH3)2), 34.76 (C4), 37.94 (CH2),
49.68 (CH2–CO), 58.80 (OCH2), 76.90 (C–COOEt),
111.71, 113.19, 120.10, 126.25, 126.62, 128.13, 129.84,
130.83, 131.70, 134.46, 144.18, 148.67, 151.64, 153.65,
154.05, 154.30 (16C, Ar–C), 168.91 (C=OOC2H5), 195.14
(C=O), MS: 585.1 [M ? H]?, 587.2 [M ? 2?H]?, 589.2
[M ? 4?H]?, 591.2 [M ? 6?H]?.
Ethyl 2-amino-4-(2-chloro-6-methyl(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-chlorophenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5f): yield 77 %, m.p.
281–283 °C, Anal. Calcd. for C30H30Cl2N4O3 (565.49 g/
mole): C 63.72, H 5.35, N 9.91 % Found: C 63.87, H 5.21,
N 10.05 %. IR (KBr, cm-1): 3460 and 3350 (asym. and
sym. str. of –NH2), 1655 (C=O), 1640 (C=O), 760 (C–Cl).
1H NMR (400 MHz, DMSO-d6): d 0.86 (s, 3H, CH3), 0.96
(t, 3H, CH3), 0.98 (s, 3H, CH3), 1.87–2.74 (m, 4H,
2 9 CH2), 2.48 (s, 3H, Ar–CH3), 3.92 (q, 2H, OCH2), 5.23
(s, 1H, quinoline H4), 6.66–8.13 (m, 10H, Ar–H and NH2),
9.20 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d:
14.76 (CH3), 21.51 (Ar–CH3), 26.99, 29.44 (2C, CH3),
32.06 (C(CH3)2), 34.19 (C4), 37.93 (CH2), 49.71 (CH2–
CO), 58.78 (OCH2), 77.47 (C–COOEt), 111.57, 113.68,
Ethyl 2-amino-4-(2-chloro-(3-quinolyl))-7,7-dimethyl-
5-oxo-1-(4-methylphenylamino)-1,4,6,7,8-pentahydro quin-
oline-3-carboxylate (5i): yield 73 %, m.p. 220–222 °C,
Anal. Calcd. for C30H31ClN4O3 (531.05 g/mole): C 67.85,
H 5.88, N 10.55 % Found: C 68.04, H 5.97, N 10.36 %. IR
(KBr, cm-1): 3420 and 3330 (asym. and sym. str. of
1
–NH2), 1670 (C=O), 1640 (C=O), 765 (C–Cl). H NMR
(400 MHz, DMSO-d6): d 0.85 (s, 3H, CH3), 0.97 (t, 3H,
CH3), 1.01 (s, 3H, CH3), 1.87–2.75 (m, 4H, 2 9 CH2), 2.47
123

Med Chem Res
(s, 3H, Ar–CH3), 3.91 (q, 2H, OCH2), 5.26 (s, 1H, quino-
line H4), 6.79–8.19 (m, 11H, Ar–H and NH2), 9.10 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6) d: 14.78 (CH3),
21.28 (Ar–CH3), 26.93, 29.17 (2C, CH3), 32.03 (C(CH3)2),
34.37 (C4), 38.04 (CH2), 49.81 (CH2–CO), 58.47 (OCH2),
77.08 (C–COOEt), 111.65, 113.24, 120.42. 126.39, 126.67,
128.18, 130.55, 131.31, 138.78, 144.34, 147.42, 148.59,
150.43, 153.12, 154.78, 157.05 (16C, Ar–C), 169.05
(C=OOC2H5), 194.93 (C=O), MS: 531.2 [M ? H]?, 533.2
[M ? 2?H]?.
C 63.72, H 5.35, N 9.91 % Found: C 63.91, H 5.60, N
9.67 %. IR (KBr, cm-1): 3435 and 3360 (asym. and sym. str.
of –NH2), 1660 (C=O), 1645 (C=O), 765 (C–Cl). 1H NMR
(400 MHz, DMSO-d6): d 0.89 (s, 3H, CH3), 0.97 (t, 3H,
CH3), 1.02 (s, 3H, CH3), 1.86–2.77 (m, 4H, 2 9 CH2), 2.44
(s, 3H, Ar–CH3), 3.91 (q, 2H, OCH2), 5.23 (s, 1H, quinoline
H4), 6.76–8.28 (m, 10H, Ar–H and NH2), 9.03 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6) d: 14.75 (CH3), 21.22 (Ar–
CH3), 26.95, 29.07 (2C, CH3), 32.05 (C(CH3)2), 34.42 (C4),
38.10 (CH2), 49.73 (CH2–CO), 58.78 (OCH2), 77.36 (C–
COOEt), 111.65, 113.24, 122.25, 127.54, 128.64, 130.15,
131.27, 134.57, 135.65, 143.74, 145.70, 148.06, 150.86,
153.29, 154.37, 154.93 (16C, Ar–C), 168.64 (C=OOC2H5),
195.07 (C=O), MS: 565.2 [M ? H]?, 567.2 [M ? 2?H]?,
569.2 [M ? 4?H]?.
Ethyl 2-amino-4-(2-chloro-6-methyl(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-methylphenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5j): yield 72 %, m.p.
244–246 °C, Anal. Calcd. for C31H33ClN4O3 (545.07 g/
mole): C 68.31, H 6.10, N 10.28 % Found: C 68.14, H 5.99,
N 10.12 %. IR (KBr, cm-1): 3440 and 3350 (asym. and sym.
Ethyl 2-amino-4-(2-chloro-(3-quinolyl))-7,7-dimethyl-
5-oxo-1-(4-fluorophenylamino)-1,4,6,7,8-pentahydro quin-
oline-3-carboxylate (5m): yield 79 %, m.p. 228–230 °C,
Anal. Calcd. for C29H28ClFN4O3 (535.01 g/mole): C
65.10, H 5.28, N 10.47 % Found: C 64.94, H 5.40, N
10.63 %. IR (KBr, cm-1): 3430 and 3325 (asym. and sym.
1
str. of –NH2), 1665 (C=O), 1645 (C=O), 745 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.87 (s, 3H, CH3), 0.96 (t,
3H, CH3), 1.00 (s, 3H, CH3), 1.85–2.75 (m, 4H, 2 9 CH2),
2.45 (s, 3H, Ar–CH3), 2.47 (s, 3H, Ar–CH3), 3.90 (q, 2H,
OCH2), 5.23 (s, 1H, quinoline H4), 6.73–8.16 (m, 10H, Ar–H
and NH2), 9.14 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
d6) d: 14.76 (CH3), 21.33 (Ar–CH3), 21.54 (Ar–CH3), 27.04,
29.38 (2C, CH3), 32.06 (C(CH3)2), 34.53 (C4), 37.98 (CH2),
49.63 (CH2–CO), 58.67 (OCH2), 77.21 (C–COOEt), 112.05,
113.42, 125.52, 126.34, 128.73, 130.06, 131.27. 132.65,
134.88, 138.35, 141.22, 144.61, 147.13, 150.01, 153.56,
154.23 (16C, Ar–C), 168.88 (C=OOC2H5), 194.97 (C=O),
MS: 545.2 [M ? H]?, 547.2 [M ? 2?H]?.
1
str. of –NH2), 1665 (C=O), 1640 (C=O), 745 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.87 (s, 3H, CH3), 0.95
(t, 3H, CH3), 0.99 (s, 3H, CH3), 1.84–2.75 (m, 4H,
2 9 CH2), 3.98 (q, 2H, OCH2), 5.27 (s, 1H, quinoline H4),
6.74–8.29 (m, 11H, Ar–H and NH2), 9.13 (s, 1H, NH). 13
C
NMR (100 MHz, DMSO-d6) d: 14.77 (CH3), 27.06, 29.22
(2C, CH3), 32.10 (C(CH3)2), 34.28 (C4), 38.10 (CH2),
49.81 (CH2–CO), 58.62 (OCH2), 77.47 (C–COOEt),
111.34, 113.65, 119.75, 120.54, 127.25, 127.88, 130.05,
130.27, 138.43, 145.60, 147.35, 147.86, 150.24, 153.11,
154.52, 157.34 (16C, Ar–C), 168.25 (C=OOC2H5), 194.85
(C=O), MS: 535.2 [M ? H]?, 537.2 [M ? 2?H]?.
Ethyl 2-amino-4-(2-chloro-6-methoxy(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-methylphenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5k): yield 76 %, m.p.
207–209 °C, Anal. Calcd. for C31H33ClN4O4 (561.07 g/
mole): C 66.36, H 5.93, N 9.99 % Found: C 66.50, H 6.09,
N 10.16 %. IR (KBr, cm-1): 3430 and 3355 (asym. and
sym. str. of –NH2), 1660 (C=O), 1640 (C=O), 740 (C–Cl).
1H NMR (400 MHz, DMSO-d6): d 0.88 (s, 3H, CH3), 0.95
(t, 3H, CH3), 0.99 (s, 3H, CH3), 1.84–2.76 (m, 4H,
2 9 CH2), 2.45 (s, 3H, Ar–CH3), 3.87 (s, 3H, Ar–OCH3),
3.89 (q, 2H, OCH2), 5.25 (s, 1H, quinoline H4), 6.73–8.18
(m, 10H, Ar–H and NH2), 9.11 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.72 (CH3), 21.25 (Ar–CH3),
27.02, 29.09 (2C, CH3), 32.01 (C(CH3)2), 34.32 (C4),
38.06 (CH2), 49.79 (CH2–CO), 55.16 (Ar–OCH3), 58.64
(OCH2), 77.08 (C–COOEt), 105.77, 111.75, 113.21,
120.69, 128.25, 129.41, 130.52, 131.54, 134.11, 138.74,
141.03, 144.52, 147.25, 148.35, 154.85, 157.12 (16C, Ar–
C), 168.23 (C=OOC2H5), 194.87 (C=O), MS: 561.2
[M ? H]?, 563.2 [M ? 2?H]?.
Ethyl 2-amino-4-(2-chloro–6-methyl(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-fluorophenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5n): yield 77 %, m.p.
284–286 °C, Anal. Calcd. for C30H30ClFN4O3 (549.04 g/
mole): C 65.63, H 5.51, N 10.20 % Found: C 65.31, H
5.28, N 10.42 %. IR (KBr, cm-1): 3390 and 3320 (asym.
and sym. str. of –NH2), 1670 (C=O), 1645 (C=O), 750
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 0.86 (s, 3H,
CH3), 0.96 (t, 3H, CH3), 1.02 (s, 3H, CH3), 1.82–2.75
(m, 4H, 2 9 CH2), 2.44 (s, 3H, Ar–CH3), 3.95 (q, 2H,
OCH2), 5.22 (s, 1H, quinoline H4), 6.76–8.19 (m, 10H,
Ar–H and NH2), 9.16 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) d: 14.72 (CH3), 21.43 (Ar–CH3), 26.92,
29.04 (2C, CH3), 32.06 (C(CH3)2), 34.25 (C4), 38.01
(CH2), 49.77 (CH2–CO), 58.59 (OCH2), 77.53 (C–
COOEt), 112.07, 113.56, 118.92, 126.16, 126.41, 127.68,
131.05, 132.63, 134.66, 138.52, 141.21, 144.35, 148.12,
150.32, 154.88, 157.02 (16C, Ar–C), 169.12 (C=
OOC2H5), 194.89 (C=O), MS: 549.2 [M ? H]?, 551.2
[M ? 2?H]?.
Ethyl 2-amino-4-(2,6-dichloro(3-quinolyl))-7,7-dime-
thyl-5-oxo-1-(4-methylphenylamino)-1,4,6,7,8-pentahydro
quinoline-3-carboxylate (5l): yield 81 %, m.p. 268–
270 °C, Anal. Calcd. for C30H30Cl2N4O3 (565.49 g/mole):
123

Med Chem Res
Ethyl 2-amino-4-(2-chloro–6-methoxy(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-fluorophenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5o): yield 71 %, m.p.
245–247 °C, Anal. Calcd. for C30H30ClFN4O4 (565.04 g/
mole): C 63.77, H 5.35, N 9.92 % Found: C 63.92, H 5.59,
N 9.65 %. IR (KBr, cm-1): 3380 and 3345 (asym. and sym.
127.26, 127.83, 128.22, 130.02, 130.11, 131.54, 138.36,
141.58, 147.43, 147.51, 150.61, 153.24, 154.85 (16C, Ar–
C), 168.90 (C=OOC2H5), 194.88 (C=O), MS: 547.2
[M ? H]?, 549.2 [M ? 2?H]?.
Ethyl 2-amino-4-(2-chloro-6-methyl(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-methoxyphenylamino)-1,4,6,7,8-pen-
tahydro quinoline-3-carboxylate (5r): yield 74 %, m.p.
231–233 °C, Anal. Calcd. for C31H33ClN4O4 (561.07 g/
mole): C 66.36, H 5.93, N 9.99 % Found: C 66.11, H 5.71,
N 10.24 %. IR (KBr, cm-1): 3395 and 3320 (asym. and
sym. str. of –NH2), 1665 (C=O), 1640 (C=O), 760 (C–Cl).
1H NMR (400 MHz, DMSO-d6): d 0.89 (s, 3H, CH3), 0.95
(t, 3H, CH3), 0.99 (s, 3H, CH3), 1.87–2.75 (m, 4H,
2 9 CH2), 2.47 (s, 3H, Ar–CH3), 3.89 (s, 3H, Ar–OCH3),
3.97 (q, 2H, OCH2), 5.22 (s, 1H, quinoline H4), 6.89–8.29
(m, 10H, Ar–H and NH2), 9.16 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.79 (CH3), 21.47 (Ar–CH3),
26.96, 28.03 (2C, CH3), 32.08 (C(CH3)2), 34.64 (C4),
37.98 (CH2), 49.72 (CH2–CO), 55.73 (OCH3), 58.70
(OCH2), 77.22 (C–COOEt), 112.08, 113.45, 118.21,
126.45, 127.14, 127.85, 130.20, 132.55, 134.64, 138.46,
141.31, 144.26, 149.75, 150.43, 153.25, 154.46 (16C, Ar–
C), 168.92 (C=OOC2H5), 195.03 (C=O), MS: 561.2
[M ? H]?, 563.2 [M ? 2?H]?.
1
str. of –NH2), 1665 (C=O), 1645 (C=O), 765 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.87 (s, 3H, CH3), 0.97 (t,
3H, CH3), 1.00 (s, 3H, CH3), 1.84–2.77 (m, 4H, 2 9 CH2),
3.87 (s, 3H, Ar–OCH3), 3.91 (q, 2H, OCH2), 5.27 (s, 1H,
quinoline H4), 6.79–8.23 (m, 10H, Ar–H and NH2), 8.98
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 14.78
(CH3), 26.96, 29.09 (2C, CH3), 32.08 (C(CH3)2), 34.33
(C4), 38.07 (CH2), 49.88 (CH2–CO), 55.82 (OCH3), 58.69
(OCH2), 77.57 (C–COOEt), 105.24, 111.25, 113.64,
118.12, 122.57, 128.37, 130.28, 134.78, 138.22, 141.85,
144.02, 147.58, 148.75, 154.17, 157.02, 157.34 (16C, Ar–
C), 168.92 (C=OOC2H5), 194.78 (C=O), MS: 565.2
[M ? H]?, 567.2 [M ? 2?H]?.
Ethyl 2-amino-4-(2,6-dichloro(3-quinolyl))-7,7-dime-
thyl-5-oxo-1-(4-fluorophenylamino)-1,4,6,7,8-pentahydro
quinoline-3-carboxylate (5p): yield 73 %, m.p. 261–
263 °C, Anal. Calcd. for C29H27Cl2FN4O3 (569.45 g/
mole): C 61.17, H 4.78, N 9.84 % Found: C 61.40, H 4.54,
N 9.61 %. IR (KBr, cm-1): 3400 and 3350 (asym. and sym.
Ethyl 2-amino-4-(2-chloro-6-methoxy(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-methoxyphenylamino)-1,4,6,7,8-pen-
tahydro quinoline-3-carboxylate (5s): yield 79 %, m.p.
210–212 °C, Anal. Calcd. for C31H33ClN4O5 (577.07 g/
mole): C 64.52, H 5.76, N 9.71 % Found: C 64.79, H 5.43,
N 10.46 %. IR (KBr, cm-1): 3430 and 3365 (asym. and
sym. str. of –NH2), 1665 (C=O), 1640 (C=O), 755 (C–Cl).
1H NMR (400 MHz, DMSO-d6): d 0.85 (s, 3H, CH3), 0.96
(t, 3H, CH3), 1.00 (s, 3H, CH3), 1.86–2.77 (m, 4H,
2 9 CH2), 3.84 (s, 3H, Ar–OCH3), 3.88 (s, 3H, Ar–OCH3),
3.95 (q, 2H, OCH2), 5.25 (s, 1H, quinoline H4), 6.90–8.28
(m, 10H, Ar–H and NH2), 9.09 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.73 (CH3), 26.92, 28.07 (2C,
CH3), 32.05 (C(CH3)2), 34.55 (C4), 37.91 (CH2), 49.84
(CH2–CO), 55.73 (Ar–OCH3), 55.78 (Ar–OCH3), 58.72
(OCH2), 77.46 (C–COOEt), 105.25, 111.68, 113.61,
118.41, 122.42, 129.38, 130.29, 134.62, 138.33, 140.28,
141.25, 147.46, 148.53, 153.12, 154.65, 157.49 (16C, Ar–
C), 169.01 (C=OOC2H5), 194.91 (C=O), MS: 577.2
[M ? H]?, 579.2 [M ? 2?H]?.
1
str. of –NH2), 1675 (C=O), 1640 (C=O), 750 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.89 (s, 3H, CH3), 0.96 (t,
3H, CH3), 1.01 (s, 3H, CH3), 1.86–2.76 (m, 4H, 2 9 CH2),
3.93 (q, 2H, OCH2), 5.26 (s, 1H, quinoline H4), 6.89–8.27
(m, 10H, Ar–H and NH2), 8.91 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.77 (CH3), 27.00, 29.03 (2C,
CH3), 32.02 (C(CH3)2), 34.49 (C4), 37.98 (CH2), 49.61
(CH2–CO), 58.74 (OCH2), 77.75 (C–COOEt), 112.09,
113.21, 120.25, 124.11, 126.87, 129.52, 130.67, 131.44,
134.62, 135.33, 141.35, 144.71, 148.31, 151.41, 154.34,
156.59 (16C, Ar–C), 169.02 (C=OOC2H5), 195.18 (C=O),
MS: 569.2 [M ? H]?, 571.2 [M ? 2?H]?, 573.2
[M ? 4?H]?.
Ethyl 2-amino-4-(2-chloro-(3-quinolyl))-7,7-dimethyl-
5-oxo-1-(4-methoxyphenylamino)-1,4,6,7,8-pentahydro
quinoline-3-carboxylate (5q): yield 72 %, m.p. 273–
275 °C, Anal. Calcd. for C30H31ClN4O4 (547.04 g/mole):
C 65.87, H 5.71, N 10.24 % Found: C 66.07, H 5.96, N
9.96 %. IR (KBr, cm-1): 3430 and 3340 (asym. and sym.
1
str. of –NH2), 1670 (C=O), 1645 (C=O), 760 (C–Cl). H
Ethyl 2-amino-4-(2,6-dichloro(3-quinolyl))-7,7-dime-
thyl-5-oxo-1-(4- methoxyphenylamino)-1,4,6,7,8-pentahy-
dro quinoline-3-carboxylate (5t): yield 83 %, m.p.
247–249 °C, Anal. Calcd. for C30H30Cl2N4O4 (581.49 g/
mole): C 61.97, H 5.20, N 9.64 % Found: C 62.27, H 5.38,
N 9.49 %. IR (KBr, cm-1): 3450 and 3370 (asym. and sym.
NMR (400 MHz, DMSO-d6): d 0.88 (s, 3H, CH3), 0.96 (t,
3H, CH3), 0.99 (s, 3H, CH3) 1.86–2.77 (m, 4H, 2 9 CH2),
3.89 (s, 3H, Ar–OCH3), 3.95 (q, 2H, OCH2), 5.27 (s, 1H,
quinoline H4), 6.84–8.23 (m, 11H, Ar–H and NH2), 9.09
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 14.72
(CH3), 26.92, 29.01 (2C, CH3), 32.05 (C(CH3)2), 34.27
(C4), 38.01 (CH2), 49.55 (CH2–CO), 55.80 (OCH3), 58.79
(OCH2), 77.50 (C–COOEt), 111.88, 113.15, 120.44,
1
str. of –NH2), 1675 (C=O), 1645 (C=O), 745 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.83 (s, 3H, CH3), 0.97 (t,
3H, CH3), 1.03 (s, 3H, CH3), 1.85–2.77 (m, 4H, 2 9 CH2),
123

Med Chem Res
3.84 (s, 3H, Ar–OCH3), 3.99 (q, 2H, OCH2), 5.28 (s, 1H,
quinoline H4), 6.93–8.29 (m, 10H, Ar–H and NH2), 9.13
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 14.71
(CH3), 26.99, 28.05 (2C, CH3), 32.01 (C(CH3)2), 34.28
(C4), 37.95 (CH2), 49.89 (CH2–CO), 55.75 (Ar–OCH3),
58.76 (OCH2), 77.35 (C–COOEt), 111.20, 113.35, 118.41,
126.32, 126.83, 127.06, 130.25, 131.64, 134.79, 135.27,
140.02, 144.15, 148.61, 151.46, 153.74, 154.85 (16C, Ar–
C), 168.97 (C=OOC2H5), 194.96 (C=O), MS: 581.2
[M ? H]?, 583.2 [M ? 2?H]?, 585.2 [M ? 4?H]?.
Ethyl 2-amino-4-(2-chloro-(3-quinolyl))-7,7-dimethyl-
5-oxo-1-(4-bromophenylamino)-1,4,6,7,8-pentahydro quin-
oline-3-carboxylate (5u): yield 81 %, m.p. 266–268 °C,
Anal. Calcd. for C29H28BrClN4O3 (595.91 g/mole): C
58.45, H 4.74, N 9.40 % Found: C 58.16, H 4.42, N
9.63 %. IR (KBr, cm-1): 3440 and 3385 (asym. and sym.
N 9.11 %. IR (KBr, cm-1): 3430 and 3365 (asym. and sym.
1
str. of –NH2), 1660 (C=O), 1645 (C=O), 765 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.87 (s, 3H, CH3), 0.96 (t,
3H, CH3), 1.00 (s, 3H, CH3), 1.86–2.77 (m, 4H, 2 9 CH2),
3.82 (s, 3H, Ar–OCH3), 3.94 (q, 2H, OCH2), 5.23 (s, 1H,
quinoline H4), 6.75–8.27 (m, 10H, Ar–H and NH2), 9.10
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 14.77
(CH3), 26.95, 28.05 (2C, CH3), 32.07 (C(CH3)2), 34.40
(C4), 37.90 (CH2), 49.89 (CH2–CO), 55.75 (Ar–OCH3),
58.71 (OCH2), 77.31 (C–COOEt), 105.28, 112.20, 113.64,
120.37, 122.46, 128.74, 129.14, 130.55, 135.24, 137.37,
141.62, 146.37, 147.16, 148.18, 152.22, 157.63 (16C, Ar–
C), 169.02 (C=OOC2H5), 195.09 (C=O), MS: 625.1
[M ? H]?, 627.1 [M ? 2?H]?, 629.1 [M ? 4?H]?.
Ethyl 2-amino-4-(2,6-dichloro(3-quinolyl))-7,7-dime-
thyl-5-oxo-1-(4-bromophenylamino)-1,4,6,7,8-pentahydro
quinoline-3-carboxylate (5x): yield 87 %, m.p. 273–
275 °C, Anal. Calcd. for C29H27BrCl2N4O3 (630.36 g/
mole): C 55.26, H 4.32, N 8.89 % Found: C 54.98, H 4.64,
N 9.01 %. IR (KBr, cm-1): 3440 and 3360 (asym. and sym.
1
str. of –NH2), 1660 (C=O), 1640 (C=O), 770 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.87 (s, 3H, CH3), 0.95 (t,
3H, CH3), 1.01 (s, 3H, CH3), 1.83–2.74 (m, 4H, 2 9 CH2),
3.91 (q, 2H, OCH2), 5.26 (s, 1H, quinoline H4), 6.87–8.23
(m, 11H, Ar–H and NH2), 9.16 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.77 (CH3), 26.92, 28.01 (2C,
CH3), 32.04 (C(CH3)2), 34.52 (C4), 37.90 (CH2), 49.67
(CH2–CO), 58.72 (OCH2), 77.51 (C–COOEt), 111.39,
113.47, 120.12, 124.03, 127.08, 127.56, 130.20, 130.87,
131.45, 134.75, 138.43, 145.21, 145.88, 147.63, 150.14,
154.57 (16C, Ar–C), 169.01 (C=OOC2H5), 194.93 (C=O),
MS: 595.1 [M ? H]?, 597.1 [M ? 2?H]?, 599.2
[M ? 4?H]?.
1
str. of –NH2), 1670 (C=O), 1645 (C=O), 755 (C–Cl). H
NMR (400 MHz, DMSO-d6): d 0.89 (s, 3H, CH3), 0.97 (t,
3H, CH3), 1.02 (s, 3H, CH3), 1.85–2.77 (m, 4H, 2 9 CH2),
3.98 (q, 2H, OCH2), 5.25 (s, 1H, quinoline H4), 6.79–8.21
(m, 10H, Ar–H and NH2), 9.15 (s,1H, NH). 13C NMR
(100 MHz, DMSO-d6) d: 14.77 (CH3), 26.94, 28.07 (2C,
CH3), 32.04 (C(CH3)2), 34.28 (C4), 37.92 (CH2), 49.71
(CH2–CO), 58.75 (OCH2), 77.51 (C–COOEt), 111.41,
113.75, 120.01, 126.41, 127.05, 128.14, 129.25, 130.44,
131.61, 132.08, 134.34, 135.20, 144.52, 148.26, 151.23,
154.77 (16C, Ar–C), 169.00 (C=OOC2H5), 194.99 (C=O),
MS: 629.1 [M ? H]?, 631.1 [M ? 2?H]?, 633.1
[M ? 4?H]?.
Ethyl 2-amino-4-(2-chloro-6-methyl(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-bromophenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5v): yield 84 %, m.p.
203–205 °C, Anal. Calcd. for C30H30BrClN4O3 (609.94 g/
mole): C 59.07, H 4.96, N 9.19 % Found: C 59.22, H 5.27,
N 9.01 %. IR (KBr, cm-1): 3385 and 3340 (asym. and sym.
1
str. of –NH2), 1665 (C=O), 1640 (C=O), 750 (C–Cl). H
Conclusions
NMR (400 MHz, DMSO-d6): d 0.89 (s, 3H, CH3), 0.97 (t,
3H, CH3), 0.99 (s, 3H, CH3), 1.85–2.76 (m, 4H, 2 9 CH2),
2.48 (s, 3H, Ar–CH3), 3.95 (q, 2H, OCH2), 5.24 (s, 1H,
quinoline H4), 6.77–8.25 (m, 10H, Ar–H and NH2), 9.06
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 14.74
(CH3), 21.43 (Ar–CH3), 26.99, 28.07 (2C, CH3), 32.05
(C(CH3)2), 34.71 (C4), 37.95 (CH2), 49.85 (CH2–CO),
58.75 (OCH2), 77.44 (C–COOEt), 111.54, 113.70, 120.04,
126.21, 126.93, 127.42, 131.02, 132.65, 134.24, 138.66,
141.88, 144.52, 148.23, 150.03, 153.41, 154.33 (16C, Ar–
C), 169.10 (C=OOC2H5), 194.95 (C=O), MS: 609.1
[M ? H]?, 611.1 [M ? 2?H]?, 613.1 [M ? 4?H]?.
Ethyl 2-amino-4-(2-chloro-6-methoxy(3-quinolyl))-7,7-
dimethyl-5-oxo-1-(4-bromophenylamino)-1,4,6,7,8-penta-
hydro quinoline-3-carboxylate (5w): yield 81 %, m.p.
255–257 °C, Anal. Calcd. for C30H30BrClN4O4 (625.94 g/
mole): C 57.56, H 4.83, N 8.95 % Found: C 57.79, H 5.07,
In conclusion, we have developed an efficient procedure
for the synthesis of N-arylamino biquinoline derivatives,
which are often encountered in molecules of biologically
active compounds. Particularly, valuable features of this
method achieved by both microwave irradiation and con-
ventional heating include high yields, broad substrate scope
and convenient operation. The antimicrobial results
revealed that numbers of compounds were found to be the
most active against C. tetani and B. subtilis compared with
rest of the employed species. Among all the compounds,
5a, 5f and 5q exhibited good inhibition against E. coli.
Compounds 5k and 5u showed superior activity against
S. typhi. Compound 5u also exhibited excellent activity
against S. pneumoniae. Antifungal activity of the com-
pounds shows that many compounds are found to be potent
against C. albicans. Finally, these compounds represent
123

Med Chem Res
derivatives and investigation of their antimicrobial activities.
Arkivoc vii:292–302
new structure scaffolds that could be further optimized for
future development of more potent and selective antimi-
crobial agents.
Ladani NK, Patel MP, Patel RG (2010) A convenient one-pot
synthesis of some new 3-(2-phenyl-6-(2-thienyl)-4-pyridyl)hy-
droquinolin-2-ones under microwave irradiation and their anti-
microbial activities. Phosphorus Sulfur Silicon 185:658–662
Lichitsky BV, Yarovenko VN, Zavarzin IV, Krayushkin MM (2000)
Reactions of cyclic enhydrazinoketones with arylidene deriva-
tives of malononitrile. Synthesis of fused N-substituted 1,4-
dihydropyridines. Russ Chem Bull 49:1251–1254
Makawana JA, Patel MP, Patel RG (2011) Synthesis and in vitro
antimicrobial evaluation of penta-substituted pyridine deriva-
tives bearing the quinoline nucleus. Med Chem Res. doi:
10.1007/s00044-010-9568-6
Acknowledgments The authors are thankful to Head, Department
of Chemistry, Sardar Patel University for providing 1H-NMR and
13C-NMR spectroscopy and research facilities. We are also thankful
to Oxygen Healthcare Research Pvt. Ltd., Ahmedabad for providing
mass spectroscopy facilities, Vaibhav Laboratories, Ahmedabad,
Gujarat, India for the FT-IR, SICART, Vallabh Vidyanagar for ele-
mental analysis and Dhanji P. Rajani, Microcare Laboratory, Surat,
Gujarat, India for antimicrobial screening of the compounds reported
herein. One of the authors is grateful to UGC, New Delhi for
Research Fellowship in Sciences for Meritorious Students.
Meth-Cohn O, Bramha NA (1978) A versatile new synthesis of
quinolines, thienopyridine and related fused pyridines. Tetrahe-
dron Lett 23:2045–2048
Mungra DC, Patel MP, Patel RG (2009) An efficient one-pot
synthesis and in vitro antimicrobial activity of new pyridine
derivatives bearing the tetrazoloquinoline nucleus. Arkivoc
xiv:64–74
Mungra DC, Patel MP, Patel RG (2011) Microwave-assisted synthesis
of some new tetrazolo[1,5-a]quinoline-based benzimidazoles
catalyzed by p-TsOH and investigation of their antimicrobial
activity. Med Chem Res 20:782–789
Naik HRP, Naik HSB, Naik TRR, Naika HR, Gouthamchandra K,
Mahmood R, Ahamed BMK (2009) Synthesis of novel
benzo[h]quinolines: wound healing, antibacterial, DNA binding
and in vitro antioxidant activity. Eur J Med Chem 44:981–989
National Committee for Clinical Laboratory Standards (2002)
Performance standards for antimicrobial susceptibility testing:
twelfth informational supplement. ISBN 1-56238-454-6, M100-
S12 (M7)
Nirmal JP, Patel MP, Patel RG (2009) Microwave-assisted synthesis
of some new biquinoline compounds catalyzed by DMAP and
their biological activities. Indian J Chem 48B:712–717
Shah NK, Patel MP, Patel RG (2009a) One-pot, multicomponent
condensation reaction in neutral conditions: synthesis, charac-
terization, and biological studies of fused thiazole[2,3-b]quinaz-
olinone derivatives. Phosphorus Sulfur Silicon 184:2704–2719
Shah NK, Patel MP, Patel RG (2009b) Reaction of 3-aminocyclohex-
2-en-1-ones with arylidenemalononitriles; synthesis, character-
ization and antimicrobial activity of some new quinoline bearing
pyrazole nucleus. Indian J Chem 48B:1170–1173
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