Synthesis and in-vitro antimicrobial activity of secondary and tertiary amines containing 2-chloro-6-methylquinoline moiety

Article abstract of DOI:10.1002/ardp.201000352

A number of secondary and tertiary amines bearing 2-chloro-6- methylquinoline were synthesized by nucleophilic substitution reaction of 3-(chloromethyl)-2-chloro-6-methylquinoline with substituted aromatic primary and secondary amines in presence of catal

Full text of DOI:10.1002/ardp.201000352

474
Arch. Pharm. Chem. Life Sci. 2011, 344, 474–480
Short Communication
Synthesis and In-vitro Antimicrobial Activity of Secondary
and Tertiary Amines Containing 2-Chloro-6-methylquinoline
Moiety
Suresh Kumar1, Sandhya Bawa1, Darpan Kaushik1, and Bibhu P. Panda2
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University),
New Delhi, India
2 Pharmaceutical Biotechnology Laboratory, Faculty of Pharmacy, Jamia Hamdard (Hamdard University),
New Delhi, India
A number of secondary and tertiary amines bearing 2-chloro-6-methylquinoline were synthesized by
nucleophilic substitution reaction of 3-(chloromethyl)-2-chloro-6-methylquinoline with substituted
aromatic primary and secondary amines in presence of catalytic amount of triethylamine (TEA) and
K2CO3. All the compounds were characterized by combined use of IR, 1H-NMR, 13C-NMR, mass spectral
data, and microanalyses. The newly synthesized quinolinyl amines were screened in vitro for
their antifungal activity against Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus
purpureus MTCC 369, Penicillium citrinum NCIM 768 and for antibacterial activity strains viz.
Escherichia coli NCTC 10418, Staphylococcus aureus NCTC 65710, and Pseudomonas aeruginosa NCTC
10662 by agar diffusion technique. Results of the preliminary screening revealed that some of the
compounds mainly those with electron withdrawing groups in the phenyl ring showed promising
antifungal activity.
Keywords: Antimicrobial activity / 2-Chloro-6-methylquinoline / Secondary amines / Tertiary amines
Received: November 16, 2010; Revised: December 26, 2010; Accepted: January 19, 2011
DOI 10.1002/ardp.201000352
Introduction
antimalarial [7], anticancer [8], antiviral [9], anticonvulsant [10],
antiinflammatory [11], antitubercular [12], antidepressant
[13], etc. Recent literature is enriched with progressive
findings on various and improved method for synthesis of
quinoline derivatives [14]. Moreover, this benzofused hetero-
aromatic ring has been studied and exploited immensely
than any other heterocycle for the development of potent
pharmacological agents which includes Montelukast
The emergence of multi-drug resistance strains of bacteria
and fungi such as methicilin resistant Staphylococcus aureus
(MRSA) and Candida species have made treatment of infec-
tious disease difficult and over the time has become a serious
medical problem [1–3]. The mechanism of resistant is con-
tinuously evolving in pathogenic bacteria to currently used
antimicrobial and to combat this problem, discovery of novel
and potent antimicrobial agents is still a best way to develop
effective therapy. Searching for structure with potential bio-
logical activities we concentrated our attention on quinoline
and its congeners which possess diverse and potent pharma-
cological activities [4] such as antibacterial [5], antifungal [6],
(antiasthmatic),
Saquinavir
(antiviral),
Aripiprazole
(antipsychotic), etc. Fascinated by multifarious bioactivity
of quinoline various researchers and scientists are still
engaged in developing potent molecule based on quinoline
such as Rao et al. [15] have reported the synthesis of multi-
substituted quinolines from Baylis-Hillman adduct and
tested for antimicrobial activity. Likewise various polyfunc-
tionalized 2-(hetero)arylquinolines were prepared by
Kouznetsov et al. [16] through imino Diels–Alder reactions
and evaluated for antifungal activity. Prompted by these
findings and in continuation of our research for bioactive
Correspondence: Suresh Kumar, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062,
India.
E-mail: sureshkr.2006@gmail.com
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2011, 344, 474–480
Synthesis and in-vitro antimicrobial activity of secondary and tertiary
475
O
HN
H3C
H3C
H
N
1
Cl
N
4n
Cl
Cl
R
a
e
HN
OH
H3C
c
H3C
H3C
b
N
Cl
N
Cl
N
3
Cl
X
2
(4a-m)
d
R = H, CH3, OCH3, F, Cl, Br, NO2
X = CH2, O, N-CH3
N
H3C
N
Cl
(4o-q)
Scheme 1. Synthetic route to (4a–q). Reagent and conditions: (a) NaBH4, methanol, r.t.; (b) SOCl2, dry benzene, reflux; (c) Appropriate
aromatic primary amine/ethanol, TEA, reflux; (d) Potassium carbonate/ acetone, reflux.
molecules based on quinoline [17–19], we address here the
synthesis and in-vitro antimicrobial activity of some new
secondary and tertiary amines containing 2-chloro-6-
methylquinoline.
observed in range of 3400–3440 cmꢀ1 and 1020–
1050 cmꢀ1 respectively. The successful reduction quinoline
aldehyde 1 was confirmed by 1H-NMR spectrum of compound
2 which showed a sharp singlet at d 4.66 equivalent to two
protons of –CH2OH, and a broad singlet at d 5.45 arising due
to OH. The fact was also confirmed by absence of signal due to
aldehydic proton and DEPT-135 spectrum of 2 in which a
negative (or inverse) peak was observed originating due to
CH2 at d 57.83. In 1H-NMR spectrum of compound 3 the signal
arising due to methylene protons of -CH2Cl function was
observed at d 4.87 and signal due to methylene carbon was
observed at d 43.17 in its 13C-NMR spectrum. The signal due to
methylene protons of -CH2Cl function undergoes diamag-
netic shift on nucleophilic substitution with amines in com-
pounds (4a–4n) at d 4.45–4.60 which may be attributed due to
weak electron withdrawing effect of N compare to Cl. The NH
proton of the -CH2NH- appeared as singlet to broad singlet at
d 4.10–4.25 integrating one proton which was D2O-exchange-
able. Furthermore in 13C-NMR spectrum, –CH2Cl carbon of
intermediate 3 resonated at d 43.17 which underwent slight
paramagnetic shift in compounds 4a, 4b, and 4c at d 46.15,
46.03, and 45.66, respectively. This confirmed the successful
substitution of chloromethyl group with amino group of
anilines in compounds (4a–4n). While in 1H-NMR spectra
of tertiary amines (4o–4q) the methylene protons of the
(–CH2N<) was resonated at slight upfield values at d 3.61–
Results and discussion
Chemistry
The synthetic approach adopted to obtain the target com-
pounds is depicted in Scheme 1. The principle intermediate 3
was prepared in excellent yield in two sequential steps by
reducing 2-chloro-3-formyl-6-methylquinoline 1 with NaBH4
in methanol to afford 2-chloro-3-hydroxymethyl-6-methylqui-
noline 2, which was subsequently converted into 2-chloro-3-
chloromethyl-6-methylquinoline 3 by the action of SOCl2 in
dry benzene. The secondary amines (4a–4n) were synthesized
by nucleophilic substitution reaction of 3 with appropriate
primary amines in absolute ethanol in presence of base
triethyl amine (TEA). While the tertiary amines were (4o–
4q) were synthesized in presence of potassium carbonate in
acetone.
The structure of compounds was established on the basis of
IR, 1H-, and 13C-NMR, and mass spectral data. The absorption
bands for all the compounds in IR-spectra were observed in
the range of 1610–1636 cmꢀ1 corresponding to C N. The NH
–
–
stretching and C–N stretching vibrations of CH2NH- were
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www.archpharm.com

476
S. Kumar et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 474–480
3.65 comparable to secondary amines (4a–4n). The aromatic
protons of the substituted phenyl ring resonated at values d
6.69 to d 7.23, whereas that of quinoline observed at d 7.58–
8.10. The structure assigned to compounds was in full agree-
ment with their reported details [20, 21]. The fact was also
confirmed by the FAB-MS spectrometry of some prototype
compounds 4a, 4b, and 4c which registered molecular ion
peak at m/z 283, 317, and 297, respectively. A fragment peak
of C11H8ClNþ was observed at m/z 190 due to loss of HCl in
mass spectrum of compound 3. This fragment peak of
activity. Compounds which exhibited excellent activity
include 4b, 4k, 4m, and 4n. It also appears from antifungal
activity data that compounds were more active towards
Aspergillus strain and less active against Monascus purpureos
MTCC 369 and Penicillium citrinum NCIM 768 strain. The ter-
tiary amines (4o, 4p, 4q) were found to possess weak anti-
fungal activity against all the strains.
Antibacterial activity
Among the compounds tested for their antibacterial activity
against Escherichia coli NCTC 10418, Staphylococcus aureus NCTC
65710, Pseudomonas aeruginosa NCTC 10662, none of the com-
pound exhibited moderate to good antibacterial actvity and
only some of compounds were poorly active against
Escherichia coli NCTC 10418 and Staphylococcus aureus NCTC
65710. While compounds did not any show growth inhibi-
tory effects against Pseudomonas aeruginosa NCTC 10662.
C
11H8ClNþ at m/z 190 was also present in mass spectra of
compound 4a, 4b, and 4c.
Antimicrobial activity
Antifungal activity
All the synthesized compounds (4a–q) were tested in vitro for
their antifungal activity against Aspergillus niger MTCC 281,
Aspergillus flavus MTCC 277, Monascus purpureos MTCC 369, and
Penicillium citrinum NCIM 768 by cup plate agar diffusion Conclusion
method [22, 23]. Terbinafine was used as references drug
and results are summarized in Table 3.
In the present investigation a series of secondary and tertiary
All the compounds with 2-chloro-6-methylquinolin-3-yl
system (4a–q) exhibited variable antifungal activity against
the test organism at a concentration of 200 mg/mL and were
found to be comparatively less active than the Terbinafine.
From the results reported in Table 3, it appears that among
the compounds tested eight compounds 4b, 4c, 4d, 4e, 4g, 4k,
4m, and 4n revealed good growth inhibitory effects against
Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, while
other derivatives showed moderate to weak antifungal
quinolinyl amines synthesized by nucleophilic substitution
was reported. All the compounds were tested for antifungal
and antibacterial activity against four fungal and three bac-
terial strains. The results of antimicrobial screening revealed
that for antifungal activity presence of electron withdrawing
groups (Cl, Br, F) in phenyl ring seems to be optimum and
replacement of phenyl ring with aliphatic cycles like piper-
idine, morpholine, etc. in 4o, 4p, 4q result in sharp decrease
in antifungal activity. These compounds (4a–4q) were poorly
Table 1. Physicochemical data of quinolinyl amines (4a–q).
Compd No.
R/X
Yielda (%) M.P. (C)
Mol. for (Mol. wt.)
C, H, N analysis calcd. (found)
Rf.b
clog Pc
C
H
N
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
H
4-Cl
4-CH3
4-Br
3-Cl
74
70
77
72
68
67
72
52
73
63
68
70
66
61
43
51
47
158
205
C17H15ClN2 (282.76)
C17H14Cl2N2 (317.21)
72.21 (72.38) 5.35 (5.33)
64.37 (64.21) 4.45 (4.42)
72.84 (72.61) 5.77 (5.79)
56.46 (56.32) 3.90 (3.89)
64.37 (64.20) 4.45 (4.43)
69.12 (69.30) 5.48 (5.51)
67.89 (67.72) 4.69 (4.72)
9.91 (9.96)
8.83 (8.87)
9.44 (9.48)
7.75 (7.78)
8.83 (8.85)
8.96 (9.01)
9.31 (9.34)
0.37 4.08 ꢁ 0.25
0.48 4.86 ꢁ 0.42
0.36 4.54 ꢁ 0.25
0.38 5.25 ꢁ 0.36
0.40 5.21 ꢁ 1.17
0.35 3.90 ꢁ 0.27
0.39 4.53 ꢁ 0.36
175–176 C18H17ClN2 (296.79)
213 C17H14BrClN2 (361.66)
171–172 C17H14Cl2N2 (317.21)
134–136 C18H17ClN2O (312.79)
4-OCH3
4-F
182
C17H14ClFN2 (300.75)
4-NO2
3-CH3
2-CH3
3-Cl, 4-F
2-Cl
3,4-(Cl)2
–
CH2
221–223 C17H14ClN3O2 (327.76) 62.30 (62.17) 4.31 (4.28) 12.82 (12.87) 0.35 4.53 ꢁ 0.28
118
125
C18H17ClN2 (296.79)
C18H17ClN2 (296.79)
72.84 (72.67) 5.77 (5.75)
72.82 (72.64) 5.77 (5.78)
60.91 (61.11) 3.91 (3.94)
64.37 (64.22) 4.45 (4.43)
58.06 (58.27) 3.73 (3.72)
72.84 (73.02) 5.77 (5.80)
69.93 (69.67) 6.97 (7.02) 10.19 (10.26) 0.35 3.71 ꢁ 0.35
65.10 (65.33) 6.19 (6.23) 10.12 (10.21) 0.32 2.13 ꢁ 0.41
66.31 (66.02) 6.96 (7.01) 14.50 (14.57) 0.35 1.87 ꢁ 0.57
9.44 (9.46)
9.44 (9.45)
8.36 (8.37)
8.83 (8.85)
7.97 (7.98)
9.44 (9.49)
0.33 4.54 ꢁ 0.25
0.35 4.54 ꢁ 0.25
0.44 5.77 ꢁ 1.17
0.38 4.59 ꢁ 0.32
0.45 5.86 ꢁ 1.17
0.42 4.37 ꢁ 0.28
142–143 C17H13Cl2FN2 (335.20)
165–166 C17H14Cl2N2 (317.21)
148–150 C17H13Cl3N2 (351.65)
210–212 C18H17ClN2 (296.79)
125–126 C16H19ClN2 (274.78)
O
N-CH3
138 C15H17ClN2O (276.76)
148–150 C16H20ClN3 (289.80)
a
b
c
Recrystallization from ethanol/methanol/chloroform mixture. Benzene/acetone (9.5:0.5). ACD lab software 12.0 version
(freeware).
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Arch. Pharm. Chem. Life Sci. 2011, 344, 474–480
Synthesis and in-vitro antimicrobial activity of secondary and tertiary
477
Table 2. IR, 1H-, 13C-NMR, and mass spectral data of compound (4a–q).
Compd. Chemical Names, IR, and mass spectral data
No
1H-NMR (300 MHz, CDCl3) and 13C-NMR (75 MHz, CDCl3) spectral
data
4a
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-aniline
–
1029 (C–N), 754 (C–Cl). FAB-MS m/z: 283 (Mþ), 285
(M þ 2), 190 (C11H8ClNþ)
1H-NMR d: 2.51 (s, 3H, CH3), 4.20 (s, 1H, NH, D2O-exchangeble), 4.59 (s, 2H,
CH2), 6.67 (d, 2H, H-20 & 60, J ¼ 7.32 Hz), 6.77 (t, 1H, H-40, J ¼ 7.14 Hz),
7.14–7.19 (m, 2H, H-30 & 50), 7.53–7.55 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8,
J ¼ 7.89 Hz), 8.09 (s, 1H, H-4). 13C-NMR d: 18.97 (CH3), 46.15 (CH2), 112.52,
117.03, 126.99, 127.47, 128.22, 130.02, 132.71, 136.49, 143.05, 147.17,
148.19
IR (KBr) cmꢀ1: 3402 (N–H), 1620 (C N), 1595 (C C),
–
–
–
4b
4c
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-4-chloroaniline
IR (KBr) cmꢀ1: 3411 (N–H), 1612 (C N), 1596 (C C),
1H-NMR d: 2.53 (s, 3H, CH3), 4.25 (s, 1H, NH, D2O-exchangeble), 4.56 (s, 2H,
CH2), 6.62 (d, 2H, H-20 & 60, J ¼ 7.54 Hz), 7.04 (d, 2H, H-30 & 50,
J ¼ 7.51 Hz), 7.54–7.57 (m, 2H, H-5 & H-7), 7.90 (d, 1H, H-8, J ¼ 7.62 Hz),
8.07 (s, 1H, H-4). 13C-NMR d: 18.9 (CH3), 46.03 (CH2), 113.5, 119.09, 125.64,
127.74, 128.0, 129.95, 132.6, 135.95, 137.03, 146.7, 148.89
1H-NMR d: 2.25 (s, 3H, Ph-CH3), 2.51 (s, 3H, CH3), 4.24 (s, 1H, NH, D2O-
exchangeble), 4.56 (s, 2H, CH2), 6.57 (d, 2H, H-20 & 60, J ¼ 7.21 Hz), 7.00 (d,
2H, H-30 & 50, J ¼ 7.13 Hz), 7.55–7.58 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8,
J ¼ 8.13 Hz), 8.08 (s, 1H, H-4). 13C-NMR d: 18.11 (CH3), 21.48 (CH3), 45.66
(CH2), 112.95, 118.09, 126.34, 127.34, 127.70, 129.35, 130.43, 132.25,
135.95, 137.03, 145.35, 147.17, 148.89
–
–
–
–
1036 (C–N), 729 (C–Cl). FAB-MS m/z: 317 (Mþ), 319
(M þ 2), 190 (C11H8ClNþ)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-4-methylaniline
IR (KBr) cmꢀ1: 3407 (N–H), 1613 (C N), 1590 (C C),
–
–
–
–
1024 (C–N), 758 (C–Cl). FAB-MS m/z: 297 (Mþ), 299
(M þ 2), 190 (C11H8ClNþ)
4d
4e
4f
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-4-bromoaniline
–
1H-NMR d: 2.52 (s, 3H, CH3), 4.24 (s, 1H, NH, D2O-exchangeble), 4.55 (s,
2H, CH2), 6.61 (d, 2H, H-20 & 60, J ¼ 7.59 Hz), 7.06 (d, 2H, H-30 & 50,
J ¼ 7.62 Hz), 7.54–7.57 (m, 2H, H-5 & H-7), 7.93 (d, 1H, H-8, J ¼ 7.91 Hz),
8.09 (s, 1H, H-4)
IR (KBr) cmꢀ1: 3417 (N–H), 1635 (C N), 1596 (C C),
1036 (C–N), 729 (C–Cl)
–
–
–
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-3-chloroaniline
1H-NMR d: 2.52 (s, 3H, CH3), 4.21 (s, 1H, NH), 4.59 (s, 2H, CH2), 6.49 (d, 1H,
H-60, J ¼ 7.24 Hz), 6.62 (s, 1H, H-20), 6.71 (d, 1H, H-40, J ¼ 7.05 Hz), 7.06 (t,
1H, H-50, J ¼ 7.47 Hz), 7.52–7.56 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8,
J ¼ 8.07 Hz), 8.08 (s, 1H, H-4)
IR (KBr) cmꢀ1: 3422 (N–H), 1625 (C N), 1585 (C C),
–
–
–
–
1052 (C–N), 759 (C–Cl)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-4-methoxyaniline
1H-NMR d: 2.51 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 4.23 (s, 1H, NH), 4.54 (s, 2H,
CH2), 6.61 (d, 2H, H-20 & 60, J ¼ 7.57 Hz), 6.79 (d, 2H, H-30 & 50,
J ¼ 7.28 Hz), 7.54–7.58 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 8.00 Hz),
8.08 (s, 1H, H-4)
IR (KBr) cmꢀ1: 3312 (N–H), 1610 (C N), 1593 (C C),
–
–
–
–
1027 (C–N),751 (C–Cl)
4g
4h
4i
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-4-fluoroaniline
1H-NMR d: 2.52 (s, 3H, CH3), 4.25 (s, 1H, NH), 4.55 (s, 2H, CH2), 6.60 (d, 2H,
H-20 & 60, J ¼ 7.53 Hz), 7.08 (d, 2H, H-30& 50, J ¼ 7.52 Hz), 7.54–7.57 (m,
2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 7.47 Hz), 8.06 (s, 1H, H-4)
1H-NMR d: 2.53 (s, 3H, CH3), 4.23 (s, 1H, NH), 4.57 (s, 2H, CH2), 6.60 (d, 2H,
H-20 & 60, J ¼ 7.58 Hz), 7.03 (d, 2H, H-30 & 50, J ¼ 7.53 Hz), 7.53–7.57 (m,
2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 7.93 Hz), 8.09 (s, 1H, H-4)
1H-NMR d: 2.24 (s, 3H, CH3), 2.52 (s, 3H, CH3), 4.21 (s, 1H, NH), 4.57 (s, 2H,
CH2), 6.47 (bs, 2H, H-20 & 60), 6.59 (d, 1H, H-40, J ¼ 7.81 Hz), 7.06 (t, 1H, H-50,
J ¼ 7.47 Hz), 7.51–7.55 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 8.07 Hz),
8.08 (s, 1H, H-4)
IR (KBr) cmꢀ1: 3410 (N–H), 1635 (C N), 1596 (C C),
–
–
–
–
1034 (C–N), 728 (C–Cl)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-4-nitroaniline
IR (KBr) cmꢀ1: 3421 (N–H), 1632 (C N), 1602 (C C),
–
–
–
–
1039 (C–N), 765 (C–Cl)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-3-methylaniline
IR (KBr) cmꢀ1: 3426 (N–H), 1612 (C N), 1598 (C C),
–
–
–
–
1039 (C–N), 760 (C–Cl)
4j
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-2-methylaniline
1H-NMR d: 2.26 (s, 3H, Ph-CH3), 2.51 (s, 3H, CH3), 4.21 (s, 1H, NH), 4.58 (s,
2H, CH2), 6.54 (d, 1H, H-60, J ¼ 7.26 Hz), 6.79–6.96 (m, 3H, phenyl-H),
7.56–7.60 (d, 2H, H-5 & H-7), 7.93 (d, 1H, H-8, J ¼ 7.71 Hz), 8.07 (s, 1H, H-4)
1H-NMR d: 2.53 (s, 3H, CH3), 4.24 (s, 1H, NH), 4.59 (s, 2H, CH2), 6.57 (d, 1H,
H-60, J ¼ 7.76 Hz), 6.72 (s, 1H, H-20), 7.18 (d, 1H, H-50, J ¼ 7.80 Hz), 7.55–
7.59 (m, 2H, H-5 & H-7), 7.93 (d, 1H, H-8, J ¼ 7.95 Hz), 8.09 (s, 1H, H-4)
1H-NMR d: 2.53 (s, 3H, CH3), 4.20 (s, 1H, NH), 4.58 (s, 2H, CH2), 6.59 (d, 1H, H-
60, J ¼ 7.31 Hz), 6.79–6.88 (m, 2H, phenyl-H), 7.02 (d, 1H, H-30, J ¼ 7.23 Hz),
7.56–7.59 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 7.96 Hz), 8.05 (s, 1H, H-4)
1H-NMR d: 2.52 (s, 3H, CH3), 4.23 (s, 1H, NH), 4.58 (s, 2H, CH2), 6.56 (d, 1H,
H-60, J ¼ 7.80 Hz), 6.73 (s, 1H, H-20), 7.19 (d, 1H, H-50, J ¼ 7.83 Hz), 7.58–
7.61 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 8.01 Hz), 8.10 (s, 1H, H-4)
IR (KBr) cmꢀ1: 3432 (N–H), 1636 (C N), 1606 (C C),
–
–
–
–
1035 (C–N), 744 (C–Cl)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-3-chloro-4-fluro-
aniline
4k
IR (KBr) cmꢀ1: 3431 (N–H), 1630 (C N), 1598 (C C),
–
–
–
–
1025 (C–N), 763 (C–Cl)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-2-chloroaniline
4l
IR (KBr) cmꢀ1: 3412 (N–H), 1630 (C N), 1590 (C C),
–
–
–
–
1036 (C–N), 759 (C–Cl)
N-[(2-Chloro-6-methylquinolin-3-yl)methyl]-3,4-dichloroani-
line
4m
IR (KBr) cmꢀ1: 3402 (N–H), 1620 (C N), 1595 (C C),
–
–
–
–
1029 (C–N), 754 (C–Cl)
N-Benzyl-1-(2-chloro-6-methylquinolin-3-yl)methanamine
4n
1H-NMR d: 2.52 (s, 3H, CH3), 3.79 (s, 2H, CH2-benzyl), 4.10 (s, 1H, NH), 4.45 (s,
2H, CH2), 6.68 (d, 2H, H-20 & 60, J ¼ 7.32 Hz), 6.78 (t, 1H, H-40, J ¼ 7.14 Hz),
7.14–7.19 (m, 2H, H-30 & 50), 7.54–7.57 (m, 2H, H-5 & H-7), 7.90–7.93 (d, 1H,
H-8, J ¼ 7.78 Hz), 8.10 (s, 1H, H-4)
IR (KBr) cmꢀ1: 3394 (N–H), 1631 (C N), 1597 (C C),
–
–
–
–
1036 (C–N), 756 (C–Cl)
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478
S. Kumar et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 474–480
Table 2. (continued )
Compd. Chemical Names, IR, and mass spectral data
No
1H-NMR (300 MHz, CDCl3) and 13C-NMR (75 MHz, CDCl3) spectral
data
4o
4p
4q
2-Chloro-6-methyl-3-(piperidin-1-ylmethyl) quinoline
–
1H-NMR d: 1.69–1.79 (m, 6H, 3 CH2), 2.52 (s, 3H, CH3), 3.44–3.47 (t, 4H,
CH2, J ¼ 5.1 Hz), 3.61 (s, 2H, CH2), 7.52–7.55 (m, 2H, H-5 & H-7), 7.89 (d,
1H, H-8, J ¼ 7.96 Hz), 8.03 (s, 1H, H-4)
IR (KBr) cmꢀ1: 1622 (C N), 1589 (C C), 1038 (C–N),
758 (C–Cl)
2-Chloro-6-methyl-3-(morpholin-4-ylmethyl) quinoline
–
–
–
1H-NMR d: 2.51 (s, 3H, CH3), 2.49 (d, 4H, 2 CH2, J ¼ 4.7 Hz), 3.51 (d, 4H, 2
CH2, J ¼ 4.8 Hz), 3.65 (s, 2H, CH2), 7.53–7.56 (m, 2H, H-5 & H-7), 7.91 (d,
1H, H-8, J ¼ 7.8 Hz), 8.04 (s, 1H, H-4).
IR (KBr) cmꢀ1: 1634 (C N), 1601 (C C), 1026 (C–N),
–
–
–
–
748 (C–Cl)
2-Chloro-6-methyl-3-[(4-methylpiperazin-1-yl)methyl]quino-
line
1H-NMR d: 2.51 (s, 3H, CH3), 2.60 (d, 4H, 2 CH2, J ¼ 4.7 Hz), 2.95 (d, 4H, 2
CH2, J ¼ 4.8 Hz), 3.31 (s, 3H, N-CH3), 3.64 (s, 2H, CH2), 7.49 (m, 2H, H-5
and H-7), 7.90 (d, 1H, H-8, J ¼ 7.8 Hz), 8.04 (s, 1H, H-4)
IR (KBr) cmꢀ1: 1629 (C N), 1593 (C C), 1041 (C–N),
–
–
–
–
763 (C–Cl)
(M þ 2). Anal. calcd. for C11H10ClNO: C, 63.62; H, 4.85; N, 6.75.
active against bacterial strains. The quinolinyl amines deriva-
tives discovered in this study may provide valuable thera-
peutic intervention for the treatment of microbial diseases,
especially against fungal Aspergillus sp.
Found: C, 63.53; H, 4.83; N, 6.78%.
2-Chloro-3-(chloromethyl) -6-methylquinoline (3)
To
a solution of compound 2 (2.07 g, 0.01 mol) in dry
benzene (30 mL), SOCl2 (1.54 g, 0.013 mol) was added and the
mixture refluxed for 4 h. Solvent was evaporated under reduced
pressure and the residue was dissolved in ether, washed with
10% NaHCO3 and twice with water. Dried over Na2SO4 and
concentrated in vacuo to give a residue which was crystallized
from methanol.
Experimental
Materials & method
All the chemicals were supplied by E. Merck (Germany) and S. D.
Fine chemicals (India). Melting points were determined by the
open tube capillary method and are uncorrected. IR spectra were
recorded as KBr (pellet) on Bio Rad FT-IR spectrophotometer and
1H-NMR spectra recorded at 300 MHz Bruker spectrophotometer
using DMSO-d6 and CDCl3 as a solvent. Mass spectra were
recorded on JEOL SX102/DA-6000 mass spectrometer and elemen-
tal analysis on vario EL III CHNOS-Elementar analyzer. Thin Layer
Chromatography (TLC) was performed to monitor progress of the
reaction and purity of the compounds, spot being located under
iodine vapor or UV-light. Solvents were purified using standard
procedure.
Yield 85%, M.p. 1408C, IR (KBr) cmꢀ1: 1620 (C C), 1595 (C N),
–
–
–
–
754 (C–Cl), 1H-NMR (300 MHz, CDCl3) d: 2.53 (s, 3H, CH3), 4.87
(s, 2H, CH2), 7.55–7.57 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8,
J ¼ 7.5 Hz), 8.17 (s, 1H, H-4)). 13C-NMR (CDCl3, 75 MHz) d: 21.48
(CH3), 43.17 (CH2), 125.91, 127.12, 127.93, 129.06, 135.76, 141.13,
147.16, 149.31. FAB-MS: 226 (Mþ), 227 (M þ 1), 228 (M þ 2), 190
(M-HCl)/190 (C11H8ClNþ). Anal. calcd. for C11H9Cl2N: C, 58.43;
H, 4.01; N, 6.19. Found: C, 58.30; H, 4.03; N, 6.22%.
General method for the preparation of compounds (4a–n)
To a mixture of compound 3 (0.68 g, 0.003 mol) and appropri-
ately substituted phenyl/benzyl amine (0.003 mol) in 25 mL of
absolute ethanol, 1 mL of triethylamine (TEA) was added and
refluxed for 12–15 h. After completion of the reaction, the con-
tent of the flask reduced to half and left overnight. The crystal-
line mass obtained was filtered off, washed with water, dried and
recrystallized from ethanol.
Chemistry
The starting material 2-chloro-3-formyl-6-methylquinoline was
prepared according to the literature method [22].
Preparation of (2-chloro-6-methyl quinolin-3-yl)-
methanol (2)
To a solution of 1 (0.01 mol) in absolute methanol, solid sodium
borohydride (0.012 mol) was added portion wise over a period of
30 min. with constant stirring at room temperature. After that
solvent was evaporated under reduced pressure and the residue
was triturated with water and the crystalline product was fil-
tered, washed with water and dried. The product was recrystal-
lized from methanol.
Synthesis of compounds (4o–4q)
An equimolar mixture of compound 3 (0.68 g, 0.003 mol) and
appropriate secondary amine (0.003 mol) was stirred and
refluxed in anhydrous acetone (30 mL) in presence of anhydrous
potassium carbonate for 4–6 h. The reaction mixture was
filtered, washed with acetone. The solvent was evaporated
and the residue was dissolved in ethyl acetate, washed with
water (3 ꢂ 20 mL). The organic layer was dried over anhydr.
sodium sulfate and evaporated under reduced pressure. The
residue obtained was recrystallized from methanol/chloroform
mixture.
Yield, 86.0%, M.p. 172–1748C. IR (KBr) cmꢀ1: 1595 (C N), 1615
–
–
(C C), 3630 (OH), 751 (C– Cl). 1H-NMR (300 MHz, CDCl3) d: 2.52
–
–
(s, 3H, CH3), 4.66 (s, 2H, CH2), 5.45 (bs, 1H, OH, D2O-exchangeble),
7.54–7.57 (m, 2H, H-5 & H-7), 7.92 (d, 1H, H-8, J ¼ 7.74 Hz), 8.06
(s, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) d: 18.94 (CH3), 57. 83 (CH2),
126.17, 126.96, 127.84, 130.54, 131.97, 135.49, 142.06, 148.02.
DEPT-135 (CDCl3); (-ve) 57.83 (CH2). FAB-MS m/z: 208 (Mþ), 210
The physicochemical data and spectral details of compounds
(4a–q) are presented in Tables 1 and 2, respectively.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 474–480
Synthesis and in-vitro antimicrobial activity of secondary and tertiary
479
Table 3. Antifungal and antibacterial activity data of quinolinyl amines (4a–q)
Compd. No
Zone of inhibition in mm (mean ꢁ S.D.) n ¼ 3
Antifungal activity Antibacterial activity
A. niger
A. flavus
M. purpureus
P. citrinum
E. coli
S. aureus
P. aerurginosa
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
9.47 ꢁ 0.58
13.76 ꢁ 0.81
10.59 ꢁ 0.91
12.16 ꢁ 0.55
12.03 ꢁ 0.30
9.76 ꢁ 0.47
12.0 ꢁ 0.36
8.03 ꢁ 0.25
7.5 ꢁ 0.98
10.90 ꢁ 0.52
10.80 ꢁ 0.36
8.33 ꢁ 0.50
11.06 ꢁ 0.56
10.56 ꢁ 0.28
10.40 ꢁ 0.51
10.93 ꢁ 0.83
8.83 ꢁ 0.64
6.10 ꢁ 0.62
—
15.83 ꢁ 0.45
7.93 ꢁ 0.58
13.93 ꢁ 1.05
13.53 ꢁ 0.65
—
6.70 ꢁ 0.36
7.93 ꢁ 0.49
5.43 ꢁ 0.32
7.03 ꢁ 0.60
6.86 ꢁ 0.66
7.13 ꢁ 0.40
—
4.24 ꢁ 0.80
5.69 ꢁ 0.65
—
4.43 ꢁ 0.23
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7.00 ꢁ 0.34
—
7.20 ꢁ 0.65
—
7.13 ꢁ 0.37
5.2 ꢁ 0.60
4.04 ꢁ 0.85
8.73 ꢁ 0.60
—
—
6.83 ꢁ 0.30
4.85 ꢁ 0.55
5.64 ꢁ 0.63
5.73 ꢁ 0.30
—
5.62 ꢁ 0.47
8.13 ꢁ 0.50
7.93 ꢁ 0.15
—
—
—
—
—
—
—
—
—
—
8.06 ꢁ 0.80
14.06 ꢁ 0.35
8.13 ꢁ 0.51
15.86 ꢁ 0.60
13.06 ꢁ 1.06
6.44 ꢁ 1.50
6.25 ꢁ 0.80
6.10 ꢁ 1.05
Nt
—
9.50 ꢁ 0.69
10.76 ꢁ 0.28
6.26 ꢁ 0.68
9.26 ꢁ 0.47
10.58 ꢁ 0.35
—
5.17 ꢁ 0.73
4.81 ꢁ 0.58
5.21 ꢁ 0.65
4.90 ꢁ 0.65
7.52 ꢁ 0.98
6.49 ꢁ 1.50
6.02 ꢁ 1.05
21.37 ꢁ 0.33
Nt
4.91 ꢁ 1.05
4.01 ꢁ 0.36
4.28 ꢁ 0.25
—
8.09 ꢁ 1.10
6.68 ꢁ 1.00
7.14 ꢁ 0.90
19.45 ꢁ 0.55
Nt
—
7.86 ꢁ 0.40
8.09 ꢁ 0.80
—
—
4p
4q
5.52 ꢁ 1.06
7.21 ꢁ 1.00
Nt
24.78 ꢁ 0.55
—
—
Nt
5.82 ꢁ 0.93
—
18.37 ꢁ 0.65
Nt
Ciprofloxacin
Terbinafine
Nt
19.58 ꢁ 0.68
21.58 ꢁ 0.37
20.83 ꢁ 1.12
(—) Indicate absence of activity; Nt, not tested.
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Antimicrobial activity
The newly synthesized compounds (4a–q) were tested against a
panel of bacterial strains viz. Escherichia coli NCTC 10418,
Staphylococcus aureus NCTC 65710, Pseudomonas aeruginosa NCTC
10662 and fungal strains viz. Aspergillus niger MTCC 281, Aspergillus
flavus MTCC 277, Monascus purpureus MTCC 369, Penicillium citrinum
NCIM 768 by cup-plate method [19, 20]. Potato dextrose agar
(PDA) and nutrient agar were used as culture medium for anti-
fungal and antibacterial activity, respectively. Using an agar
punch, wells were made on seeded agar plates and a concen-
tration of 200 mg/mL of test compounds in DMSO was added into
each well, labeled previously. A control was also prepared using
solvent DMSO. The petriplates were maintained at 308C for 72 h
for fungi and 378C for 24 h for bacteria. Antimicrobial activity
was determined by measuring zone of inhibition in millimeter
and data have been presented as (n ¼ 3, mean ꢁ S.D.) and com-
pared with standard Terbinafine (200 mg/mL) and Ciprofloxacin
(200 mg/mL) and results have been summarized in Table 3.
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The authors are grateful to the University Grant Commission (UGC), New
Delhi, India, for the award of UGC-JRF to SK. The authors also thankful to
Jamia Hamdard for providing necessary facility and CDRI, Lucknow, India
for providing mass spectral data.
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The authors have declared no conflict of interest.
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