Design and synthesis of 2-chloroquinoline derivatives as non-azoles antimycotic agents

Article abstract of DOI:10.1007/s00044-010-9463-6

A series of secondary amines (4-19) containing 2-chloroquinoline as lipophilic domain have been synthesizedbased on the structural requirements essential for allylamine/benzylamine antimycotics by nucleophilic substitutionreaction of 3-chloromethyl-2-chlo

Full text of DOI:10.1007/s00044-010-9463-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1340–1348
DOI 10.1007/s00044-010-9463-6
ORIGINAL RESEARCH
Design and synthesis of 2-chloroquinoline derivatives
as non-azoles antimycotic agents
•
•
•
Suresh Kumar Sandhya Bawa Sushma Drabu
Bibhu P. Panda
Received: 22 September 2009 / Accepted: 1 October 2010 / Published online: 6 November 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of secondary amines (4–19) containing
2-chloroquinoline as lipophilic domain have been synthe-
sized based on the structural requirements essential for
allylamine/benzylamine antimycotics by nucleophilic sub-
stitution reaction of 3-chloromethyl-2-chloroquinoline 3
with various aliphatic and aromatic amines in absolute
ethanol in the presence of triethylamine. Some N-methyl
derivatives (20–25) were also synthesized by N-methyla-
tion using (CH3)2SO4/NaH. The structures of newly syn-
thesized compounds were established by the combined use
of IR, 1H-NMR, 13C-NMR, and Mass spectra. Compounds
4–25 were screened in vitro at conc. of 200 g/ml for their
antifungal activity against Aspergillus niger MTCC 281,
Aspergillus flavus MTCC 277, Monascus purpureus
MTCC 369, and Penicillium citrinum NCIM 768 by cup-
plate method using Terbinafine as a references drug.
Among the secondary amines, compounds 4, 5, 8, 10, 14,
and 16 exhibited potential antifungal activity and their
corresponding N-methyl (20–25) derivatives also showed
further increase in antifungal activity against fungal strain
Aspergillus niger MTCC 281, Aspergillus flavus MTCC
277. Compounds 3-chloro-N-[(2-chloroquinolin-3-yl)me-
thyl]-4-fluoro-N-methylaniline (24) and 3,4-dichloro-N-
[(2-chloroquinolin-3-yl)methyl]-N-methylaniline (25) were
the most potent derivatives of the series.
Keywords 2-Chloroquinoline ꢀ Nucleophilic
substitution ꢀ Antifungal activity ꢀ Lipophilicity
Introduction
Among the non-azole antifungal agents allylamine are the
synthetic antimycotics that selectively inhibit fungal
squalene epoxidase enzyme like Terbinafine (Favre and
Ryder, 1997). Naftifine was the first representative of this
class. Further research and development in this direction
led to the discovery of Terbinafine, Butenafine, Tolnafate,
and SDZ 87.469. Investigation into the structure of allyl-
amine derivatives revealed some common structural fea-
tures. In general all these compounds have (a) a lipophilic
bicyclic aromatic ring system as lipophilic domain (L-1),
(b) another bulky lipophilic group (phenyl, tert-butyl) as a
side chain (L-2), finally (c) the two lipophilic domain
linked by a spacer of appropriate length with polar center
(NMe) at defined position (P) (Nussbaumer et al., 1991,
1994; Stutz et al., 1986).
Searching for structures with potential biological activ-
ity, we directed our attention to the quinoline derivatives,
which are known to possess very good antifungal and
antibacterial properties (Acharya et al., 2008; Rizk et al.,
´ˇ
´
2005; Munawar et al., 2008; Strigacova et al., 2000;
Prisyazhnyuk et al., 1984; Musiol et al., 2006) and Clio-
quinol is a marketed antifungal drug having a quinoline
group (Delgado and Remers, 2005). All these facts
encouraged us to design some new targeted molecules
possessing critical structural features resembling allyla-
mine antimycotics. It was envisaged in the present inves-
tigation to undertake the synthesis of a series of structural
analogues of Butenafine having 2-chloroquinoline moiety
with the aim to find new and more potent antifungal agents.
S. Kumar (&) ꢀ S. Bawa ꢀ S. Drabu
Department of Pharmaceutical Chemistry, Faculty of Pharmacy,
Jamia Hamdard, New Delhi 110062, India
e-mail: sureshkr.2006@gmail.com
B. P. Panda
Pharmaceutical Biotechnology Lab, Faculty of Pharmacy,
Jamia Hamdard, New Delhi 110062, India
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Med Chem Res (2011) 20:1340–1348
1341
Fig. 1 Chemical structures and
structural features of some
antifungal agents Butenafine,
Naftifine, compounds 4–16, 19,
20–25, and SDZ 87.469
In our study, 2-chloroquinoline was employed as lipophilic
bicyclic aromatic ring analogue of naphthalene (L-1)
which is linked to another lipophilic group (substituted
phenyl or benzyl, L-2) at 3-position of the quinoline with a
spacer of –CH2NH–, –CH2NHCH2–, and CH2N(CH3)–
(Fig. 1) (Nussbaumer et al., 1991).
range 1595–1640 cm-1. In 1H-NMR spectra of intermediate
3 showed a sharp singlet at d 4.82 equivalent to two proton of
–CH2Cl, which undergoes diamagnetic shift in compounds
4–18 at d 4.54–4.59 due to weak electron withdrawing effect
of N when compared to Cl. This is considered to be a strong
confirmation for the substitution of 3 with amines. The NH
proton of the –CH2NH– appeared as singlet to broad singlet
at d 4.23–4.39 integrating one proton which is D2O-ex-
changeble. Furthermore in 13C-NMR spectra, –CH2Cl car-
bon of compound 3 resonated at d 43.03 which underwent
slight paramagnetic shift in compounds 4, 5, 6, 7, and 9 to d
45.17–46.63. This also confirmed the successful substitution
of chloromethyl group with amino group of anilines in
compounds 4–19. The fact was also supported by the FAB-
MS spectrometry of some selected compounds 4, 5, 6, 7, and
9 which registered molecular ion peak at m/z 269, 303, 283,
348, 299, and 287, respectively. A fragment peak of
C10H6ClN? at 175 was found to be common in their mass
Results and discussion
Chemistry
The reaction sequence for the synthesis of compounds
2-chloro-3-(substituted phenyl/butyl/cyclohexylamino)meth-
ylquinoline (4–18), N-benzyl-1-(2-chloroquinolin-3-yl)meth-
anamine (19), and N-[(2-chloroquinolin-3-yl)methyl]-N-
methyl-substituted-aniline (20–25) is outlined in Scheme 1.
The required key intermediate was prepared in excellent
yield from reported 2-chloro-3-formylquinoline (1) via its
reduction with solid NaBH4 in methanol to afford 2-chloro-
3-hydroxymethylquinoline (2), followed by chlorination
with SOCl2 in dry benzene gave 3-(chloromethyl)-2-chlo-
roquinoline (3). The target compounds 4–19 were prepared
in excellent yield by nucleophilic substitution reaction of 3
with various aliphatic and aromatic amines in absolute
ethanol in the presence of base triethylamine (TEA).
N-methylation of some of the compounds was also carried
out using (CH3)2SO4/NaH to give compounds 20–25. Both
1
spectra. In the H-NMR spectra of compound 20–25, the
characteristic N–CH3 signal appeared as singlet integrating
for three protons at values ranging from d 2.20 to 2.24, while
the peak due to NH disappeared. In 13C-NMR of compound
20, the N–CH3 signal appeared at d 39.17. The FAB-MS
spectrum of compound 20 showed an increase in molecular
ion peak at m/z 283. All these facts confirmed the successful
N-methylation in compounds 20–25. The spectral details of
individual compound have been given in experimental
section.
1
analytical and spectral data (IR, H, 13C-NMR, and Mass)
of all the synthesized compounds were in full agreement with
the proposed structures. In the IR spectra of compounds
4–19, the band representing C–N and N–H of –CH2NH–
Antifungal activity
All the secondary amines and N-methyl derivatives with 2-
chloroquinoline moiety displayed variable growth inhibi-
tory effects against the test organism at concentration of
appeared at 1020–1050 cm-1 and 3400–3440 cm-1
,
respectively. Peak due to C=N vibration was observed in the
123

1342
Med Chem Res (2011) 20:1340–1348
Scheme 1 Synthetic route to
compounds 4–25. Reagent and
conditions: (a) NaBH4,
O
H
methanol, r.t.; (b) SOCl2, dry
benzene, reflux; (c) Appropriate
aromatic/aliphatic primary
amine/ethanol, TEA, reflux; (d)
NaH/(CH3)2SO4
N
a
Cl
1
OH
X
N
b
Cl
Cl
2
HN
Cl
HN
c
c
N
4-16
N
Cl
N
Cl
3
d
19
c
X
c
H3C
N
HN
H3C
Cl
HN
Cl
N
20-25
Cl
N
18
N
17
200 lg/ml in DMSO in Table 2. Among the series of
compounds 4–19, compounds 4, 5, 7, 8, 10, 15, and 19
showed good antifungal activity while the compounds 14
and 16 showed excellent activity against the fungal strain
Aspergillus niger MTCC 281 and Aspergillus flavus MTCC
277. Compounds 6, 9, 11, 12, 13, 17, and 18 exhibited
moderate to low antifungal activity. In general, compounds
were more active against the Aspergillus strain as compared
to two other strains viz. Monascus purpureus MTCC 369
and Penicillium citrinum NCIM 768. The compounds 17
and 18 were found to be inactive against these two strains.
Compounds 4, 5, 8, 10, 14, and 16 were found to be most
potent in the antifungal screening and therefore converted
into their N-methyl (20–25) derivatives and tested for any
increase in antifungal activity. All six N-methyl derivatives
were found to show slight increment in antifungal activity
against fungal strain Aspergillus niger MTCC 281, Asper-
gillus flavus MTCC 277, Monascus purpureus MTCC 369,
and Penicillium citrinum NCIM 768 as indicated by increase
in zone of inhibition as shown in Table 2. The lipophilicity
is one of the most important physical properties of biolog-
ically active compounds. This thermodynamic parameter
describes the partitioning of drug between an aqueous and a
organic phase, and its characterized by partition (logP) or
distribution coefficient (logD). This quantitative parameter
was also determined by fragment-based algorithm using
ACD/CLogP 12.0 software. The lipophilicity of the com-
pounds is well known to play an important role in antifungal
activity (Arnoldi and Merlini, 1990), our results demonstrate
that simply by increasing the lipophilic character of the
compound the activity increased, as observed for most
potent compounds 24, 25 whose Clog P values was found to
be 5.86 and 5.95, respectively. The antifungal activity order
of used substituents in the present series was as follows 3,
4-(Cl)2 [ 3, 4-Cl, F [ Cl, F, H, NO2, CH3, OCH3. But there
is slight variation in this order against the fungal stain.
Conclusion
Examination of the in vitro antifungal activity profile for
differently substituted novel 2-chloro-3-(substitutedami-
no)methylquinoline derivatives against the test fungal
strains, provide a preliminary SAR. The use of 2-chloro-
quinoline as structural analogue or as isostere of naphtha-
lene seems to be valuable and fruitful nucleus for antifungal
activity. The replacement of phenyl ring with aliphatic
groups like butyl/cyclohexyl led to decrease in antifungal
activity. The effect of electron releasing groups like CH3,
OCH3 substituted on the phenyl ring on antifungal activity
123

Med Chem Res (2011) 20:1340–1348
1343
was not found to be prominent, but antifungal activity
increases when the phenyl ring was substituted with elec-
tron withdrawing groups like F, Cl, Br, while the NO2
derivatives showed decrease in zone of inhibition. More-
over, significant increase in antifungal activity was
observed for dihalo-substituted derivatives (14, 16). When
the spacer between the two lipophilic domain was increased
from –CH2NH– to –CH2NHCH2– in compound 19 a slight
increase in zone of inhibition was found for these deriva-
tives. Moreover, increase in activity was also observed
when –CH2NH– of compounds 4, 5, 8, 10, 14, and 16 were
converted into N–CH3 derivatives in compounds 20–25.
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 prod-
uct was filtered, washed with water, and dried. The product
was recrystallized from methanol.
Yield, 86.0%; mp. 160–162°C; IR (KBr) cm-1: 3340
1
(O–H), 1614 (C=C), 1592 (C=N), 765 (C–Cl). H-NMR
(300 MHz, DMSO-d6): d 4.77 (s, 2H, CH2), 5.45 (s, 1H,
OH, D2O-exchangeble), 7.53–7.58 (t, 1H, H-6,
J = 7.0 Hz), 7.67–7.72 (t, 1H, H-7, J = 6.9 Hz), 7.83–7.86
(d, 1H, H-5, J = 7.5 Hz), 7.97–8.00 (d, 1H, H-8,
J = 8.0 Hz), 8.36 (s, 1H, H-4). 13C-NMR (DMSO-d6,
75 MHz): d 59.94 (CH2), 126.41, 127.08, 127.45, 127.76,
129.94, 133.87, 135.71, 146.00, 148.37. FAB-MS: m/z 194
(M). Anal. Calcd for C10H8ClNO: C, 62.03; H, 4.16; N,
7.23. Found: C, 61.81; H, 4.18; N, 7.26%.
Experimental
Chemistry
Preparation of 3-(chloromethyl)-2-chloroquinoline (3)
Melting points were determined by the open capillary
method with electrical melting point apparatus and are
uncorrected. IR spectra were recorded as KBr (pallet) on
To a solution of compound 2 1.94 g (0.01 mol) in dry
benzene, 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 vacuvo to give a residue
which was crystallized from methanol.
1
Bio Rad FT-IR spectrophotometer and H and 13C-NMR
spectra recorded on Bruker DPX 300 MHz spectropho-
tometer using DMSO-d6 or CDCl3 as an NMR solvent.
TMS used as internal standard and chemical shift data
reported in parts per million (in ppm) where s, bs, d, t, and
m designated as singlet, broad singlet, doublet, triplet,
and multiplet, respectively. Mass spectra were recorded
on JEOL SX102/DA-6000 mass spectrometer using
m-Nitrobenzylalcohol as a matrix and elemental analysis
on Vario-EL III CHNOS-Elemantar 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.
Yield, 80%; mp. 116°C; IR (KBr) cm-1: 1620 (C=C),
1
1590 (C=N), 754 (C–Cl). H-NMR (300 MHz, CDCl3): d
4.82 (s, 2H, CH2), 7.54–7.59 (t, 1H, H-6, J = 7.2 Hz),
7.71–7.76 (t, 1H, H-7, J = 7.5 Hz), 7.81–7.83 (d, 1H, H-5,
J = 7.9 Hz), 8.00–8.03 (d, 1H, H-8, J = 8.3 Hz), 8.26 (s,
1H, H-4). 13C-NMR (CDCl3, 75 MHz): d 43.03 (CH2),
126.91, 127.38, 127.45, 128.12, 128.89, 130.87, 138.60,
147.12, 149.51. FAB-MS: m/z 214 (M ? 2), 212 (M?).
Anal. Calcd for C10H7Cl2N: C, 56.63, H, 3.33; N, 6.60.
Found: C, 56.46; H, 3.31; N, 6.63%.
2-Chloro-3-formylquinoline needed in the study was
prepared by Vilsmeier-Haack reaction according to the
literature method (Meth-Cohn et al., 1981).
Yield, 63.0%; mp. 150–151°C; IR (KBr) cm-1: 1693
General method for the synthesis of compounds 4–19
1
(C=O), 1620 (C=C), 1595 (C=N), 752 (C–Cl). H-NMR
(300 MHz, DMSO-d6): d 7.65–7.70 (t, 1H, H-6, J =
7.4 Hz), 7.88–7.93 (t, 1H, H-7, J = 7.1 Hz), 8.00–8.02 (d,
1H, H-5, J = 8.0 Hz), 8.08–8.11 (d, 1H, H-8, J = 8.4 Hz),
8.78 (s, 1H, H-4), 10.58 (s, 1H, CHO). 13C-NMR (DMSO-d6,
75 MHz): d 125.93, 126.12, 127.39, 127.75, 129.65, 133.31,
135.09, 140.99, 148.28, 188.71 (CHO). FAB-MS: m/z 194
(M ? 2, 45%), 192 (M?) Anal. Calcd for C10H8ClNO: C,
62.68; H, 3.16; N, 7.31. Found: C, 62.50; H, 3.15; N, 7.33%.
To a mixture of compound 3 (0.003 mol) and vari-
ous substituted phenyl/cyclohexyl/butyl primary amine
(0.003 mol) in 20 ml of absolute ethanol, 1 ml of triethyl-
amine (TEA) was added and refluxed for 12–15 h. After
completion of the reaction, content of the flask reduced to half
and left overnight. The crystalline mass obtained was filtered
off, washed with water, dried, and recrystallized from ethanol
to give 4–19. The physicochemical data of compound is
presented in Table 1 and spectral data 4–19 are given below.
2-Chloro-3-(hydroxymethyl)-quinoline (2)
2-Chloro-3-(phenylamino)methylquinoline (4)
To
a solution of 2-chloro-3-formylquinoline 1.92 g
(0.01 mol) in absolute methanol, solid sodium borohydride
0.46 g (0.012 mol) was added portion wise over a period of
IR (KBr) cm-1: 3402 (N–H), 1620 (C=C), 1595 (C=N),
1
1029 (C–N), 754 (C–Cl). H-NMR (300 MHz, CDCl3): d
123

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Med Chem Res (2011) 20:1340–1348
Table 1 Physicochemical data of compounds 4–25
Compd. no
X
Yielda (%)
m.p. (°C)
Mol. formula
C16H13ClN2
Mol. wt
ClogPb
Rfc.
4
H
74.5
70
81
77
68
70
72
51
73
75
69
72
70
53
42
58
52
55
51
48
43
52
136–138
125–126
118–120
155
268.74
303.18
282.76
347.63
303.18
298.76
286.73
313.73
282.76
282.76
321.17
303.18
337.63
274.78
248.75
282.76
282.76
317.21
317.21
300.75
335.20
351.65
3.62 0.25
4.40 0.42
4.08 0.25
4.79 0.35
4.75 1.17
3.44 0.26
4.07 0.35
4.07 0.27
4.08 0.25
4.08 0.25
5.31 1.17
4.13 0.32
5.40 1.17
4.07 0.26
3.60 0.26
3.91 0.28
4.71 0.26
5.12 0.41
5.67 0.28
4.80 0.66
5.86 0.76
5.95 0.43
0.38
0.42
0.36
0.39
0.40
0.34
0.39
0.36
0.35
0.36
0.43
0.38
0.43
0.40
0.37
0.41
0.37
0.39
0.40
0.42
0.39
0.41
5
4-Cl
C
16H12Cl2N2
C17H15ClN2
6
4-CH3
4-Br
7
C
C
16H12BrClN2
16H12Cl2N2
8
3-Cl
145
9
4-OCH3
4-F
95–97
C17H15ClN2O
16H12ClFN2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
a
140
C
4-NO2
3-CH3
2-CH3
3-Cl, 4-F
2-Cl
168–170
104
C16H12ClN3O2
C17H15ClN2
C17H15ClN2
121
176–178
135
C
C
16H11Cl2FN2
17H12Cl2N2
3,4-(Cl)2
Cyclohexyl
Butyl
Benzyl
H
182–183
59–61
C16H11Cl3N2
C
C
C
C
C
C
C
C
16H19ClN2
14H17ClN2
17H15ClN2
17H15ClN2
17H14Cl2N2
17H14Cl2N2
17H14ClFN2
17H13Cl2FN2
47
179–181
182–183
163–165
196–197
203–205
223–225
261–262
4-Cl
3-Cl
4-F
3-Cl, 4-F
3,4-(Cl)2
C17H13Cl3N2
After recrystallization from ethanol
ACD/CLogP 12.0 software
Benzene:acetone (9.5:0.5)
b
c
4.29 (s, NH, D2O-exchangeble), 4.59 (s, 2H, CH2),
6.63–6.66 (d, 2H, H-20 and 60, J = 7.3 Hz), 6.73–6.78 (t,
1H, H-40, J = 6.6 Hz), 7.16–7.18 (d, 2H, H-30 and 50,
J = 7.1 Hz), 7.49–7.54 (t, 1H, H-6, J = 7.0 Hz),
7.67–7.76 (m, 2H, H-5 and H-7), 8.00–8.03 (d, 1H, H-8,
J = 7.7 Hz), 8.16 (s, 1H, H-4). 13C-NMR (CDCl3,
75 MHz): d 45.17 (CH2), 112.67, 115.98, 126.46, 127.09,
128.37, 128.93, 131.51, 136.60, 140.12, 146.04, 148.31.
FAB-MS m/z: 269 (M)?, 271 (M ? 2)?.
Anal. Calcd for C16H12Cl2N2: C,. 63.38; H, 3.99; N, 9.24.
Found: C, 63.25; H, 4.02; N, 9.27%.
2-Chloro-3-(4-methylphenylamino)methylquinoline (6)
IR (KBr) cm-1: 3407 (N–H), 1613 (C=C), 1590 (C=N),
1
1024 (C–N), 758 (C–Cl). H-NMR (300 MHz, CDCl3): d
2.23 (s, 3H, CH3), 4.25 (s, 1H, NH, D2O-exchangeble),
4.56 (s, 2H, CH2), 6.55–6.57 (d, 2H, H-20 and 60,
J = 6.8 Hz), 6.98–7.00 (d, 2H, H-30 and 50, J = 6.9 Hz),
7.52–7.57 (t, 1H, H-6, J = 7.2 Hz), 7.70–7.76 (m, 2H, H-5
and H-7), 8.01–8.03 (d, 1H, H-8, J = 7.9 Hz), 8.16 (s, 1H,
H-4). 13C-NMR (CDCl3, 75 MHz): d 20.32 (CH3), 46.02
(CH2), 113.08, 127.0, 127.46, 128.10, 129.87, 130.91,
136.60, 144.92, 146.79, 149.88. FAB-MS m/z: 283 (M?),
285 (M ? 2)?. Anal. Calcd for C17H15ClN2: C, 72.21; H,
5.35; N, 9.91. Found: C, 72.02; H, 5.38; N, 9.95%.
2-Chloro-3-(4-chlorophenylamino)methylquinoline (5)
IR (KBr) cm-1: 3411 (N–H), 1612 (C=C), 1596 (C=N),
1
1036 (C–N), 729 (C–Cl). H-NMR (300 MHz, CDCl3): d
4.39 (bs, 1H, NH, D2O-exchangeble), 4.54–4.56 (d, 2H,
CH2, J = 5.56 Hz), 6.53–6.56 (d, 2H, H-20 and 60,
J = 8.5 Hz), 7.10–7.13 (d, 2H, H-30 and 50, J = 8.5 Hz),
7.51–7.56 (t, 1H, H-6, J = 7.4 Hz), 7.68–7.76 (m, 2H, H-5
and H-7), 8.00–8.03 (d, 1H, H-8, J = 8.3 Hz), 8.09 (s, 1H,
H-4). 13C-NMR (CDCl3, 75 MHz): d 46.23 (CH2), 113.86,
125.36, 126.48, 127.75, 129.12, 129.94, 131.67, 137.43,
145.91, 149.24. FAB-MS m/z: 303 (M)?, 305 (M ? 2)?.
3-(4-Bromophenylamino)methyl-2-chloroquinoline (7)
IR (KBr) cm-1: 3417 (N–H), 1635 (C=C), 1596 (C=N),
1
1036 (C–N), 729 (C–Cl). H-NMR (300 MHz, CDCl3): d
4.28 (s, 1H, NH, D2O-exchangeble), 4.55 (s, 2H, CH2),
123

Med Chem Res (2011) 20:1340–1348
1345
6.60–6.62 (d, 2H, H-20 and 60, J = 7.9 Hz), 7.05–7.7.03 (d,
2H, H-30 and 50, J = 8.0 Hz), 7.51–7.55 (t, 1H, H-6,
J = 7.11 Hz), 7.67–7.76 (m, 2H, H-5 and H-7), 8.02–8.04
(d, 1H, H-8, J = 8.1 Hz), 8.15 (s, 1H, H-4). 13C-NMR
(CDCl3, 75 MHz): d 45.63 (CH2), 109.81, 114.53, 127.19,
127.46, 128.13, 130.20, 132.10, 136.50, 146.16, 146.86,
149.73. FAB-MS m/z: 348 (M)?, 350 (M ? 2)?. Anal.
Calcd for C16H12BrClN2: C, 55.28; H, 3.48; N, 8.06.
Found: C, 55.06; H, 3.51; N, 8.11%.
2-Chloro-3-(4-nitrophenylamino)methylquinoline (11)
IR (KBr) cm-1: 3421 (N–H), 1632 (C=C), 1602 (C=N), 1039
(C–N), 765 (C–Cl). 1H-NMR (300 MHz, CDCl3): d 4.26 (s,
1H, NH, D2O-exchangeble), 4.55 (s, 2H, CH2), 6.57–6.60 (d,
2H, H-20 and 60, J = 7.9 Hz), 7.05–7.07 (d, 2H, H-30 and 50,
J = 8.1 Hz), 7.49–7.53 (t, 1H, H-6, J = 7.1 Hz), 7.69–7.75
(m, 2H, H-5 and H-7), 8.01–8.03 (d, 1H, H-8, J = 8.1 Hz)
8.15 (s, 1H, H-4). Anal. Calcd for C16H12ClN3O2: C, 61.25;
H, 3.86; N, 13.39. Found: C, 61.39; H, 3.83; N, 13.44%.
2-Chloro-3-(3-chlorophenylamino)methylquinoline (8)
2-Chloro-3-(3-methylphenylamino)methylquinoline (12)
IR (KBr) cm-1: 3422 (N–H), 1625 (C=C), 1585 (C=N),
IR (KBr) cm-1: 3426 (N–H), 1612 (C=C), 1598 (C=N),
1
1052 (C–N), 759 (C– Cl). H-NMR (300 MHz, CDCl3): d
1
1039 (C–N), 760 (C–Cl). H-NMR (300 MHz, CDCl3): d
4.44 (s, 1H, NH, D2O-exchangeble), 4.56 (s, 2H, CH2),
6.50–6.52 (d, 1H, H-60, J = 7.2 Hz), 6.62 (s, 1H, H-20),
6.70–6.72 (d, 1H, H-40, J = 7.0 Hz), 7.05–7.08 (t, 1H, H-50,
J = 7.4 Hz), 7.53–7.56 (t, 1H, H-6, J = 7.1 Hz), 7.71–7.77
(m, 2H, H-5 and 7), 8.03–8.01 (d, 1H, H-8, J = 7.8 Hz),
8.10 (s, 1H, H-4). Anal. Calcd for C16H12Cl2N2: C,. 63.38;
H, 3.99; N, 9.24. Found: C, 63.20; H, 3.96; N, 9.28%.
2.25 (s, 3H, CH3), 4.29 (bs, 1H, NH, D2O-exchangeble),
4.56 (s, 2H, CH2), 6.46 (bs, 2H, H-20 and 60), 6.56–6.59 (d,
1H, H-40 J = 6.7 Hz), 7.03–7.06 (t, 1H, H-50, J = 7.0 Hz),
7.51–7.54 (t, 1H, H-6, J = 6.9 Hz), 7.67–7.76 (m, 2H, H-5
and H-7), 8.00–8.03 (d, 1H, H-8, J = 7.7 Hz), 8.15 (s, 1H,
H-4). Anal. Calcd for C17H15ClN2: C, 72.21; H, 5.35; N,
9.91. Found: C, 72.45; H, 5.32; N, 9.94%.
2-Chloro-3-(4-methoxyphenylamino)
2-Chloro-3-(2-methylphenylamino)methylquinoline (13)
methylquinoline (9)
IR (KBr) cm-1: 3432 (N–H), 1636 (C=C), 1606 (C=N),
IR (KBr) cm-1: 3312 (N–H), 1610 (C=C), 1593 (C=N),
1
1
1035 (C–N), 744 (C–Cl). H-NMR (300 MHz, CDCl3): d
1027 (C–N), 751 (C– Cl). H-NMR (300 MHz, CDCl3): d
2.26 (s, 3H, CH3), 4.28 (s, 1H, NH), 4.57 (s, 2H, CH2),
6.53–6.55 (d, 1H, H-60, J = 7.2 Hz), 6.79–6.98 (m, 3H,
phenyl-H), 7.49–7.54 (t, 1H, H-6, J = 7.0 Hz), 7.68–7.79
(m, 2H, H-5 and H-7), 8.02–8.04 (d, 1H, H-8, J = 7.7 Hz),
8.16 (s, 1H, H-4). Anal. Calcd for C17H15ClN2: C, 72.21;
H, 5.35; N, 9.91. Found: C, 72.43; H, 5.37; N, 9.95%.
3.37 (s, 3H, OCH3), 4.23 (s, 1H, NH, D2O-exchangeble),
4.53 (s, 2H, CH2), 6.58–6.61 (d, 2H, H-20 and 60,
J = 7.9 Hz), 6.76–6.78 (d, 2H, H-30 and 5’, J = 8.0 Hz),
7.50–7.54 (t, 1H, H-6, J = 7.1 Hz), 7.67–7.76 (m, 2H, H-5
and H-7), 8.00–8.03 (d, 1H, H-8, J = 8.1 Hz), 8.16 (s, 1H,
H-4). 13C-NMR (CDCl3, 75 MHz): d 46.10 (CH2), 55.13
(OCH3), 112.54, 115.08, 125.29, 127.73, 128.41, 129.93,
131.27, 141.55, 145.47, 149.78, 157.34. FAB-MS m/z: 299
(M)?, 301 (M ? 2)?. Anal. Calcd for C17H15ClN2O: C,
68.34; H, 5.06; N, 9.38. Found: C, 68.57; H, 5.03; N, 9.42%.
2-Chloro-3-(3-chloro-4-flourophenylamino)
methylquinoline (14)
IR (KBr) cm-1: 3431 (N–H), 1630 (C=C), 1598 (C=N),
1
1025 (C–N), 763 (C–Cl). H-NMR (300 MHz, CDCl3): d
2-Chloro-3-(4-flourophenylamino)methylquinoline (10)
4.29 (s, 1H, NH), 4.56 (s, 2H, CH2), 6.47–6.49 (d, 1H, H-60,
J = 8.1 Hz), 6.72 (s, 1H, H-20), 7.17–7.19 (d, 1H, H-50,
J = 8.1 Hz), 7.54–7.57 (t, 1H, H-6, J = 7.0 Hz), 7.71–7.79
(m, 2H, H-5 and H-7), 8.02–8.05 (d, 1H, H-8, J = 8.3 Hz)
8.09 (s, 1H, H-4). Anal. Calcd for C16H11Cl2FN2: C, 59.83;
H, 3.45; N, 8.72. Found: C, 59.65; H, 3.48; N, 8.77.
IR (KBr) cm-1: 3410 (N–H), 1635 (C=C), 1596 (C=N),
1
1034 (C–N), 728 (C– Cl). H-NMR (300 MHz, CDCl3): d
4.27 (s, 1H, NH, D2O-exchangeble), 4.56 (s, 2H, CH2),
6.56–6.58 (d, 2H, H-20 and 60, J = 7.6 Hz), 7.07–7.09 (d,
2H, H-30 and 50, J = 7.3 Hz), 7.52–7.56 (t, 1H, H-6,
J = 7.1 Hz), 7.71–7.77 (m, 2H, H-5 and H-7), 8.01–8.04
(d, 1H, H-8, J = 7.9 Hz), 8.13 (s, 1H, H-4). 13C-NMR
(CDCl3, 75 MHz): d 46.24 (CH2), 113.81, 115.68, 115.97,
127.12, 127.29, 127.44, 128.08, 130.13, 130.45, 135.74,
136.58, 143.48, 146.79, 149.80, 154.52, 157.64. FAB-MS
m/z: 287 (M)?, 289 (M ? 2)?. Anal. Calcd for
C16H12ClFN2: C, 67.02; H, 4.22; N, 9.77. Found: C, 67.26;
H, 4.20; N, 9.81%.
2-Chloro-3-(2-chlorophenylamino)methylquinoline (15)
IR (KBr) cm-1: 3412 (N–H), 1630 (C=C), 1590 (C=N),
1
1036 (C–N), 759 (C–Cl). H-NMR (300 MHz, CDCl3): d
4.28 (s, 1H, NH, D2O-exchangeble), 4.56 (s, 2H, CH2),
6.58–6.60 (d, 1H, H-60, J = 7.2 Hz), 6.78–7.03 (m, 3H,
phenyl-H), 7.52–7.57 (t, 1H, H-6, J = 7.4 Hz), 7.77–7.69
123

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Med Chem Res (2011) 20:1340–1348
(m, 2H, H-5 and H-7), 8.01–8.04 (d, 1H, H-8, J = 8.3 Hz)
8.10 (s, 1H, H-4). Anal. Calcd for C16H12Cl2N2: C,. 63.38;
H, 3.99; N, 9.24. Found: C, 63.22; H, 3.96; N, 9.27%.
suspension in DMF and the reaction mixture was stirred at
25°C for 60 min. Dimethyl sulfate 0.36 g (0.0028 mol) was
added, and the reaction mixture was stirred for a further
6–8 h and then quenched with water (30 ml). The product
was collected, dried, and crystallized from methanol.
2-Chloro-3-(3,4-dichlorophenylamino)methylquinoline
(16)
N-[(2-chloroquinolin-3-yl)methyl]-N-methylaniline (20)
IR (KBr) cm-1: 3402 (N–H), 1620 (C=C), 1595 (C=N), 1029
(C–N), 754 (C–Cl). 1H-NMR (300 MHz, CDCl3): d 4.27 (s,
1H, NH, D2O-exchangeble), 4.55 (s, 2H, CH2), 6.45–6.47 (d,
1H, H-60, J = 8.1 Hz), 6.71 (s, 1H, H-20), 7.18–7.20 (d, 1H,
H-50, J = 8.1 Hz), 7.55–7.58 (t, 1H, H-6, J = 7.1 Hz),
7.72–7.78 (m, 2H, H-5 and H-7), 8.01–8.04 (d, 1H, H-8,
J = 8.3 Hz) 8.08 (s, 1H, H-4). Anal. Calcd for C16H11Cl3N2:
C,56.92;H, 3.28;N, 8.30. Found:C,56.77;H, 3.30;N, 8.34%.
IR (KBr) cm-1: 1634 (C=C), 1599 (C=N), 1024 (C–N),
1
759 (C–Cl). H-NMR (300 MHz, CDCl3): d 2.23 (s, 3H,
N–CH3), 4.47 (s, 2H, CH2), 6.61–6.64 (d, 2H, H-20 and 60,
J = 7.4 Hz), 6.74–6.79 (m, 1H, H-40), 7.14–7.17 (d, 2H,
H-30 and 50, J = 7.2 Hz), 7.49–7.54 (t, 1H, H-6,
J = 7.1 Hz), 7.68–7.78 (m, 2H, H-5 and H-7), 8.01–8.04
(d, 1H, H-8, J = 7.3 Hz), 8.13 (s, 1H, H-4). 13C-NMR
(CDCl3, 75 MHz): d 39.17 (N–CH3) 45.83 (CH2), 112.73,
116.19, 126.33, 127.07, 127.92, 128.13, 129.75, 131.21,
136.76, 146.90, 148.83. FAB-MS m/z: 283 (M)?, 285
(M ? 2)?. Anal. Calcd for C17H15ClN2: C, 72.21; H, 5.35;
N, 9.91. Found: C, 72.04; H, 5.38; N, 9.97%.
2-Chloro-3-(cyclohexylamino)methylquinoline (17)
IR (KBr) cm-1: 3411 (N–H), 1612 (C=C), 1596 (C=N),
1
1036 (C–N), 729 (C– Cl). H-NMR (300 MHz, CDCl3): d
4.39 (bs, 1H, NH, D2O-exchangeble), 4.54 (d, 2H, CH2),
7.51–7.56 (t, 1H, H-6, J = 7.3 Hz), 7.68–7.76 (m, 2H, H-5
and H-7), 8.00–8.03 (d, 1H, H-8, J = 8.3 Hz) 8.09 (s, 1H,
H-4). Anal. Calcd for C16H19ClN2: C,. 69.93; H, 6.97; N,
10.19. Found: C, 69.70; H, 7.03; N, 10.26%.
4-Chloro-N-[(2-chloroquinolin-3-yl)methyl]-N-
methylaniline (21)
IR (KBr) cm-1: 1619 (C=C), 1598 (C=N), 1041 (C–N), 743
(C–Cl). 1H-NMR (300 MHz, CDCl3): d 2.21 (s, 3H, N–CH3),
4.48 (s, 2H, CH2), 6.50–6.53 (d, 2H, H-20 and 60, J = 8.4 Hz),
7.11–7.14 (d, 2H, H-30 and 50, J = 8.1 Hz), 7.51–7.56 (t, 1H,
H-6, J = 7.3 Hz), 7.69–7.78 (m, 2H, H-5 and H-7), 7.99–8.02
(d, 1H, H-8, J = 8.1 Hz), 8.11(s, 1H, H-4). FAB-MSm/z:317
(M)?, 319 (M ? 2)?. Anal. Calcd for C17H14Cl2N2: C,.
64.37; H, 4.45; N, 8.83. Found: C, 64.17; H, 4.51; N, 8.86%.
2-Chloro-3-(butylamino)methylquinoline (18)
IR (KBr) cm-1: 3312 (N–H), 1610 (C=C), 1593 (C=N),
1
1027 (C–N), 751 (C–Cl). H-NMR (300 MHz, CDCl3): d
4.23 (s, 1H, NH, D2O-exchangeble), 4.53 (s, 2H, CH2),
7.50–7.54 (t, 1H, H-6, J = 7.1 Hz), 7.67–7.76 (m, 2H, H-5
and H-7), 8.00–8.03 (d, 1H, H-8, J = 8.1 Hz) 8.16 (s, 1H,
H-4). Anal. Calcd for C14H17ClN2: C, 67.60; H, 6.89; N,
11.26. Found: C, 67.79; H, 6.93; N, 11.32%.
3-Chloro-N-[(2-chloroquinolin-3-yl)methyl]-N-
methylaniline (22)
N-Benzyl-1-(2-chloroquinolin-3-yl)methanamine (19)
IR (KBr) cm-1: 1630 (C=C), 1589 (C=N), 1047 (C–N),
759 (C–Cl). 1H-NMR (300 MHz, CDCl3): d 2.24 (s, 3H, N-
CH3), 4.46 (s, 2H, CH2), 6.48–6.50 (d, 1H, H-60,
J = 7.1 Hz), 6.64 (s, 1H, H-20), 6.71–6.73 (d, 1H, H-40,
J = 7.1 Hz), 7.02–7.06 (t, 1H, H-50, J = 7.4 Hz),
7.54–7.57 (t, 1H, H-6, J = 7.2 Hz), 7.70–7.77 (m, 2H, H-5
and H-7), 8.00–8.03 (d, 1H, H-8, J = 7.7 Hz), 8.10 (s, 1H,
H-4). Anal. Calcd for C17H14Cl2N2: C, 64.37; H, 4.45; N,
8.83. Found: C, 64.56; H, 4.49; N, 8.87%.
IR (KBr) cm-1: 3428 (N–H), 1631 (C=C), 1592 (C=N),
1
1027 (C–N), 760 (C–Cl). H-NMR (300 MHz, CDCl3): d
3.81 (s, 2H, CH2-Benzyl), 4.07 (bs, NH, D2O-exchange-
ble), 4.41 (s, 2H, CH2), 6.65–6.68 (d, 2H, H-20 and 60, J =
7.71 Hz), 6.72–6.77 (m, 1H, H-4, Ph-H), 7.19–7.22 (m, 2H,
H-30 and 50), 7.48–7.53 (t, 1H, H-6, J = 7.11 Hz), 7.65–7.75
(m, 2H, H-5 and H-7), 8.01–8.04 (d, 1H, H-8, J = 7.53 Hz),
8.10 (s, 1H, H-4). Anal. Calcd for C17H15ClN2: C, 72.21;
H, 5.35; N, 9.91. Found: C, 72.06; H, 5.39; N, 97.96%.
N-[(2-chloroquinolin-3-yl)methyl]-4-fluoro-N-
methylaniline (23)
Synthesis of compounds 20–25
IR (KBr) cm-1: 1632 (C=C), 1590 (C=N), 1037 (C–N),
1
Sodium hydride 0.14 g (0.0056 mol) was suspended in dry
DMF (15 ml) and compounds 4/5/8/10/14/16 (0.002 mol)
dissolved in DMF (15 ml) was added to the sodium hydride
763 (C–Cl). H-NMR (300 MHz, CDCl3): d 2.23 (s, 3H,
N–CH3), 4.45 (s, 2H, CH2), 6.53–6.56 (d, 2H, H-20 and 60,
J = 7.5 Hz), 7.10–7.13 (d, 2H, H-30 and 50, J = 7.6 Hz),
123

Med Chem Res (2011) 20:1340–1348
1347
Table 2 Antifungal activity data of compounds 4–25
Compd. no.
X
ClogP
Zone of inhibition in mm (Mean SD)
A. niger MTCC 281 A. flavus MTCC 277 M. purpureus MTCC 369 P. citrinum NCIM 768
4
H
3.62 0.25 11.97 0.67
4.40 0.42 15.86 0.48
4.08 0.25 10.90 0.43
4.79 0.35 13.66 0.96
4.75 1.17 13.40 0.70
3.44 0.26 10.76 0.47
4.07 0.35 14.76 1.05
12.36 0.61
16.0 0.72
12.80 0.60
10.46 0.75
11.63 0.76
12.96 0.46
15.03 0.65
8.33 0.25
10.10 0.62
7.03 0.55
19.66 0.66
10.60 0.90
18.73 0.65
–
7.70 0.79
9.73 0.60
7.63 0.55
8.0 0.72
9.63 0.61
7.66 0.47
9.80 0.55
7.70 0.55
7.60 0.36
6.40 0.36
11.50 0.65
7.33 0.40
9.70 0.55
–
8.06 0.55
10.33 0.40
8.06 0.37
9.86 0.30
8.03 0.51
7.63 0.49
8.53 0.58
6.13 0.47
5.73 0.32
7.03 0.51
9.73 0.41
7.06 0.37
8.76 0.20
–
5
4-Cl
6
4-CH3
4-Br
7
8
3-Cl
9
4-OCH3
4-F
10
11
4-NO2
3-CH3
2- CH3
3-Cl,4-F
2-Cl
4.07 0.27
4.08 0.25
4.08 0.25
8.06 0.25
9.53 0.75
8.66 0.35
12
13
14
5.31 1.17 17.76 0.55
4.13 0.32 13.90 0.68
5.40 1.17 19.60 1.05
15
16
3,4-(Cl)2
17
Cyclohexyl 4.07 0.26
6.27 1.05
9.47 0.55
18
Butyl
Benzyl
H
3.60 0.26
8.25 0.65
14.49 0.96
14.16 0.55
17.73 0.43
12.08 0.36
17.15 0.75
20.82 0.94
19.52 0.31
25.13 0.59
–
–
19
3.91 0.28 15.69 1.00
4.71 0.26 13.24 0.83
5.12 0.41 17.08 0.65
5.67 0.28 15.21 1.03
4.80 0.66 15.86 0.26
5.86 0.76 19.44 1.00
5.95 0.43 21.13 0.86
8.40 0.35
8.09 0.46
10.46 0.93
9.63 1.00
11.46 0.71
13.07 0.55
10.43 0.59
26.24 1.00
9.06 0.32
9.74 1.03
9.85 0.55
11.14 0.73
9.77 0.48
10.41 0.28
11.05 0.87
21.77 0.97
20
21
4-Cl
22
3-Cl
23
4-F
24
3-Cl, 4-F
3,4-(Cl)2
–
25
Terbinafine
–
24.71 0.98
7.51–7.55 (t, 1H, H-6, J = 7.0 Hz), 7.70–7.77 (m, 2H, H-5
and H-7), 8.01–8.04 (d, 1H, H-8, J = 7.8 Hz), 8.11 (s, 1H,
H-4). Anal. Calcd for C16H12ClFN2: C, 67.02; H, 4.22; N,
9.77. Found: C, 67.26; H, 4.20; N, 9.81%.
J = 8.7 Hz), 6.74 (s, 1H, H-20), 7.20–7.22 (d, 1H, H-50,
J = 8.1 Hz), 7.57–7.60 (t, 1H, H-6, J = 7.1 Hz),
7.73–7.80 (m, 2H, H-5 and H-7), 8.00–8.03 (d, 1H, H-8,
J = 8.4 Hz), 8.11 (s, 1H, H-4). Anal. Calcd for
C16H11Cl3N2: C, 56.92; H, 3.28; N, 8.30. Found: C, 56.77;
H, 3.30; N, 8.34%.
3-Chloro-N-[(2-chloroquinolin-3-yl)methyl]-4-fluoro-
N-methylaniline (24)
Antifungal activity
IR (KBr) cm-1: 1629 (C=C), 1593 (C=N), 1039 (C–N), 760
1
(C–Cl). H-NMR (300 MHz, CDCl3): d 2.20 (s, 3H, N–
The newly synthesized compounds were screened in vitro
for their antifungal activity against Aspergillus niger
MTCC 281, Aspergillus flavus MTCC 277, Monascus
purpureus MTCC 369 and Penicillium citrinum NCIM 768
in DMSO (100%) by cup-plate method (Varma et al.,
1998; Cruickshank et al. 1975). Potato dextrose agar (Hi-
media, Mumbai India) was used as culture medium. Nor-
mal saline with tween 80 (0.01%) was used to make sus-
pension of fungal spore for lawning. Fifty milliliters of
PDA medium was poured into each petri dish (15 cm
diameter). 5 mL of the spore suspension was spread over
the solid agar medium and plates were dried in incubator at
37° for 1 h. Using an agar punch, wells were made on these
seeded agar plates and solutions of 200 lg/mL of test
CH3), 4.45 (s, 2H, CH2), 6.42–6.44 (d, 1H, H-60,
J = 8.2 Hz), 6.75 (s, 1H, H-20), 7.16–7.18 (d, 1H, H-50,
J = 8.0 Hz), 7.54–7.57 (t, 1H, H-6, J = 7.1 Hz), 7.72–7.80
(m, 2H, H-5 and H-7), 8.01–8.04 (d, 1H, H-8, J = 8.2 Hz),
8.07 (s, 1H, H-4). Anal. Calcd for C16H11Cl2FN2: C, 59.83;
H, 3.45; N, 8.72. Found: C, 59.65; H, 3.48; N, 8.77.
3,4-Dichloro-N-[(2-chloroquinolin-3-yl)methyl]-N-
methylaniline (25)
IR (KBr) cm-1: 1627 (C=C), 1598 (C=N), 1041 (C–N),
1
756 (C–Cl). H-NMR (300 MHz, CDCl3): d 2.21 (s, 3H,
CH3), 4.49 (s, 2H, CH2), 6.44–6.46 (d, 1H, H-60,
123

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Med Chem Res (2011) 20:1340–1348
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compounds in DMSO were added into each well, labeled
previously. A control was also prepared using solvent
DMSO. The petri plate were prepared in triplicate and
maintained at 30° for 72 h. Antifungal activity was deter-
mined by measuring zone of inhibition in millimeter and
results were reported as (Mean zone of inhibition Stan-
dard Deviation). Activity of each compound was compared
with standard Terbinafine (100 lg/mL) and results have
been summarized in Table 2.
Acknowledgments The author (SK) is thankful to the University
Grant Commission (UGC), New Delhi, India, for the award of UGC-
JRF. The authors are also thankful to Department of pharmaceutical
chemistry, faculty of pharmacy, Jamia Hamdard for providing nec-
essary facility and CDRI, Lucknow, India for recording FAB-MS
spectral data.
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