Development of 8-benzyloxy-substituted quinoline ethers and evaluation of their antimicrobial activities

Article abstract of DOI:10.1007/s00044-014-1217-4

A series of 8-benzyloxy-substituted quinoline ethers (2a-n) compounds were synthesized. All synthesized compounds were screened in vitro for their preliminary antimicrobial activities against two Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), two Gram-positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis), and a fungal species (Aspergillus niger). Among all synthesized compounds, compound 2e showed a significant growth inhibitory activity with MIC value 3.125 μg/mL which was comparable to 8-hydroxyquinoline (2.5 μg/mL) and terbinafine (1.25 μg/mL) against A. niger.

Full text of DOI:10.1007/s00044-014-1217-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2015) 24:1568–1577
DOI 10.1007/s00044-014-1217-4
ORIGINAL RESEARCH
Development of 8-benzyloxy-substituted quinoline ethers
and evaluation of their antimicrobial activities
•
Po-Yee Chung Roberto Gambari Yi-Xin Chen Chor-Hing Cheng
•
•
•
•
Zhao-Xiang Bian Albert Sun-Chi Chan Johnny Cheuk-On Tang
•
•
•
Polly Hang-Mei Leung Chung-Hin Chui Kim-Hung Lam
•
Received: 10 April 2014 / Accepted: 1 August 2014 / Published online: 2 September 2014
Ó Springer Science+Business Media New York 2014
Abstract A series of 8-benzyloxy-substituted quinoline
ethers (2a–n) compounds were synthesized. All synthe-
sized compounds were screened in vitro for their
preliminary antimicrobial activities against two Gram-
negative bacteria (Pseudomonas aeruginosa and Esche-
richia coli), two Gram-positive bacteria (Staphylococcus
aureus and Staphylococcus epidermidis), and a fungal
species (Aspergillus niger). Among all synthesized com-
pounds, compound 2e showed a significant growth inhibi-
tory activity with MIC value 3.125 lg/mL which was
comparable to 8-hydroxyquinoline (2.5 lg/mL) and terbi-
nafine (1.25 lg/mL) against A. niger.
Introduction
Both bacteria and fungi are pathogens to cause human
infections. The evolution of microbial infections is of para-
mount concern over the world. The common types of bac-
terial species that induce various infections include
Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli
(E. coli), Staphylococcus aureus (S. aureus), and Staphylo-
coccus epidermidis (S. epidermidis). P. aeruginosa is a
Gram-negative bacterium with minimal growth require-
ments to survive in diverse habitats. It is an opportunistic
pathogen which leads to various diseases such as pneumonia,
urinary tract infections, wound and burn infections, bacter-
aemia, and septicaemia in non-immune hosts (Kerr and
Snelling, 2009; Weiser et al., 2014). E. coli is also a Gram-
negative microorganism that causes urinary tract infections,
septicemia, neonatal meningitis, pneumonia, intra-abdomi-
nal infections, and surgical wound infections (Johnson et al.,
2013). S. aureus is a Gram-positive pathogen that results in
various humaninfections from superficial skin and soft tissue
infections to life-threatening endocarditis, toxic-shock syn-
drome, and necrotizing pneumonia, leading to high human
morbidity and mortality worldwide (Ewa et al., 2012; Lowy,
1998; Verkade and Kluytmans, 2014). S. epidermidis is also
a Gram-positive bacterium which resides in human skin and
mucosal surfaces. It is a common cause of indwelling med-
ical device infections including intravascular and intrathecal
catheter systems, pace maker electrodes, urinary tract cath-
eters, and a range of polymeric and metal implants (Otto,
2009; Ziebuhr et al., 2006). S. epidermidis-associated
infections tend to invade immunocompromised and long-
term hospitalized patients (Ziebuhr et al., 2006). Aspergillus
species causes a variety of infections in lung transplant
receipts and immunocompromised patients (Singh and Pat-
erson, 2005; Walsh et al., 2008), particularly Aspergillus
Keywords 8-Hydroxyquinoline ꢀ A549 cells ꢀ
Antimicrobial ꢀ Aspergillus niger
P.-Y. Chung ꢀ C.-H. Cheng ꢀ J. C.-O. Tang ꢀ K.-H. Lam (&)
State Key Laboratory of Chirosciences, Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hong Kong, China
e-mail: kim.hung.lam@polyu.edu.hk
R. Gambari
Department of Life Sciences and Biotechnology, Centre of
Biotechnology, University of Ferrara, Ferrara, Italy
Y.-X. Chen
Department of Chemistry, Guangzhou University, Guangzhou,
China
Z.-X. Bian ꢀ A. S.-C. Chan ꢀ C.-H. Chui (&)
Clinical Division, School of Chinese Medicine, Hong Kong
Baptist University, Hong Kong, China
e-mail: chchui@hkbu.edu.hk
P. H.-M. Leung
Department of Health Technology and Informatics, The Hong
Kong Polytechnic University, Hong Kong, China
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niger (A. niger) which is a mold potentially causing asper-
gillosis (Melissa et al., 2008), and pulmonary oxalosis
(Procop and Johnston, 1997; Roehrl et al., 2007). It has been
reported that death may result from the pulmonary and renal
oxalosis caused by A. niger fungus ball due to the oxalate
crystal deposition (Kuwabara and Shibayama, 2012; Roehrl
et al., 2007). The formation of calcium oxalate crystal is due
to the reaction between oxalic acid which is the side product
of the fermentation by A. niger (Oda et al., 2013) and calcium
in tissue or blood (Kuwabara and Shibayama, 2012). The
massive deposition of calcium oxalate crystals in lung results
in cell death or lung damage (Roehrl et al., 2007). Therefore,
there is a necessity to develop an agent with an effective
growth inhibitory activity against A. niger. Quinoline
derivatives are bioactive heterocyclic compounds which
have superior importance in pharmaceutical science, tar-
geting to antitumor (Chan et al., 2013; Chen et al., 2013;
El-Agrody et al., 2013), antimalarials (Kaur et al., 2010),
anticonvulsants (He et al., 2012), and antimicrobials
(Banerjee et al., 2014; Vandekerckhove et al., 2013; Sahu
et al., 2013). For instance, Shi et al. reported that their syn-
thesized 6-methoxy-8-[(2-furanylmethyl)amino]-4-methyl-
5-(3-trifluoromethylphenyloxy)quinoline was effective for
T47D breast cancer cells (Shi et al., 2008). Tavares and
coworkers reported the preparation of a series of 6-quinoli-
nyl chalcones and their strong activity against P. brasiliensis
as well as for MCF-7 and TK-10 cancer cells (Tavares et al.,
2011). Bulky functionality on quinoline moiety core offered
good bioactivity, such as 4-alkoxy-2-phenylquinoline
derivatives and 8-methyl-2-aryl-5-alkylaminoquinolines
were reported to possess biological activities and can be
employed as potent antiplatelet agents (Ko et al., 2001) and
corticotropin-releasing factor-1 (CRF1) receptor antagonists
(Kunitoshi et al., 2012), respectively. Rojas Ruiz et al.
reported the 4-benzylamino-7-chloroquinolines and
4-amino-7-chloroquinoline-thiazolidinone derivatives were
effective antimalarial agents (Rojas Ruiz et al., 2011), while
Krishnakumar reported that their quinoline carboxylates are
moderate antibacterial activity against Bacillus subtilis and
Vibrio cholera (Krishnakumar et al., 2012). Wu et al.
reported the preparation quinoline-4-methyl esters as human
nonpancreatic secretory phospholipase competitive inhibi-
tors (Wu et al., 2011). In addition, researches also reported
that oxime ether (Parthiban et al., 2009) and aryl ether (Xu
et al., 2007) can be used in the design of novel antifungal
agent. There are numerous conditions have been developed
for the aromatic ether synthesis and one of the effective
methodologies is the O-alkylation under phase transfer
catalysis. Yadav and co-worker reported a preparation
method with high selectivity for the synthesis of benzyl-2-
naphthyl ether from b-naphthol and benzyl chloride via
multiphase transfer catalysis (Yadav and Bisht, 2004). A
novel preparation of substituted aromatic ether using phase
transfer catalyzed alkylation of substituted acetophenone
with alkyl bromide in a biphasic system was also reported
(Yadav and Desai, 2006). Functions of phase transfer agent
are to facilitate the interphase transfer of species and to
maintain the transfer of anionic reactant from aqueous phase
to organic phase in liquid–liquid system. Quaternary
ammonium salt is a preferential phase transfer catalyst
because of their inexpensiveness and stabilities in alkaline
condition (Landini et al., 1986). Among the quaternary
ammonium salts, tetrabutylammonium bromide (TBAB) is
one of the common catalysts for phase transfer catalyzed
alkylation, including S-alkylation, N-alkylation, and
O-alkylation (Liu and Wang, 2008; Denton, 2010; Sahu
et al., 2013). During the time, our group reported that the
8-alkoxy-substituted and 8-benzyloxy-substituted quinal-
dine show antitumor activity against Hep3B, A549, HKESC-
1, and KYSE260 cell lines (Chan et al., 2013). Recently, we
have reported the preparation of 8-hydroxyquinoline deriv-
atives as potential antibiotics against S. aureus (Lam et al.,
2014a). Thus, the approach of this study is to develop
effective antimicrobial agents targeting to both Gram-neg-
ative and Gram-positive bacteria as well as A. niger by
synthesizing a series of 8-hydroxyquinoline derivatives
using O-alkylation.
Experimental
Materials and methods
All reagents were purchased from Sigma-Aldrich, Ger-
many. A series of 8-benzyloxy-substituted quinoline ethers
(2a–n) was synthesized using a known convenient syn-
thetic procedure under mild condition via a simple nucle-
ophilic substitution reaction (Sahu et al., 2013). All the
synthesized compounds are characterized by 1H NMR, 13
C
NMR, and mass spectrometry. NMR spectra were recorded
on a Brucker DPX400. Fourier transform spectrometer
using CDCl3 as solvent unless otherwise specified. To a
solution of 8-hydroxyquinoline (0.29 g, 2 mmol) in
dichloromethane (20 mL), benzyl halide (RX, 1.80 mmol,
where X = Br or Cl), tetra butyl ammonium bromide
(TBAB,1.5 wt%), and 10 % aqueous potassium hydroxide
(20 mL) were added. The reaction mixture was stirred at
room temperature and monitored by thin layer chroma-
tography. After the reaction was completed, the organic
layer was washed with water and dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the crude product was purified by silica gel
(230-400 mesh size) column chromatography (n-hexane:
ethyl acetate = 5:1).
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Med Chem Res (2015) 24:1568–1577
8-(3-methoxybenzyloxy)-quinoline (2a)
115.66 (C, Ar–C), 120.09 (C, Ar–C), 121.67 (C, Ar–C),
126.52 (C, Ar–C), 129.13 (C, Ar–C), 129.55 (C, Ar–C),
132.68 (C, Ar–C), 135.93 (C, Ar–C), 140.52 (C, Ar–C),
149.46 (C, Ar–C), 154.22 (C, Ar–C), 161.25 (C, Ar–C),
163.70 (C, Ar–C); HRMS (ESI): Calcd. for C16H13NOF
[M?H]?, 254.0981. found 254.0968. Melting Point =
101.4–103.1 °C; Yield = 74 %.
1H NMR (400 MHz, CDCl3): d 3.80 (s, 3H, OCH3), 5.46
(s, 2H, OCH2), 6.85-6.87 (m, 1H, Ar–H), 7.04–7.06 (m,
1H, Ar–H), 7.11–7.13 (m, 2H, Ar–H), 7.38-7.40 (m, 3H,
Ar–H), 7.44–7.48 (m, 1H, Ar–H), 8.15 (dd, 1H,
J = 6.8 Hz, 1.6 Hz, Ar–H), 8.99–9.00 (m, 1H, Ar–H); 13
C
NMR (100 MHz, CDCl3): d 55.25 (C, CH3), 70.70 (C,
OCH2), 109.99 (C, Ar–C), 112.43 (C, Ar–C), 113.47 (C,
Ar–C), 119.29 (C, Ar–C), 119.89 (C, Ar–C), 121.61 (C,
Ar–C), 126.59 (C, Ar–C), 129.69 (C, Ar–C), 135.89 (C,
Ar–C), 138.68 (C, Ar–C), 149.37 (C, Ar–C), 159.93 (C,
Ar–C); HRMS (ESI): Calcd. for C17H16NO2 [M?H]?,
266.1181. found 266.1178. Yield = 36 %.
8-(3-bromobenzyloxy)-quinoline (2e)
1H NMR (400 MHz, CDCl3): d 5.43 (s, 2H, OCH2), 7.03
(dd, 1H, J = 4.8 Hz, 2.0 Hz, Ar–H), 7.24–7.26 (m, 1H,
Ar–H), 7.41–7.49 (m, 5H, Ar–H), 7.71 (s, 1H, Ar–H), 8.17
(dd, 1H, J = 6.8 Hz, 1.6 Hz, Ar–H), 9.01 (dd, 1H,
J = 2.4 Hz, 1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3):
d 69.98 (C, OCH2), 109.94 (C, Ar–C), 120.25 (C, Ar–C),
121.71 (C, Ar–C), 122.76 (C, Ar–C), 125.74 (C, Ar–C),
126.54 (C, Ar–C), 129.55 (C, Ar–C), 130.14 (C, Ar–C),
130.24 (C, Ar–C), 130.99 (C, Ar–C), 135.97 (C, Ar–C),
139.30 (C, Ar–C), 140.38 (C, Ar–C), 149.45 (C, Ar–C),
154.06 (C, Ar–C); HRMS (ESI): Calcd. for C16H13NOBr
[M?H]?, 314.0181. found 314.0169. Melting Point =
50.7–52.3 °C; Yield = 67 %.
8-(benzyloxy)-quinoline (2b)
1H NMR (400 MHz, CDCl3): d 5.48 (s, 2H, OCH2), 7.05–7.07
(m, 1H, Ar–H), 7.32–7.41 (m, 5H, Ar–H), 7.45–7.48 (m,1H,
Ar–H), 7.55 (d, 2H, J = 7.2 Hz, Ar–H), 8.15 (dd, 1H,
J = 6.8 Hz, 1.6 Hz, Ar–H), 9.00 (dd, 1H,, J = 2.8 Hz,
1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3): d 70.73 (C,
OCH2), 109.90 (C, Ar–C), 119.86 (C, Ar–C), 121.61 (C, Ar–
C), 126.58 (C, Ar–C), 127.13 (C, Ar–C), 127.82 (C, Ar–C),
128.64(C, Ar–C), 129.51(C, Ar–C), 135.90(C, Ar–C), 136.97
(C, Ar–C), 149.38 (C, Ar–C), 154.34 (C, Ar–C); HRMS (ESI):
Calcd. for C16H14NO [M?H]?, 236.1075. found 236.1067.
Melting Point = 62.0–64.2 °C; Yield = 40 %.
8-(3-methylbenzyloxy)-quinoline (2f)
1H NMR (400 MHz, CDCl3): d 2.37 (s, 3H, CH3), 5.43 (s,
2H, OCH2), 7.06 (t, 1H, J = 4.4 Hz, Ar–H), 7.12–7.14 (m,
1H, Ar–H), 7.27–7.28 (m, 1H, Ar–H), 7.29–7.40 (m, 4H,
Ar–H), 7.44–7.48 (m, 1H, Ar–H), 8.15 (dd, 1H,
J = 6.4 Hz, 1.6 Hz, Ar–H), 9.00 (dd, 1H, J = 2.8 Hz,
1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3): d 21.44 (C,
CH3), 70.83 (C, OCH2), 109.86 (C, Ar–C), 119.78 (C, Ar–
C), 121.60 (C, Ar–C), 124.27 (C, Ar–C), 126.63 (C, Ar–C),
127.87 (C, Ar–C), 128.52 (C, Ar–C), 128.62 (C, Ar–C),
129.51 (C, Ar–C), 135.95 (C, Ar–C), 136.87 (C, Ar–C),
138.30 (C, Ar–C), 140.45 (C, Ar–C), 149.32 (C, Ar–C),
154.42 (C, Ar–C); HRMS (ESI): Calcd. for C17H16NO
[M?H]?, 250.1232. found 250.1226. Yield = 87 %.
8-(3,5-bis-(trifluoromethyl)benzyloxy)-quinoline (2c)
1H NMR (400 MHz, CDCl3): d 5.54 (s, 2H, OCH2), 7.07 (d,
1H, J = 7.6 Hz, Ar–H), 7.43–7.52 (m, 3H, Ar–H), 7.87 (s,
1H, Ar–H), 8.05 (s, 2H, Ar–H), 8.19 (dd, 1H, J = 6.8 Hz,
1.6 Hz, Ar–H), 9.01 (dd, 1H, J = 2.8 Hz, 1.6 Hz, Ar–H);
13C NMR (100 MHz, CDCl3): d 69.92 (C, OCH2), 110.46
(C, Ar–C), 121.10 (C, Ar–C), 121.89 (C, Ar–C), 121.97 (C,
Ar–C), 122.01 (C, Ar–C), 124.59 (C, Ar–C), 126.43 (C, Ar–
C), 127.47 (C, Ar–C), 129.68 (C, Ar–C), 131.51 (C, Ar–C),
131.85 (C, Ar–C), 132.18 (C, Ar–C), 132.51 (C, Ar–C),
136.01 (C, Ar–C), 140.50 (C, Ar–C), 149.71 (C, Ar–C),
153.88 (C, Ar–C); HRMS (ESI): Calcd. for C18H12NOF6
[M?H]?, 372.0823. found 372.0805. Melting Point =
106.3–108.6 °C; Yield = 81 %.
8-(3-phenylbenzyloxy)-quinoline (2g)
1H NMR (400 MHz, CDCl3): d 5.53 (s, 2H, OCH2), 7.10
(d, 1H, J = 4.0 Hz, Ar–H), 7.40–7.46 (m, 7H, Ar–H),
7.55–7.61 (m, 4H, Ar–H), 7.77 (s, 1H, Ar–H), 8.14–8.16
(m, 1H, Ar–H), 9.00 (s, 1H, Ar–H); 13C NMR (100 MHz,
CDCl3): d 70.77 (C, OCH2), 110.00 (C, Ar–C), 119.95 (C,
Ar–C), 121.51 (C, Ar–C), 125.93 (C, Ar–C), 126.24 (C,
Ar–C), 126.51 (C, Ar–C), 126.61 (C, Ar–C), 127.07 (C,
Ar–C), 127.35 (C, Ar–C), 128.73 (C, Ar–C), 129.09 (C,
Ar–C), 129.40 (C, Ar–C), 135.74 (C, Ar–C), 137.54 (C,
Ar–C), 140.45 (C, Ar–C), 140.69 (C, Ar–C), 141.39 (C,
Ar–C), 149.21 (C, Ar–C), 154.33 (C, Ar–C); HRMS (ESI):
8-(4-fluorobenzyloxy)-quinoline (2d)
1H NMR (400 MHz, CDCl3): d 5.42 (s, 2H, OCH2),
7.05–7.10 (m, 3H, Ar–H), 7.41–7.42 (m, 2H, Ar–H),
7.45–7.48 (m, 1H, Ar–H), 7.51-7.55 (m, 2H, Ar–H), 8.16
(dd, 1H, J = 4.4 Hz, 1.6 Hz, Ar–H), 8.99 (dd, 1H,
J = 2.8 Hz, 1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3): d
70.14 (C, OCH2), 109.90 (C, Ar–C), 115.44 (C, Ar–C),
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Med Chem Res (2015) 24:1568–1577
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Calcd. for C22H18NO [M?H]?, 312.1388. found 312.1387.
Yield = 96 %.
8-(4-(trifloromethyl)benzyloxy)-quinoline (2k)
1H NMR (400 MHz, CDCl3): d 5.53 (s, 2H, OCH2), 7.01
(dd, 1H, J = 6.0 Hz, 1.2 Hz, Ar–H), 7.38–7.45 (m, 2H,
Ar–H), 7.47–7.50 (m, 1H, Ar–H), 7.66 (s, 4H, Ar–H), 8.17
(dd, 1H, J = 6.8 Hz, 1.6 Hz, Ar–H), 9.01 (dd, 1H,
J = 2.4 Hz, 1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3):
d 69.97 (C, OCH2), 109.92 (C, Ar–C), 120.37 (C, Ar–C),
121.77 (C, Ar–C), 125.62 (C, Ar–C), 125.66 (C, Ar–C),
126.49 (C, Ar–C), 129.60 (C, Ar–C), 135.96 (C, Ar–C),
140.47 (C, Ar–C), 141.08 (C, Ar–C), 149.56 (C, Ar–C),
153.98 (C, Ar–C); HRMS (ESI): Calcd. for C17H13NOF3
[M?H]?, 304.0949. found 304.0941. Melting Point =
129.1–132.2 °C; Yield = 90 %.
8-(3-nitrobenzyloxy)-quinoline (2h)
1H NMR (400 MHz, CDCl3): d 5.54 (s, 2H, OCH2), 7.06
(dd, 1H, J = 6.0 Hz, 1.2 Hz, Ar–H), 7.41–7.51 (m, 3H,
Ar–H), 7.58 (t, 1H, J = 8.0 Hz, Ar–H), 7.93 (d, 1H,
J = 7.6 Hz, Ar–H), 8.17–8.21 (m, 2H, Ar–H), 8.43 (s, 1H,
Ar–H), 9.01-9.02 (m, 1H, Ar–H); 13C NMR (100 MHz,
CDCl3): d 69.72 (C, OCH2), 110.10 (C, Ar–C), 120.73 (C,
Ar–C), 121.83 (C, Ar–C), 122.16 (C, Ar–C), 122.93 (C,
Ar–C), 126.45 (C, Ar–C), 129.62 (C, Ar–C), 129.72 (C,
Ar–C), 133.23 (C, Ar–C), 135.98 (C, Ar–C), 139.17 (C,
Ar–C), 140.44 (C, Ar–C), 148.47 (C, Ar–C), 149.62 (C,
Ar–C), 153.84 (C, Ar–C); HRMS (ESI): Calcd. for
C16H13N2O3 [M?H]?, 281.0926. found 281.0914. Melting
Point = 83.5–85.2 °C; Yield = 58 %.
8-(4-chlorobenzyloxy)-quinoline (2l)
1H NMR (400 MHz, CDCl3): d 5.43 (s, 2H, OCH2), 7,03
(dd, 1H, J = 4.4 Hz, 2.0 Hz, Ar–H), 7.35-7.42 (m, 4H,
Ar–H), 7.48–7.50 (m, 3H, Ar–H), 8.16 (dd, 1H,
J = 6.8 Hz, 1.6 Hz, Ar–H), 9.00 (dd, 1H, J = 2.4 Hz,
1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3): d 70.02 (C,
OCH2), 109.94 (C, Ar–C), 120.17 (C, Ar–C), 121.70 (C,
Ar–C), 126.50 (C, Ar–C), 128.51 (C, Ar–C), 128.83 (C,
Ar–C), 129.56 (C, Ar–C), 133.63 (C, Ar–C), 135.48 (C,
Ar–C), 135.93 (C, Ar–C), 140.50 (C, Ar–C), 149.49 (C,
Ar–C), 154.10 (C, Ar–C); HRMS (ESI): Calcd. for
C16H13NOCl [M?H]?, 270.0686. found 270.0674. Melting
Point = 106.7–108.8 °C; Yield = 80 %.
8-(2-bromobenzyloxy)-quinoline (2i)
1H NMR (400 MHz, CDCl3): d 5.53 (s, 2H, OCH2), 7.00
(dd, 1H, J = 4.0 Hz, 2.4 Hz, Ar–H), 7.17–7.21 (m, 1H,
Ar–H), 7.31 (d, 1H, J = 7.6 Hz, Ar–H), 7.41–7.50 (m, 3H,
Ar–H), 7.61–7.67 (m, 2H, Ar–H), 8.17 (dd, 1H,
J = 6.8 Hz, 1.6 Hz, Ar–H), 9.01-9.02 (m, 1H, Ar–H); 13C
NMR (100 MHz, CDCl3): d 70.03 (C, OCH2), 109.86 (C,
Ar–C), 120.19 (C, Ar–C), 121.70 (C, Ar–C), 121.76 (C,
Ar–C), 126.62 (C, Ar–C), 127.69 (C, Ar–C), 128.60 (C,
Ar–C), 129.09 (C, Ar–C), 129.54 (C, Ar–C), 132.54 (C,
Ar–C), 135.92 (C, Ar–C), 136.03 (C, Ar–C), 140.42 (C,
Ar–C), 149.47 (C, Ar–C), 153.94 (C, Ar–C); HRMS (ESI):
Calcd. for C16H13NOBr [M?H]?, 314.0181. found
314.0169. Melting Point = 109.5–111.1 °C; Yield =
91 %.
8-(4-bromobenzyloxy)-quinoline (2m)
1H NMR (400 MHz, CDCl3): d 5.42 (s, 2H, OCH2), 7.02 (dd,
1H, J = 4.8 Hz, 2.0 Hz, Ar–H), 7.40–7.46 (m, 5H, Ar–H),
7.52 (d, 2H, J = 8.4 Hz, Ar–H), 8.16 (dd, 1H, J = 6.8 Hz,
1.6 Hz, Ar–H), 9.00 (dd, 1H, J = 2.4 Hz, 1.6 Hz, Ar–H);
13C NMR (100 MHz, CDCl3): d 70.05 (C, OCH2), 109.95
(C, Ar–C), 120.19 (C, Ar–C), 121.70 (C, Ar–C), 126.50 (C,
Ar–C), 128.80 (C, Ar–C), 129.56 (C, Ar–C), 131.78 (C, Ar–
C), 135.94 (C, Ar–C), 136.02 (C, Ar–C), 140.49 (C, Ar–C),
149.49 (C, Ar–C), 154.07 (C, Ar–C); HRMS (ESI): Calcd.
for C16H13NOBr [M?H]?, 314.0181. found 314.0166.
Melting Point = 124.6–126.8 °C; Yield = 80 %.
8-(4-(trifluoromethoxy)benzyloxy)-quinoline (2j)
1H NMR (400 MHz, CDCl3): d 5.45 (s, 2H, OCH2), 7.05
(dd, 1H, J = 3.2 Hz, 2.8 Hz, Ar–H), 7.25 (d, 2H,
J = 8.4 Hz, Ar–H), 7.42–7.49 (m, 3H, Ar–H), 7.59 (d, 2H,
J = 8.4 Hz, Ar–H), 8.17 (dd, 1H, J = 6.8 Hz, 1.6 Hz, Ar–
H), 8.98 (dd, 1H, J = 2.8 Hz, 1.6 Hz, Ar–H); 13C NMR
(100 MHz, CDCl3): d 69.93 (C, OCH2), 109.85 (C, Ar–C),
119.19 (C, Ar–C), 120.23 (C, Ar–C), 121.17 (C, Ar–C),
121.70 (C, Ar–C), 126.50 (C, Ar–C), 128.69 (C, Ar–C),
129.56 (C, Ar–C), 135.67 (C, Ar–C), 135.92 (C, Ar–C),
140.48 (C, Ar–C), 148.82 (C, Ar–C), 149.50 (C, Ar–C),
154.13 (C, Ar–C); HRMS (ESI): Calcd. for C17H13NO2F3
[M?H]?, 320.0898. found 320.0912. Melting Point =
102.3–105.0 °C; Yield = 41 %.
8-(4-nitrobenzyloxy)-quinoline (2n)
1H NMR (400 MHz, CDCl3): d 5.57 (s, 2H, OCH2), 7.00 (d,
1H, J = 6.8 Hz, Ar–H), 7.39–7.52 (m, 3H, Ar–H), 7.73 (d,
2H, J = 8.8 Hz, Ar–H), 8.19 (dd, 1H, J = 6.8 Hz, 1.6 Hz,
Ar–H), 8.26 (d, 2H, J = 8.8 Hz, Ar–H), 9.02 (dd, 1H,
J = 2.8 Hz, 1.6 Hz, Ar–H); 13C NMR (100 MHz, CDCl3): d
69.62 (C, OCH2), 110.02 (C, Ar–C), 120.73 (C, Ar–C),
121.88 (C, Ar–C), 123.94 (C, Ar–C), 126.43 (C, Ar–C),
123

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Med Chem Res (2015) 24:1568–1577
127.50 (C, Ar–C), 129.65 (C, Ar–C), 136.02 (C, Ar–C),
140.43 (C, Ar–C), 144.51 (C, Ar–C), 147.61 (C, Ar–C),
149.66 (C, Ar–C), 153.74 (C, Ar–C); HRMS (ESI): Calcd.
for C16H13N2O3 [M?H]?, 281.0926. found 281.0939.
Melting Point = 151.4–153.2 °C; Yield = 76 %.
compounds. Compounds 2e, 8HQ, and doxorubicin (as
positive control) with the starting concentration of 20 lg/
mL were incubated with cells for a further period of 48 h.
DMSO (0.1 %) was used as a vehicle control. The cyto-
toxicity assessment was conducted by sulforhodamine B
protein staining method. Cells were fixed with trichloro-
acetic acid, washed with deionized water, and stained
with sulforhodamine B. Afterwards, cells were washed
again with acetic acid. Photomicrographs of lung cells
were captured and optical absorptions were then measured
at 575 nm after dissolving in Tris-base buffer using a
Perkin Elmer Victor V multiwell plate reader (Lam et al.,
2014b, c).
Determination of MICs
The concentration of bacteria was adjusted to about 1 x 106
cell/mL while the concentration of A. niger was adjusted to
about 1 9 103 cell/mL. The MIC values of synthesized
compounds were determined by the broth dilution method.
Various concentrations of compounds were added from a
starting concentration of 100 lg/mL (stocks were prepared
as 100 mg/mL in dimethylsulfoxide, DMSO) and they were
diluted serially. Methicillin was used as a positive control for
S. aureus (started at 50 lg/mL) and vancomycin was used as
positive control for S. epidermidis (started at 50 lg/mL).
Terbinafine was used as positive control and 8-HQ (both
started at 40 lg/mL) for A. niger. DMSO (0.1 %) was used
as a vehicle control. The samples with bacteria and A. niger
were then incubated at 37 °C for 24 h and 25 °C for 48 h,
respectively. The minimum concentrations of compounds
that induced a complete growth inhibition will be recorded
as MIC values (Lam et al., 2014a, b).
Results and discussion
Synthesis of 8-benzyloxy-substituted quinoline ethers
8-hydroxyquinoline (8HQ) can be functionalized by
alkylation at hydroxyl group through different synthetic
routes. Bringmann et al. discovered a series of Leishman-
icidal quinolinium salts where the alkylation step of
8-hydroxyquinoline using alkyl halide and potassium car-
bonate (K2CO3) under reflux in acetone for 2 days, and the
high product yield can be achieved (75-99 %) (Bringmann
et al., 2013). Albrecht et al. reported that bis-(8-hydroxy-
quinoline) derivative can be prepared from Williamson
ether synthesis using the excess amount of 3,30-dichloro-
isobene with about 30 % yield (Albrecht et al., 2006). Sahu
et al. reported a methodology for the synthesis of bis-
quinolines through alkylation, which provide excellent
yields, short reaction time, and mild reaction condition.
Owing to the reported advantages, we explore the appli-
cation on the synthesis of substituted quinoline ethers
through the similar synthetic protocol (Sahu et al., 2013).
The effect of solvent, amount of catalyst used, and reaction
time on the product yield were investigated, and the results
were summarized in Table 1.
Zone of inhibition study
Aspergillus niger was used to study the antibacterial
activity of compound 2e and 8-HQ against its grown in
culture. A. niger was diluted with potato dextrose broth and
plated on the potato dextrose agar plate and the holes were
created on the agar using a sterile transfer pipette. The
tested compounds, DMSO (as negative control) and terbi-
nafine (as positive control) were placed in the holes of agar.
The plates were then incubated at 25 °C and the inhibition
zones (mm, in terms of diameter) of fungi on the agar
plates were recorded.
Among the three parameters studied, we found that the
effect of catalyst amount used is the most critical factor
governing the product yield (entries 1–4), whereas either
using dichloromethane or chloroform as solvent can
achieve comparable yield (entries 4–5). Therefore, we
focused on the use of dichloromethane as solvent and
TBAB in 1.5 wt % in the subsequent study due to the
easier operation and better product yield. Owing to the
easily preparation and the potential applications of the
substituted quinoline ethers, the present work reported the
synthesis of a series of 8-benzyloxy-substituted quinoline
ethers using a known convenient synthetic procedure
Cytotoxicity assay
Human alveolar basal epithelial A549 cells were removed
from sterile cell culture flasks with trypsin and neutralized
with fetal bovine serum. After washing with phosphate
buffered saline and centrifugation, cells were re-sus-
pended in complete cell culture medium at a concentra-
tion of approximately 1 9 105 cells/mL and counted
manually using a haematocytometer under an inverted
microscope. A549 cells seeded in the 96 wells microtitre
plates for 24 h were prepared for the screening of our
under mild condition via
a
simple nucleophilic
123

Med Chem Res (2015) 24:1568–1577
1573
Table 1 Synthesis of 8-benzyloxy-substituted quinoline ethers under
various conditions
Entry
Solvent
Phase transfer catalyst
Yield (%)
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
None
N.D.
25
40
40
40
4
2
TBAB (0.5 wt%)
TBAB (1.0 wt%)
TBAB (1.5 wt%)
TBAB (1.5 wt%)
TBAB (1.5 wt%)
TBAB (1.5 wt%)
TBAB (1.5 wt%)
TBAB (1.5 wt%)
TBAB (1.5 wt%)
3
4
5
6
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7a
8b
9b,c
10b,d
41
41
23
39
Fig. 1 Antibacterial screening. All the compounds were at 100 lg/
mL and samples were incubated for 24 h. Positive control was
ciprofloxacin at 100 lg/mL and negative control with 0.1 % of
DMSO. Here are the representative results from three independent
experiments and similar results obtained
N.D. not detected
All reactions were carried out at room temperature for 7 h with
stirring and solvent volume (aqeuous/organic) equals to 5 mL/5 mL
was employed
a
Solvent volume (aqeuous/organic) equals to 10/10 mL was
employed
aeruginosa and E. coli, and two Gram-positive bacteria, S.
aureus and S. epidermidis. All of them did not inhibit Gram-
negative bacterial growth. Even compounds 2a, 2b, 2e, and
2f showed certain degree of antibacterial activities on
Gram-positive bacteria (Table 2). They were much weaker
than the mother compound 8HQ. Therefore, we did not go
further to study their antibacterial activities. Figure 2 shows
the antifungal screening of all compounds against A. niger.
Compounds 2a, 2b, 2d, 2e, 2f, and 2h exhibited the anti-A.
niger activity at the concentration of 100 lg/mL in the
initial screening. We further examined their antifungal
effects and their minimum inhibitory concentrations (MICs)
against A. niger are shown in Table 2. Six compounds in
these series were found to have the inhibitory effects, with
the MICs ranged from 3.125 to 25 lg/mL. Among the
tested compounds, compound 2e possessed the strongest
antifungal activity. Compounds 2a, 2d, and 2f also exhib-
ited a satisfactory growth inhibition against A. niger (MIC
of 12.5 lg/mL for three cases). According to the results in
Table 2, the presence of unsubsituted phenyl ring (Com-
pound 2b) showed a growth inhibitory effect and enhanced
by introducing the meta-substitution on phenyl ring
(Compounds 2a, 2e, 2f). However, the growth inhibitory
b
Solvent volume (aqeuous/organic) equals to 20/20 mL was
employed
c
Reaction was carried out for 3 h
d
Reaction was carried out for 12 h
Scheme 1 Reagents: (a) 10 % KOH, TBAB, CH2Cl2, RX, r.t
substitution reaction (Scheme 1) (Chan et al., 2013; Sahu
et al., 2013).
Antimicrobial activity
Figure 1 shows the antibacterial screening of all synthe-
sized compounds against two Gram-negative bacteria, P.
123

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Med Chem Res (2015) 24:1568–1577
Table 2 In vitro antimicrobial activities of 8-benzyloxy-substituted
quinoline ethers against microorganisms
Table 2 continued
Entry
R
MIC (lg/mL)
S.
S.
A.
aureus epidermidis niger
2h
[100
[100
[100
[100
25
Entry
2a
R
MIC (lg/mL)
S. S.
A.
aureus epidermidis niger
2i
[100
25
12.5
12.5
2j
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
[100
2b
2c
50
25
25
2k
2l
[100
[100
[100
2d
2e
[100
[100
[100
12.5
2m
2n
25
3.125
2f
25
100
12.5
8HQ
H
–
0.8
0.8
2.5
Methicillin
3.125
N.D.
N.D.
N.D.
6.25
N.D.
N.D.
N.D.
1.25
Vancomycin –
Terbinafine
–
N.D. Not determined
2g
[100
[100
[100
Three independent experiments were conducted for each compound
and similar results were obtained
effect was reduced in the presence of para-substitution on
phenyl ring, except for compound 2d. In terms of meta-
substitution, the presence of electron donating group
123

Med Chem Res (2015) 24:1568–1577
1575
Fig. 2 Anti-A. niger screening. All the compounds were at 100 lg/
mL and samples were incubated for 48 h. Positive control was
terbinafine at 5 lg/mL and negative control with 0.1 % of DMSO.
Here are the representative results from three independent experi-
ments and similar results obtained
Fig. 4 Cell viability of compound 2e toward human alveolar basal
epithelial A549 cells. Each experiment was conducted in triplicate
and a mean was obtained. Three independent experiments were
performed. Results are shown as mean SD
zone = 18.73 0.97 mm) when compared with the same
concentration of the mother compound 8-HQ (inhibition
zone = 16.03 0.81 mm). Results suggested that com-
pound 2e and the mother compound 8-HQ could effectively
inhibit the fungal growth on the agar plate. The negative
control DMSO did not show any inhibition zone while the
positive control terbinafine did exhibit a noticeable zone of
clearance on the agar disk.
Fig. 3 Zone of clearance (mm, in terms of diameter) of compound 2e
and the mother compound 8-HQ
(Compounds 2a and 2f) had a lower growth inhibition than
that of electron withdrawing group (Compound 2e), except
for the nitro group. Hence, the phenyl ring with electronic
withdrawing groups may not be the major factor contrib-
uting to the antifungal effect, while the substitution at meta
position may be a critical factor leading to the antifungal
activity. Furthermore, comparing with the parent molecule
(8HQ), the antifungal activity was reduced due to the O-
substitution and it may indicate the hydroxyl group at C-8
position of quinoline which may be a significant moiety
toward the inhibition of A. niger. The zone of clearance of
compound 2e and the mother compound 8-HQ is shown in
Fig. 3. Compound 2e at a concentration of 3 lg showed a
comparable growth inhibition against A. niger (inhibition
Cytotoxicity study
As compound 2e showed attractive anti-A.niger activity
and A. niger is a common pathogen to cause lung infec-
tions. Therefore, we further studied the effect of compound
2e toward human alveolar basal epithelial A549 cells. The
compound 2e possessed the MIC of 3.125 lg/mL against
A. niger after 48-h incubation was shown to has a mild
cytotoxicity against A549 cells, with the IC50 of about
9 lg/mL after 48-h incubation (Fig. 4). At a concentration
of 10 lg/mL, compound 2e induced certain degree of cell
death which was similar to that of 8HQ (Fig. 5). Doxoru-
bicin as a positive control showed extensive cell death at
the same concentration.
123

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Med Chem Res (2015) 24:1568–1577
Fig. 5 Representative
morphological investigation of
human alveolar basal epithelial
A549 cells. (a) Untreated
control, (b) 10 lg/mL
doxorubicin, (c) 10 lg/mL
8HQ, and (d) 10 lg/mL
compound 2e
Chan SH, Chui CH, Chan SW, Kok SHL, Chan D, Tsoi MYT, Leung
PHM, Lam AKY, Chan ASC, Lam KH, Tang JCO (2013)
Synthesis of 8-hydroxyquinoline derivatives as novel anti-tumor
agents. ACS Med Chem Lett 4:170–174
Chen ZF, Wei JH, Liu YC, Liu M, Gu YQ, Huang KB, Wang M,
Liang H (2013) High antitumor activity of 5,7-dihalo-8-quino-
linolato cerium complexes. Eur J Med Chem 68:454–462
Denton JR (2010) One-Pot Desulfonylative Alkylation of N-Sulfonyl
Azacycles Using Alkoxides Generated by Phase-Transfer Catal-
ysis. Synthesis 5:775–782
Conclusion
In conclusion, we have developed a series of 8-benzyloxy-
substituted quinoline ethers (2a–n) compounds. Their
antibacterial and anti-A. niger activities were examined. Of
which, compound 2e showed a significant growth inhibi-
tory activity against A. niger with mild cytotoxicity toward
human alveolar basal epithelial A549 cells.
El-Agrody AM, Abd-Rabboh HSM, Al-Ghamdi AM (2013) Synthe-
sis, antitumor activity, and structure–activity relationship of
some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[40,50:6,5]
pyrano[3,2-h]quinoline derivatives. Med Chem Res 22:
1339–1355
Acknowledgments We acknowledge the financial support from
Innovation Technology Commission to ABCT, The Hong Kong
Polytechnic University and the research Grant: 30-13-135 (FRG1/13-
14/035) (Dr. C. H. Chui) from Hong Kong Baptist University. Pro-
fessor R. Gambari is supported by AIRC (IG-13575). Lastly, Miss Po-
Yee Chung would like to thank the chief supervision of Dr.
Kim-Hung Lam.
´
Ewa B, Maciej W, Marcin S, Grzegorz D, Michał Z, Jan P, Jozef O
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