Synthesis and evaluation of antibacterial activity of 7-alkyloxy-4,5- dihydro-imidazo[1,2-a]quinoline derivatives

Article abstract of DOI:10.1016/j.ejmech.2012.12.034

In this study, a series of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline derivatives was synthesized and tested for their antibacterial activity against various bacterial strains. Most of the compounds exhibited potential antibacterial activity against g

Full text of DOI:10.1016/j.ejmech.2012.12.034

European Journal of Medicinal Chemistry 60 (2013) 451e455
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journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of antibacterial activity of 7-alkyloxy-4,5-
dihydro-imidazo[1,2-a]quinoline derivatives
,
a
b
a
a
a
b
a,
**
Xian-Yu Sun a , Rui Wu , Xiang Wen , Li Guo , Chang-Ping Zhou , Jian Li , Zhe-Shan Quan , Jun Bao
*
a College of Animal Science and Technique, Bayi Agriculture University, Daqing 163319, Heilongjiang, PR China
b College of Pharmacy, Yanbian University, No. 1829, JuZi Street, Yanji 133000, Jilin, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, a series of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline derivatives was synthesized and
tested for their antibacterial activity against various bacterial strains. Most of the compounds exhibited
potential antibacterial activity against gram-negative and gram-positive bacteria. Compound 7p (7-
heptyloxy-4,5-dihydro-imidazo[1,2-a]quinoline) was found to be the most potent inhibitor. The
Received 22 October 2012
Received in revised form
11 December 2012
Accepted 17 December 2012
Available online 26 December 2012
minimum inhibitory concentration (MIC) of compound 7p against Escherichia coli was 0.5
than that of reference agent ciprofloxacin and amoxicillin. Furthermore, compound 7p exhibited
a modest activity against several gram-negative bacterial strains at a dose range of 2e64 g/mL.
mg/mL, better
m
Keywords:
Synthesis
Ó 2013 Elsevier Masson SAS. All rights reserved.
Imidazo[1,2-a]quinoline
Antibacterial activity
1. Introduction
derivatives, we introduced an imidazole ring at the first and
second positions of the quinoline ring and designed a novel ser-
ies of imidazo[1,2-a]quinoline derivatives. Herein, we report
the synthesis of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline
derivatives and evaluation of their experimental antimicrobial
activity in vitro.
Several antibiotics are widely prescribed for the treatment of
respiratory tract infections; however, novel antimicrobial drugs
remain in demand because of the increasing global prevalence of
drug-resistant pathogens. Therefore, development of antibacterial
compounds with novel structural features and activity against
resistant pathogens is necessary.
2. Chemistry
Quinoline derivatives have attracted considerable interest
because of their diverse biological activities, such as anti-
microbial [1], anti-depressant [2], anti-convulsant [3], anti-
malarial [4], and anti-inflammatory [5] activities. In our labora-
tory, we had prepared several quinoline-derived heterocyclic
compounds [6e8], but none of them were found to possess
antimicrobial active. Previous biological data have revealed that
small heterocycles, e.g. imidazole [9], pyrazole [10], thiophene,
and furane, can be beneficial substituents, resulting in increased
biological activity [11,12]. These results encouraged us to inves-
tigate small heterocycles like imidazole, which would ultimately
allow the introduction of a diverse set of substituted heterocycles
to gain further knowledge of the structureeactivity relationships.
Therefore, to further investigate the activity of quinoline
We designed a series of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]
quinoline derivatives (7ae7s) and synthesized them according to
Scheme 1. Compound 3 was synthesized according to a method
described previously [2]. The starting material 6-hydroxy-3,4-
dihydro-2(1H)-quinolone (1) was treated with benzyl chloride in
a solution of sodium hydroxide in ethanol to yield 6-alkoxy-3,4-
dihydroquinolin-2(1H)-one (2). 6-Alkoxy-3,4-dihydroquinolin-
2(1H)-thione (3) was prepared by the reaction of compound 2 with
phosphorous pentasulphide in the presence of triethylamine in
acetonitrile. Subsequently, thione 3 was treated with amino-
acetaldehyde dimethyl acetal to yield intermediate 4. Compound 4
was isolated and subsequently heated in acetic acid without any
treating it with other reagents to yield compound 5. Catalytic
hydrogenation (Pd/C, H2) of compound 5 provided the scaffold 6.
Finally, test derivatives were prepared by the reaction of scaffold 6
with an appropriate alkyl halide. All the synthesized compounds
were confirmed by 1H NMR, mass spectrometry, and elemental
analyses.
* Corresponding author. Tel.: þ86 459 6819198.
** Corresponding author. Tel./fax: þ86 459 6819002.
E-mail addresses: sxianyu@163.com (X.-Y. Sun), jbao@neau.edu.cn (J. Bao).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.12.034

452
X.-Y. Sun et al. / European Journal of Medicinal Chemistry 60 (2013) 451e455
O
HO
O
a
c
b
Bn
Bn
N
H
S
N
H
O
N
H
O
1
2
3
O
O
HO
d
e
Bn
Bn
O
N
H
N
N
N
N
N
O
6
4
5
RO
f
N
N
7a-7s
Scheme 1. Synthesis of target compounds 7ae7s. (a) BnCl, NaOH, ethanol, reflux; (b) P2S5, TEA, CH3CN, reflux; (c) aminoacetaldehyde dimethyl acetal, TEA, ethanol, reflux; (d)
AcOH, 100 ꢀC (e) H2, Pd/C, ethanol, 60 ꢀC; (f) RX, NaOH, DMF, 80 ꢀC.
3. Results and discussions
compound 5 with no substitution on the phenyl ring had a weaker
activity against S. aureus than that of compounds 7ae7k with
different substitutions on the phenyl ring. This showed that the
introduction of substitutions benefited the antibacterial activity
against S. aureus. We found that the Br atom contributed more to
the inhibitory activity against S. aureus than the F and Cl atoms.
All the synthesized compounds were screened for their in vitro
antibacterial activity against gram-positive bacteria Staphylococcus
aureus and gram-negative bacteria Escherichia coli. Minimum
inhibitory concentrations (MIC) were determined using the serial
dilution technique. We used ciprofloxacin and amoxicillin as
reference compounds in the evaluation of antibacterial activity and
Compounds 7c, 7f, and 7i inhibited S. aureus at 50
mg/mL. This
indicated that the position of the halogen atom on the phenyl ring
greatly influenced the antibacterial activity, with the para-
substituted compounds being more active than the ortho- and
meta-substituted compounds. Derivatives 7j and 7k, containing
electron-donating groups (p-CH3 and p-CH3O), had MIC values
measured the MIC in mmol/mL units.
As shown in Table 1, most of the synthesized compounds
showed modest antibacterial activity in vitro against both gram-
positive and gram-negative strains. Further, the results showed
that the synthesized compounds exhibited a little stronger inhibi-
tory activity against E. coli than against S. aureus.
against S. aureus of 50 mg/mL and 100 mg/mL, respectively. Thus,
there was no significant difference between the activity of
compounds containing electron-donating groups and those con-
taining electron-withdrawing groups. Among compounds 7le7s,
compounds 7p, 7q, and 7r were moderately active against
A study of the data shown in Table 1 shows that all 20 test
compounds exhibited antibacterial activity against S. aureus (MIC:
50e200
mg/mL). Among the benzyl-substituted derivatives,
S. aureus at 50
The synthesized compounds exhibited antibacterial activity
against E. coli in the dose range of 0.5e100 g/mL. Most of the
compounds containing a substituted benzyl ring (7ae7k) exhibited
antibacterial activity against E. coli at 50 g/mL with compound 7i
(with p-Br substitution) and compound 7j (with p-CH3 substitu-
tion) active at 25 g/mL. Furthermore, analysis of the inhibitory
activity of compounds 7le7s against E. coli showed that the length
of the alkyl chain appeared to have a direct impact on the anti-
bacterial activity of the 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]
quinoline derivatives. As the alkyl chain length increased in the
compounds starting from 7l onwards, the MIC gradually decreased,
with the compound 7p (with an n-heptyl substituent) being the
most active. However, this trend reversed when the alkyl chain
consisted of more than 7 carbon atoms. Compound 7p with an MIC
mg/mL.
Table 1
m
Inhibitory activitya of compounds 5, 7ae7s, and controls against bacteria.
Compound
R
MICb
(
mg/mL) vs.
MICb
(mg/mL) vs.
m
S. aureus
E. coli
5
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
C6H5CH2
200
150
150
50
150
150
50
100
100
50
50
50
50
50
100
50
50
50
50
25
25
50
50
50
50
16
0.5
25
50
50
1
m
(o-F)C6H4CH2
(m-F)C6H4CH2
(p-F)C6H4CH2
(o-Cl)C6H4CH2
(m-Cl)C6H4CH2
(p-Cl)C6H4CH2
(o-Br)C6H4CH2
(m-Br)C6H4CH2
(p-Br)C6H4CH2
(p-CH3)C6H4CH2
(p-CH3O)C6H4CH2
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C9H19
n-C10H21
e
50
100
150
150
100
75
50
50
50
100
16
value of 0.5 mg/mL against E. coli was the most potent inhibitor and
showed better activity than that shown by the reference agents
ciprofloxacin and amoxicillin.
In view of its promising antibacterial activity, compound 7p was
further evaluated against a range of gram-negative bacteria,
including Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus
vulgaris, Salmonella, and Pasteurella. These bacteria easily cause
severe infection illness or food poisoning, and at the same time,
they are widely applied to the antimicrobial activity screening
experiments [13e16]. A study of the data in Table 2 showed that
compound 7p exhibited inhibitory activity against P. aeruginosa, P.
7p
7q
7r
7s
Ciprofloxacin
Amoxicillin
e
25
150
a
Anti-bacterial testing was carried out in triplicate.
MIC values represent the average of 3 readings.
b

X.-Y. Sun et al. / European Journal of Medicinal Chemistry 60 (2013) 451e455
453
Table 2
spectra were recorded using AV-300 FT-NMR spectrometer (Bruker
BioSpin AG, Fallanden, Switzerland). Chemical shifts are reported in
ppm relative to tetramethylsilane. Mass spectra were recorded on
an HP1100LC/MSD electrospray ionization mass spectrometer (ESI-
MS) (Agilent Technologies, Santa Clara, CA, USA). Elemental anal-
yses were performed using a 204Q CHN Rapid Analyzer instrument
(PerkinElmer, Fremont, CA). All chemicals were purchased from
SigmaeAldrich Chemical Corporation (Shanghai, China). All other
chemicals were of analytical grade.
Inhibitory activitya of compound 7p and controls against gram-negative bacterial
strains.
Gram-negative
strains
7p (MIC,b
Amoxicillin
Ciprofloxacin
m
g/mL)
(MIC,b
m
g/mL)
(MIC,b
mg/mL)
Pseudomonas aeruginosa
K. pneumoniae
Proteus vulgaris
Salmonella
16
>128
16
64
2
16
>128
>128
>128
16
4
4
128
>128
128
Pasteurella
Intermediates 2 and 3 were synthesized according to the
methods previously described in literature [2]. The detailed
procedures for preparing compounds 4e7 are described below.
a
Anti-bacterial testing was carried out in triplicate.
MIC values represent the average of 3 readings.
b
vulgaris, Salmonella, and Pasteurella at a dose of 64
The MIC of 7p against P. aeruginosa was 16 g/mL, which was
similar to that of the control amoxicillin and weaker than that of
ciprofloxacin (4 g/mL). Both compound 7p and amoxicillin did not
exhibit antibacterial activity against K. pneumoniae at 128 g/mL.
Compound 7p with an MIC value of 16 g/mL was 8-fold more
mg/mL or less.
5.2. 7-Benzyloxy-4,5-dihydro-imidazo[1,2-a]quinoline (5)
m
A
mixture of compound
3
(10 g, 37.2 mmol), 2,2-
m
dimethoxyethylamine (3.9 g, 37.2 mmol), and DIPEA (15 mL) in
ethanol (100 mL) was stirred and heated to reflux. After confirming
theendof thereaction by TLC after 6 h, thereactionmixturewasdried
under reduced pressure to yield compound 4 as crude yellow oil.
A solution of compound 4 in acetic acid (50 mL) was stirred for
2 h at 100 ꢀC. The reaction was cooled and evaporated to dryness
under reduced pressure to give a dark solid that was dissolved in
ethyl acetate (200 mL) and water (200 mL). The organic layer was
separated and washed with water (200 mL) followed by brine
(200 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was purified by TLC on silica
gel (ethyl acetate) to give 5 as a yellow solid (3.5 g; overall yield of 2
m
m
potent than the controls amoxicillin and ciprofloxacin against P.
vulgaris. Furthermore, 7p exhibited antibacterial activity against
Salmonella at 64
128 g/mL. Notably, compound 7p exhibited stronger inhibitory
activity (MIC: 2 g/mL) against Pasteurella than that of the controls
amoxicillin (MIC: 16 g/mL) and ciprofloxacin (MIC: 128 g/mL).
mg/mL, whereas the two controls were inactive at
m
m
m
m
The present study revealed that these bacterial effects were
mainly influenced by lipid-hydro partition coefficient of the test
compounds. Interestingly, all the reported compounds show better
antibacterial activity against Gꢁ bacteria than Gþ bacteria. For these
effects may be somewhat specific, we hypothesized that the
changes in cell wall permeability lead to dissipation of the poten-
tial. It is well-known that the cell wall of Gþ bacteria is mainly
composed of a network structure formed by the peptidoglycan.
While the cell wall of Gꢁ bacteria consists of a lower content of the
peptidoglycan, teichoic acid and a higher content of lipids. More-
over, affinity trapping of antibacterial molecules by the cell wall and
clogging of the outer layers of peptidoglycan by bound antibacterial
molecules were considered to be the mechanism of antibacterial
resistance [17]. Yet the exact explanations on these antibacterial
activities require an understanding of membrane packing, perme-
ability, and partition behavior on a molecular basis.
steps, 34.1%). M.p. 189e191 ꢀC. 1H NMR (300 MHz, CDCl3):
3.10 (m, 4H, H-4, H-5), 5.08 (s, 2H, eOCH2e), 6.92e7.43 (m, 10H, He
Ar). MS (m/z): 277 (M þ 1). Analyses Calcd. for C18H16N2O: C,
78.24%; H, 5.84%; N, 10.14%. Found: C, 78.30%; H, 5.81%; N, 10.09%.
d 2.89e
5.3. 7-Hydroxy-4,5-dihydro-imidazo[1,2-a]quinoline (6)
A mixture of compound 5 (3.5 g, 12.7 mmol) and Pd/C (1 g, 60%
H2O) in ethanol (50 mL) was stirred under an atmosphere of
hydrogen for 6 h at 60 ꢀC. After the solution was cooled, the reaction
mixture was filtered and evaporated to give a moderate yield of
compound 6. The compound was used directly in the next step
without further purification.
4. Conclusions
5.4. General synthetic procedure for target compounds 7ae7s
We have synthesized a series of novel imidazo[1,2-a]quinoline
derivatives and evaluated their antibacterial activity against gram-
positive and gram-negative bacteria. Most of the compounds
exhibited modest antibacterial activity against gram-negative
bacteria except for compound 7p. Compound 7p with an MIC
To a solution of compound 6 (0.1 g, 0.54 mmol) and sodium
hydroxide (0.032 g, 0.8 mmol) in DMF (10 mL) was added the
relevant alkyl halide of equivalent molarity, and the mixture was
stirred at 80 ꢀC until the completion of the reaction, which was as
confirmed by TLC. The reaction was cooled and evaporated to
dryness in vacuum. Target compounds 7ae7s were obtained after
purification of the crude residues on a silica gel column (ethyl
acetate). The yields, melting points, and spectral data for each
compound are provided below.
value of 0.5 mg/mL against E. coli was the most potent inhibitor and
showed better activity than that shown by the reference agents
ciprofloxacin and amoxicillin. This suggests that hybrid compounds
containing quinoline and imidazole moieties may possess better
antibacterial properties. The results of this evaluation suggest that
further development of such compounds may be of therapeutic
interest.
5.4.1. 7-(2-Fluoro-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7a)
Yield 85%; m.p. 189e191 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.95e
5. Experimental procedures
3.09 (m, 4H, H-4, H-5), 5.05 (s, 2H, eOCH2e), 6.92e7.57 (m, 9H, He
Ar). MS m/z 295 (M þ 1). Anal. Calcd. for C18H15FN2O: C, 73.45; H,
5.14; N, 9.52. Found: 73.51; H, 5.11; N, 9.49.
5.1. Chemistry
The reactions were monitored by thin layer chromatography
(TLC) on silica gel plates precoated with F254. The developed plates
were examined under a UV lamp (254 nm). Melting points were
determined in open capillary tubes and are uncorrected. 1H NMR
5.4.2. 7-(3-Fluoro-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7b)
Yield 80%; m.p. 175e177 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.96e
3.10 (m, 4H, H-4, H-5), 5.02 (s, 2H, eOCH2e), 6.88e7.45 (m, 9H, He

454
X.-Y. Sun et al. / European Journal of Medicinal Chemistry 60 (2013) 451e455
Ar). MS m/z 295 (M þ 1). Anal. Calcd. for C18H15FN2O: C, 73.45; H,
C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.55; H, 5.89; N,
9.07.
5.14; N, 9.52. Found: 73.51; H, 5.12; N, 9.48.
5.4.3. 7-(4-Fluoro-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
5.4.12. 7-Propoxy-4,5-dihydro-imidazo[1,2-a]quinoline (7l)
Yield 74%; m.p. 108e110 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.98e
1.03 (t, 3H, eCH3), 1.82e1.85 (m, 2H, eCH2e), 2.96e3.09 (m, 4H, H-
4, H-5), 3.94e3.97 (t, 2H, eOCH2e), 6.85e7.37 (m, 5H, HeAr). MS
m/z 229 (M þ 1). Anal. Calcd. for C14H16N2O: C, 73.66; H, 7.06; N,
12.27. Found: C, 73.72; H, 7.01; N, 12.23.
(7c)
Yield 86%; m.p. 167e169 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.96e
3.12 (m, 4H, H-4, H-5), 5.04 (s, 2H, eOCH2e), 6.91e7.41 (m, 9H, He
Ar). MS m/z 295 (M þ 1). Anal. Calcd. for C18H15FN2O: C, 73.45; H,
5.14; N, 9.52. Found: 73.50; H, 5.12; N, 9.49.
5.4.4. 7-(2-Chloro-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
5.4.13. 7-Butoxy-4,5-dihydro-imidazo[1,2-a]quinoline (7m)
(7d)
Yield 83%; m.p. 117e119 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.97e
Yield 79%; m.p. 178e180 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.97e
1.02 (t, 3H, eCH3), 1.48e1.55 (m, 2H, eCH2e), 1.80e1.83 (m, 2H, e
CH2e), 2.98e3.10 (m, 4H, H-4, H-5), 3.96e4.00 (t, 2H, eOCH2e),
6.81e7.32 (m, 5H, HeAr). MS m/z 243 (M þ 1). Anal. Calcd. for
C15H18N2O: C, 74.35; H, 7.49; N, 11.56. Found: C, 74.41; H, 7.46; N,
11.51.
3.09 (m, 4H, H-4, H-5), 5.14 (s, 2H, eOCH2e), 6.95e7.50 (m, 9H, He
Ar). MS m/z 311 (M þ 1), 313 (Mþ3). Anal. Calcd. for C18H15ClN2O: C,
69.57; H, 4.86; N, 9.01. Found: C, 69.62; H, 4.83; N, 8.98.
5.4.5. 7-(3-Chloro-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7e)
5.4.14. 7-Pentoxy-4,5-dihydro-imidazo[1,2-a]quinoline (7n)
Yield 88%; m.p. 166e168 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.95e
Yield 89%; m.p. 135e137 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.92e
3.08 (m, 4H, H-4, H-5), 5.09 (s, 2H, eOCH2e), 6.88e7.52 (m, 9H, He
Ar). MS m/z 311 (M þ 1), 313 (M þ 3). Anal. Calcd. for C18H15ClN2O:
C, 69.57; H, 4.86; N, 9.01. Found: C, 69.61; H, 4.84; N, 8.97.
0.97 (t, 3H, eCH3), 1.34e1.83 (m, 6H, e(CH2)3e), 2.96e3.13 (m, 4H,
H-4, H-5), 3.91e3.96 (t, 2H, eOCH2e), 6.81e7.47 (m, 5H, HeAr). MS
m/z 257 (M þ 1). Anal. Calcd. for C16H20N2O: C, 74.97; H, 7.86; N,
10.93. Found: C, 75.04; H, 7.82; N, 10.88.
5.4.6. 7-(4-Chloro-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7f)
5.4.15. 7-Hexyloxy-4,5-dihydro-imidazo[1,2-a]quinoline (7o)
Yield 79%; m.p. 161e163 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.93e
Yield 80%; m.p. 126e128 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.92e
3.11 (m, 4H, H-4, H-5), 5.11 (s, 2H, eOCH2e), 6.94e7.48 (m, 9H, He
Ar). MS m/z 311 (M þ 1), 313 (M þ 3). Anal. Calcd. for C18H15ClN2O:
C, 69.57; H, 4.86; N, 9.01. Found: C, 69.63; H, 4.84; N, 8.99.
0.99 (t, 3H, eCH3), 1.32e1.79 (m, 8H, e(CH2)4e), 2.98e3.15 (m, 2H,
H-4, H-5), 3.93e3.99 (t, 2H, eOCH2e), 6.90e7.44 (m, 5H, HeAr). MS
m/z 271 (M þ 1). Anal. Calcd. for C17H22N2O: C, 75.52; H, 8.20; N,
10.36. Found: C, 75.59; H, 8.15; N, 10.30.
5.4.7. 7-(2-Bromo-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7g)
5.4.16. 7-Heptyloxy-4,5-dihydro-imidazo[1,2-a]quinoline (7p)
Yield 85%; m.p. 192e194 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.99e
Yield 90%; m.p. 119e121 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.87e
3.10 (m, 4H, H-4, H-5), 5.15 (s, 2H, eOCH2e), 6.93e7.62 (m, 9H, He
Ar). MS m/z 355 (M þ 1), 357 (M þ 3). Anal. Calcd. for C18H15BrN2O:
C, 60.86; H, 4.26; N, 7.89. Found: C, 60.90; H, 4.24; N, 7.86.
0.94 (t, 3H, eCH3), 1.35e1.88 (m, 10H, e(CH2)5e), 2.96e3.14 (m, 2H,
H-4, H-5), 3.93e3.98 (t, 2H, eOCH2e), 6.92e7.50 (m, 5H, HeAr). MS
m/z 285 (M þ 1). Anal. Calcd. for C18H24N2O: C, 76.02; H, 8.51; N,
9.85. Found: C, 76.09; H, 8.47; N, 9.82.
5.4.8. 7-(3-Bromo-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7h)
5.4.17. 7-Octyloxy-4,5-dihydro-imidazo[1,2-a]quinoline (7q)
Yield 73%; m.p. 181e183 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.92e
Yield 76%; m.p. 109e111 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.88e
3.07 (m, 4H, H-4, H-5), 5.19 (s, 2H, eOCH2e), 6.91e7.58 (m, 9H, He
Ar). MS m/z 355 (M þ 1), 357 (M þ 3). Anal. Calcd. for C18H15BrN2O:
C, 60.86; H, 4.26; N, 7.89. Found: C, 60.91; H, 4.23; N, 7.84.
0.90 (s, 3H, eCH3), 1.27e1.56 (m, 10H, e(CH2)5e), 1.76e1.84 (m, 2H,
eCH2e), 2.96e3.10 (m, 4H, H-4, H-5), 3.95e4.00 (t, 2H, eOCH2),
6.81e7.37 (m, 4H, HeAr). MS m/z 299 (M þ 1). Anal. Calcd. for
C19H26N2O: C, 76.47; H, 8.78; N, 9.39. Found: C, 76.55; H, 8.73; N,
9.35.
5.4.9. 7-(4-Bromo-benzyloxy)-4,5-dihydro-imidazo[1,2-a]quinoline
(7i)
Yield 78%; m.p. 172e174 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.96e
5.4.18. 7-Nonoxy-4,5-dihydro-imidazo[1,2-a]quinoline (7r)
3.10 (m, 4H, H-4, H-5), 5.02 (s, 2H, eOCH2e), 6.85e7.54 (m, 9H, He
Ar). MS m/z 355 (M þ 1), 357 (M þ 3). Anal. Calcd. for C18H15BrN2O:
C, 60.86; H, 4.26; N, 7.89. Found: C, 60.92; H, 4.22; N, 7.83.
Yield 83%; m.p. 88e100 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.86e
0.89 (s, 3H, eCH3), 1.22e1.57 (m, 12H, e(CH2)6e), 1.74e1.87 (m, 2H,
eCH2e), 2.97e3.12 (m, 4H, H-4, H-5), 3.97e4.02 (t, 2H, eOCH2),
6.88e7.42 (m, 4H, HeAr). MS m/z 313 (M þ 1). Anal. Calcd. for
C20H28N2O: C, 76.88; H, 9.03; N, 8.97. Found: C, 76.95; H, 8.99; N, 8.91.
5.4.10. 7-(4-Methyl-benzyloxy)-4,5-dihydro-imidazo[1,2-a]
quinoline (7j)
Yield 89%; m.p. 161e163 ꢀC; 1H NMR (CDCl3, 300 MHz):
d
2.45 (s,
5.4.19. 7-Decoxy-4,5-dihydro-imidazo[1,2-a]quinoline (7s)
3H, eCH3), 2.96e3.10 (m, 4H, H-4, H-5), 5.07 (s, 2H, eOCH2e),
6.88e7.47 (m, 9H, HeAr). MS m/z 291 (M þ 1). Anal. Calcd. for
C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.65; H, 6.21; N,
9.60.
Yield 89%; m.p. 84e86 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 0.84e
0.87 (s, 3H, eCH3), 1.22e1.85 (m, 16H, e(CH2)8e), 2.93e3.09 (m,
4H, H-4, H-5), 3.98e4.07 (t, 2H, eOCH2), 6.82e7.36 (m, 4H, HeAr).
MS m/z 327 (M þ 1). Anal. Calcd. for C21H30N2O: C, 77.26; H, 9.26; N,
8.58. Found: C, 77.32; H, 9.226; N, 8.53.
5.4.11. 7-(4-Methyloxy-benzyloxy)-4,5-dihydro-imidazo[1,2-a]
quinoline (7k)
5.5. Evaluation of antibacterial activity in vitro
Yield 87%; m.p. 177e179 ꢀC; 1H NMR (CDCl3, 300 MHz):
d 2.95e
3.09 (m, 4H, H-4, H-5), 3.83 (s, 3H, eOCH3), 5.03 (s, 2H, eOCH2e),
6.88e7.38 (m, 9H, HeAr). MS m/z 307 (M þ 1). Anal. Calcd. for
MIC values of compounds 5 and 7ae7s against several bacterial
strains were measured using the broth microdilution method in 96-

X.-Y. Sun et al. / European Journal of Medicinal Chemistry 60 (2013) 451e455
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Acknowledgment
We are grateful for the financial support from the Heilongjiang
Young College Academic Backbone Project (1252G041), Animal
Good Farming Innovation Team Project (2010TD05), and the
Doctoral Research Start Foundation (B2011-10) of Heilongjiang Bayi
Agriculture University.
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