Design, Synthesis, and Dual Evaluation of Quinoline and Quinolinium Iodide Salt Derivatives as Potential Anticancer and Antibacterial Agents

Article abstract of DOI:10.1002/cmdc.202000002

A series of novel quinoline and quinolinium iodide derivatives were designed and synthesized to discover potential anticancer and antibacterial agents. With regard to anticancer properties, in vitro cytotoxicities against three human cancer cell lines (A-549, HeLa and SGC-7901) were evaluated. The antibacterial properties against two strains, Escherichia coli (ATCC 29213) and Staphylococcus aureus (ATCC 8739), along with minimum inhibitory concentration (MIC) values were evaluated. The target alkyliodine substituted compounds exhibited significant antitumor and antibacterial activity, of which compound 8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quinolin-5-ium (12) was found to be the most potent derivative with IC₅₀ values of 4.45±0.88, 4.74±0.42, 14.54±1.96, and 32.12±3.66 against A-549, HeLa, SGC-7901, and L-02 cells, respectively, stronger than the positive controls 5-FU and MTX. Furthermore, compound 12 had the most potent bacterial inhibitory activity. The MIC of this compound against both E. coli and S. aureus was 3.125 nmol ? mL^?1, which was smaller than that against the reference agents amoxicillin and ciprofloxacin.

Full text of DOI:10.1002/cmdc.202000002

Accepted Article
Title: Design, synthesis, and dual evaluation of novel quinoline and
quinolinium iodide salt derivatives as potential anticancer and
antibacterial agents
Authors: Guofan Jin, Fuyan Xiao, Zhenwang Li, Xueyong Qi, Lei Zhao,
and Xianyu Sun
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: ChemMedChem 10.1002/cmdc.202000002
Link to VoR: http://dx.doi.org/10.1002/cmdc.202000002
A Journal of
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10.1002/cmdc.202000002
ChemMedChem
FULL PAPER
Design, synthesis, and dual evaluation of novel quinoline and
quinolinium iodide salt derivatives as potential anticancer and
antibacterial agents
Guofan Jin[a]*, Fuyan Xiao[a], Zhenwang Li[b], Xueyong Qi[a], Lei Zhao[c] and Xianyu Sun[b]*
[a]
[b]
[c]
Pro. G.F Jin, Dr. X. Y. Qi, F. Y. Xiao
School of Pharmacy
Jiangsu University
Zhenjiang 212013, China
E-mail: 1000004770@ujs.edu.cn
Pro. X. Y. Sun, Z. W. Li
College of Animal Science and Technique
Bayi Agriculture University
Daqing 163319, Heilongjiang, China
E-mail: sxianyu@163.com
Dr. L. Zhao
Siping Institute for food and Drug Control
Siping 136000, China
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
series of novel quinoline and quinolinium iodide
due to various features,7-10 such as complexity, diversification, and
continuity. In many studies reported in recent years, a strategy to increase
the apoptosis activity has been proposed,11-14 and it was considered to be
a potential cancer treatment method. This is a programmed cellular suicide
process that removes damaged cells from multicellular organisms at the
cellular level that is inactivated.15, 16 Quinoline compounds can induce and
regulate some transcription factors to mediate apoptosis and metabolism,
and inhibit the occurrence of cancer and tumors. In addition, quinoline
compounds have been confirmed in related studies, which can be effective
in inhibiting the development and progression of cancer and tumors.17-21
On the other hand, infectious diseases recently have faced major
challenges in the world. The number of people with various plagues and
deaths has increased considerably. Therefore, the direction of developing
new broad-spectrum antibacterial drugs is also more diversified, trended,
and comprehensive.22-25 This is reflected mainly in the structural
modification of existing antibiotics, the improvement of the antibacterial
spectrum, the reduction of side effects, and the tendency to overcome and
contain drug resistance. Thiazolidinone and quinolones are the most
commonly used synthetic antibacterial drugs since 2014,26-28 and their
antibacterial spectrum is Gram-positive and Gram-negative bacteria. The
derivatives were designed and synthesized to discover potential
anticancer and antibacterial agents. All of the active structure
compounds were identified by nuclear magnetic resonance (NMR),
such as 1H-NMR, 13C-NMR, infrared radiation (IR), high resolution
mass spectrometry (HR-MS) and Carlo Erba Instruments CHNS-O
EA1108 spectra analysis. With regard to the anticancer properties,
the in vitro cytotoxicity against three human cancer cell lines (A-549,
Hela and SGC-7901) were evaluated. The antibacterial properties
against two human bacterial strains, Escherichia coli (ATCC 29213)
and Staphylococcus aureus (ATCC 8739), along with minimum
inhibitory concentration (MIC) values were evaluated. The target
alkyliodine substituted compounds, exhibited significant antitumor
and
antibacterial
activity,
of
which
compound
8-((4-
(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-
[1,3]dioxolo[4,5-g]quinolin-5-ium (12) was found to be the most potent
derivative with IC50 values of 4.45±0.88, 4.74±0.42, 14.54±1.96, and
32.12±3.66 against A-549, Hela, SGC-7901, and L-02 cells,
respectively, stronger than the positive control 5-FU and MTX.
Furthermore, compound 12 had the most potent bacterial inhibitory
activity. The MIC of this compound against Escherichia coli (ATCC
29213) and Staphylococcus aureus (ATCC 8739) was 3.125 nmol·mL-
1, which was smaller than that of the reference agents, amoxicillin and
ciprofloxacin.
structural uniqueness of quinoline is not only used widely in energy,
30
agriculture, organic luminescent materials,29,
etc., but also plays an
important role in medicine, including antibacterial,31 anti-cancer,32 anti-
tumor,33 and anti-HIV.34 Quinoline is a specific inhibitor of bacteria type II
topoisomerase, namely DNA gyrase.35-40 The compounds have potential
anticancer and antitumor effects owing to the structural similarity between
the two gyrase enzymes.
Introduction
Based on the development of comprehensive drugs, such as cancer
and viral infections at home and abroad,41,42 this group has attempted to
modify the active target of quinoline, i.e., an iodoalkyl chain was introduced
into the nitrogen in the auto-assembly zone of the 1st position. The
introduction of a hydrophilic aromatic cyclic amine onto the carbonyl group
at the 4-position, in which DNA is combined, helped improve the water
solubility as well as the anti-cancer and anti-proliferative effects in vitro.
Cancer and infections are the most serious problems that need to be
solved. With the continuous improvement of human health requirements,
research and development of new drugs has accelerated.1 The existing
drugs are no longer sufficient for a variety of refractory diseases, which
requires further improvement of longer-term effective comprehensive
drugs.2-6
Cancer is a disease that is difficult to cure; it exhibits abnormal
metabolic processes in living organisms for a variety of reasons, mainly
Results and Discussion
1
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Figure 1. Schematic diagram of the overall design of quinoline derivatives.
method, the concept of auto-assembly effects of drug-aggregation induced
by multi-aromatic iodine quaternary ammonium salt (Fig-1).
The docking result suggested there were several key interactions
between the 4-position and Human topoisomerase I, among which two key
H-bonds were formed between the NH group or aryl-O-aryl interacts with
the catalytic residue of DG 112 and LYS 425, respectively.
Design
According to existing reports, most studies have focused on the synthesis
of new quinolones. The overall aims of the authors were to design new
quinoline and quinoliunium iodine salt derivatives based on the important
structural features of DNA gyrase.43,44 The candidate structure was
designed to take hydrophobic or hydrophilic aryl rings and / or quaternary
amine salt moieties linked to the quinoline core at the 1- and 4-positions.
Based on retaining the quinoline core, an attempt was made to modify the
1- and 4- positions. The 1, 3-dioxolane base of the quinoline core itself is
a very important structure-effect group, and the water-soluble and activity
of the ethyl ester group on the entire structure cannot be ignored. First, the
carbonyl group at the 1-position is often an important part of the hydrogen
bond energy level with DNA. The oxygen atom is converted to a secondary
amine to increase the binding energy to DNA. In addition, the introduction
of an arylamine can increase the lipophilic amine and the external protein
increased the π-H hydrogen bonding ability. Second, the Schiff base
tertiary amine drugs of the 4-position are a dynamic self-assembly area.
To optimize the auto-assembly activity, methyl iodide and iodine propane
were introduced, and their conversion to quaternary ammonium salts to
facilitate the positively and negatively charged differential induction of an
auto-assembled superstructure were examined. Finally, different designs
of quinoline and quinoline iodide salts were proposed to examine their
effects on the anticancer and antibacterial dual activities. These drugs are
also used widely in many anticancer and antibacterial studies because of
the similar heterocyclic iodide structure.45,46 The synthesis of the target
compound was carried out according to the outlined synthetic scheme, and
the anticancer and antibacterial activities of the derivative were evaluated.
Among them, quinoline was selected as the starting structure for further
optimization for the following reasons: 1) a simple method to synthesize
the chemical structure and develop a series of novel quinoline derivatives;
2) from the docking result (Fig-2) showing quinolone 4-position aromatic
amine or aryl ether, the NH group or aryl-O-aryl interacts with the catalytic
residue through hydrogen bonding (H-bond); and 3) for the first proposed
Chemistry
The novel 7-(ethoxycarbonyl)-8-(arylamino)-[1,3]dioxolo[4,5-g]quinolin-5-
ium iodide derivatives were synthesized according to Scheme-1. Ethyl-8-
chloro-[1,3]dioxolo[4,5-g]quinoline-7-carboxylate47
intermediate
was
prepared by the condensation of malonic acid with the corresponding
reagent in the presence of the condition through a four step process. The
reaction of the intermediate with benzylamine in anhydrous acetonitrile
under reflux overnight resulted in the ethyl 8-(aryl)-[1,3]dioxolo[4,5-
g]quinolone -7-carboxylate derivatives 1~4. The iodination of 1, 2, 3, and
4 with an excess of iodomethane or iodopropane under reflux provided the
target compounds, 5-12, in moderate yield. The chemical structures of all
the synthesized new compounds were characterized by 1H NMR, 13C NMR,
IR, HRMS, and CHNS-O EA1108.
The IR spectrum showed a strong band at 1470-1485 cm-1 due to
quaternary amine groups in addition to a band at 1400-1500 cm-1 assigned
to the amine of iodine salt. The 1H NMR spectrum revealed the presence
of blunt singlet signals assigned to the -NH- proton at 8.84-10.36 ppm, -N-
CH- at 8.95-9.10 ppm, and O-CH2-O at 6.08-6.10 ppm for two protons. In
contrast, iodoalkane substituted derivatives -NH- proton at 10.27-11.59
ppm, the -N+-CH- at 9.07-9.38 ppm, and O-CH2-O at 6.18-6.29 ppm,
respectively. The 13C NMR spectra indicated the ketone functional groups:
the presence of singlet signals at 165.9-168.2 ppm corresponding to C=O
carbons, and alkane iodine salt singlet signals at 10.0-15.0 ppm.
Biology
2
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10.1002/cmdc.202000002
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O
O
O
O
O
O
Cyclohexane
Triethoxy methane
Ac2O, ZnCl2
reflux, 4h
+
CH3CH2OH
O
O
O
O
HO
OH
NH2SO3H, H2SO4
reflux, 3h
O
Benzene
reflux, 3h
Benzo[d][1,3]dioxol-5-amine
O
O
O
Cl
O
POCl3
H
O
O
K2CO3
ACN
O
N
O
O
O
R1 NH2
NaHCO3, H2O
reflux
+
N
R1
R1
NH
O
NH
N
O
O
O
O
O
R2I
OEt
OEt
ACN
N
R2
I
1
2
1
5
6
7
8
9
R = -CH2CH2Ph; R = -CH3
1
R = -CH2CH2Ph
1
2
1
R = -CH2CH2Ph(OCH3)2; R = -CH3
2
3
4
R = -CH2CH2Ph(OCH3)2
1
2
1
R = -CH2Ph; R = -CH3
R = -CH2Ph
1
2
1
R = -PhOCH2Ph; R = -CH3
R = -PhOCH2Ph
1
2
R = -CH2CH2Ph; R = -CH2CH2CH3
1
2
10
R = -CH2CH2Ph(OCH3)2; R = -CH2CH2CH3
1
2
11
12
R = -CH2Ph; R = -CH2CH2CH3
1
2
R = -PhOCH2Ph; R = -CH2CH2CH3
Scheme 1. General synthetic route of quinoline derivatives.
Table 1. In vitro growth inhibitory activity (IC50μM) of compounds 1-12 against human lung cancer cell line (A549), human hela cell line (HeLa), human gastric
carcinoma cell line (SGC-7901), normal hepatocyte cell line (L02) and normal lung cell line (IMR-90) by the MTT assay.
Compounds
R1
IC50
R2
A549
Hela
SGC-7901
L-02
IMR-90
1
2
3
4
5
6
7
8
9
10
11
12
5-FU
MTX
-CH2CH2Ph
-CH2CH2Ph(OCH3)2
-CH2Ph
-
-
-
31±6.25
94±4.63
46±18.96
17±0.95
54±5.39
>120
49±5.42
47±8.39
55±4.58
>120
73±6.55
73±4.83
>120
>120
36±0.98
>120
30±2.06
45±14.13
44±3.95
>120
39±1.82
4.7±0.42
109±2.81
107±1.97
>120
>120
>120
>200
>200
>200
>200
139±13.60
>200
125±9.67
124±8.45
127±9.58
>200
121±15.18
32±3.66
>200
>200
>200
>200
>200
>200
-PhOCH2Ph
-CH2CH2Ph
-CH2CH2Ph(OCH3)2
-CH2Ph
-PhOCH2Ph
-CH2CH2Ph
-CH2CH2Ph(OCH3)2
-CH2Ph
-
-CH3
-CH3
-CH3
-CH3
>120
89±1.80
114±1.81
74±4.99
85±11.62
89±2.89
>120
92±2.76
14±1.96
113±1.07
84±7.47
>200
182±27.66
173±22.49
169±15.28
>200
>200
109±10.17
>200
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-
38±7.32
4.4±0.88
98±0.72
60±9.14
-PhOCH2Ph
-
-
-
18±13.10
>200
IC50: Each value was averaged by three parallel groups of eight repeats and calculated using a SigmaPlot software.
Evaluation of cytotoxicity activity in vitro
02 cell line (L02) and nomal lung cell line (IMR-90) by MTT (3-(4,5-
dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assay.48-53 The
anticancer drug 5-FU (5-fluoro-2,4(1H, 3H)pyrimidinedione) and MTX
(methotrexate) were co-assayed as the positive control. All compounds
tested were dissolved in DMSO and then diluted by the culture medium
before the treatment of cultured cells.
Compounds 1-12 were assessed for their anti-proliferative activity in five
cell lines, namely the human lung cancer cell line (A549), human hela cell
line (HeLa), human gastric carcinoma cell line (SGC-7901), normal liver L-
3
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All synthesized 1- and 4-substituted ethyl-8-arylamino-[1,3]dioxolo[4,5-
obtain final concentrations of 1-50 nmol mL-1. A standardized suspension
of the test bacterium was inoculated and incubated for 24-48 h at 37 °C,
and the lowest concentration of the compounds that prevented the
development of visible growth was then analyzed by calculating the
minimal inhibitory concentrations (MIC values). Ciprofloxacin and
amoxicillin were used as controls and assayed under identical conditions.
All experiments were performed in triplicate.
g]quinoline-7-carboxylate
and
ethyl-8-arylamino-[1,3]dioxolo[4,5-
g]quinoliniumiodoalkyl-7-carboxylate derivatives were tested on the
human cancer cell lines; the data is listed in Table-1 and the fitted curved
is showed in Figure S-16.
Compared to the non-substituted iodoalkane compounds, all acquired
compounds with iodoalkane substitution at the 1-position (7, 8, 11, and 12)
showed significantly improved potency. Regarding substitution at the 4-
position on ethyl-8-arylamino- [1,3]dioxolo[4,5-g]quinoline-7-carboxylate,
the effects of the aromatic ring appeared to have low activities. This is
because the substitution of the 4-position into the bulky-aromatic ring leads
to blocking of docking site of NH and DNA which affects the activity of the
compound considerably (1~4). Therefore, the introduction of branched
chains in the aromatic ring site was to alleviate steric hindrance, but the
effect was still not satisfied, and unsatisfactory results were obtained (IC50
> 120). In addition, on the normal hepatocyte cell line (L02) and normal
lung cell line (IMR 90), IC50 values (>200 μM) clearly indicated that the
compounds had the same potency as the reference drug 5-FU.
In general, all compounds exhibited promising antibacterial activity
against the bacterial strains tested in comparison with the reference drugs.
Compounds 7, 8, 11, and 12 showed eight~four times higher antibacterial
activity against E. coli than ammoxicillin and ciprofloxacin with MIC values
of 6.25~3.125 nmol/mL. In addition, these compounds also showed
eight~four times higher antibacterial activity against S. aureus than
amoxicillin and ciprofloxacin with MIC values of 6.25~3.125 μg/mL. In
conclusion, compounds 7, 8, 11, and 12 showed higher antibacterial
activity against E. coli and S. aureus to that of amoxiicillin and ciprofloxacin.
In particular, compound 12 showed excellent antibacterial activity.
Nevertheless, compounds (1~4) did not show obvious activity compared
to the reference drug (Table-2).
Regarding the various R2, the pyridine ring with an alkyl-iodine
substituted at the para-position (5~12) exhibited better potency than non-
substituted position (1~4). The para-substituted pyridine ring with a methyl
(8) or propygroup (12) appeared to contribute concurrently to the potency.
In contrast to the other analogs, 12 with aromatic ether substitution at R1
also demonstrated good enzymatic potency. To explore the binding modes
of the ethyl-8-arylamino-[1,3]dioxolo[4,5-g]quinoliniumiodoalkyl- 7-
carboxylate, one of the most active inhibitors 12 was selected as a
representative and docked to the crystal structure of human
topoisomerase I (PDB: 1TL8). The docking of 12 in Fig. 3a displayed a free
energy of the binding affinity of -9.3 kcal/mol. The 3D binding model of
compound 12 in the binding site of the enzyme displayed mainly hydrogen
bond acceptor interactions through the oxygen of benzodioxoles with
TPC11, between the carbonyl oxygen and base DA113, between the
oxygen of arylamine and amino acid residue Lys425, and hydrogen bond
donor interaction between the N at the 4-position and base DG112. The
compound also displayed π-π interactions of arylamine-substituted group
and DG112, and CH-π interactions of arylamine-substituted group and
base DA113. The binding mode also displayed other hydrophobic and
cation interactions. Molecular docking is an intuitive way to preliminarily
simulate the binding of compound 12 to the action site. And these intensive
interactions make it a robust combination with Top I which was thought to
be the target of quinoline in the effect of anticancer. Thus, the reason for
obvious efficacy of 12 was explicated from another perspective by the
binding mode.
Lipophilicity
Lipophilicity is a major physico-chemical parameter to consider in drug
design. This property has
a
considerable impact on in vivo
pharmacokinetic parameters as well on the drug efficacy. A proper lipo-
solubility of drugs to make it possible to pass through the biofilm, and a
well-turned water-solubility is expected to facilitate the humoral transport
of the drug. N-octanol/water partition coefficient (i.e., ClogP) was
calculated on ACD/Labs website.
Compound 1~12 were investigated for their lipophilicity as well and the
data is shown in table-2. Compound 5~12 alkyliodine substituted at the 1-
position in pyridine with the 4-position N-phenyl substituent showed quite
different result on N-octanol/water partition coefficient by comparing to
unsubstituted 1~4. By considering the substituted at 1-position 5~12, it
appears that iodomethyl group series and iodopropane group showed
exactly different trend. In the series of 5~8, methy iodine substitution at 1-
position shows the decreased logP values, as observed by comparing 1
(unsustitution, logP
(unsustitution, logP
=
=
2.53) to
1.56) to
5
6
(methy iodine, logP
(methy iodine, logP
=
=
2.27),
1.22),
2
3
(unsustitution, logP = 2.18) to 7 (methy iodine, logP = 1.97), and 4
(unsustitution, logP = 2.09) to 8 (methy iodine, logP = 1.88).
On the contrary, replacement of a methyl substituent by a iodopropane
group leads to higher molecular weight compounds, with significantly
higher ClogP values. Indeed, for 9~12, a series of substituents with an
iodopropane group, ClogP values was getting higher, by comparing with
their respective previous compounds 1~4.
According to the above analysis, compound 12 exhibited significant
growth inhibition with an IC50 of 4.4±0.88, 4.7±0.42, and 14±1.96 against
A-549, Hela, and SGC-7901, respectively.
Derivatives 1~4 are preliminary compounds constitute by quinoline,
and with a 4-position N-phenyl substituent on the pyridine ring. The
influence of the nature of the 4-position N substitute group on the
lipophilicity of quinolines was also studied. By comparing four quinolines
1~4, it appears that the substitution by none oxygen group showed higher
ClogP values. Thus, the presence of an oxygen atom directly influences
the lipophilicity of the studied compounds, it may explain the weak
contribution in global molecular lipophilicity.
Evaluation of antibacterial activity in vitro
The newly synthesized compound 1-12, were evaluated for their
antibacterial activity by determining the MIC against Escherichia coli
(ATCC 29213) and Staphylococcus aureus (ATCC 8739). The test
compounds dissolved in DMSO were added to the culture medium (brain
heart infusion for S. mutans and Müller-Hinton agar for other bacteria) to
4
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10.1002/cmdc.202000002
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FULL PAPER
5 and 6 with 9 and 10, respectively. In particularly, 6 and 10 showed the
weak inhibitory to cancer cell lines (>120 to A549, Hela), which were
substituted at 4-position by methoxy-phenethylamine. Besides the
hindrance effect by bulky-aromatic group, this can also be interpreted by
the low lipophilicity (i.e., ClogP, Table-2) which may bring about the low
cell membrane permeability, thereby, influenced the effectiveness of the
derivatives. Although iodomethane and iodopropane were introduced at
the same 1-position, and aromatic groups were introduced at the 4-position,
the activities exhibited by them were different greatly.
Structure-activity relationship (SAR)
Based on the SAR studies and from the obtained biological results, the un-
substituted 1~4 did not exhibit potential anticancer and antibacterial
activities. In contrast, 5~12 alkyliodine substituted at the 1-position in
pyridine with the 4-position N-phenyl substituent possessed the highest
dual activity against all cancer cell and strains tested. The alkyliodine
substituents at the 1-position was introduced, such as iodomethyl group in
7 and 8 with iodopropane group in 11 and 12, respectively, containing an
iodine quaternary ammonium salt group, and the anticancer activity
against some cancer cells was more significant than that of 5-FU and MTX.
Moreover, the antibacterial activity against certain strains showed higher
activity compared to amoxicillin and ciprofloxacin.
This type of decrease in activity may due be to the large space
conformation, hindered space combined with enzyme-binding pocket
conflict, or that the 4-position aromatic amine group hinders the ability to
combine with the DNA.
The conversion of a 4-position carbonyl group to a hydrophobic
aromatic amine group to obtain 1~4 compounds, and most of these
structures contained a hydrophobic group, and had little effect on the
activity of the cancer cells and strains. Accordingly, iodoalkyl was
introduced further to obtain 5~12 compounds. Among these compounds,
compounds 7 and 8 with 11 and 12 exhibiting extremely high activity in
terms of double inhibition. On the other hand, other iodo quaternary
ammonium salt derivatives were not as strong as expected, and only had
a general inhibitory effect on cancer cells and strains, such as compounds
Among all the derivatives containing an iodo quaternary ammonium
salt group, the compounds substituted at the 1- and 4-positions all
exhibited extremely high dual activity. Preliminary synthetic SAR studies
have shown that to obtain better dual activity, the 1-position on the mother
structure should contain odd-numbered atoms in chain of hydrophobic
groups and the 4-position should include hydrophobic aromatic amine
groups to have a positive impact on the structure of dual activity.54,55
Table 2. Antibacterial screening in terms of the MIC (μg/mL) for the tested compounds in reference to Amoxicillin and Ciprofloxacin, respectively.
Compound
R1
MICa / (nmol.mL-1)
ClogPb
R2
Escherichia coli
Staphylococcus aureus
1
2
3
4
5
6
7
8
-CH2CH2Ph
-CH2CH2Ph(OCH3)2
-CH2Ph
-
-
-
> 50
25
> 50
6.25
25
12.5
6.25
6.25
50
6.25
6.25
3.125
50
> 50
50
25
6.25
12.5
6.25
12.5
3.125
50
2.53
1.56
2.18
2.09
2.27
1.22
1.97
1.88
2.89
2.11
2.85
2.67
-PhOCH2Ph
-CH2CH2Ph
-CH2CH2Ph(OCH3)2
-CH2Ph
-PhOCH2Ph
-CH2CH2Ph
-CH2CH2Ph(OCH3)2
-CH2Ph
-
-CH3
-CH3
-CH3
-CH3
9
10
11
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-CH2CH2CH3
-
25
6.25
3.125
25
12
-PhOCH2Ph
-
Amoxicillin
Ciprofloxacin
-
-
25
12.5
[a] MIC (minimum inhibitory concentration) values represent the average of three readings; [b] calculated on ACD/Labs website.
covalent complex with a 22 base pair DNA duplexprotein (PDB ID: 1TL8).
The docking of 7 displayed a free energy of the binding affinity of -9.6
kcal/mol. Compound 7 exhibited one hydrogen bond acceptor interaction
between the carbonyl oxygen of ester group and TPC11 in addition to the
ionic interactions with the amino acid residues Arg364, Lys425, Lys436,
and Lys532. Moreover, compound 7 also exhibited π-π interactions of
quinolone pyridine ring with base DT10, DA113, and TPC11 in addition to
π-π stacking interactions between the quinoline benzene ring and TPC11,
arylamine phenzene and base DG112, respectively. These π-π stacking
interactions make a significant contribution to stabilizing the docking
structure.
Molecular docking study
AutoDock Vina 1.1.2. software was used to perform docking
simulations.56,57 In the present study, the derivatives were designed based
on the quinoline core, depending on the former studies on the mechanism
of anticancer and antibacterial activity. The 3D crystal structure of human
topoisomerase I and S. aureus DNA gyrase (Topo II) reported in Protein
Data Bank (PDB) were used as the receptor for docking studies (PDB ID:
1TL8, 2XCT).58-62 The co-crystallized structure of the target proteins were
downloaded from the PDB and prepared for docking using the docking
program AutoDockVina 1.1.2. and MGLTools. The docking result was
analyzed and optimized by Pymol 1.5.6. (Fig-2).
The docking of 7 in Fig. 2b (DNA gyrase) displayed a free energy of the
binding affinity of -8.1 kcal/mol. Compound 7 exhibited hydrogen bond
acceptor interactions between the oxygen of benzodioxoles and base
DC12, and the hydrogen bond donor interaction between N at the 4-
The other two compounds were docked as comparative objects. The
3D ligand interactions of the combination in Fig. 2a showed the binding
pattern of selected derivative 7 to Human DNA topoisomerase I in the
5
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10.1002/cmdc.202000002
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position and base DG9. In addition, π-π stacking interactions occur
between the quinolone pyridine ring and two bases DA13 or DG9 in
addition to π-π interactions of the quinolone phenyl ring and base DA13,
DC12. The π-π interaction also existed in the arylamine phenyl ring and
base DT8, in addition to the cation-π interaction of the arylamine phenyl
ring and amino acid residue Arg458.
A series of arylamine-substituted iodo quaternary amine embedded
quinolone derivatives were synthesized. Coupling of the aryamine
functional groups produced the target compounds, the iodo quaternary
amine could be further substituted to produce the final compound in
moderate yield. To lay the foundation for the subsequent development of
pharmacological toxicology with better novel quinoline compounds, and
design and synthesize a series of new quinoline derivatives with iodoalkyl
and arylamine groups at the 1- and 4-positions of the functional side chain,
new quinoline and quinolinium iodine salt derivatives were prepared, in
addition, their anticancer and antibacterial effects were studied as well. It
is showed that the 1-position substituted compounds had salient activity
comparing to unsubstituted one. The relationship between the structure
activity and molecular docking was also evaluated with derivatives as new
comprehensive drugs. The effects of introducing functional groups, and
the importance and specificity of the odd substituted chains on the overall
structure activity were examined. This study confirmed that the
compounds with odd atoms in substituted chains at 4-position firmly
showed dual activity. Nevertheless, more follow-up research will be
needed.
The anticancer docking of 11 in Fig. 2c displayed the free energy of the
binding affinity of -9.5 kcal/mol. As shown in Fig. 2c, the 3D ligand
interactions of compound 11 showed π-π interactions not only between
the pyridine ring and base DA113 or DT10 or TPC11, but also the π-π
stacking interactions of quinoline benzene ring and TPC or DT10, as well
as between arylamine phenzene and base DG112. Compound 11 also
displayed a hydrogen bond acceptor interaction of the carbonyl oxygen of
ester group and TPC11 in addition to ionic interactions with the amino acid
residues, Arg364, Lys425, Lys436 and Lys532.
Antibacterial docking of 11 in Fig. 2d displayed a free energy of the
binding affinity of -8.1 kcal/mol. Docking of compound 11 displayed mainly
π-π interactions between the pyridine ring, quinoline benzene ring, and
base DA13 and DG9 in addition to arylamine phenzene and amino acid
residues Arg458. In addition, the hydrogen bond acceptor interaction
between the oxygen of benzodioxoles and base DC12 in addition to the
cation-π interaction of arylamine phenzene and amino acid residue
Arg1122 were noted.
Experimental Section
Materials and Methods
The docking of 12 in Fig. 2e displayed a free energy of the binding
affinity of -9.3 kcal/mol. In contrast, the docking of compound 12 displayed
hydrogen bond acceptor interactions mainly between the oxygen of
benzodioxoles and TPC11, between the carbonyl oxygen and base
DA113, between the oxygen of arylamine and amino acid residue Lys425,
hydrogen bond donor interaction between N at the 4-position and base
DG112. In addition, compound 12 displayed π-π interactions of arylamine-
substituted group and DG112, in addition to CH-π interactions of the
arylamine-substituted group and base DA113.
All solvents and reagents were commercially purchased and used as
received and employed further purification. Moisture-sensitive reactions
were performed under nitrogen atmosphere. Dichloromethane and
acetonitrile were distilled over calcium hydride. All glassware including
needles and syringes were torch flame or oven-dried and kept in a
desiccator before use. The reaction products were isolated and purified by
column chromatography (silica gel 200~230 mesh). Thin-layer
chromatography (TLC) was used to monitor the progress of the reaction.
Analysis of TLC results at 254 nm and 360 nm wavelengths under UV
lamps. Characterization of the products at each stage by NMR
spectroscopy, 1H, and 13C NMR spectra were recorded on Bruker Avance
II spectrometer in CDCl3 (400 MHz for 1H and100 MHz for 13C); chemical
shifts are expressed in ppm, versus internal tetramethylsilane (TMS) = 0
for 1H and 13C. Coupling constants (J) are given in Hz. Elemental analyses
were performed using a Carlo Erba Instruments CHNS-O EA1108
analyser. IR spectra of samples were recorded on a Nicolet avato-370 FT-
IR analyzer using KBr disks. Carlo Erba Instruments CHNS-O EA1108
analyser and HR-MS (FAB) (Jeol LTD JMS-HX 110/110A) were performed
by the Chosun University of the Republic of Korea.
The binding mode also displayed other hydrophobic and cation
interactions. Docking of 12 in Fig. 2f displayed a free energy of the binding
affinity of -9.4 kcal/mol. Compound 12 displayed CH-π interactions mainly
between the arylamine-substituted group and base DA13 or DG9 in
addition to other CH-π interactions of quinoline benzene ring and amino
acid residue Phe1123. It also displayed hydrogen bond acceptor between
carbonyl oxygen and base DA13, π-π interaction between quinoline
pyridine ring and base DT8, besides cation-π interactions of amino acid
residues Arg1122, Arg458 and quinoline core, arylamine-substituted group,
respectively.
The scores of all the affinity scores caculated by molecular docking
software are listed in the Table-3. According to the table, compounds 7, 11
and 12 have acceptable values to match the good inhibitory activities on
the proliferation of cancer cells, with the scores are in the range of - 9.6 ~
- 9.3. However, the level of scoring is not the only criterion to judge the
combining abilit. In addition, various interactions are also the reasons for
the robust binding with the receptor. For example, the presentence of four
hydrogen bonds in the conjugate of compound 12 and enzyme makes the
binding site more stable, thus, inhibitory activity of compound 12 is the
most prominent.
General Procedure for the Synthesis of 1-4
Ethyl 8-chloro-[1,3]dioxolo[4,5-g]quinoline-7- carboxylate (1.0 eq.) was
added to a solution of the arylamine compound (2.5 eq.) in dry acetonitrile
(10 mL) and stirred at 80°C for 8-10 h. Thin layer chromatography was
used to monitor the progress of the reaction. The solvent was added to 10
mL water with 5 mL dichloromethane and extracted 3 times. The organic
layer was dried anhydrous magnesium sulfate and filtered. The residue
was purified by column chromatography (EtOAc:petroleum ether = 1:8) to
produce a yellowish solid.
Conclusions
6
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10.1002/cmdc.202000002
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Figure 2. 3D binding mode of derivatives 7, 11 and 12 in the binding site of Human topoisomerase I (PDB ID: 1TL8; a, c and e) and S. aureus DNA gyrase (Topo II,
PDB ID: 2XCT; b, d and f).
Table 3. Docking score obtained for compounds 7, 11 and 12.
PDB
code
Entry
Affinity
(kcal·mol-1)
score
Interaction with receptor
7
-9.6
-9.5
-9.3
-8.1
-8.1
-9.4
DT 10, DA 113, DG 112, TPC 11, ARG 364, LYS 425, LYS 436, LYS 532.
DT 10, DA 113, DG 112, TPC 11, ARG 364, LYS 425, LYS 436, LYS 532.
DA 113, DG 112, TPC 11, LYS 425.
DA 13, DG 9, DC 12, DT 8, ARG 458.
DA 13, DG 9, DC 12, ARG 1122, ARG 458.
1TL8
11
12
7
11
12
2XCT
DA 13, DT 8, DG 13, ARG 1122, ARG 458, PHE 1123.
7
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10.1002/cmdc.202000002
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Ethyl 8-(phenethylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carboxylate 1
A yellow solid (1.1 g, 84.8%): 1H NMR (400MHz, CDCl3, ppm): δ 8.96 (s,
1H), 8.87 (s, 1H,), 7.47 (s, 1H), 7.33–7.25 (m, 6H), 6.10 (s, 2H), 4.40–4.37
(m, 2H), 3.97 (m, 2H), 3.05–3.01 (t, J = 7.2Hz, 7.6Hz, 2H), 1.44–1.40 (t, J
= 7.2Hz, 3H). 13C NMR (100MHz, CDCl3, ppm): δ 168.6, 156.4, 151.2,
150.0, 149.6, 146.0, 138.1, 128.8, 128.6, 126.8, 115.0, 106.7, 104.0, 102.0,
101.9, 60.6, 50.7, 37.6, 14.4.
8-((3,4-dimethoxyphenethyl)amino)-7-(ethoxycarbonyl)-5-methyl-[1,3]
dioxolo[4,5-g]quinolin-5-ium iodide 6
A yellow solid (0.38 g, 94%) yield. IR (KBr pellet, cm−1): ν (N+) 1476 (strong
br). 1H NMR (400MHz, CDCl3, ppm): δ 10.36 (s, 1H), 9.16 (s, 1H), 7.76 (s,
1H), 7.41 (s, 1H), 6.89–6.85 (m, 3H), 6.28 (s, 2H), 4.45 (m, 2H), 4.17 (s,
2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.11–3.07 (t, J = 6.4Hz, 6.8Hz, 2H), 1.49–
1.45 (t, J = 7.2Hz, 3H). 13C NMR (100MHz, CDCl3, ppm): δ 166.0, 154.9,
149.1, 148.2, 148.0, 147.4, 138.9, 135.8, 129.3, 121.0, 114.2, 112.5, 111.6,
104.5, 104.2, 102.4, 97.7, 62.7, 56.0, 56.0, 54.2, 51.2, 45.0, 14.3. HR-MS
(FAB) calcd for C24H27IN2O6 (M+- I-) m/z 439.1864, observed 439.1859.
Calcd for C24H27IN2O6: C, 50.89; H, 4.81; N, 4.95. Found: C, 50.85; H, 4.82;
N, 4.84.
Ethyl 8-((3,4-dimethoxyphenethyl)amino)-[1,3]dioxolo[4,5-g]quinoline-7-
carbox ylate 2
A yellowish solid (1.3 g, 85.0%): 1H NMR (400MHz, CDCl3, ppm): δ 8.95
(s, 1H), 7.50 (s, 1H), 7.32–7.28 (m, 2H), 6.85–6.81 (m, 3H), 6.11 (s, 2H),
4.37–4.34 (m, 2H), 3.97–3.96 (d, J = 5.2 Hz, 2H), 3.90–3.88 (d, J = 6.8 Hz,
6H), 3.00–2.96 (t, J = 7.2Hz, 2H), 1.43–1.40 (t, J = 7.2Hz, 3H). 13C NMR
(100MHz, CDCl3, ppm): δ 166.6, 156.4, 151.3, 149.0, 147.9, 146.0, 130.7,
120.7, 115.0, 112.3, 111.5, 106.7, 103.8, 102.1, 102.0, 60.6, 55.9, 55.8,
50.9, 37.2, 14.3.
8-(benzylamino)-7-(ethoxycarbonyl)-5-methyl-[1,3]dioxolo[4,5-g]quin
olin-5-ium iodide 7
A yellow solid (0.2 g, 48%) yield. IR (KBr pellet, cm−1): ν (N+) 1481 (strong
br). 1H NMR (400MHz, CDCl3, ppm): δ 10.66 (s, 1H), 9.25(s, 1H) 7.78(d, J
= 1.6Hz, 1H), 7.46–7.39 (m, 6H), 6.28 (s, 2H), 5.11–5.10 (d, J = 5.6Hz,
2H), 4.43–4.37 (t, J = 7.2Hz, 5H), 1.47–1.43 (t, J = 7.2Hz, 3H). 13C NMR
(100MHz, CDCl3, ppm): δ 165.9, 155.0, 148.2, 147.6, 139.1, 135.5, 129.4,
128.7, 127.5, 116.5, 114.2, 104.4, 104.2, 102.9, 97.8, 62.8, 54.2, 45.0,
14.2. HR-MS (FAB) calcd for C21H21IN2O4 (M+- I-) m/z 365.1496, observed
365.1501. Calcd for C21H21IN2O4: C, 51.23; H, 4.30; N, 5.69. Found: C,
51.22; H, 4.32; N, 5.58.
Ethyl 8-(benzylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carboxylate 3
A yellowish solid (1.0 g, 79.2%): 1H NMR (400MHz, CDCl3, ppm): δ 10.01
(s, 1H), 9.01–7.28 (m, 8H), 6.09 (s, 2H), 4.87–4.89 (d, J = 6.4Hz, 2H),
4.37–4.35 (d, J = 6.8Hz, 2H), 1.40 (s, 3H) 13C NMR (100MHz, CDCl3,
ppm): δ 168.6, 156.5, 151.3, 149.9, 149.7, 146.2, 138.6, 128.9, 127.8,
127.1, 114.9, 106.7, 104.4, 101.9, 60.7, 52.5, 14.3.
Ethyl 8-((4-(benzyloxy)phenyl)amino)-[1,3]dioxolo[4,5-g]quinoline-7-
carboxylate 4
8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-methyl-[1,3]dio
xolo[4,5-g]quinolin-5-ium iodide 8
A yellowish solid (1.2 g, 70.0%): 1H NMR (400MHz, CDCl3, ppm): δ 10.50
A yellow solid (0.16 g, 39%) yield. IR (KBr pellet, cm−1): ν (N+) 1474 (strong
br). 1H NMR (400MHz, CDCl3, ppm): δ 11.70 (s, 1H), 9.45(s, 1H), 7.47–
7.37(m, 6H), 7.22–7.20(d, J = 8.4Hz, 2H), 7.06–7.03 (t, J = 8.8Hz, 6Hz,
3H), 6.20 (s, 2H), 5.13 (s, 2H, ), 4.51–4.48 (t, J = 7.2Hz, 5H), 1.54–1.50 (t,
J = 6.8Hz, 3H). 13C NMR (100MHz, CDCl3, ppm): δ 166.2, 158.4, 155.1,
155.0, 147.9, 147.6, 139.5, 136.2, 131.7, 128.6, 128.2, 127.5, 126.0, 116.5,
114.2, 104.3, 104.0, 103.8, 97.8, 70.4, 63.0, 45.6, 14.4. HR-MS (FAB)
calcd for C27H25IN2O5 (M+- I-) m/z 457.1758, observed 457.1752. Calcd for
C27H25IN2O5: C, 55.49; H, 4.31; N, 4.79. Found: C, 55.47; H, 4.30; N, 4.74.
(s, 1H), 9.10 (s, 1H)，7.74–7.28 (m, 6H), 7.01–6.90 (m, 5H), 6.02 (s, 2H),
5.08 (s, 2H), 4.44–4.42 (t, J = 6.8Hz, 2H), 1.47–1.44 (t, J = 7.2Hz, 3H). 13
C
NMR (100MHz, CDCl3, ppm): δ 168.5, 152.3, 151.6, 149.0, 146.1, 136.8,
135.8, 128.6, 128.0, 127.5, 124.1, 115.7, 115.1, 106.1, 102.7, 101.9, 70.4,
61.1, 50.4, 14.3.
General Procedure for the Synthesis of 5-12.
Excess of iodoalkane (5.0 equiv.) was slowly added to a dry acetonitrile (5
7-(ethoxycarbonyl)-8-(phenethylamino)-5-propyl-[1,3]dioxolo[4,5-g]
quinolin-5-ium iodide 9
mL)
solution
of
compound
7-(ethoxycarbonyl)-8-(arylamino)-
[1,3]dioxolo[4,5-g]quinoline (1.0 equiv.) in seal tube, and was stirred for 2–
4 h. The precipeted solide was filtered, to produce the correspondence
compound 5~12.
A white powder (0.31 g, 71%) yield. IR (KBr pellet, cm−1): ν (N+) 1485
(strong br). 1H NMR (400MHz, CDCl3, ppm): δ 10.37-10.37 (d, J = 0.4Hz,
1H), 9.21 (s, 1H), 7.76 (s, 1H), 7.39–7.29 (m, 6H), 6.30 (s, 2H), 4.75–4.71
(t, J = 7.6Hz, 2H), 4.50–4.44 (m, 2H), 4.21–4.20 (d, J = 5.2Hz, 2H), 3.18–
3.15 (t, J = 7.2Hz, 2H), 2.02–1.97 (m, 2H), 1.51–1.47 (t, J = 7.2Hz, 3H),
1.08 (s, 3H). 13C NMR (100MHz, CDCl3,ppm): δ 165.9, 157.2, 155.0, 148.0,
146.5, 137.9, 136.7, 128.9, 128.9, 127.2, 114.6, 104.6, 104.3, 102.6, 97.5,
62.8, 58.2, 50.9, 36.5, 22.2, 14.5, 10.9. HR-MS (FAB) calcd for
C24H27IN2O4 (M+- I-) m/z 407.1965, observed 407.1963. Calcd for
C24H27IN2O4: C, 53.94; H, 5.09; N, 5.24. Found: C, 53.92; H, 5.11; N, 5.26.
7-(ethoxycarbonyl)-5-methyl-8-(phenethylamino)-[1,3]dioxolo[4,5-g]
quinolin-5-ium iodide 5
A yellow solid (0.38 g, 90%) yield. IR (KBr pellet, cm−1): ν (N+) 1483 (strong
br). 1H NMR (400MHz, CDCl3, ppm): δ 10.35 (d, J = 1.2Hz, 1H), 9.16 (s,
1H), 7.73 (s, 1H), 7.42 (s, 1H), 7.36–7.29 (m, 5H), 6.28 (s, 2H), 4.47-4.41
(m, 2H), 4.32 (s, 3H), 4.17-4.16 (t, J = 2Hz, 2H), 3.16-3.12 (t, J = 6.8 Hz,
7.2Hz，2H), 1.48-1.44 (t, J = 7.2 Hz, 3H). 13C NMR (100MHz, CDCl3,
ppm): δ 166.0, 157.1, 154.9, 148.0, 147.5, 138.9, 136.7, 129.0, 128.9,
127.2, 114.2, 104.2, 102.6, 97.7, 97.7, 62.7, 54.2, 50.7, 44.9, 14.3 HR-MS
(FAB) calcd for C22H23IN2O4 (M+- I-) m/z 379.1652, observed 379.1659.
Calcd for C22H23IN2O4: C, 52.19; H, 4.58; N, 5.53. Found: C, 52.25; H, 4.61;
N, 5.52.
8-((3,4-dimethoxyphenethyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]
dioxolo[4,5-g]quinolin-5-ium iodide 10
A white powder (0.27 g, 63%) yield. IR (KBr pellet, cm−1): ν (N+) 1477
(strong br). 1H NMR (400MHz, CDCl3, ppm): δ 10.28-10.27 (d, J = 0.8Hz,
1H), 9.08 (s, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 6.87 (s, 1H), 6.80-6.79 (d, J =
8
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4Hz, 2H), 6.25 (s, 2H), 4.65–4.61 (t, J = 7.2Hz, 2H), 4.41–4.36 (m, 2H),
4.17 (s, 2H), 3.85–3.80 (d, J = 20Hz, 6H), 3.06–3.03 (t, J = 6.0Hz, 2H),
1.93–1.89 (t, J = 7.2Hz, 2H), 1.44–1.40 (t, J = 7.2Hz, 3H), 1.03–0.99 (t, J
= 7.2Hz, 3H). 13C NMR (100MHz, CDCl3, ppm): δ 165.9, 154.9, 149.1,
148.1, 147.9, 146.5, 137.8, 137.8, 129.2, 121.0, 114.5, 112.5, 111.6, 104.8,
104.3, 102.4, 97.4, 62.7, 58.2, 56.1, 56.0, 51.3, 36.0, 22.2, 14.5, 10.9. HR-
MS (FAB) calcd for C26H31IN2O6 (M+- I-) m/z 467.2177, observed 467.2174.
Calcd for C26H31IN2O6: C, 52.53; H, 5.26; N, 4.71. Found: C, 52.58; H, 5.19;
N, 4.68.
shocked for 10 min. The optical density of the samples was measured at
490 nm on a microplate luminometer. The cell viability is expressed as the
percentage change in absorbance compared to the control values.
In vitro antimicrobial evaluation
The synthetic compounds 1~12 against two bacterial strains were
measured using the broth microdilution method in 96-well plates, and the
MIC values were determined. The MIC is defined as the lowest
concentration of test sequences that completely inhibit growth. The
microorganisms used in the present study were S. aureus (ATCC 29213)
and E. coli (ATCC 8739). This was placed on the inoculated muller-Hinton
agar plates, and the test compounds were dissolved in DMSO to obtain
final concentrations of 1-50 nmol·mL-1. The final bacterial concentration
was approximately 106 CFU mL-1. The MIC values were measured after
incubation for 24 h at 37 °C. Ciprofloxacin and amoxicillin were used as
controls and assayed under identical conditions. All experiments were
performed in triplicate.
8-(benzylamino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dioxolo[4,5-g]quin
olin-5-ium iodide 11
A white powder (0.31 g, 70%) yield. IR (KBr pellet, cm−1): ν (N+) 1475
(strong br). 1H NMR (400MHz, CDCl3, ppm): δ 10.69 (s, 1H), 9.28–9.27 (t,
J = 1.2Hz, 1H), 7.84–7.83 (m, 1H), 7.43(s, 6H), 6.29 (s, 2H), 5.14–5.13 (d,
J = 5.2Hz, 2H), 4.77 (s, 2H), 4.43–4.42 (d, J = 6.8Hz, 2H), 2.03–2.02 (d, J
= 7.2Hz, 2H), 1.48–1.44 (t, J = 7.2Hz, 3H), 1.12–1.08 (t, J = 7.2Hz, 3H).
13C NMR (100MHz, CDCl3, ppm): δ 165.8, 155.1, 148.1, 146.6, 137.9,
135.5, 129.3, 128.6, 127.4, 114.6, 104.7, 104.2, 103.0, 100.0, 97.5, 62.8,
58.2, 53.6, 22.2, 14.4, 10.9. HR-MS (FAB) calcd for C23H25IN2O4 (M+- I-)
m/z 393.1809, observed 393.1807. Calcd for C23H25IN2O4: C, 53.09; H,
4.84; N, 5.38. Found: C, 53.12; H, 4.83; N, 5.39.
Molecular docking
AutoDock Vina software package version 1.1.2 was used to perform
docking simulations. The target 3D crystal structure of human
topoisomerase I and S. aureus DNA gyrase (Topo II) in Protein Data Bank
(PDB) were downloard (PDB ID: 1TL8, 2XCT) and prepared for docking
using the docking program AutoDockVina 1.1.2. and MGLTools. The
docking result was analyzed and optimized by Pymol 1.5.6.
8-((4-(benzyloxy)phenyl)amino)-7-(ethoxycarbonyl)-5-propyl-[1,3]dio
xolo[4,5-g]quinolin-5-ium iodide 12
A white powder (0.32 g, 77%) yield. IR (KBr pellet, cm−1): ν (N+) 1474
(strong br). 1H NMR (400MHz, CDCl3, ppm): δ 11.59 (s, 1H), 9.38 (s, 1H),
7.39–7.28 (m, 6H), 7.15–7.14 (d, J = 6.8Hz, 2H), 7.12–7.00 (d, J = 8.8Hz,
3H), 6.18 (s, 2H), 5.06 (s, 2H), 4.78 (s, 2H), 4.44–4.43 (d, J = 4.8Hz, 2H),
2.01 (s, 2H), 1.47–1.46 (d, J = 4Hz, 3H), 1.08–1.07 (d, J = 3.2Hz, 3H). 13
C
NMR (100MHz, CDCl3, ppm): δ 166.2, 158.4, 155.2, 154.7, 147.6, 138.4,
136.2, 131.5, 128.6, 128.2, 127.5, 126.0, 116.5, 114.5, 104.5, 104.2, 103.8,
97.5, 70.4, 63.1, 58.6, 22.5, 14.5, 11.0. HR-MS (FAB) calcd for
C29H29IN2O5 (M+- I-) m/z 485.2071, observed 485.2064. Calcd for
C29H29IN2O5: C, 56.87; H, 4.77; N, 4.57. Found: C, 56.85; H, 4.72; N, 4.56.
Acknowledgements
This study was supported financially by the scientific research foundation
of Jiangsu University (Grant No. 5501290005).
Conflict of Interest statement
In vitro cytotoxicity
The authors declare no conflict of interest.
The three cancer cell lines (A549, SGC-7901, and Hela) and normal cell
lines (normal liver L-02 cells and normal lung IMR 90 cells), were acquired
from the American Type Culture Collection (Manassas, VA, USA). A549
and SGC-7901 cells were cultured routinely in RPMI-1640, and Hela and
L-02 cells were cultured routinely in DMEM. The medium was
supplemented with 10% fetal bovine serum (FBS). The cells were
maintained at sub-confluence at 37oC in humidified air containing 5% CO2.
The cells were monitored daily and maintained at an 80% cell density.
The cytotoxicity of the tested samples was measured against each cell
line using the MTT Cell Viability Cancer cells (A549, SGC-7901 and Hela)
and normal human cells lines (liver L-02 cells and lung IMR 90 cells) were
harvested during the logarithmic phase of growth. All the cells were seeded
in 96-well plates at 104 cells/well and then treated with various
concentrations (1, 3, 10, 30, or 100 µmol/mL) of 5-FU, methotrexate and
the tested samples for 24 h. The MTT solution (20 µL; 5 mg/mL) was added
to each well, and the cells were cultured for 4 h at 37oC. The supernatants
were removed, and resolved with 100 µL of DMSO, and the cells were
Keywords: quinoline and quinolinium iodide • anticancer •
antibacterial • human cancer • human bacterial strains
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Entry for the Table of Contents
We prepared a series of novel quinoline and quinolinium iodide derivatives starting from Ethyl 8-chloro-[1,3]dioxolo[4,5-g]quinoline-7-
carboxylate and the arylamine compounds to discover potential anticancer and antibacterial agents. The target compounds 12 was
found to be the most potent derivative with IC50 values, stronger than the positive control 5-FU and MTX. Furthermore, compound 12
had the most potent inhibitory activity. The MIC of this compound against test cells were 3.125 nmol.mL-1, which was smaller than
that of the reference agents, amoxicillin and ciprofloxacin.
11
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