Structural analogues of quinoline alkaloids: Straightforward route to [1,3]dioxolo[4,5-c]quinolines with antibacterial properties

Article abstract of DOI:10.1002/jhet.3886

Compounds bearing [1,3]dioxolo-quinoline scaffolds have been found in quinoline-based natural products; the only exception is the [1,3]dioxolo[4,5-c]quinoline moiety with a rare occurrence in both natural and synthetic derivatives. In this article, we report the preparation of diversely substituted and functionalized [1,3]dioxolo[4,5-c]quinolines using [1,3]dioxolo[4,5-c]quinoline-4-carbaldehyde (DQC) as the common intermediate. DQC was synthesized on a large scale from anthranilic acid and chloroacetone as the starting materials, with the rearrangement of acetonyl-anthranilate as the key step. The developed method allows for the simple preparation of [1,3]dioxolo[4,5-c]quinolines with various C2 substituents on the quinoline scaffold. Additionally, the synthetic route was successfully applied to the preparation of 3-hydroxyquinoline-4(1H)-ones. The target compounds were tested against representative Gram-positive/negative bacteria, and two derivatives exhibited submicromolar minimum inhibitory concentrations against Micrococcus luteus.

Full text of DOI:10.1002/jhet.3886

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Received: 27 October 2019
DOI: 10.1002/jhet.3886
Revised: 6 December 2019
Accepted: 18 December 2019
A R T I C L E
Structural analogues of quinoline alkaloids:
Straightforward route to [1,3]dioxolo[4,5-c]quinolines with
antibacterial properties
Radim Horák | Kamil Kořistek | Veronika Šamšulová | Ludmila Slaninová |
Martin Grepl | Lubomír Kvapil | Petr Funk | Pavel Hradil | Miroslav Soural
Department of Organic Chemistry,
Abstract
Faculty of Science, Palacký University, 17.
listopadu 12 Olomouc, Czech Republic
Compounds bearing [1,3]dioxolo-quinoline scaffolds have been found in
quinoline-based natural products; the only exception is the [1,3]dioxolo[4,5-c]
quinoline moiety with a rare occurrence in both natural and synthetic deriva-
tives. In this article, we report the preparation of diversely substituted and
functionalized [1,3]dioxolo[4,5-c]quinolines using [1,3]dioxolo[4,5-c]quinoline-
4-carbaldehyde (DQC) as the common intermediate. DQC was synthesized on
a large scale from anthranilic acid and chloroacetone as the starting materials,
with the rearrangement of acetonyl-anthranilate as the key step. The devel-
oped method allows for the simple preparation of [1,3]dioxolo[4,5-c]quinolines
with various C2 substituents on the quinoline scaffold. Additionally, the syn-
thetic route was successfully applied to the preparation of 3-hydroxyquinoline-
4(1H)-ones. The target compounds were tested against representative Gram-
positive/negative bacteria, and two derivatives exhibited submicromolar mini-
mum inhibitory concentrations against Micrococcus luteus.
Correspondence
Miroslav Soural, Department of Organic
Chemistry, Faculty of Science, Palacký
University, 771 46 Olomouc, Czech
Republic.
Email: miroslav.soural@upol.cz
Funding information
Ministerstvo Pru˚ myslu a Obchodu, Grant/
Award Number: FV20250
1 | INTRODUCTION
quinoline alkaloids contain the cyclic methylenedioxy
moiety, which results in [1,3]dioxolo-quinolines.
Synthetic derivatives with the molecular framework
resembling the structure of natural compounds are
important derivatives in the field of drug discovery.[1]
The main scaffolds of natural products have been fre-
quently used as templates for the design of ligands to
either improve their affinity for biological targets or to
modify their pharmacological properties. In the field of
natural products, an important and large group of com-
pounds with diverse biological effects are the quinoline
alkaloids.[2,3] These compounds are typically simple quin-
Depending on the mutual annellation of dioxole and
quinoline rings, these heterocycles can be classified as
[1,3]dioxolo[4,5-b]quinolines I, [1,3]dioxolo[4,5-c]quino-
lines II, [1,3]dioxolo[4,5-f]quinolines III, [1,3]dioxolo
[4,5-g]quinolines IV, and [1,3]dioxolo[4,5-h]quinolines
V (Figure 1). Within the group of quinoline alkaloids,
derivatives based on [1,3]dioxolo-quinolines I, III, IV,
and V have already been reported. The most frequently
studied types of these compounds are [1,3]dioxolo[4,5-g]
quinolines IV and [1,3]dioxolo[4,5-h]quinolines V, with
the group of Orixa japonica alkaloids and furoquinolones
being the best-known representatives. Similarly, syn-
thetic compounds derived from IV have been widely
oline derivatives that possess alkoxy groups in different
[4]
positions on the main scaffold.
Apart from the most
commonly occurring methoxy groups, specific types of
J Heterocyclic Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

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HORÁK ET AL.
FIGURE 1 Isomeric [1,3]dioxolo-
quinolines, examples of related alkaloids and
their reported biological properties[5–14] [Color
figure can be viewed at wileyonlinelibrary.com]
reported in the literature.[15–25] In contrast, the [1,3]dio-
xolo[4,5-c]quinolines II have not been isolated from nat-
ural sources, and the synthetic derivatives of such
heterocycles are an unexplored group of compounds,
undoubtedly due to the problematic synthetic availability
of the [1,3]dioxolo[4,5-c]quinoline scaffold. Inspired by
this fact, we decided to develop a simple approach to
[1,3]dioxolo[4,5-c]quinolines with variable substitution
on the quinoline scaffold. With respect to the large num-
ber of antibacterial and antitumor quinoline derivatives
reported to date, the activity of the synthesized com-
pounds against representative bacterial strains was eluci-
dated, and the most promising results are reported in this
article.
DMF
O
O
NMP
reflux
K
2CO3
rt
OH
COOH
NH2
Cl
O
O
+
O
N
H
%
NH2
1
2
3
85
%
4
70
O
O
THF
SeO2
reflux
,
Br2
CH2
O
O
DMF,
reflux
O
N
N
60
6
%
5
70
%
DQC
SCHEME 1 Preparation of the key intermediates 5 and 6
4 was obtained. Alkylation with dibromomethane yielded
4-methyl-[1,3]dioxolo[4,5-c]quinoline 5, which was fur-
ther oxidized using selenium dioxide to [1,3]dioxolo
[4,5-c]quinoline-4-carbaldehyde 6 (DQC). The developed
conditions were successfully used to synthesize the key
intermediates in good yields that were scaled up to 50 g
(compound 5) and 10 g (compound 6).
2 | RESULTS AND DISCUSSION
Synthesis of the key intermediate began from anthranilic
acid 1 (Scheme 1). After alkylation with chloroacetone 2,
the resulting 2-oxopropyl 2-aminobenzoate 3 was sub-
jected to rearrangement in boiling N-methylpyrrolidin-
2-one,[26] and 3-hydroxy-2-methylquinolin-4(1H)-one
To demonstrate the applicability of DQC for structural
diversification using nucleophiles, compound
6 was

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HORÁK ET AL.
3
subjected to reductive alkylation with 1-methylpiperazine,
to condensation with hydrazine hydrate or to Corey-Fuchs
reaction with dibromomethane/triphenylphosphine,[27]
which yielded the corresponding products 7-9 (Scheme 2).
Furthermore, the reduction of DQC with sodium borohy-
dride afforded primary alcohol 10, and the reaction of DQC
with the Ohira-Bestmann reagent gave alkyne derivative 11
which can be further applied in the conjugation with
azides.[28] It is worth mentioning that except for DQC 6,
compounds 9-11 with reactive functionalities represent use-
ful intermediates to prepare other derivatives of [1,3]dioxolo
[4,5-c]quinoline based on, for example, acylation or cycload-
dition reactions. Finally, intermediate 6 was successfully
hydrolyzed with hydrochloric acid to 3-hydroxyquinolin-4
(1H)-one derivative 12 (see the wider application of this
reaction later in the text). Not only DQC 6, but also
4-methyl-[1,3]dioxolo[4,5-c]quinoline 5 can be considered
as the reactive compound suitable for further modification
of the [1,3]dioxolo[4,5-c]quinoline scaffold in the C2 posi-
tion. To demonstrate the reactivity of picoline-like methyl
group toward electrophiles, compound 5 was subjected to
reaction with butyllithium followed by addition of represen-
tative aldehydes (Scheme 3). In each case, the
corresponding secondary alcohols 13a-f were obtained.
Compounds 13 were further reacted with methanesulfonyl
chloride in pyridine which yielded 2-styryl-[1,3]dioxolo
[4,5-c]quinolines 14a-d. Derivatives bearing cyclopentyl
(13c) or 3-thienyl (13e) moiety gave after reaction with
MsCl/pyridine a mixture of unknown compounds with
traces of product. In the case of t-butylaldehyde and
pyridine-3-carbaldehyde, alcohols 13a and 13d were not iso-
lated but directly converted to styryl derivatives 14a, 14c
respectively. The smooth hydrolysis of the [1,3]dioxolo
[4,5-c]quinoline scaffold (see compound 12 in Scheme 2)
indicated further applicability of the developed procedures
in the field of 3-hydroxyquinolin-4(1H)-ones (3HQs).
2-Aryl-3HQs have been recently intensively studied as flavo-
nol analogues, and their significant fluorescent and cyto-
toxic properties have been reported.[29–32]
It was proven that 2-aryl-3HQs interact with the elonga-
tion factor in the gamendazole binding site and that the
3-hydroxy-4-oxo moiety is directly involved in the structure
of the pharmacophore.[33] On the other hand, 3HQs gener-
ally suffer from very low solubility resulting from an inter-
molecular hydrogen bond mediated by the 3-hydroxy
group.[32] The limited solubility of 3HQs results in problem-
atic bioavailability, and two different approaches (micellar
dispersion and liposomal solubilization) have previously
been suggested to overcome this problem.[34,35] In this
regard, 2-aryl-[1,3]dioxolo[4,5-c]quinolines may serve as
suitable prodrugs with better solubility and better ability to
release the parent 3HQ after administration in vivo. Obvi-
ously, 2-aryl-[1,3]dioxolo[4,5-c]quinolines are not accessible
from intermediates 5 or 6, but the set of dioxolo-quinolines
was prepared from the corresponding 3HQs (15a-e), which
were pre-synthesized using previously published
1-methyl piperazine
NaBH3CN
O
MeOH, AcOH
O
N
-10°C
N
N
7 55%
hydrazine
hydrate
pyridine, rt
O
O
O
O
N
N
8 79%
NH2
O
CBr4/PPh3
DCM, rt
Br
N
9 57%
Br
O
O
N
NaBH4
MeOH, 5°C
O
O
OH
N
Ohira-Bestmann
reagent
6
10 80%
K2CO3
MeOH, rt
O
O
N
11 80%
H2O, HCl
reflux
O
OH
O
N
H
12 75%
SCHEME 2 Reaction of DQC 6 with nucleophiles
SCHEME 3 Reaction of intermediate 5 with aldehydes

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4
HORÁK ET AL.
procedures.[26,36] The formation of 2-aryl-[1,3]dioxolo[4,5-c]
quinolines from 2-aryl-3HQs (Scheme 4) was applicable to a
broad range of starting 2-aryl-3HQs; dichloroacetic acid and
dichloroacetamide were also used to cyclize the dioxole
scaffold to provide 16f and 16g (see structures in experimen-
tal section). To our delight, the solubility of compounds 16
compared to 3HQs 15 was significantly higher, and their
hydrolysis with hydrochloric acid smoothly afforded the
corresponding 2-aryl-3HQs. Similarly, hydrolysis of repre-
sentative 2-styryl-[1,3]dioxolo[4,5-c]quinolone 14a yielded
the corresponding 2-styryl-3HQ 17.
The prepared [1,3]dioxolo[4,5-c]quinolines were tested
for their antibiotic activity against representative Gram-
positive (Bacillus subtilis, ATCC 6633; Micrococcus luteus,
ATCC 10240; Mycobacterium vaccae, DSM 43514; Staphylo-
coccus aureus, CCM 2524), and Gram-negative (Pseudomo-
nas aeruginosa, CCM 3955; Escherichia coli, CCM 3954)
bacteria using the agar diffusion assay.[37] (E)-4-styryl-[1,3]
dioxolo[4,5-c]quinoline 16b and (E)-4-(3,3-dimethylbut-
1-en-1-yl)-[1,3]dioxolo[4,5-c]quinoline 14a displayed notice-
able antibacterial activities against M. luteus when tested at
2 mM, as indicated by the large inhibition zones (dia-
meter ≥ 20 mm). These derivatives were subjected to a fur-
ther assay[38] to determine their minimum inhibitory
concentration (MIC). The MIC value against M. luteus was
0.2 μmol/L for both compounds, reaching the MIC of the
control compound (ciprofloxacin, 0.26 μmol/L). In contrast,
(E)-3-hydroxy-2-styrylquinolin-4(1H)-one 15b (as the hydro-
lytic 3HQ analogue of 16b) exhibited an order of magnitude
higher MIC (3.13 μmol/L) against the same bacteria, which
indicates the positive influence of the [1,3]dioxolo[4,5-c]
quinoline scaffold on the resulting antibacterial activity.
The other tested compounds were inactive.
3 | CONCLUSION
4-Methyl-[1,3]dioxolo[4,5-c]quinoline and [1,3]dioxolo
[4,5-c]quinoline-4-carbaldehyde can be simply synthe-
sized on a multigram scale from anthranilic acid and
used as the key intermediates to access diverse [1,3]dio-
xolo[4,5-c]quinolines. These heterocycles resemble the
structure of well-known quinoline alkaloids but have not
been studied to date. The developed approach allows for
the simple preparation of target compounds with variable
C2 substitutions, and further modification of the quino-
line moiety at the C5-8 positions is available in the case
of variously substituted anthranilic acids. The biological
potential of [1,3]dioxolo[4,5-c]quinolines was demon-
strated by an antibacterial assay in which two com-
pounds inhibited M. luteus with MIC values equal to
ciprofloxacin. The [1,3]dioxolo[4,5-c]quinoline scaffold
was readily hydrolyzed to the 3-hydroxyquinolin-4(1H)-
one moiety, and for this reason, compounds 5 and 6 can
be used as starting materials to prepare 3HQs that are
not accessible by traditional methods based on anthrani-
late rearrangement.[34] Additionally, 2-aryl-[1,3]dioxolo
[4,5-c]quinolines might be used as prodrugs of the cyto-
toxic 3-hydroxyquinolin-4(1H)-ones to overcome their
solubility problems.
4 | EXPERIMENTAL SECTION
4.1 | General information
Reactions were monitored by thin layer chromatography
(TLC) Merck Kieselgel 60F254. Compounds were visual-
ized under UV light (254 nm). Column chromatography
was performed on silica gel (VWR, 40-63 mesh). The
purity of all compounds was determined by LC/MS
(Waters 2695) with PDA detector (Waters, Milford, Mas-
sachusetts) and quadrupole mass spectrometer (hybrid
Q-TOF micro mass spectrometer) using electrospray ioni-
zation ESI (Waters MS Technologies, Manchester, United
Kingdom). Liquid chromatography was carried out using
C18 reversed-phase column. Elution was by 0.01 M
ammonium acetate (A) and acetonitrile/water (90/10)
(B) with a linear gradient (0.6 mL/min). 1H and 13C
NMR spectra were measured on Jeol ECA400II
(400 MHz) at 23ꢀC and reported in ppm. NMR spectra
were recorded in CDCl3 or DMSO-d6 as a solvent. The
1H and 13C chemical shifts were referenced to the cen-
tral signal of the solvent: CDCl3 (d = 7.26 (1H), d = 77.0
(13C)); and DMSO-d6 (d = 2.50 (1H) and d = 39.43
(13C)). Assignments were made with the aid of APT,
HMQC, HMBC experiments. HPLC-HRMS analyses were
Br2/K
CH2
2CO3
rt
DMF,
O
O
OH
O
R
N
H
R
N
15
a-e
16
59-78%
HCl/H2O
reflux
a
b
c
d
e
R = Phenyl
R = (E)-β–Styryl
R = 2-Thienyl
R = 2-Furyl
R = 2-Selenyl
SCHEME 4 Conversion of [1,3]dioxolo[4,5-c]quinolines to
3HQs and vice versa [Color figure can be viewed at
wileyonlinelibrary.com]
performed
on
reverse
phase
gradient
using