Synthesis and antimicrobial activity of sulfur derivatives of quinolinium salts

Article abstract of DOI:10.3390/molecules23010218

A novel method for cleavage of the dithiine ring in 5,12-(dimethyl)-thioqinantrenium bis-chloride 1 “via” reaction with sodium hydrosulfide leads to 1-methyl-3-mercaptoquinoline-4(1H)-thione 2. Further transformation of thiol and thione functions of compound 2 leads to a series of sulfide and disulfide derivatives of quinolinium salts 4 and 6. 1-Methyl-4-chloro-3-benzylthioquinoline chloride 8 was obtained by N-alkylating 4-chloro-3-benzylthioquinoline using dimethyl sulfate. Antimicrobial activity of the obtained compounds was investigated using six Gram-positive and six Gram-negative bacterial strains, as well as Candida albicans yeast. Greater activity was demonstrated towards Gram-positive strains. MIC values for compounds and with benzylthio 4d and benzoylthio 4f substituents in 3-quinoline position were found to be in the 0.5–1 μg/mL range, at a level similar to that of ciprofloxacin (reference). Compounds 4d and 4f also demonstrated interesting antifungal properties (MIC = 1).

Full text of DOI:10.3390/molecules23010218

molecules
Article
Synthesis and Antimicrobial Activity of Sulfur
Derivatives of Quinolinium Salts
Anna Empel 1, Ewa Kisiel 1, Robert D. Wojtyczka 2 ID , Małgorzata Ke˛pa 2, Danuta Idzik 2,
Aleksander Sochanik 3, Tomasz J. Wa˛sik 2 and Andrzej Zie˛ba 1,
*
1
Department of Organic Chemistry, School of Pharmacy and Division of Laboratory Medicine in Sosnowiec,
Medical University of Silesia in Katowice, Jagiellon´ska 4, 41-200 Sosnowiec, Poland;
anna.nycz00@gmail.com (A.E.); e_kisiel@o2.pl (E.K.)
Department and Institute of Microbiology and Virology, School of Pharmacy and Division of Laboratory
Medicine in Sosnowiec, Medical University of Silesia in Katowice, Jagiellon´ska 4, 41-200 Sosnowiec, Poland;
rwojtyczka@sum.edu.pl (R.D.W.); mkepa@sum.edu.pl (M.K.); didzik@sum.edu.pl (D.I.);
twasik@sum.edu.pl (T.J.W.)
2
3
Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Mamorial
˙
Cancer Center and Institute of Oncology, Wybrzeze AK 15, 44-101 Gliwice, Poland;
aleksander.sochanik@io.gliwice.pl
*
Correspondence: zieba@sum.edu.pl; Tel.: +48-32-364-1603
Received: 7 December 2017; Accepted: 18 January 2018; Published: 20 January 2018
Abstract:
5,12-(dimethyl)-thioqinantrenium bis-chloride
leads to 1-methyl-3-mercaptoquinoline-4(1H)-thione
functions of compound leads to a series of sulfide and disulfide derivatives of quinolinium
salts and . 1-Methyl-4-chloro-3-benzylthioquinoline chloride was obtained by N-alkylating
A
novel
method
for
cleavage
“via” reaction with sodium hydrosulfide
. Further transformation of thiol and thione
of
the
dithiine
ring
in
1
2
2
4
6
8
4-chloro-3-benzylthioquinoline using dimethyl sulfate. Antimicrobial activity of the obtained
compounds was investigated using six Gram-positive and six Gram-negative bacterial strains,
as well as Candida albicans yeast. Greater activity was demonstrated towards Gram-positive strains.
MIC values for compounds and with benzylthio 4d and benzoylthio 4f substituents in 3-quinoline
position were found to be in the 0.5–1 µg/mL range, at a level similar to that of ciprofloxacin
(reference). Compounds 4d and 4f also demonstrated interesting antifungal properties (MIC = 1).
Keywords: quinolinium salts; antimicrobial activity; minimal inhibitory concentration
1. Introduction
Increasing bacterial resistance to antibiotics has become a very serious medical problem for
health care systems worldwide [1,2]. This situation requires continued efforts in searching for novel
classes of compounds with antimicrobial activities. The rising number of reports concerning microbial
resistance to antibiotics has led to the expression of concerns over imminent incurability of some
pathogen-caused diseases. Quinoline stands out prominently among pharmacologically active
compounds [3]. Its structural motif is present in many naturally-occurring compounds that show
interesting biological properties. Quinine, the first effective antimalarial drug isolated from cinchona
tree bark, provides a good example. Based on its established structure novel synthetic antimalarial
drugs were obtained, such as chloroquine, primaquine and mefloquine [
compounds include streptonigrin, produced by Streptomyces flocculus, an aminoquinone antitumor
and antibacterial antibiotic [ ] and camptothecin, a cytotoxic quinoline alkaloid isolated from the bark
and stem of Camptotheca acuminata (Camptotheca, happy tree). Derivatives of the latter, topotecan and
irinotecan, are anticancer drugs [ ]. An important group of chemotherapeutics with quinoline motif
4]. Other examples of similar
5
6
Molecules 2018, 23, 218; doi:10.3390/molecules23010218
www.mdpi.com/journal/molecules

Molecules 2018, 23, 218
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are 4-quinolone derivatives effective against Gram-negative bacteria [
7
,8]. Quinoline ring systems
have often been included when designing novel synthetic or semi-synthetic compounds with different
pharmacological properties. Numerous quinoline derivatives, offering a broad spectrum of activity,
have been reported. They include compounds with anticancer [
antimicrobial [14 15], anticonvulsant [16 17], antiinflamatory [17 18] and cardiovascular [19
Substantial antimicrobial activity was demonstrated by 4-aminoquinoline salts [21 23]. There have
been also reports concerning such activity in cases of sulfide derivatives of quinoline [24]. In our
previous papers, we described the synthesis of 1,3,4-trisubstituted derivatives of quinoline salts [25 26].
9–
11], antimycobacterial [12
,13],
,
,
,
,
20] activity.
–
,
Since initial trials demonstrated their strong antimicrobial properties we decided to investigate and
report in here the activity of such derivatives against a wider panel of reference strains; we also report
synthesis of novel derivatives.
2. Results and Discussion
2.1. Chemistry
5,12-Dialkylthioquintrenediinium bis-salts
1 were obtained by alkylating thioquinantrene
(1,4-dithiino[2,3-c,5,6-c0]diquinoline) [24]. The previously described reaction of thioquinantrene ring
opening requires gaseous hydrogen sulfide. The novel method described herein based on using sodium
hydrosulfide is safer, less cumbersome, and does not require disposition of excess hydrogen sulfide.
Reactions of salts
complete consumption of salts
on aza-activated positions 7a and 14a of salts
salts . As the result of this reaction, two molecules of 1-methyl-3-mercaptoquinoline-4(1H)-thione
1
with sodium hydrosulfide in pyridine solution at room temperature occur with
. The reaction occurs by nucleophilic attack of hydrosulfide anion
, which leads to the opening of the 1,4-dithiin ring of
1
1
1
2
are formed (Scheme 1). This compound was obtained previously via reaction of salt
sulfide [27], but its structure has not been confirmed spectroscopically.
1
with hydrogen
2
1
3
4
S
14
S
13
+
12N
SH
14a
CH3
NaSH
2Cl -
2
N 5
CH3
Py / 20 oC
11
10
N
7a
S
+
6
7
CH3
8
9
1
2
Scheme 1. Synthesis of compounds 2.
Use of sodium hydrosulfide increases the speed of compound
1 dithiine ring cleavage. This is
the result of the stronger nucleophilic properties of hydrosulfide anion as compared to the hydrogen
sulfide molecule. The perquisite of reaction with hydrogen sulfide has been the use of pyridine as
solvent (proton acceptor). Reaction with NaSH does not require the presence of a proton acceptor
(it also proceeds in other solvents, e.g., ethanol, albeit much more slowly). The reaction products
1
are easily soluble in pyridine. H-NMR spectrum of compound
2 in CDCl3 solution lacks a signal
from thiol proton, which may be the result of its interaction with thiocarbonyl sulfur atom (C=S)
in 4-quinoline position (Scheme 2). This is corroborated by the 13C-NMR spectrum of compound
in which C4quinolinyl signal occurs at
= 134.64 ppm. The signal from thiocarbonyl carbon in 13C-NMR
2,
δ
spectrum should be present above 180 ppm [28]. It appears that the hydrogen bond does not much
affect the IR spectrum of this type of compound. A strong band corresponding to C=S stretching
vibrations in compound 2
occurs at 1107 cm−1, whereas for compound 3a, which lacks such interactions,
the band is present at 1112 cm−1. The elemental composition of compound
spectrum and the results of elemental analysis.
2 is confirmed by MS

Molecules 2018, 23, 218
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H
+
S
H
S
S
S
H
_
S
S
N
N
N
CH3
CH3
CH3
2
A
B
Scheme 2. Interaction between thiol proton and thione sulfur atom and the tautomeric structures of
compound 2.
Reactions of
benzyl chloride and benzoyl chloride) occurred, as expected, on 3-quinoline thiolate sulfur,
and led to their respective 1-methyl-3-thioquinoline-4(1H)-thione derivatives with 73%–83% yield.
The 13C-NMR spectra for compounds
show signal from the C4quinolinyl carbon occurring in the
2 in aqueous sodium hydroxide with alkylating or acylating agents (allyl chloride,
3
3
characteristic range for thiocarbonyl carbon, and this additionally confirms the structure of
the substrate of these reactions. Alkylating of thione function in the 4-quinoline position of compound
2,
3
was carried out at 70 ◦C, using excess of alkylating agents (dimethyl sulfate, butyl bromide or benzyl
chloride) as reaction milieu (Scheme 3). The reactions led to the respective quinoline salts
quantitative yield.
4 with
SR1
S
S
5
R1X
70oC
SR
X -
4
SR
4a
SH
NaOH / H2O
RX
6
7
3
2
N
N
+
8a N 1
CH3
8
CH3
CH3
4(a-f)
3(a-c)
2
R
R1
X
R
4a Allyl
4b Allyl
4c Allyl
4d Benzyl
4e Benzoyl
4f Benzoyl
Methyl
Butyl
Benzyl
Butyl
Methyl
Butyl
CH3SO4
Br
Cl
Br
CH3SO4 [26]
Br
3a
3b
3c
Allyl
Benzyl [27]
Benzoyl [26]
Scheme 3. Synthesis of compounds 3 and 4.
1-Methyl-3-mercaptoquinoline-4(1H)-thione
function is easily oxidized. Compounds were transformed into di(1-methylquinoline-4(1H)-thione-3-yl)
disulfide by reacting ( ) in DMF with atmospheric oxygen or ethanolic iodine (Scheme 4).
2 in substance is stable, whereas in solution the thiol
2
5
2
Both procedures gave disulfide 5 with quantitative yield.
S
O2 (Procedure A)
S
S
SH
I2 (Procedure B)
S
S
DMF, 20oC
N
N
N
CH3
CH3
CH3
2
5
Scheme 4. Synthesis of disulfide 5.
Alkylating disulfide
5 occurred as S-alkylation of both thione groups and led to bis-salts 6
(Scheme 5). The reaction speed is temperature-dependent. At room temperature, only trace reaction is
observed. Reaction mixes showed no sign of mono-alkylation products, i.e., resulting from alkylation
of a single thione group. As in the case of compounds 3, the bis-salts 6 were obtained with quantitative

Molecules 2018, 23, 218
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◦
yield when reactions were performed at 80 C and with excess of alkylating agent (dimethyl sulfate) as
the reaction milieu.
S
SCH3
S
SCH3
5
5'
4
4'
4'a
4a
S
S
S
S
(CH3)2SO4
80oC
6
7
6'
7'
3
2
3'
2'
8'a
8a N 1
CH3
1'N
N
+
CH3
N
2 CH3SO4-
+
8'
8
CH3
CH3
5
6
Scheme 5. Synthesis of bis-methyl sulfide 6.
Salt
by N-alkylating 4-chloro-3-thiobenzylquinoline
The reaction proceeds easily at 60 ◦C, leading to salts 8 with quantitative yield.
8
with chlorine atoms instead of thioalkyl groups in the 4-quinoline position was obtained
7
derivatives using dimethyl sulfate (Scheme 6).
Cl
Cl
5
8
4
4a
SCH2C6H5
SCH2C6H5 (CH3)2SO4
60oC
6
7
3
2
-
CH3SO4
8a
N
N
+
1
CH3
8
7
Scheme 6. Synthesis of salt 8.
2.2. Biological Activity
The examined derivatives of quinolinium salts demonstrated activity (0.5–512
µg/mL
concentration range) against both Gram-positive and Gram-negative bacteria, as well as against
Candida albicans, a yeast-like fungus. However, greater activity was found against Gram-positive
bacteria such as Staphylococcus, Streptococcus, Micrococcus and Bacillus. In almost all cases, the tested
compounds were more active against Staphylococcus aureus methicillin-sensitive strains, although
activity also remained very high for methicillin-resistant strains (MRSA). Most likely, the high
activity of the tested compounds results from structural features of the bacterial wall. In the case of
Gram-negative bacteria, the examined compounds were active in the 8–512 µg/mL range. As in the
case of Gram-positive bacteria, the highest activity against Gram-negative strains was demonstrated
by derivatives 4d and 4f. The lowest activity of sulfur derivatives of quinolinium salts was found for
Gram-negative bacteria of Pseudomonas genus. Compounds 4d and 4f were also highly active against
yeast-like fungus Candida albicans (MIC = 1). In order to examine the effect of thioalkyl group on
the activity of the tested compounds their structure was modified via introduction of chlorine atoms
instead of thioalkyl groups into the 4-quinoline position (compound
6), as well as introducing disulfide
groups in the 3-quinoline position (compound ), respectively. The obtained results demonstrate
8
that the lack of the thioalkyl group in the 4-quinoline position considerably decreases antimicrobial
activity, whereas the compound with the disulfide group shows activity comparable to those of
compounds 4(a–c), i.e., derivatives containing the allylthio group in the 3-position.
We previously reported the activity of 1,3,4-trisubstituted 4-aminoquinoline salts [22,23].
These compounds also demonstrated activity against Gram-positive and Gram-negative bacteria.
However, the structural modification achieved by introducing thioalkyl substituents instead of
alkylamine ones in the 4-quinoline position markedly increased their antibacterial and antifungal
activity. The MIC values reported here for Gram-positive bacteria are comparable to those of
ciprofloxacin (reference). This may suggest the need for a continuing search effort for novel types of
sulfur derivatives of quinoline salts, as well as the assessment of antibacterial activity using not only
standard strains, but also clinically relevant ones.

Molecules 2018, 23, 218
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3. Materials and Methods
3.1. Chemistry
Melting points are uncorrected. NMR spectra were recorded using a Bruker Ascend
600 spectrometer (Bruker, Billerica, MA, USA). To assign the structures, the following 2D experiments
were employed: 1H-13C gradient selected HSQC and HMBC sequences. Standard experimental
1
conditions and standard Bruker programs were used. The H- and 13C-NMR spectral data are
given relative to the TMS signal at 0.0 ppm. HR mass spectra were recorded with Bruker Impact−I1I
(Bruker, Billerica, MA, USA). Solid-state infrared spectra were recorded in the range of 4000–1000 cm
using the Shimadzu IRAffinity-1 FTIR spectrometer (Shimadzu, Kyoto, Japan) and KBr pellet method.
CHNS elemental analysis was performed using EuroVector 3018 analyser (EuroVector, Pavia, Italy).
Total halides were determined using titration (after mineralization) with mercuric nitrate solution.
3.1.1. Synthesis of 1-Methyl-3-(mercapto)quinoline-4(1H)-thione 2
Sodium hydrosulfide hydrate (2.5 mmol) was added to the mixture of bis-chloride (
1
) (0.419 g,
◦
1 mmol) in 10 mL of dry pyridine, and the whole was mixed at 20 C for 1 h. The mixture was poured
into 100 mL of water. The formed precipitate was filtered off, washed with water and dried over
calcium chloride in desiccator with concomitant argon atmosphere.
1-Methyl-3-(mercapto)quinoline-4(1H)-thione (
1107 (C=S); (CDCl3), 600 MHz) (ppm): 4.01 (s, 3H, NCH3), 7.50–7.54 (m, 1H, H6), 7.54–7.58 (m, 1H,
H8), 7.68–7.72 (m, 1H, H7), 8.06 (s, 1H, H2), 8.97–9.01 (m, 1H, H5); 13C-NMR (DMSOd-6, 150.9 MHz)
2
). Yield 87%; m.p. 258 ◦C; IR (KBr, cm−1):
ν
:
max
δ
δ
(ppm): 42.30 (NCH3), 116.16 (C8), 126.37 (C6), 126.89 (C3), 130.82 (8a), 131.36 (C7), 131.64 (4a),
132.37 (C5), 133.20 (C2), 134.64 (C4); ESI-HRMS Calcd for C10H10NS2 ([M + H]+): 208.0254,
Found: 208.0254; Anal. Calcd for C10H9NS2: C 57.94, H 4.38, N 6.76, S 30.93. Found: C 57.87, H
4.31, N 6.73, S 30.85.
3.1.2. General Procedure for Synthesis of 1-Methyl-3-thioquinoline-4(1H)-thione Derivatives 3
1 mmol (0.207 g) 1-methyl-3-mercaptoquinoline-4(1H)-thione (2) was added dropwise with
stirring into 50 mL of 5% aqueous sodium hydroxide. An alkylating agent or acylating (1.25 mmol)
was added dropwise with stirring for 1 h. The formed precipitate was filtered off, washed with
water and dried over calcium chloride in vacuum desiccator. The raw product was purified through
recrystallization from ethanol.
◦
1
1-Methyl-3-(allylthio)quinoline-4(1H)-thione (3a). Yield 78%; m.p. 212–214 C; H-NMR (DMSOd-6
600 MHz) (ppm): 3.66 (d, J = 6.6 Hz, 2H, SCH2CH), 4.08 (s, 3H, NCH3), 5.10-5-18 (m, 1H, CH=CH2),
5.23–5.35 (m, 1H, CH=CH2), 5,78–6.00 (m, 1H, C =CH2), 7.48–7.58 (m, 1H, H6), 7.75–7.82 (m, H, H7),
7.83–7.88 (m, 1H, H8), 8.02 (s, 1H, H2), 8.76–8.83 (m, 1H, H5); 13C-NMR (DMSOd-6, 150.9 MHz)
34.46 (SCH2), 42.17 (NCH3), 118.23 (C8), 118.62 ( H2=CH), 126.17 (C6), 129.31 (C5), 131.54 (C4a),
132.07 (CH2=
,
δ
H
δ:
C
C
H), 132.11 (C7), 134.05 (C3), 135.31 (C8a) 136.12 (C2), 187.09 (C4); ESI-HRMS Calcd for
C13H14NS2 ([M + H]+): 248.0567, Found: 248.0564; Anal. Calcd for C13H13NS2: C 63.12, H 5.30, N 5.66,
S 25.92. Found: C 63.07, H 5.24, N 5.58, S 25.89.
1-Methyl-3-(benzylthio)quinoline-4(1H)-thione (3b). Yield 83%; m.p. 204–206 ◦C; 1H-NMR (DMSOd-6
600 MHz) (ppm): 4.07 (s, 3H, NCH3), 4.21 (s, 2H, SCH2), 7.32–7.37 (m, 3H, Harom), 7.41–7.44 (m, 2H,
Harom), 7.53–7.58 (m, 1H, H6), 7.79–7.83 (m, 1H, H7), 7.85–7.89 (m, 1H, H8), 8.12 (s, 1H, H2),
8.79–8.83 (m, 1H, H5); 13C-NMR (DMSOd-6, 150.9 MHz)
(ppm): 36.23 (CH2), 42.18 (NCH3),
,
δ
δ
118.28 (C8), 126.21 (C6), 127.60 (H1benzyl), 128.98 (C2,C6benzyl), 129.32 (C5), 129.60 (C3,C5benzyl),
132.03 (C4benzyl), 132.132.15 (C7), 132.46 (C4a), 135.34 (C8a), (C2), 137.50 (C3), 186.65 (C4); ESI-HRMS
Calcd for C17H15NS2 ([M + H]+): 298.0724, Found: 298.0714; Anal. Calcd for C17H15NS2: C 68.65,
H 5.08, N 4.71, S 21.56. Found: C 68.54, H 5.01, N 4.65, S 21.50.

Molecules 2018, 23, 218
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1-Methyl-3-(benzoylthio)quinoline-4(1H)-thione (3c). Yield 73%; m.p. 210–212 ◦C; 1H-NMR (DMSOd-6
600 MHz) (ppm): 4.07 (s, 3H, NCH3), 7.60–7.67 (m, 3H, Harom), 7.72–7.78 (m, 1H, Harom),
7.88–7.95 (m, 2H, Harom), 8.01–8.05 (m, 1H, H8), 8.68 (s, 1H, H2), 8.86–8.90 (m, 1H, H5);
13C-NMR (DMSOd-6, 150.9 MHz)
(ppm): 41.94 (NCH3), 118.68 (C8), 121.41 (C1benzoyl),
,
δ
δ
127.07 (C4benzoyl), 127.56 (C3,C5benzoyl), 129.74 (C2,C6benzoyl), 130.73 (C5), 133.33 (C7), 133.45 (C3),
134.60 (C6), 136.39 (C4a), 136.66 (C8a), 145.68 (C2), 188.99 (CO), 193.19 (C4); ESI-HRMS Calcd for
C17H14NOS2 ([M + H]+): 312.0517, Found: 312.0515; Anal. Calcd for C17H13NOS2: C 65.57, H 4.21,
N 4.50, S 20.59. Found: C 65.51, H 4.14, N 4.47, S 20.55.
3.1.3. General Procedure for Synthesis of 1-Methyl-3-thio-4-thioquinolinium Derivatives Salts (4)
The mixture (suspension) of thione (
3
) (1 mmol) and alkylating agents (5 mmol) was stirred and
◦
heated at 80 C for 3 h. Unreacted alkylating agents were removed by vacuum distillation. Then 5 mL
of dry ethanol was added. The mixture was refluxed for 5 min and cooled down to room temperature.
The solid was filtered off and washed with dry ethanol.
1-Methyl-3-(allylthio)-4-(methylthio)quinolinium methyl sulfate (4a). Yield 95%; oil; 1H-NMR (D2O,
600 MHz)
4.41 (s, 3H, NCH3), 5.00–5.05 (m, 1H, CH=CH2), 5.09–5.17 (m 1H, CH=CH2), 5.74–5.85 (m, 1H,
=CH2), 7.75–7.79 (m, 1H, H6), 7.93–7.98 (m, 1H, H7), 8.08–8.13 (m, 1H, H8), 8.44–8.48 (m, 1H,
H5), 8.78 (s, 1H, H2); 13C-NMR (D2O, 150.9 MHz)
(ppm): 19.38 (OCH3), 35.95 (SCH2), 45.07 (NCH3),
55.31 (SCH3), 118.81 (C8), 119.36 (CH= H2),127.56 (C5), 130.03 (C4a), 130.41 (C6), 131.89 ( H=CH2),
δ (ppm): 2.53 (s, 3H, SCH3), 3.55 (s, 3H, OCH3), 3.67–3.74 (d, 2H, J = 6.6 Hz, SCH2CH),
C
H
δ
C
C
134.71 (C7), 135.05 (C8a), 136.27 (C3), 146.48 (C2), 158.91 (C4); ESI-HRMS Calcd for C14H16NS2
([M]+): 262.0724, Found: 262.0722; Anal. Calcd for C15H19NO4S3: C 48.24, H 5.13, N 3.75, S 25.75.
Found: C 48.20, H 5.08, N 3.67, S 25.70.
1-Methyl-3-allylthio-4-(butylthio)quinolinium bromide (4b). Yield 91%; m.p. 168 ◦C dec.; 1H-NMR (D2O,
600 MHz)
SCH2CH2), 3.00–3.12 (t, J = 7.2 Hz, SCH2CH2), 3.70–3.78 (d, 2H, J = 6.0 Hz, SCH2CH), 4.43 (s, 3H,
NCH3), 5.03–5.08 (m, 1H, CH=CH2), 5.12–5.20 (m 1H, CH=CH2), 5.73–5.84 (m, 1H, C =CH2),
7.73–7.82 (m, 1H, H6), 7.91–8.00 (m, 1H, H7), 8.08–8.12 (m, 1H, H8), 8.48–8.54 (m, 1H, H5), 8.79 (s, 1H,
H2); 13C-NMR (D2O, 150.9 MHz)
(ppm): 12.63 ( H3CH2), 21.03 (CH3CH2), 31.54 (SCH2 H2),
35.72 (S H2CH), 37.06 (S H2CH2), 45.22 (NCH3), 118.80 (C8), 119.45 (CH= H2), 127.72 (C5),
130.53 (C6), 130.86 (C4a), 131.80 (C =CH2), 134.65 (C7), 136.15 (C8a), 136.55 (C3), 145.84 (C2),
δ (ppm): 0.55–0.750 (t, J = 7.2 Hz, 3H, CH2CH3), 1.10–1.25 (m, 2H, CH2CH3), 1.25–1.40 (m, 2H,
H
δ
C
C
C
C
C
H
156.69 (C4); ESI-HRMS Calcd for C17H22NS2 ([M]+): 304.1193, Found: 304.1191; Anal. Calcd for
C17H22BrNS2: C 53.12, H 5.77, Br 20.79, N 3.64, S 16.68. Found: C 53.05, H 5.71, Br 20.70, N 3.59, S 16.63.
1-Methyl-3-allylthio-4-(benzylthio)quinolinium chloride (4c). Yield 93%; m.p 183 ◦C dec; 1H-NMR
(D2O, 600 MHz)
δ
(ppm): 3.62–3.68 (d, J = 6.6 Hz, 2H, SCH2CH), 4.02 (s, 2H, SCH2), 4.32 (s, 3H,
=CH2),
NCH3), 5.02–5.09 (m, 1H, CH=CH2), 5.11–5.18 (m, 1H, CH=CH2), 5.64–5.75 (m, 1H C
H
6.71–6.76 (m, 2H, Hbenzyl), 6.81–6.90 (m, 3H, Hbenzyl), 7.58–7.64 (m, 1H, H6), 7.83–7.89 (m, 1H,
H7), 7.96–8.01 (m, 1H, H8), 8.13–8.18 (m, 1H, H5), 8.65 (s, 1H, H2); 13C-NMR (D2O, 150.9 MHz)
δ
(ppm): 35.32 (SCH2CH), 40.23 (SCH2), 45.44 (NCH3), 118.73 (C8), 119.83 (CH=CH2), 127.42 (C4benzyl),
127.71 (C5), 128.41 (C2,C6benzyl), 128.76 (C3,C5benzyl), 128.86 (C1benzyl), 130.72 (C6), 131.09 (C4a),
131.47 (CH=CH2), 134.60 (C7), 135.79 (C8a), 138.25 (C3), 145.13 (C2), 152.90 (C4); ESI-HRMS Calcd for
C20H20NS2 ([M]+): 338.1037, Found: 338.1037; Anal. Calcd for C20H20ClNS2: C 64.24, H 5.39, Cl 9.48,
N 3.75, S 17.15. Found: C 64.17, H 5.35, Cl 9.41, N 3.69, S 17.11.
◦
1
1-Methyl-3-benzylthio-4-(butylthio)quinolinium bromide (4d). Yield 90%; m.p. 140 C dec.; H-NMR
(DMSOd-6, 600 MHz) (ppm): 0.73–0.82 (t, J = 7.2 Hz, 3H, CH2CH3), 1.28–1.37 (m, 2H, CH2CH3),
δ
1.39–1.46 (m, 2H, SCH2CH2), 3.15–3.20 (t, J = 7.2 Hz, 2H, SCH2CH2), 4.64 (s, 1H, SCH2), 4.67 (s, 3H,
NCH3), 7.28–7.34 (m, 1H, H4benzyl), 7.34–7.40 (m, 2H, H3,H5benzyl), 7.45–7.48 (m, 2H, H2,H6benzyl),
8.05–8.10 (m, 1H, H6), 8.20–8.23 (m, 1H, H7), 8.47–8.51 (m, 1H, H8), 8.70–8.74 (m, 1H, H5),

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9.56 (s, 1H, H2); 13C-NMR (DMSOd-6, 150.9 MHz)
δ (ppm): 13.76 (CH3CH2), 21.56 (CH3CH2),
32.10 (SCH2CH2), 36.80 (SCH2), 37.43 (SCH2CH2) 45.81 (NCH3), 120.53 (C8), 127.68 (C5),
128.34 (C4benzyl), 129.32 (C3,C5benzyl), 129.68 (C2,C6benzyl), 130.92 (C4a), 131.35 (C6), 134.59 (C1benzyl),
135.93 (C7), 136.41 (C8a), 138.36 (C3), 147.06 (C2), 153.07 (C4); ESI-HRMS Calcd for C21H24NS2 ([M]+):
354.1350, Found: 354.1351; Anal. Calcd for C21H24BrNS2: C 58.06, H 5.57, Br 18.39, N 3.22, S 14.76.
Found: C 57.91, H 5.50, Br 18.35, N 3.15, S 14.74.
◦
1-Methyl-3-benzoylthio-4-(methylthio)quinolinium methyl sulfate (4e). Yield 95%; m.p. 98 C dec.; 1H-NMR
(D2O, 600 MHz) (ppm): 2.53 (s, 3H, SCH3), 3.51 (s, 3H, OCH3), 4.36 (s, 3H, NCH3), 7.25–7.31 (m,
δ
2H, H3,H5benzoyl), 7.44–7.49 (m, 1H, H4benzoyl), 7.70–7.78 (m, 2H, H2,H6benzoyl), 7.80–7.86 (m, 1H,
H6), 8.04–8.09 (m, 1H, H7), 8.12–8.17 (m, 1H, H8), 8.47–8.52 (m, 1H, H5), 9.03 (s, 1H, H2); 13C-NMR
(D2O, 150.9 MHz)
δ (ppm): 20.88 (SCH3), 44.93 NCH3), 55.28 (OCH3), 119.13 (C8), 125.11 (C3),
127.58 (C3,C5benzoyl), 128.60 (C5), 129.14 (C2,C6benzoyl), 129.66 (C4a), 130.63 (C6), 134.29 (C1benzoyl),
135.30 (C4benzoyl), 136.50 (C7), 137.39 (C8a), 151.46 (C2), 167.62 (C4), 189.08 (CO), ESI-HRMS Calcd for
C18H16NOS2 ([M]+): 326.0673, Found: 326.0672; Anal. Calcd for C19H19NO5S3: C 52.16, H 4.38, N 3.20,
S 21.98: Found: 52.08, H 4.31, N 3.15, S 21.95.
◦
1
1-Methyl-3-benzoylthio-4-(butylthio)quinolinium bromide (4f). Yield 89%; m.p. 112 C dec.; H-NMR
(DMSOd-6, 600 MHz) (ppm): 0.45–0.53 (t, J = 7.2 Hz, 3H, CH2CH3), 1.00–1.11 (m, 2H, CH2CH3),
1.19–1.25 (m, 2H, SCH2C 2), 3.00–3.09 (t, J = 7.2 Hz, 2H, SC 2CH2), 4.43 (s, 3H, NCH3), 7.35–7.40 (m,
δ
H
H
2H, H3,H5benzoyl), 7.53–7.57 (m, 1H, H4benzoyl), 7.80–7.84 (m, 2H, H2,H6benzoyl),. 7.84–7.88 (m, 1H,
H6), 8.07–8.12 (m, 1H, H7), 8.18–8.23 (m, 1H, H8), 8.60–8.64 (m, 1H, H5), 9.14 (s, 1H, H2); 13C-NMR
(DMSOd-6, 150.9 MHz) δ (ppm): 12.52 (CH2CH3), 20.91 (CH2CH3), 31.54 (SCH2CH2), 38.79 (SCH2CH2),
45.08 (NCH3), 119.16 (C8), 126.69 (C3), 127.64 (C3,C5benzoyl), 129.00 (C5), 129.24 (C2,C6benzoyl),
130.57 (C4a), 130.77 (C6), 134.42 (C1benzoyl), 135.39 (C4benzoyl), 136.53 (C7), 137.56 (C8a), 151.63 (C2),
166.03 (C4), 189.51 (CO); ESI-HRMS Calcd for C21H22NOS2 ([M]+): 368.1143, Found: 368.1134;
Anal. Calcd for C21H22BrNOS2: C 56.25, H 4.94, Br 17.82, N 3.12, S 14.30. Found: C 56.14, H 4.86,
Br 17.74, N 3.07, S 14.25.
3.1.4. Synthesis of Di(1-methylquinoline-4(1H)-thione-3-yl) Disulfide (5)
Procedure (A). Air was passed through the solution of 1-methyl-3-mercaptoquinoline-4(1H)-thione
(2) (1 mmol, 0.207g) in dry DMF (50 mL) at rt over 1 h. The solid product was filtered off and washed
with dry ether. The mixture of raw product and 10 mL dry ethanol was refluxed for 5 min and cooled
down to room temperature. The solid product was filtered off and washed with dry ethanol.
Procedure (B). To the solution of 1-methyl-3-mercaptoquinoline-4(1H)-thione (2) (1 mmol, 0.207 g)
in dry DMF (50 mL) a solution of 1.5 mmol (0.381 g) of iodine in 5 mL of ethanol was added over
1 h with stirring (rt). The solid product was filtered off and washed with dry ether. The mixture of
raw product and 10 mL dry ethanol was refluxed for 5 min and cooled down to room temperature.
The solid product was filtered off and washed with dry ethanol.
Di(1-methylquinoline-4(1H)-thione-3-yl) disulfide (
5
δ
). Yield: Procedure A: 92%, Procedure B: 95%;
m.p. 301–302 ◦C; 1H-NMR (DMSOd-6, 600 MHz)
(ppm): 4.05 (s, 6H, NCH3, N0CH3), 7.60–7.65 (m,
0
0
0
0
2H, H6, H6 ), 7.83–7.87 (m, 2H, H7, H7 ), 7.90–7.94 (m, 2H, H8, H8 ), 8.34 (s, 2H, H2,H2 ), 8.76–8.80 (m,
2H, H5,H50); ESI-HRMS Calcd for C20H16N2S4 ([M]2+): 206.0098, Found: 206.0092; Anal. Calcd for
C20H16N2S4: C 58.22, H 3.91, N 6.79, S 31.08. Found: C 58.17, H 3.86, N 6.74, S 31.05.
3.1.5. Synthesis of Bis-Methyl Sulfate di(1-methyl-4-(methylthio)quinolinium-3-yl) Disulfide 6
The mixture of compounds (
5
) (1 mmol) and dimethyl sulfate (5 mmol) was stirred and heated
◦
at 80 C for 2 h. Then, 10 mL of dry ethanol was added. The mixture was refluxed for 5 min and cooled
down to room temperature. The solid was filtered off and washed with dry ethanol. The raw product
was purified through recrystallization from ethanol.

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Bis-methyl sulfate di(1-methyl-4-(methylthio)quinolinium-3-yl) disulfide (
6
) Yield 94%; m.p. 120 ◦C dec.;
1H-NMR (DMSOd-6, 600 MHz)
δ
(ppm): 2.80 (s, 6H, OCH3), 3.31 (s, 6H, SCH3,S0CH3), 4.62 (s, 6H,
NCH3,N0CH3), 8.12–8.15 (m, 2H, H6,H06), 8.29–8.33 (m, 2H, H7,H07), 8.53–8.56 (m, 2H, H8,H08),
8.72–8.76 (m, 2H, H5,H05), 9.62 (s, 2H, H2,H02);.13C-NMR (DMSOd-6, 150.9 MHz)
(ppm): 21.24 (C),
δ
46.14 (C), 53.24 (C), 120.77 (C8), 128.15 (C5), 130.02 (C4a), 131.58 (C6), 135.14 (C7), 135.89 (C3),
137.65 (C8a), 148.46 (C2), 158.13 (C4); ESI-HRMS Calcd for C22H22N2S4 ([M]2+): 221.0333, Found:
221.0322; Anal. Calcd for C24H28N2O8S6: C 43.36, H 4.24, N 4.21, S 28.93, Found: C 43.27, H 4.19,
N 4.17, S 28.90.
3.1.6. Synthesis of 1-Methyl-4-chloro-3-(benzylthio)quinolinium Methyl Sulfate (8)
The mixture◦(suspension) of compounds (
7) (1 mmol) and dimethyl sulfate (5 mmol) was stirred
and heated at 80 C for 2 h. Then, 5mL of dry ethanol was added. The mixture was refluxed for 5 min
and cooled down to the room temperature. The solid was filtered off and washed with dry ethanol.
The raw product was purified through recrystallization from ethanol.
1
1-Methyl-4-chloro-3-(benzylthio)quinolinium methyl sulfate (
(DMSOd-6, 600 MHz)
3H, H4benzyl), 7.32–7.43 (m, 2H, H3,H5benzyl), 7.43–7.50 (m, 2H, H2,H6benzyl) 8.10–8.18 (m, 1H,
H6), 8.23–8.27 (m, 1H, H7), 8.48–8.59 (m, 2H, H5,H8), 9.68 (s, 1H, H2), 13C-NMR (DMSOd-6
150.9 MHz) ppm): 37.32 (CH2), 45.95 (NCH3), 53.29 (OCH3), 120.59 (C5), 126.02 (C8), 127.22 (C4a),
8
). Yield 89%; m.p. 204 ◦C dec.; H-NMR
δ
(ppm): 3.70 (s, 3H, OCH3.), 4.64 (s,2H, CH2), 4.67 (s, 3H, NCH3), 7.26–7.32 (m,
,
δ
128.43 (C4benzyl), 129.38 (C3,C5benzyl), 129.70 (C2,C6benzyl), 132.21 (C6), 132.29 (C1benzyl), 135.54 (C7),
135.63 (C3), 137.46 (C8a), 148.67 (C4), 149.46 (C2); ESI-HRMS Calcd for C18H18ClNS ([M]+): 300.0614,
Found: 300.0612; Anal. Calcd for C18H18ClNO4S2: C 52.49, H 4.40, Cl 8.61, N 3.40, S 15.57.
Found: C 52.38, H 4.36, Cl 8.54, N 3.37, S 15.51.
3.2. Biological Assays
Analysis of antimicrobial activity was performed using the serial microdilution method
and Muelller-Hinton broth (MHB). Thirteen standard strains from ATTC collection were used
(Staphylococcus aureus ATCC 25923 (SA25923), Staphylococcus aureus ATCC 43300 (SA43300),
Staphylococccus epidermidis ATCC 12228 (SE12228), Enterococcus faecalis ATCC 29212 (E29212),
Micrococcus luteus ATCC 10240 (ML10240), Bacillus subtilis ATCC 11774 (BS11774), Escherichia coli
ATCC 11776 (EC11776), Klebsiella pneumoniae ATCC 27736 (KP27736), Proteus mirabilis ATCC 7002
(PM7002), Pseudomonas aeruginosa ATCC 27853 (PA27853), Acinetobacter baumannii ATCC 19606
(AB19606), Serratia marcescens ATCC 8100 (SM8100) and Candida albicans ATCC 60193 (CA60193).
An inoculum density of 5
96-well titration plates. The concentration range of the examined sulfur derivatives of quinolinium
×
105 cfu/mL was used. Antimicrobial activity was examined using
salts was 0.5–512
µ
g/mL As control, ciprofloxacin (CIP) was used (0.001–2
µ
g/mL range).
◦
MIC determination was performed for 20-h incubation periods at 37 C. Tests were performed in
accordance with EUCAST recommendations [29]. The results are presented in Table 1.

Molecules 2018, 23, 218
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Table 1. Evaluation of the minimum inhibitory concentration (MIC) (
derivatives against tested bacterial strains.
µg/mL) of quinolinium salt sulfur
4a
4b
4c
4d
4e
4f
6
8
CIP
S. aureus ATCC 25923
S. aureus ATCC 43300
S. epidermidis ATCC 12228
E. faecalis ATCC 29212
M. luteus ATCC 10240
B. subtilis ATCC 11774
E. coli ATCC 11776
K. pneumoniae ATCC 27736
P. mirabilis ATCC 7002
P. aeruginosa ATCC 27853
A. baumannii ATCC 19606
S. marcescens ATCC 8100
C. albicans ATCC 60193
32
128
32
128
64
64
64
64
128
256
128
64
32
16
16
32
32
32
0.5
1
1
32
2
1
1
1
4
1
16
32
32
32
64
16
32
256
128
256
16
64
32
128
32
0.25
0.5
0.25
0.5
1
128
128
128
128
128
128
128
128
256
128
64
0.5
0.5
0.5
0.5
16
32
8
64
8
16
1
1
0.5
0.5
32
64
32
256
8
16
32
4
256
128
256
128
256
256
128
128
2
128
128
128
128
64
64
128
128
512
16
64
16
0.016
0.5
0.25
0.5
0.25
1
128
64
8
1
64
16
64
64
nt
nt-not tested.
4. Conclusions
Reaction of thioquinanthrenium salts
ring and the formation of 1-methyl-3-mercaptoquinoline-4(1H)-thione
the thiol and thione groups in compound allow the series of sulfide and disulfide derivatives of
quinolinium salts and to be obtained. 1-Methyl-4-chloro-3-(benzyllthio)quinoline salt can be
1
with sodium hydrosulfide leads to cleavage of the dithiin
. Subsequent reactions of
2
2
4
6
8
synthesized by N-alkylating of 4-chloro-3-(benzylthio)quinoline using dimethyl sulfate. The obtained
compounds demonstrated greater activity against Gram-negative bacteria than Gram-positive ones.
Introduction of sulfur substituents into 4-quinoline position markedly increased activity compared
to previously reported 4-aminoquinoline derivatives. Compounds 4d and 4f with thiobenzyl and
thiobenzoyl substituents in the 3-quinoline position demonstrated activity comparable to that of
ciprofloxacine, used as reference.
The MIC values exhibited by these compounds warrant the continuing search for novel
1,3,4-trisubstituted quinoline salts with antimicrobial activity.
Acknowledgments: This work was supported by the Medical University of Silesia in Katowice, Poland.
Grant No. KNW-1-015/K/7/O.
Author Contributions: A.Z. and R.D.W. developed the concept of the work. A.Z., A.E. and E.K. carried out the
synthetic work. R.D.W., M.K. and D.I. conducted a study of the biological activity. A.Z., R.D.W., A.S. and T.J.W.
analyzed the data and wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).