Synthesis and antimicrobial activity of 3,4-bis(arylthio)maleimides

Article abstract of DOI:10.1038/s41429-018-0122-3

A series of 3,4-bis(arylthio)maleimides were synthesized and their antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria, including multidrug resistant (MDR) strains and some fungi. Most compounds turned out to be highly ac

Full text of DOI:10.1038/s41429-018-0122-3

The Journal of Antibiotics
https://doi.org/10.1038/s41429-018-0122-3
BRIEF COMMUNICATION
Synthesis and antimicrobial activity of 3,4-bis(arylthio)maleimides
Alexey A. Panov1 Sergey N. Lavrenov Alexander Y. Simonov Elena P. Mirchink Elena B. Isakova
1 ●
1 ●
1 ●
1 ●
●
Alexey S. Trenin1
Received: 27 August 2018 / Revised: 10 October 2018 / Accepted: 28 October 2018
©
The Author(s) under exclusive licence to the Japan Antibiotics Research Association 2018
Abstract
A series of 3,4-bis(arylthio)maleimides were synthesized and their antimicrobial activity was evaluated against Gram-
positive and Gram-negative bacteria, including multidrug resistant (MDR) strains and some fungi. Most compounds turned
out to be highly active, activity being dependent on substituents on phenyl rings.
The spread of antibiotic-resistant bacteria poses a sub-
stantial threat with high morbidity and mortality worldwide.
The discovery of new scaffolds derived by chemical
synthesis could open the way to alternative classes of
antimicrobial agents with new mechanism of action and
activity against multidrug resistant (MDR) species of bac-
teria and fungi [1, 2]. Maleimide derivatives are known for
their wide spectrum of biological activity [3–6]. The com-
pounds of interest—3,4-bis(phenylthio)maleimides—are
widely used by researchers for the purpose of incorporating
fluorescent tags into proteins or other modifications of
proteins and hormones, including binding them to a poly-
mer [7–10].
Also bis-(alkylthio)maleimide derivatives have been
prepared from teicoplanin pseudoaglycon by reaction of
its primary amino group with N-ethoxycarbonyl bis-
alkylthiomaleimides. Some of the new derivatives dis-
played excellent antibacterial activity against resistant
bacteria [11]. Bis(benzylthio)maleimide derivatives of
teicoplanin pseudoaglycon showed good activity against
vancomycin- and teicoplanin-resistant enterococci [12].
Antimicrobial activity of 3-(arylthio)maleimide deriva-
tives was reported [13], but antimicrobial activity of 3,4-
bis(arylthio)maleimides was not studied before. In the
present work such compounds are shown to be rather
active antimicrobial agents, capable of overcoming bac-
terial MDR.
The symmetrical 3,4-bis(arylthio)maleimides 3a–g were
synthesized by the reaction of 3,4-dibromomaleimide with
two equivalents of various thioaryl derivatives and triethy-
lamine in THF (Scheme 1).
We failed to isolate monosubstituted products 2 even
when 0.3 equivalents of thiophenol were used, carrying out
the reaction at 0 °C. Changing the solvent to less polar (i.e.
toluene) had no effect. We suggest that 3-bromo-4-(aryl-
thio)maleimide intermediate 2 is much more reactive than
dibromomaleimide 1, resulting in a mixture of disubstituted
product 3 and unreacted 1.
All compounds 3a–g were tested against Gram-positive
and Gram-negative bacteria and fungi. The minimum
inhibitory concentrations (MIC) for Gram-positive and
Gram-negative bacteria were determined by the micro-
dilution method in a cation-adjusted Müller–Hinton med-
ium in accordance with the requirements of the Institute of
Clinical and Laboratory Standards (CLSI/NCCLS) [14].
The activity of the test compounds against various cultures
of yeast and mycelial fungi was estimated using the
recommendation by CLSI/NCCLS micromethod [15, 16]
by twofold serial dilutions in the nutrient medium RPMI
1640 (liquid, with L-glutamine and without sodium
bicarbonate). Observed MIC are presented in the follow-
ing Tables 1 and 2.
All compounds were active against Gram-positive S.
aureus, S. epidermidis and S. haemoliticus. Compounds 3f
and 3g, which both have an N-methyl group at the mal-
eimide moiety, are generally less active against almost all
strains, at the same time being more active against Gram-
negative Escherichia coli and Pseudomonas aeruginosa.
However, compounds 3d and 3e show an opposite pattern.
All compounds turned out to be less active than the refer-
ence compound levofloxacin on all but three bacterial
*
Alexey A. Panov
745243@mail.ru
7
1
Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street,
Moscow, Russia, 119021

A. A. Panov et al.
3
a. Ar = 4-F-Ph, R = H
Scheme 1 Synthesis of 3,4-bis
arylthio)maleimides 3a-g
R
N
R
N
O
O
R
N
3b. Ar = 4-Cl-Ph, R = H
3c. Ar = 2-CH -Ph, R = H
3d. Ar = 4-CH3OPh, R = CH3
3
3e. Ar = 4-CH OPh, R = H
(
O
SH
3
O
Ar
THF, TEA
+
O
O
Br
S
S
Br
3
f. Ar = Ph, R = CH3
1
a-b
a: R = H
b: R = CH3
Ar
Br
S
Ar
2
3g. Ar = 4-Cl-Ph, R = CH3
Ar
a-g
1
1
3
Table 1 MIC (μg/ml) against
bacterial strains
Bacterial strains
3a
3b
3c
3d
3e
3f
3g
Levofloxacin
Staphylococcus aureus 25923 ATCC
Staphylococcus aureus 3798
4
2
1
2
4
4
4
4
1
4
1
0.5
1
4
4
4
4
4
4
8
4
4
2
1
2
4
4
4
4
1
4
4
4
4
4
4
4
2
4
2
2
1
2
2
2
1
2
0.25
32
0.5
0.25
1
Staphylococcus aureus 100КС
Staphylococcus aureus 700699 АТСС
Staphylococcus aureus 10
1
32
2
16
1
2
0.13
0.25
0.5
0.5
4
Staphylococcus aureus 5 (MRSA)
Staphylococcus epidermidis 533
Staphylococcus haemoliticus 585
Acinetobacter baumanii 5696
1
2
1
1
1
1
0.5
2
>64 >64
16 >64
>64 >64
>64 >64
Enterococcus faecium 569
1
Escherichia coli 25922 ATCC
Klebsiella pneumoniae 13883 ATCC
Proteus vulgaris 13315 ATCC
Salmonella cholerasuis 14028 ATCC
Pseudomonas aeruginosa 27853 ATCC
16 16
16 16
16 16
16 16
>64 >64 16
64 >64 16
4
4
2
2
0.06
0.25
4
>64 >64 16 >64 >64
>64 >64 16 >64 >64 0.13
>64 >64
8
8
8
4
4
1
strains. In comparison to 3-(arylthio)maleimide derivatives
vacuo and the residue was redissolved in ethyl acetate-water
(20 + 20 ml) mixture. The organic layer was separated,
washed with aq. NaHCO , dried over anhydrous Na SO
4
[
13] our compounds show mostly similar level of activity,
but wider spectrum of action.
3
2
Some compounds were also tested of fungi strains
Table 2). Even the most active compound 3g is less active
and evaporated. The residue was purified by flash chro-
matography (ethyl acetate: petroleum ether 3:1).
(
than the reference compound—amphotericin B.
3,4-Bis((4-fluorophenyl)thio)-1H-pyrrole-2,5-dione (3a)
was obtained as a yellow solid, yield 64%. Mp 145–146 °C
All the reagents were obtained commercially and used
without further purification. Melting points were determined
by an open capillary method and are uncorrected. Purity of
the compounds was checked by thin-layer chromatography
using silica-gel 60 F254-coated Al plates (Merck) and spots
1
(diethyl ether). H NMR: δ 7.13 (4 H, t, J = 9.7 Hz),
1
3
7.29–7.32 (4 H, m), 11.37 (1 H, s, NH) C NMR: δ 115.95,
116.18, 124.68, 133.25, 133.33, 135.71, 160.77, 163.21,
167.57. ESI-HRMS: calculated for C H F NO S [M + H]
16
9
2
2 2
1
13
+
were observed under UV light. H NMR and C NMR (in
350.0116, found m/z 350.0107.
DMSO-d ) spectra were recorded on a Varian VXR-400
3,4-Bis((4-chlorophenyl)thio)-1H-pyrrole-2,5-dione (3b)
6
spectrometer at 400 MHz and 100 MHz, respectively; the
chemical shift values are expressed in ppm (δ scale) using
tetramethylsilane as an internal standard. The mass spectral
measurements were carried out by ESI method on
micrOTOF-QII (Brucker Daltonics GmbH).
was obtained as a yellow solid, yield 77%. Mp 165–166 °C
1
(diethyl ether). H NMR: δ 7.26 (4 H, d, J = 8.5 Hz), 7.32
1
3
(4 H, d, J = 8.5 Hz), 11.43 (1 H, s, NH) C NMR: δ
128.20, 128.87, 132.32, 132.83, 135.80, 167.48. ESI-
+
HRMS: calculated for C H Cl NO S [M + H] 381.9525,
1
6
9
2
2 2
General method for synthesizing 3,4-bis(arylthio)mal-
eimides 3a-g: To the solution of dibromomaleimide 1a or
N-methyldibromomaleimide 1b (1 mmol) in THF (20 ml)
was added solution of the thiophenol (2.2 mmol) and trie-
thylamine (2.2 mmol) in one portion. The resulting solution
was stirred at room temperature for 1 h, then evaporated in
found m/z 381.9542.
3,4-Bis(o-tolylthio)-1H-pyrrole-2,5-dione
obtained as a yellow solid, yield 50%. Mp 149–151 °C. H
(3c)
was
1
NMR: δ 2.10 (6 H, s, CH ), 7.13 (10 H, m), 11.30 (1 H, s,
3
1
3
NH).
C NMR: δ 20.52, 126.88, 128.79, 129.04,
130.72, 132.48, 136.26, 139.32, 168.07. ESI-HRMS:

Synthesis and antimicrobial activity of 3,4-bis(arylthio)maleimides
Table 2 MIC (μg/ml) against fungi strains
Compliance with ethical standards
Compound/
Organism
Candida
albicans
ATCC
Aspergillus
niger ATCC
16404
Fusarium
oxysporum
VKM F-140
Conflict of interest The authors declare that they have no conflict of
interest.
1
4053
3
3
3
3
3
3
a
b
c
48
32
64
64
4
12
64
16
4
64
˃64
˃64
48
˃64
32
4
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8
15
2 2
3
42.0612.
5
3
,4-Bis((4-methoxyphenyl)thio)-1-methyl-1H-pyrrole-
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7
6
1
6
3
3
1
3
C
1
+
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19
17
4 2
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8
3
,4-Bis((4-methoxyphenyl)thio)-1H-pyrrole-2,5-dione
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1
(
9
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+
2
0
19
6 2
1
1
1
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3
1
3
+
HRMS: calculated for C H NO S [M + H] 328.0460,
21
21
6 2
found m/z 328.0486.
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1
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1
1
20–121 °C. H NMR: δ 2.88 (3 H, s, CH ), 7.32 (4 H, d,
3
13
J = 8.5 Hz), 7.26 (4 H, d, J = 8.5 Hz). NMR C δ: 25.01,
28.56, 129.35, 132.77, 133.36, 135.80, 166.87. ESI-
HRMS: calculated for C H Cl NO S
[M + H]+
1
1
17
11
2
2 2
3
95.9681, found m/z 395.9662.
1
Acknowledgements This study was supported by a grant from the
Russian Science Foundation (project 16-15-10300).