Antimicrobial activity of new benzazolyl N-sulfonyl amidines

Article abstract of DOI:10.1016/j.mencom.2021.07.019

The reactions of N-(benz[d]oxazol-2-yl)- or N-(benzo[d]-thiazol-2-yl)-substituted carbothioamides with sulfonyl azides proceed as replacement of thioxo substituent by the sulfonylimino group to afford the corresponding N'-sulfonylated amidines. Acetic acid thioamides react smoothly upon boiling in ethanol, while for thioamides of trifluoroacetic and benzoic acids heating to 80–90 °C was required. Among hybrid molecules thus prepared, bacteriostatic-, bactericidal- and fungistatic-active against S. aureus and C. albicans representatives were found.

Full text of DOI:10.1016/j.mencom.2021.07.019

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 495–497
Antimicrobial activity of new benzazolyl N-sulfonyl amidines
Nadezhda A. Galieva,a Dmitriy A. Saveliev,a Oleg S. Eltsov,a Vasiliy A. Bakulev,a Gert Lubec,b
Jihong Xing,c Zhijin Fan*d and Tetyana V. Beryozkina*a
a Institute of Chemical Engineering, Ural Federal University, 620002 Ekaterinburg, Russian Federation.
E-mail: tetber@mail.ru
b Paracelsus Private Medical University, A-5020 Salzburg, Austria
c College of Life Science, Hebei Agricultural University, 071001 Baoding, P. R. China
d State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
300071 Tianjin, P. R. China. E-mail: fanj@nankai.edu.cn
DOI: 10.1016/j.mencom.2021.07.019
The reactions of N-(benz[d]oxazol-2-yl)- or N-(benzo[d]-
thiazol-2-yl)-substituted carbothioamides with sulfonyl
azides proceed as replacement of thioxo substituent by
the sulfonylimino group to afford the corresponding
N'-sulfonylated amidines. Acetic acid thioamides react
smoothly upon boiling in ethanol, while for thioamides of
trifluoroacetic and benzoic acids heating to 80–90 °C was
required. Among hybrid molecules thus prepared,
bacteriostatic-, bactericidal- and fungistatic-active against
S. aureus and C. albicans representatives were found.
antibacterial
activity
O
R3
O
S
S
N
R3SO2N3
N
R1
N
R2
R1
R2
N
X
N
H
X
H
X = S, O
20 examples
Keywords: thioamides, sulfonamides, amidines, benzoxazole, benzothiazole, cycloaddition, antimicrobial activity.
Various benzothiazole derivatives exhibit antitumor1 and
antibacterial activity against gram-positive and gram-negative
bacteria.2 Benzoxazoles are structural isosters of the
nitrogenous bases of adenine and guanine, which allows them
to easily interact with biological receptors.3 On the other hand,
N-sulfonyl amidines as a new chemotype of organic compounds
inhibit cell differentiation and destroy bone tissue, and exhibit
antiresorptive activity,4 inhibit the transport of dopamin5 and
casein kinase.6
Hybrid molecules containing simultaneously benzoxazole or
benzothiazole moieties and an N-sulfonyl amidine group are not
described. However, the combination of these bioactive residues
can change the spectrum of their action and lead to substances
that exhibit different types of activity. Therefore, the synthesis of
such compounds is of interest in terms of searching for new
biologically active substances in this series.
conditions, namely, boiling in ethanol the thioamide/azide
mixture in 1:2 molar ratio (for experimental details, see Online
Supplementary Materials). Under these conditions, a series of
S
O
N
N
i
R1
R1
Me
Me
N
N
X
X
H
H
1a–c
2a–c
R1 = H, X = S
R1 = F, X = S
1a, 2a
1b, 2b
1c, 2c
R1 = H, X = O
O
O
S
R2
N
N
3a–g
R1
ii
Me
N
X
H
4a–o
Among the known methods for the synthesis of N-sulfonyl
amidines,7 we focused on the recently elaborated method based
on reaction of thioamides with sulfonyl azides. It was previously
used for the preparation of methylene active5,8 and hetero-
aromatic9 sulfonyl amidines, as well as sulfonyl amidines
containing a fragment of 2-aminobenzimidazole.6
In this study, we have employed the reaction of thioamides
with azides for the synthesis of novel biologically active
compounds containing benzoxazole and benzothiazole fragments
and the sulfonylamidine function (Scheme 1). Starting
thioamides 2 were synthesized by a two-step method from
aminobenzazoles and the corresponding acylation reagent
(acetyl chloride, trifluoroacetic anhydride or benzoyl chloride)
with subsequent thionation of formed amides 1 with the
Lawesson’s reagent.10 By varying the solvent type, temperature,
and reagent ratio using thioamides 2a,c and sulfonyl azide 3b
as the model compounds, we determined the optimal process
R1 = H, R2 = Me, X = S, 62%
4a
4b R1 = H, R2 = Ph, X = S, 53%
O
O
R1 = H, R2 = 4-MeC6H4, X = S, 63%
R1 = H, R2 = 4-FC6H4, X = S, 59%
R1 = H, R2 = 4-MeOC6H4, X = S, 62%
R1 = H, R2 = 4-O2NC6H4, X = S, 80%
R1 = H, R2 = benzo[c][1,2,5]-
S
4c
N3
R2
4d
4e
4f
3a–g
R2 = Me
R2 = Ph
a
b
c
d
e
f
4g
R2 = 4-MeC6H4
R2 = 4-FC6H4
thiadiazol-4-yl, X = S, 80%
R1 = F, R2 = 4-MeC6H4, X = S, 49%
R1 = F, R2 = 4-FC6H4, X = S, 55%
R1 = H, R2 = Me, X = O, 71%
4h
4i
4j
4k
4l
4m
4n
4o
R2 = 4-MeOC6H4
R2 = 4-O2NC6H4
R1 = H, R2 = Ph, X = O, 50%
R1 = H, R2 = 4-MeC6H4, X = O, 70%
R1 = H, R2 = 4-FC H , X = O, 61%
g R2 =
6
4
N
N
R1 = H, R2 = 4-MeOC6H4, X = O, 58%
R1 = H, R2 = benzo[c][1,2,5]-
thiadiazol-4-yl, X = O, 63%
S
Scheme 1 Reagents and conditions: i, Lawesson’s reagent (0.55 equiv.),
1,4-dioxane, reflux, 10–21 h; ii, 3a–g (2 equiv.), EtOH, reflux, 2–21 h.
© 2021 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 495 –

Mendeleev Commun., 2021, 31, 495–497
new sulfonyl amidines 4a–o was obtained from thioamides 2a–c
Table 1 Antimicrobial activity of amidines 4d,f,h,j,m,n,t.
and sulfonylazides 3a–g (see Scheme 1).†
Antimicrobial activity/µg ml–1
Contrary to thioamides 2a–c, their analogues 2d,e bearing
either trifluoromethyl or phenyl substituents at the C(S)NH2
group did not react with sulfonyl azides under the above
conditions. We found that the desired reaction could be promoted
by heating neat reactants at 80–90 °C to afford N-sulfonyl
amidines 4p–t in 55–68% yields (Scheme 2).‡
The structure of N-sulfonyl amidines 4a–t was confirmed by
1H and 13C NMR spectroscopy, including 2D HMBC and HSQC
experiments, and by mass spectrometry. In mass spectra of the
electron impact of all compounds, there was a peak for the
molecular ion. In the 1H NMR spectra of compounds 4a–o, the
signals for the Me protons at the amidine C atom appeared in the
region of 2.56–2.82 ppm, and all the spectra contained the
required number of signals of aromatic protons. In the spectra of
amidines 4a–o,s,t, there were signals for NH protons at 11.85–
12.90 ppm. In the 13C NMR spectra of all compounds 4, the
diagnostic signals for the amidine carbon were observed at
162.5–166.1 ppm (4a–o,s,t) and 150.7 ppm (4p–r). Existence of
N-sulfonyl amidines in tautomeric form bearing NH group was
proved by 1H–15N 2D HSQC spectra earlier.5
The proposed mechanism for the formation of target
compounds 4 includes the 1,3-dipolar cycloaddition of the C=S
bond of thioamides 2 to the azide group of sulfonyl azides 3,
accompanied by the release of molecular nitrogen and elemental
sulfur from the initially formed 1,2,3,4-thiatriazoline, which was
established previously.8 The observed deceleration of the
reaction by the introduction of an electron-acceptor substituent
into a thioamide molecule is in agreement with the reaction of a
cycloaddition with inverse electronic demand.
Seven synthesized amidines 4d,f,h,j,m,n,t were tested for
antimicrobial activity. Using the Gen5 software, the dependence
of optical density indicators on the growth of bacterial and yeast
cells was determined in different concentrations of chemical
compounds. The analysis of the obtained data showed that five
of these compounds exhibit antimicrobial activity against
S. aureus and yeast fungi C. albicans. At the same time, all
Entry Amidine
S. aureus
E. coli
C. albicans
MIC MBC
MICa MBCb
MIC MBC
1
2
3
4
5
6
7
8
9
4d
7.8
2.0
–
500.0
500.0
–
–
–
–
–
15.6
2.0
–
–
–
4f
4h
–
–
–
4j
2.0 1000.0
–
–
3.9
2.0
7.8
–
–
4m
1.0
2.0
–
500.0
–
–
–
4n
–
–
–
–
–
4t
–
–
–
dioxidinec
fluconazolec
62.5 1000
3.9
–
62.5
–
–
–
–
–
6.25
12.5
culture
control
10
+++ +++
+++ +++
+++
+++
a Minimal inhibitory concentration. b Minimal bactericidal concentration;
‘–’ is the absence of antimicrobial activity in the studied concentrations;
‘+++’ is the growth of microorganisms. c The antimicrobial effect of the
studied compounds was compared with that of dioxidine11 and fluconazole.12
compounds are not active against gram-negative bacteria E. coli
(Table 1).
Compound 4d inhibits the growth of S. aureus at a
concentration of 7.8 µg ml–1, and the death of culture comes
from exposure to the substance at
a concentration of
500.0 µg ml–1, its fungistatic effect is observed at a concentration
of 15.6 µg ml–1. Compounds 4f,j,n have a high inhibition activity
and inhibit the growth of S. aureus at a concentration of
2.0 µg ml–1, the bactericidal effect of compound 4j is manifested
at a concentration of 1000.0 µg ml–1, and compound 4f at a
concentration of 500.0 µg ml–1. Compounds 4f,j,n have a
fungistaticeffectintherangeofconcentrationsof2.0–7.8 µg ml–1
against C. albicans. More pronounced bacteriostatic, bactericidal
and fungistatic action is exhibited by compound 4m: at a
concentration of 1.0 µg ml–1, bactericidal action at
500.0 µg ml–1, and fungistatic action at a concentration of
2.0 µg ml–1 against the yeast C. albicans. Thus, compound 4m
can be considered as a leader, which will be the object of further
studies.
O
O
S
R2
In summary, the synthetic methodology based on the
reaction of thioamides with sulfonyl azides was successfully
used to obtain hybrids of benzoxazole(thiazole) and N-sulfonyl
amidine with good yields. A number of sulfonyl azides,
including mesyl azide and arylsulfonyl azides with electron-
donating (Me, MeO) and electron-withdrawing (F, NO2,
benzo[c][1,2,5]thiazol-4-yl) substituents reacted smoothly
with benzazolyl thioamides to form the target compounds.
Antimicrobial activity tests showed that most of the compounds
possessed bacterio- and fungistatic activity, and compound 4m
bearing a fluorophenylsulfonyl substituent at the amidine
fragment demonstrated the highest bacteriostatic, fungistatic
and bactericidal activity.
S
N
N
N
3b–d
R1
i
R1
N
N
S
S
H
H
2d,e
4p–t
p R1 = CF3, R2 = Ph, 65%
R1 = CF
R1 = Ph
d
e
3
q R1 = CF3, R2 = 4-MeC6H4, 55%
r R1 = CF3, R2 = 4-FC6H4, 55%
s R1 = R2 = Ph, 60%
t R1 = Ph, R2 = 4-MeC6H4, 68%
Scheme 2 Reagents and conditions: i, 3b–d (2 equiv.), neat, 80–90 °C,
9–17 h.
†
General method for the synthesis of N'-sulfonyl amidines 4a–o.
This work was supported in part by the Russian Science
Foundation (grant no. 18-13-00161, prolongation), the National
Natural Science Foundation of China (grant no. 31872007) and
the Tianjin Development Program for Innovation and
Entrepreneurship (grant no. 2018-18).
Theauthorsthanktheheadofresearchlaboratory‘Bactericide’
at the Perm State National Research University Svetlana
Balandina for tests of antimicrobial activity.
A solution of the corresponding thioamide 2a–c (1.0 mmol, 1.0 equiv.)
and sulfonyl azide 3a–g (2.0 mmol, 2.0 equiv.) in anhydrous ethanol
(4 ml) was refluxed for 9–21 h. The reaction mixture was cooled, the
formed precipitate was collected by filtration and crystallized from
ethanol. For compound characterization, see Online Supplementary
Materials.
‡
General method for the synthesis of N'-sulfonyl amidines 4p–t.
A mixture of the corresponding thioamide 2d,e (1.0 mmol, 1.0 equiv.)
and sulfonyl azide 3b–d (2.0 mmol, 2.0 equiv.) was heated at 80–90 °C
in an oil bath for 9–17 h. The reaction mixture was cooled, and small
amount of ethanol was added. The formed precipitate was filtered off and
crystallized from ethanol. For compound characterization, see Online
Supplementary Materials.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2021.07.019.
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Mendeleev Commun., 2021, 31, 495–497
8 L. Dianova, V. Berseneva, T. Beryozkina, I. Efimov, M. Kosterina,
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Received: 18th February 2021; Com. 21/6456
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