Synthesis and biological evaluation of novel cyanuric acid-tethered tris-pyridinium derivatives

Article abstract of DOI:10.1016/j.mencom.2021.04.028

Novel tris(4-alkylaminopyridin-1-ium) trichlorides with alkylcyanuric spacer were synthesized by quaternization of 4-alkylaminopyridines with tris(2-chloroethyl) cyanurate. The obtained compounds were evaluated for microbiological activity against five pathogenic bacterial strains (Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Acinobacter baumannii, Pseudomonas aeruginosa). The results indicate the presence of pronounced antibacterial properties in this group of compounds.

Full text of DOI:10.1016/j.mencom.2021.04.028

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 368–369
Synthesis and biological evaluation of novel cyanuric
acid-tethered tris-pyridinium derivatives
a
a
a,b
Anatoly N. Vereshchagin,* Nikita A. Frolov, Alexandra P. Minaeva,
c
a,b
a
Elena V. Detusheva, Yana V. Derkach and Mikhail P. Egorov
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. E-mail: vereshchagin@ioc.ac.ru
D. I. Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russian Federation
State Research Center for Applied Microbiology & Biotechnology, 142279 Obolensk, Serpukhov District,
Moscow Region, Russian Federation
b
c
DOI: 10.1016/j.mencom.2021.05.028
ꢀ
ꢀ
N
Novel tris(4-alkylaminopyridin-1-ium) trichlorides with
alkylcyanuric spacer were synthesized by quaternization of
N
ꢀ
2n ꢁ 1Cn
O
N
Cnꢀ2n ꢁ 1
ꢁ
ꢁ
N
N
N
N
4
-alkylaminopyridines with tris(2-chloroethyl) cyanurate.
Cl−
Cl−
The obtained compounds were evaluated for microbiological
activity against five pathogenic bacterial strains (Escherichia
coli, Klebsiella pneumoniae, Staphylococcus aureus,
Acinobacter baumannii, Pseudomonas aeruginosa). The
results indicate the presence of pronounced antibacterial
properties in this group of compounds.
O
O
ꢇg mlꢈ1
n ꢅ ꢆ−12
Bacteria
MIC
MBC
Cl−
N
ꢁ
S. aureus
E. coli
ꢂ
ꢃ2
ꢃ2
1ꢄ
ꢄꢃ
1ꢄ
12ꢉ
ꢄꢃ
12ꢉ
12ꢉ
K. pneumoniae
A. baumannii
P. aeruginosa
ꢀN
Cnꢀ2n ꢁ 1
Keywords: tris-quaternary ammonium compounds, pyridinium salts, biological activity, antibacterial agents.
For many years, quaternary ammonium compounds (QACs) have
been included in most antiseptics and disinfectants that are used
from household and agricultural to hospital and industrial business.
conclusively proven,3,4 the threat of the spread of bacterial resistance
is more urgent than ever, primarily in regard to the main QACs
on the pharmaceutical market (see Online Supplementary
Materials, Figure S1). The solution to this problem lies in the
synthesis of new compounds exhibiting biocidal properties using
1
The COVID pandemic that played out in 2020 led to a significant
increase in the widespread use of antiseptics, including QACs.
Recent studies show that in more than 90% of dust samples
analyzed during the pandemic, QACs were detected, and their
average concentration has doubled compared to the period before
5
a structure-activity relationship approach.
Earlier, our research group has reported the synthesis and study
of the antibacterial and antifungal activity of bis-QACs based on
2
6-10
COVID. While the effectiveness of QACs against the viral strains
pyridine with aromatic spacers.
This work is focused on
responsible for the spread of this pandemic has not yet been
obtaining trimeric QACs (for examples, see Figure S2). With a
O
N
ꢀ
O
N
ꢁ
ꢀO
Oꢀ
Cl
Cl
C ꢀ
C ꢀ
n
2n ꢁ 1
n
2n ꢁ 1
N
N
N
N
ꢀ
N
Nꢀ
i
O
O
O
O
O
N
ꢄꢄꢅ
ꢁ
ꢁ
N
N
N
N
Oꢀ
Cl
ꢂCl−
O
O
v
ꢃ0−ꢄꢂꢅ
N
ꢁ
n 2n +1
C ꢀ
ꢀN
a n ꢈ ꢉ
b n ꢈ ꢃ
c n ꢈ ꢄ
d n ꢈ 10
e n ꢈ 11
f n ꢈ 12
O
ii−iv
ꢆ2−ꢃꢇꢅ
ꢀ
2n −1
C
n −1
Oꢀ
Nꢀ
ꢀ
2n ꢁ 1 n
C
N
ꢃa−f
ꢂa−f
ꢄa−f
Scheme 1 Reagents and conditions: i, SOCl (3.3 equiv.), PhH, 80ºC, 9 h; ii, SOCl (1.3 equiv.), DMF (0.1 equiv.), PhMe, 110ºC, 3 h; iii, 4-aminopyridine
2
2
(
0.8 equiv.), Et N (1.2 equiv.), CH Cl , 40ºC, 2 h; iv, LiAlH (2 equiv.), THF, 66ºC, 6 h; v, 2 (1 equiv.), 4a-f (3.3 equiv.), butan-1-ol, 117ºC, 3 days.
3 2 2 4
©
2021 Mendeleev Communications. Published by ELSEVIER B.V.
–
368 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2021, 31, 368–369
-
1
Table 1 MIC/MBC values (mg ml ) for prepared QACs.
MIC/MBCa
Compound
S. aureus
E. coli
K. pneumoniae
A. baumannii
P. aeruginosa
5
5
5
5
5
5
CPC
BAC
a
a, n = 7
b, n = 8
c, n = 9
d, n = 10
e, n = 11
f, n = 12
8/16
8/16
16/16
32/32
32/63
32/125
500/>500
125/250
8/8
63/250
32/125
32/125
32/125
63/500
500/500
63/500
500/500
250/250
125/125
16/250
63/250
63/250
8/16
63/125
16/32
16/63
32/63
4/16
63/125
125/125
250/250
500/500
500/500
>500/>500
63/250
125/250
16/32
125/250
4/8
>500/>500
Reference strains of microorganisms Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603, Staphylococcus aureus ATCC 43300,
Acinobacter baumannii ATCC 15308, Pseudomonas aeruginosa ATCC 27853.
large abundance of works on mono- and bis-QACs, it is surprising
that multi-QACs (QACs with three or more heads) are studied
scarcely (Figure S3).1
The reported study was funded by RFBR, project number
20-33-70232.
1-18
As a starting platform (Scheme 1), we used tris(2-chloroethyl)
cyanurate 2, which is easily obtained by treatment of the
correspondingalcohol1withthionylchloride(stepi). Compound 2
being a trimeric alkyl chloride looks good as a spacer for our
purpose.Thiscompoundwasfurtherintroducedintoquaternization
of 4-alkylaminopyridines, the reaction having proceeded at the
pyridinium nitrogen atom to afford the target products 5a-f
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2021.05.028.
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a-e, inhibiting growth at higher concentrations. Compound 5c
1
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1
1
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4
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cyanuric spacer have been synthesized. Their MIC and MBC values
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Received: 27th November 2020; Com. 20/6379
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