Synthesis and Antibacterial Activity of New N9-Substituted Acridine-9-amines

Article abstract of DOI:10.1134/S1070363219010298

A method for the synthesis of N⁹-substituted acridine-9-amines by reacting 9-chloroacridines with 2-(2-methyl-5- nitro-1H-imidazol-1-yl)ethanamine was developed. The synthesized compounds showed high antibacterial ability against B. subtilis bacteria compared with rivanol and metronidazole.

Full text of DOI:10.1134/S1070363219010298

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 1, pp. 157–159. © Pleiades Publishing, Ltd., 2019.
Russian Text © T.N. Kudryavtseva, K.V. Bogatyrev, P.I. Sysoev, L.G. Klimova, 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 1,
pp. 148–151.
LETTERS
TO THE EDITOR
Synthesis and Antibacterial Activity
9
of New N -Substituted Acridine-9-amines
a
a
a
b
T. N. Kudryavtseva *, K. V. Bogatyrev , P. I. Sysoev , and L. G. Klimova
a
Kursk State University, ul. Radishcheva 33, Kursk, 305000 Russia
*
e-mail: labos.kgu@mail.ru
b
Kursk State Medical University, Kursk, Russia
Received June 21, 2018; revised June 21, 2018; accepted June 26, 2018
9
Abstract—A method for the synthesis of N -substituted acridine-9-amines by reacting 9-chloroacridines with
2-(2-methyl-5- nitro-1H-imidazol-1-yl)ethanamine was developed. The synthesized compounds showed high
antibacterial ability against B. subtilis bacteria compared with rivanol and metronidazole.
Keywords: acridine-9-amines, metronidazole, antibacterial activity
DOI: 10.1134/S1070363219010298
Continuing the search for new biologically active
substances with antibacterial activity in the series of
acridine and acridine derivatives [1–3], we studied new
mobility of the chlorine atom in the position 9. The
conditions of the reactions with various amines vary
depending on the synthesis conditions and the
chemical activity of the starting materials.
9
N -substituted acridine-9-amines, the most interesting
representatives of the acridine class, with a wide
spectrum of different biological activities such as anti-
tumor, antiviral, antibacterial, and anti-inflammatory.
In pharmacology, such drugs as acriquine, amsacrine
and rivanol [4–9] are actively used. Currently, a number
of 9-aminoacridines continues to be actively studied.
The starting 9-chloroacridines 1a–1c were obtained
by known methods from commercially available anilines
and o-chlorobenzoic acid (Scheme 1).
9
The target N -substituted acridine-9-amines 2a–2c
(as hydrochlorides) were obtained by reacting 9-chloro-
acridines 1a–1c with 2-(2-methyl-5-nitro-1H-imidazol-
We synthesized compounds bearing 2- (2-methyl-5-
1
-yl)ethanamine in DMF at 110°C for 4 h with yields
nitro-1H-imidazol-1-yl)ethane fragment bound with
of 60–70% (Scheme 2).
9
the acridine structural fragment by N nitrogen atom. It
9
should be noted that the preparation of O -substituted
An alternative synthesis method based on the
alkylation of 9-aminoacridine with the corresponding
halogen derivatives, turned out to be ineffective, since
the amino group at the position 9 of acridine has a low
nucleophilicity. Thus, the reaction of 9-aminoacridine
with 1-(2-bromoethyl)-2-methyl-5-nitro-1H-imidazole
did not proceed under similar conditions.
derivatives by direct reacting 9-chloroacridine with
2
-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol did not
seem appropriate, since 9-hydroxy derivatives of
acridine are unstable compounds. For the synthesis of
9
N -substituted acridine-9-amines, 9-chloroacridine was
used because of its high reactivity associated with the
Scheme 1.
Cl
COOH
COOH
R
R
R
Cu, K CO , H O
POCl3
2
3
2
+
t
t
Cl
H N
2
N
H
N
1
а−1c
R = H (а), CH
57
3
3
(b), OCH (c).
1

1
58
KUDRYAVTSEVA et al.
Scheme 2.
O N
2
N
N
Cl
N
CH3
N
R
HN
DMF
O N
CH3
+
2
.
HCl
N
R
1
10°C
N
NH2
1а−1c
1а−1c
3 3
R = H (а), CH (b), OCH (c).
1
The H NMR spectra of compounds 2a–2c contain
the signals corresponding to the protons of acridine
nidazole) used in medicine as antibacterial agents as a
reference (see the table). The obtained data show that
compounds 2a and 2c have a high inhibitory activity
against B. subtilis bacteria, significantly exceeding by
comparison with the reference drugs rivanol and
metronidazole (almost 3 times). For other micro-
organisms, compounds 2a and 2c are also superior or
comparable to 2-(2-methyl-5-nitro-1H-imidazol-1-yl)
ethanol. It should be noted that the activity of the 2-
methoxyacridine derivative is slightly higher than that
of the unsubstituted analog.
(
(
CH groups, 7.23–8.49 ppm) and imidazole fragments
CH and CH groups, 2.49 and 8.07 ppm respectively),
as well as the quartet and triplet signals related to the
CH –CH unit at 3.21 and 4.53 ppm. In the IR spectra
there are the absorption bands of the N–H bond
3
2
2
–
1
–1
(
3437 cm ) and the nitro group (1535 cm ).
For the previously obtained acridone and acridine
derivatives, it was found that the introduction of the
methyl group slightly affects the antimicrobial activity,
so the activity of compound 2b was not studied. The
antimicrobial activity of compounds 2a and 2c was
studied in vitro against test strains of E. coli, Ps.
aeruginosa, Pr. vulgaris, S. aureus, B. subtilis, and
Candida albicans microorganisms according to the
method [10] when using ethacridine lactate (rivanol)
and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol (metro-
General procedure for the synthesis of com-
pounds 2a–2c. To a solution of 4.7 mmol of the
corresponding 9-chloroacridine in 25 mL of anhydrous
DMF was added 4.7 mmol of the corresponding
amine. The resulting mixture was stirred at 110–120°C
for 3–4 h, the reaction progress was monitored with
TLC. An excess of DMF was distilled off, the residue
Antimicrobial activity of compounds 1 and 3
Inhibition zone, mm
Е. coli
АТСС
Ps. aeruginosa
(АТСС
S. aureus
(АТСС
25923)
Candida
albicans
(NCTC2625)
Compound
с, %
Pr. vulgaris
АТСС 4636)
B. subtilis
(АТСС 6633)
(
(
2
5922)
27853)
2
2
а
1
2
1
2
1
2
1
2
14.50±0.76
16.00±0.81
11.50±0.70
14.00±0.51
11.50±0.39
12.00±0.35
12.75±0.47
14.50±0.57
11.00±0.55
11.50±0.48
09.00±0.43
09.50±0.60
20.00±0.74
21.00±0.61
12.00±1.14
15.00±0.93
12.50±0.61
13.50±0.74
13.50±0.76
17.50±0.49
14.00±0.42
22.00±0.73
12.50±0.83
15.00±0.66
19.50±0.38
23.50±0.52
25.00±0.92
26.00±0.77
22.00±0.70
25.00±0.68
17.00±1.02
20.00±0.97
29.00±0.93
34.00±0.87
41.00±0.75
42.00±0.81
14.50±0.37
15.00±0.40
14.50±0.94
15.00±1.14
13.50±0.44
16.50±0.79
15.00±0.56
15.50±0.63
20.00±0.63
25.00±0.75
13.50±0.56
15.00±0.96
c
Metronidazole
Rrivanol
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 1 2019

SYNTHESIS AND ANTIBACTERIAL ACTIVITY
159
was dissolved in 50 mL of acetone. The precipitate
was filtered off and washed several times with small
portions of acetone until the impurities and starting
materials disappeared.
acetone–ethanol, 10 : 3 : 2. IR spectra (KBr) were
recorded using an FSM 1201 Monitoring spectrometer.
Mass spectra were recorded on an ACQUITY UPLC H-
Class system equipped with UV/mass detectors
ACQUITY SQD Waters. H and C NMR spectra
were registered on a Bruker AV-600 spectrometer
from DMSO-d6 solutions. Elemental analysis was
performed on a PerkinElmer 2400 CHN analyzer.
1
13
N-[2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl]-
acridine-9-amine hydrochloride (2a). Yield 67%,
yellow crystals, mp 198–199°С, R 0.05. IR spectrum,
f
–
1
ν, cm : 3437 (N–H), 3194–2855 (С—Н), 1636, 1593,
566, 1470 (С=С), 1535 (NO ). Н NMR spectrum, δ,
ppm (J, Hz): 2.49 s (3Н, CH ), 3.20 q (2Н, С Н , J =
.0), 4.53 t (2Н, С Н , J = 6.5), 7.55 t (2Н, С Н +
С Н, J = 8.2), 7.97–8.01 m (4Н, С Н + С Н + С Н +
С Н), 8.06 s (1Н, С Н), 8.27 d (2Н, С Н + С Н, J =
1
1
2
Antibacterial activity screening of DMSO solutions
of the tested compounds with a concentration of 1.0
and 2.0% was performed in Petri dishes with agar
medium, previously seeded with test strains of
microorganisms with a microbial load of 106 microbial
cells per 1 mL. Diameter of growth inhibition zones
was measured with an accuracy of 1 mm after 24 h [10].
1
a
3
2
2
a
2
6
2
7
3
6
4
5
1b
1
8
8
%
.4), 8.59 t (1Н, NH, J = 5.9). Mass spectrum, m/z (I ,
rel
+
+
): 348 (100) [М + H] , 221 (47) [C H N – H] , 207
15 14 2
+
(
53) [C H N – H] . Found, %: С 59.27; Н 4.65; N
14 12 2
FUNDING
1
4
8.43. C H N O ·HCl. Calculated, %: C 59.45; H
19 17 5 2
.73; N 18.25.
-Methyl-N-[2-(2-methyl-5-nitro-1H-imidazol-1-
yl)ethyl]acridine-9-amine hydrochloride (2b). Yield
4%, yellow crystals, mp 197–198°С, R 0.04. IR
This work was financially supported of the Ministry
of Education and Science of the Russian Federation
(project no. 4.9516.2017 / BC).
2
6
f
–
1
CONFLICT OF INTEREST
No conflict of interests was declared by the authors.
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1
1
632, 1574, 1478 (С=С), 1535 (NO2). Н NMR
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3
1
а
2
(
(
7
.49 s (3Н, CH , imidazole), 3.22 m (2Н, С Н ), 4.52 t
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7
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4
7
2
8
1
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а
3
2
a
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8
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8
(
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 1 2019