Synthesis and study of the antibacterial and analgesic activity of 3-acyl-1,2,4,5-tetrahydro-[1,2-a]quinoxaline-1,2,4-triones

Full text of DOI:10.1023/A:1010475811489

Pharmaceutical Chemistry Journal
Vol. 35, No. 4, 2001
SYNTHESIS AND STUDY OF THE ANTIBACTERIAL
AND ANALGESIC ACTIVITY OF 3-ACYL-1,2,4,5-TETRAHYDRO-
[1,2-a]QUINOXALINE-1,2,4-TRIONES
I. V. Mashevskaya,1 R. R. Makhmudov,2 G. A. Aleksandrova,2 O. V. Golovnina,2
A. V. Duvalov,2 and A. N. Maslivets1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 4, pp. 20 – 21, April, 2001.
Original article submitted June 29, 1999.
As is known, derivatives of 1,2,3,4-tetrahydro-2-quino-
xalones possess pronounced anticonvulsant and analgesic
properties [1]. It was of interest to broaden the spectrum of
pharmacological activity of compounds belonging to this
class by modifying the base structure by annelation with a
pyrrole cycle via the 1 – 2 bond of quinoxalone. For this pur-
pose, we synthesized a series of 3-acyl-1,2,3,5-tetrahydro-
pyrrolo[1,2-a]quinoxaline-1,2,4-triones (X – XVIII) using
reactions of 3-alkoxycarbonylmethylene- and 3-phenacylide-
ne-1,2,3,5-tetrahydro-2-quinoxalones (I – IX) with oxalyl
chloride in anhydrous chloroform conducted by the method
developed in [2].
The compositions of target compounds X – XVIII were
checked by elemental analyses and their structures were con-
1
firmed by the IR and H NMR spectroscopic data. The IR
spectra of compounds XIV – XVI, XVIII exhibit absorption
bands due to the stretching vibrations of N5H group (in the
region of 3080 – 3150 cm – 1), lactam carbonyl C1=O
(1700 – 1740 cm – 1), amide carbonyl C4=O (1650 –
1690 cm – 1), and aroyl carbonyl groups (1610 – 1630 cm – 1),
as well as bands due to antisymmetric and symmetric stretch-
ing vibrations of the nitro group in compounds XVI and
XVIII (in the regions of 1520 – 1540 and 1350 – 1345 cm – 1
,
respectively).
1
The H NMR spectrum of compound XVI displays a
group of signals from aromatic protons (centered at
7.40 ppm) and a singlet due to the amide NH group
(10.97 ppm).
R2
N
R2
N
R1
O
R1
O
(COCl)2
–2HCl
COR3
N
N
H
The hydrolysis of compounds X – XVIII on boiling for
0.5 – 1 min in a dioxane – 10% hydrochloric acid mixture
leads to scission of the pyrrolidone cycle with the formation
of initial quinoxalones I – IX. Apparently, this decomposi-
tion proceeds via the stage of detachment of an oxalyl frag-
ment from intermediate oxalic acids XIX, which is typical of
the compounds belonging to this class [3].
O
R3
O
O
I – IX
X – XVIII
R1 = R2 = H; R3 = OMe (I, X), Ph (II, XI), C6H4Me-4 (III, XII),
C6H4OMe-4 (IV, XIII), C6H4Br-4 (V, XIV), C6H4NO2-4 (VI, XV)
R1 = H; R2 = R3 = Ph (VII, XVI); R1 = H, R2 = Ph, R3 = C6H4Me-4 (VIII,
XVII); R1 = NO2, R2 = H, R3 = Ph (IX, XVIII).
R2
R2
The electron donor and acceptor groups were introduced
into the para position of the benzene ring of the aroyl frag-
ment in order to study the effect of this modification on the
biological activity of these compounds.
R1
N
O
R1
N
O
COR3
H2O, H+
COR3
COCOOH
N
N
H
Pyrroloquinoxalinetriones X – XVIII were obtained with
high yields (Table 1) and appeared as dark-violet crystalline
substances melting with decomposition. These compounds
are poorly soluble in common organic solvents and are insol-
uble in water and alkanes.
O
O
X – XVIII
XIX
R2
N
R1
O
H2O, H+
–(COOH)2
N
H
O
R3
1
I – IX
Perm State University, Perm, Russia.
Institute of Natural Sciences, Perm State University, Perm, Russia.
2
196
0091-150X/01/3504-0196$25.00 © 2001 Plenum Publishing Corporation

Synthesis and Study of the Antibacterial and Analgesic Activity
EXPERIMENTAL CHEMICAL PART
197
of Escherichia coli (strain 1257) and Staphylococcus aureus
(strain 209-P) were determined by the conventional method
of double serial dilutions in a beef-infusion broth [4] and
characterized by a minimum inhibiting concentration (MIC).
The reference drugs were ethacridine lactate and phenyl
salicylate.
The IR spectra of the synthesized compounds were re-
corded on an UR-20 spectrophotometer using samples pre-
pared as nujol mulls. The 1H NMR spectra were measured on
an RYa-2310 spectrometer using DMSO-d6 as the solvent
and HMDS as the internal standard.
The analgesic activity with respect to thermal irritation
was studied on white mongrel mice weighing 18 – 22 g sub-
jected to a hot plate test [5]. The compounds were injected in
a dose of 50 mg/kg (i.p.) 30 min before placing the animals
onto a metal plate heated to 53.5°C. The drug-induced
change in the pain sensitivity was evaluated by measuring
the time of the animal staying (in seconds) on the hot plate
before the onset of a defensive response (hind paw licking).
The reference drug was voltaren.
3-Benzoyl-7-nitro-1,2,3,4-tetrahydroquinoxalone (IX).
A solution of 1.53 g (10 mmole) of 4-nitro-o-phenylen-
ediamine in 30 ml of dioxane was added with stirring to a so-
lution of 2.06 g (10 mmole) of benzoylpyruvic acid methyl
ether in 20 ml of dioxane. The mixture was boiled for
5 – 10 min and cooled. The yellow-orange precipitate of
compound IX was filtered and recrystallized from DMSO.
Compounds V – VIII were synthesized using analogous
procedures; compounds I – IV were described previously [1].
3-Benzoyl-7-nitro-1,2,4,5-tetrahydro[1,2-a]quinoxa-
line-1,2,4-trione (XVIII). To a solution of 3.0 g (10 mmole)
of compound IX in 30 ml of anhydrous dichloroethane were
added 1.23 g (10 mmole) of oxalyl chloride and the mixture
was boiled for 2.5 h. The precipitate of compound XVIII was
filtered and recrystallized from anhydrous acetonitrile.
Compounds X – XVII were synthesized using analogous
procedures (Table 1).
The incubation tests showed that compounds
VIII – XVIII exhibit a weak antibacterial activity with re-
spect to the strains studied. The effect was comparable to the
action of ethacridine lactate and exceeded that of phenyl
salicylate. All the synthesized compounds exhibited a mod-
erate analgesic activity.
TABLE 2. Acute Toxicity, Analgesic Effect, and Antibacterial
Activity of the Synthesized Compounds
EXPERIMENTAL BIOLOGICAL PART
Antibacterial activity:
Analgesic activity
MIC, mg/ml
Compounds X – XVIII were characterized with respect
to acute toxicity and analgesic and antibacterial activity
(Table 2). The acute toxicity (LD50) was determined by a
conventional method on white mongrel mice weighing
Com-
pound
LD50,
Latent period
of defensive
reflex, sec
mg/kg
Dose,
E. coli
St. aureus
mg/kg
VIII
…
…
…
…
50
…
…
2000
> 2000
500
125
> 2000
62.5
18 – 22 g [4]. The compounds were introduced with a 2%
starch jelly (0.1 ml per 10 g body weight), after which the
state of the injected mice was monitored for ten days.
The antibacterial properties of the synthesized com-
pounds with respect to the conditionally-pathogenic cultures
X
XI
> 1000
23.6 ± 8.94
(n = 6)
XII
> 1000
> 1000
> 1000
> 1000
> 1000
50
50
50
50
50
500
> 2000
2000
2000
500
250
250
500
125
500
19.8 ± 4.53
(n = 6)
XIII
XIV
XV
XVI
21.2 ± 4.79
(n = 6)
TABLE 1. Yields and Physicochemical Characteristics of the Syn-
thesized Compounds
22.5 ± 6.9*
(n = 6)
Compound
Yield, %
M.p., °C
Empirical formula
21.0 ± 4.68
(n = 6)
V
94
75
93
65
82
90
92
93
70
92
80
90
77
79
278 – 280
298 – 299
210 – 211
205 – 207
296 – 298
183 – 185
220 – 221
223 – 224
203 – 205
232 – 233
290 – 292
215 – 216
208 – 210
267 – 269
C16H11BrN2O2
C16H11N3O4
C22H16N2O2
C23H18N2O2
C16H11N3O4
C13H18N2O5
C18H10N2O4
C19H12N2O4
C19H12N2O5
C18H9BrN2O4
C18H9N3O6
C24H14N2O4
C25H16N2O4
C18H9N3O6
VI
24.3 ± 9.3*
(n = 6)
VII
VIII
IX
XVII
…
…
50
2000
250
125
XVIII
> 1000
> 2000
24.8 ± 9.4*
(n = 6)
X
XI
Voltaren
380
10
26.2 ± 0.84
(n = 6)
XII
XIII
XIV
XV
XVI
XVII
XVIII
Ethacridine lactate
Phenyl salicylate
2000
500
> 4000
–
> 4000
Control (2% starch jelly)
11.9 ± 0.3
(n = 10)
Notes: Difference from control reliable for * p < 0.05; n indicates
the number of animals in a test group.

198
I. V. Mashevskaya et al.
2. Yu. S. Andreichikov, A. N. Maslivets, L. I. Smirnova, et al., Zh.
Org. Khim., 23(7), 1534 – 1543 (1987).
3. A. N. Maslivets, L. I. Smirnova, and Yu. S. Andreichikov, Zh.
Org. Khim., 28(10), 2141 – 2148 (1992).
This study was supported by the Russian Foundation for
Basic Research, project No. 98-03-32888.
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