Synthesis and Anticonvulsive Activity of 3- and 4-Benzoylpyridine Oxime Derivatives

Article abstract of DOI:10.1007/s11094-018-1763-z

We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant action. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholinoethyloxime oxalate (1a), i.p. doses of 60 – 1

Full text of DOI:10.1007/s11094-018-1763-z

DOI 10.1007/s11094-018-1763-z
Pharmaceutical Chemistry Journal, Vol. 52, No. 1, April, 2018 (Russian Original Vol. 52, No. 1, January, 2018)
SYNTHESIS AND ANTICONVULSIVE ACTIVITY
OF 3- AND 4-BENZOYLPYRIDINE OXIME DERIVATIVES
L. A. Zhmurenko,1 T. A. Voronina,1 S. A. Litvinova,1 L. N. Nerobkova,1
I. O. Gaidukov,1 G. V. Mokrov,1 and T. A. Gudasheva1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 52, No. 1, pp. 19 – 28, January, 2018.
Original article submitted June 21, 2017.
We present here the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant ac-
tion. The most active compound in the maximum electric shock test was 4-benzoylpyridine O-2-morpholino-
ethyloxime oxalate (1a), i.p. doses of 60 – 150 mg/kg of which increased the survival of mice to 100%. The
best effect in the corasol antagonism test was obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c),
i.p. doses of 12.5 mg/kg of which increased the survival of mice to 67% and the latent period of onset of gener-
alized tonic-clonic convulsions to 52 sec. Compound 1a had low toxicity (the i.p. LD50 in mice was
316 mg/kg) and a therapeutic index of 21.
Keywords: 3- and 4-benzoylpyridine oximes, anticonvulsant activity, maximum electric shock test, corasol
antagonism test.
Every year throughout the world roughly 2.4 million people are diagnosed with epilepsy. Searches for novel anticonvulsant
substances for the prophylaxis and treatment of epilepsy are a current and relevant task as present antiepileptics do not com-
pletely satisfy clinical requirements and have a multitude of side effects [1, 2].
Studies at the V. V. Zakusov Science Research Institute of Pharmacology include the search for novel substances for the
treatment of epilepsy. This report presents the results of studies on the synthesis and investigation of compounds with potential
anticonvulsant activity among 3- and 4-benzoylpyridine oximes.
The target compounds were constructed using a pharmacophore approach. The structures of known selective serotonin
reuptake inhibitors (SSRI) were used. The main effect of SSRI is known to be the antidepressant action, though some members
of this class, such as zimelidine [3] and fluoxetine [4] (Fig. 1) show marked antiepileptic activity.
Analysis of the structures of zimelidine and fluoxetine led to the suggestion that pharmacophore elements required for
anticonvulsant activity can be identified (Fig. 2a ). The molecule should contain one amine-containing and two aromatic
pharmacophores. These groups should be joined via a linker at least three s bonds long. Working from this pharmacophore
model, we constructed a group of amine-containing 3- and 4-benzoylpyridine oxime derivatives (Fig. 2b ). The aromatic
pharmacophores in these compounds contained phenyl and pyridine rings, while the amine-containing components were a
disubstituted amine and the linker was an alkyloxime fragment.
With the aim of widening the concept of the structural requirements for compounds with anticonvulsant properties, we also
suggested using O-acylated derivatives of 3- and 4-benzoylpyridine oximes in which the amine-containing pharmacophore was
replaced with an aromatic acyl fragment (Fig. 2c ).
EXPERIMENTAL CHEMICAL SECTION
Target compounds were synthesized using the following general scheme.
1
V. V. Zakusov Science Research Institute of Pharmacology, 8 Baltiicheskaya Street, 125315 Moscow, Russia; e-mail: g.mokrov@gmail.com
42
0091-150X/18/5201-0042 © 2018 Springer Science+Business Media, LLC

Synthesis and Anticonvulsive Activity
43
Fluoxetine
Zimelidine
Fig. 1. Compounds with anticonvulsant activity used for the design of new structures.
Reaction of benzoylpyridine oximes (3a-c) [5, 6] with aminoalkylchlorides (4) in the presence of sodium hydride in DMFA
yielded bases (5a-i). Interaction of these latter with oxalic acid in ethanol yielded the corresponding 3- and 4-benzoylpyridine
O-(aminoalkyloxime) oxalates (1a-i).
Boiling of oximes 3a-c with acid chlorides 6 in the presence of triethylamine in benzene yielded 3- and 4-benzoylpyridine
O-(acyloximes) (2a-l).
The structures of target compounds 1a-i and 2a-l were verified by PMR spectroscopy and their purity by elemental analysis.
1
All compounds could exist as sin-anti isomers, like the starting oximes [6, 7]. H NMR spectroscopy was used to identify
the ratio of sin and anti isomers of the study compounds. This established that some compounds contained both isomers: 1b
(85:15), 1f (70:30), 1h (35:65), 1i (70:30), 2a (95:5), 2f (40:60), 2g (40:60), 2i (30:70), 2j (40:60), 2k (50:50), and 2l (30:70),
while several compounds consisted of only one isomer: 1a, c, d, g, 2b-e, and 2h. Published data suggest that the main isomer is
the Z isomer, as structurally similar oximes are Z isomers [7].
Melting temperatures were determined on a Kofler bench and were not corrected. Reaction courses were monitored and the
identities of study substances were confirmed by TLC in a system consisting of chloroform and methanol (9:1 or 9.5:0.5) on
Kieselgel 60 F254 plates with detection in UV light. Elemental analysis data for 3- and 4-benzoylpyridine oxime derivatives
(1a-i and 2a-l) corresponded to their molecular formulas. Physicochemical properties are shown in Table 1.
4-Benzoylpyridine O-2-morpholinoethyloxime oxalate (1a). NaH (0.90 g, 0.022 mol) in 7 ml of dry DMFA was supple-
mented dropwise with a solution of 2.24 g (0.011 mol) of 4-benzoylpyridine oxime (3a) [5] in 20 ml of DMFA with cooling with
water (10 – 15°C); the reaction was mixed for 1 h and 2.56 g (0.017 mol) of chloroethylmorpholine (base, prepared from 3.5 g
Amine-containing
group
Linker
O-Acylated 3- and 4-benzoylpyridine
Substituted 3- and
oxime derivatives
Aromatic groups
4-benzoylpyridine oximes
a
b
c
Fig. 2. Pharmacophore model of the structure of bis-aryl compounds with anticonvulsant activity (using zimelidine as an example) (a).
Amine-containing 3- and 4-benzoylpyridine oxime derivatives corresponding to this pharmacophore model (b). O-acylated derivatives of 3-
and 4-benzoylpyridine oxime derivatives (c).

44
L. A. Zhmurenko et al.
NaH, DMFA
Compound
X
N
Y
H
Z
n
NR1R2
R3
1a
H
2
1b
1c
1d
N
N
H
H
H
N
H
H
2
3
2
N(CH3)2
N(CH3)2
Cl
1e
H
N
Cl
2
1f
H
H
N
N
Cl
F
2
2
N(CH3)2
1g
1h
H
N
F
2
2
1i
H
N
N
H
F
N(CH3)2
2a
H

Synthesis and Anticonvulsive Activity
45
Compound
X
N
Y
H
Z
n
NR1R2
R3
2b
H
2c
N
N
H
H
H
H
2d
2e
2f
N
H
H
H
N
N
H
Cl
Cl
2g
2h
H
N
Cl
2i
2j
H
H
H
N
N
N
Cl
F
2k
F
2l
H
N
F
of the hydrochloride of the amine) was added and mixing was continued for a further 2 h at room temperature and 220 ml of wa-
ter was added; the reaction was extracted three times with ethyl acetate (40 ml each); extract was dried over MgSO and evapo-
4
rated; the residue (quantitative yield, as an oil) was dissolved in 5 ml of ethanol, supplemented with 0.9 g of oxalic acid in 2 ml
of ethanol; the resulting precipitate was collected by filtration; the yield was 3 g of compound 1a.
Compounds 1b-i were prepared by an analogous route. Data on compounds 1a-i are presented in Table 1. The synthesis of
compounds 1b and 1c is described in patent [8] and that of compounds 1c and 1f is described in [6].
4-Benzoylpyridine O-(3,4-dichlorobenzoyl)oxime (2a). A mixture of 0.99 g (0.005 mol) of 4-benzoylpyridine oxime (3a),
1.26 g (0.006 mol) of 3,4-dichlorobenzoyl acid chloride, and 0.60 g (0.006 mol) of dry triethylamine in 10 ml of dry benzene
was boiled for 2 h, left for one day, and treated with water (the precipitate dissolved); the benzene solution was washed with sat-
urated NaHCO solution followed by water, dried over MgSO and evaporated; the oil was triturated under petroleum ether, and
3
4
product was recrystallized from ethanol. The yield was 1.30 g.

46
L. A. Zhmurenko et al.
Compounds 2b-l were prepared by the same method. Data on compounds 2a-l are presented in Table 1.
EXPERIMENTAL BIOLOGICAL SECTION
Experiments were performed on white mongrel male mice weighing 20 – 26 g. Experimental animals were obtained from
Stolbovaya, Scientific Center for Biomedical Technologies (Moscow District). Animal keeping was in compliance with the cor-
responding rules for laboratory practice (GLP) and normative documents “Sanitary Epidemiological Requirements for the Fit-
tings, Equipment, and Facilities of Animal Houses”, approved by the Chief State Sanitary Physician, April 6, 1973, No. 1045-73
and Russian Federation Ministry of Health and Social Development Decree No. 708n, “Approval of Rules for Laboratory Prac-
tice”, August 23, 2010.
Anticonvulsant activity of 3- and 4-benzoylpyridine oxime derivatives in a model of primary generalized convulsions
evoked by maximum electric shock (MES). Each dose of compound was tested on 8-10 animals. MES was created using the
certified instrument RodentShockerRS, type 221 (Harvard Apparatus GmbH, Germany). Using special corneal electrodes, ani-
mals received electric shocks (500/300 V/mA: 144 mA, duration 0.3 sec). Tonic extension of the hind and forelimbs were re-
corded, along with deaths. The anticonvulsant effects of the test compounds were assessed in terms of the ability to prevent the
development of tonic extension and death. Compounds were given i.p. 40 min before MES [9 – 11].
Anticonvulsant activity of 3- and 4-benzoylpyridine oxime derivatives in a model of primary generalized convulsions
evoked by corasol. Each dose of compound was tested on 8 – 10 animals. Experimental groups received i.p. test compounds
dissolved in physiological saline at doses of 1 and 50 mg/kg 40 min before corasol. Control animals received the same volume
of i.p. physiological saline. Convulsive seizures were induced in the animals by s.c. administration of corasol (10 mg/kg) in the
cervical area of the back, which induced convulsions in 100% of mice. Animal observations were made 30 – 60 min after
corasol injections. The latent period of the first generalized seizure with loss of reflex turning (LP) was measured, along with the
number of dead animals [9, 12].
Acute toxicity of 3- and 4-benzoylpyridine oxime derivatives. Derivatives of 3- and 4-benzoylpyridine oximes were
given as single i.p. doses. Animal deaths were recorded to determine LD values at 24 h and 14 days after dosage. The thera-
50
peutic index (TI) was calculated as TI = LD /ED .
50
50
Results were analyzed statistically in MS Excel 2010 and BioStat 2009 (Analyst Soft Inc.). Normal data distributions were
confirmed using the Shapiro-Wilks test. Significant differences between groups were identified using the nonparametric
Kruskal-Wallis test and Fisher’s exact test.
LD values were calculated by probit analysis (Finney method) in Statplus V5.
50
The anticonvulsant activity of the compounds synthesized here was evaluated using two models in mice: the maximum elec-
tric shock method (MES) and the corasol antagonism test. The MES method modeled primary generalized seizures, i.e., grand
mal convulsive seizures [9 – 11].
In the corasol antagonism test, convulsions were induced by the chemical action of the GABA receptor antagonist corasol,
A
and these modeled primary generalized seizures of the petit mal type [9, 12].
Both models are basic tests for assessing the actions of substances with anticonvulsant activity.
RESULTS AND DISCUSSION
The actions of MES were found to induce tonic extension and death in 90% of mice. Single i.p. doses 0.25 – 150 mg/kg of
compounds 1a, 1c, 1d, 1f, 1g, 2a, 2b, 2g, 2k, and 2l decreased the proportions of animals with tonic extension and increased the
proportions of surviving animals as compared with controls. Thus, mice given compound 1a at doses of 20 and 40 mg/kg
showed disappearance of tonic convulsions and increases in survival to 67% (in both cases), while doses of 60 – 150 mg/kg in-
creased survival to 100% (Table 2). Compound 1c at a dose of 5 mg/kg significantly increased survival to 63% compared with
the 10% in controls. An increase in the dose of 1c from 20 to 40 mg/kg increased the proportion of animals without tonic exten-
sion, which led to an increase in survival to 88%. Compound 1d at a dose of 100 mg/kg prevented the development of tonic con-
vulsions in 75% of cases, and an increase in the dose to 150 mg/kg increased survival to 100%. Compound 1f at doses of 1.5 and
3 mg/kg and compound 1g at doses of 20 and 40 mg/kg increased survival of mice in the MES antagonism test to 67%. Increases
in the dose of 1f to 12.5 mg/kg decreased efficacy in terms of survival. In the case of compound 2a, the plot of the survival-dose
relationship was bell-shaped. Thus, compound 2a at a dose of 5 mg/kg promoted elimination of tonic extension and led to sur-
vival of 25% of mice, while a dose of 20 mg/kg gave a survival rate of 63% and an increase in the dose of compound 2a to
40 mg/kg decreased efficacy to 50% in terms of survival (Table 2). Compound 2b at a dose of 60 mg/kg decreased the propor-
tion of animals with tonic extension and increased the proportion of surviving animals, as compared with controls, to 67%, while
smaller doses (40, 20, and 5 mg/kg) did not produce this effect. Compounds 2g, 2k and 2l at doses of 0.25 – 10 mg/kg increased

Synthesis and Anticonvulsive Activity
47
TABLE 1. Physiochemical Properties of 3- and 4-Benzoylpyridine O-R-Oximes (1a-i and 2a-l)
Com-
Tm, °C, solvent
PMR spectra, DMSO-d6, e, J/Hz
Z
R
Yield, %
Molecular formula*
pound
1a
H
75.0 154 – 155 (eth-
anol)
2.83 (4H, m, -CH2-N-CH2-); 3.10 (2H, t,
CH2N, J = 6.0); 3.67 (4H, m, 4H, m,
CH2-O-CH2); 4.39 (2H, t, CH2O, J = 6.0);
7.35 (2H, m, 3- and 5-H Py); 7.37 – 7.51
C18H21N3O2 × H2C2O4
(5H, m, ArH); 8.71 (2H, m, 2- and 6-H Py),
5.10 av.(HDO and(COOH)2)
1b
1c
1ã
H
H
63.7 164 – 165 (eth-
anol)
2.71 (6H, s, N(CH3)2), 3.42 (2H, t, CH2N,
J = 6.0); 4.48 (2H, n, OCH2, J = 6.0); 7.37
and 7.45; 8.61 and 8.71 (4H, m, PyH), 7.39
and 7.52 (5H, m, ArH)
C16H19N3O × 1.5H2C2O4
b
2.73 (6H, s, N(CH3)2); 2.08 (2H, m, CH2 );
c
3.04 (2H, t, CH2 , J = 6.0); 4.18 (2H, t, CH2 ,
76.3 152 – 153 (eth-
anol)
C17H21N3O × H2C2O4
a
J = 6.0); 7.35 and 8.72 (4H, m, PyH), 7.42
(5H, m, ArH), 6.92 av. (HDO and (COOH)2)
Cl
46.6 177 – 178 (eth-
anol)
C20H22ClN3O6
2.92 (4H, m, CH2-N-CH2), 3.21 (2H, m,
CH2), 3.70 (4H, m, CH2-O-CH2), 4.44 (2H,
m, CH2, under HDO), 7.40 – 7.79 (4H, m,
ArH), 8.56 – 8.66 (4H, m, 2-H, 4-H, 5-H,
6-H (Py))
1d
Cl
88.6 125 – 127 (eth-
anol)
C21H24ClN3O5
1.45 (6H, m, (CH2)3 ring), 3.05 (4H, m,
CH2-N-CH2-ring), 3.36 (2H, t, NCH2,
J = 6.0), 4.49 (2H, m, CH2), 7.40 – 7.90 (7H,
m, PyH, ArH), 8.50 – 8.70 (2H, m, 2-H,
6-H)
1e
Cl
78.0 154 – 155 (eth-
anol)
C18H20ClN3O5
2.71 and 2.73 (3H, s, N(CH3)2), 3.43 (2H, m,
CH2), 4.49 (2H, m, CH2), 4.70 (av. HDO and
COOH), 7.40 – 7.60 (5H, m, 5-H (Py), ArH),
7.76 – 7.82 (1H, m, 4-H (Py)), 8.52 – 8.70
(2H, m, 2-H, 6-H (Py))
1g
1h
F
F
32.0 145 – 146 (eth-
anol)
C20H22FN3O6
3.18 (4H, m, CH2-N-CH2), 3.48 (2H, m,
CH2), 3.77 and 4.00 (4H, m, CH2-O-CH2),
4.49 (2H, m, CH2), 7.25 – 7.65 (6H, m, ArH,
PyH), 8.50 – 8.70 (2H, m, 2-H, 6-H)
70.7 152 – 153 (eth-
anol)
C21H24FN3O5
1.47 (2H, m, CH2), 1.65 (4H, m, CH2-CH2),
3.02 (4H, m, CH2-N-CH2), 3.32 (2H, m,
CH2N), 4.46 (2H, m, CH2O), 7.20 – 7.85
(6H, m, 4-H, 5-H (Py), ArH), 8.55 – 8.66
(2H, m, 2-H, 6-H(Py))
1i
F
48.0 136 – 137 (eth-
anol)
C18H20FN3O5
2.73 and 2.75 (6H, s, N(CH3)2), 3.45 and
4.48 (4H, 2 m, CH2-CH2), 7.00 – 7.50 (5H,
m, ArH, 5-H(Py)), 7.51 – 8.80 (3H, m, 2-H,
4-H, 6-H (Py))
2a
H
70.3 100 – 101 (eth-
anol)
C19H12Cl2N2O2
7.45 – 7.60 and 7.62 – 7.85 (10H, m, 5-H
ArH, Ar(Cl) and 3-H Py); 8.60 – 8.80 (2H,
m, 2-H and 6-H (Py))
2b
2c
H
H
55.5
65.5
142 – 144
C18H13N3O2
7.30 – 7.60 and 7.75 (9H, two m, ArH, 5-H
and Py); 8.67 and 8.72 (2H, two m, 6-H from
two Py); 8.72 – 8.84 (2H, m, 2-H from two
Py)
(ethyl acetate)
150 – 151
C18H13N3O2
7.20 – 7.45 and 7.45 – 7.80 (9H, two m,
ArH, 5-H and Py); 8.60 – 8.85 (4H, two m,
2-H and 6-H)
(ethyl acetate)

48
L. A. Zhmurenko et al.
TABLE 1. Continued
Com-
Z
pound
Tm, °C, solvent
PMR spectra, DMSO-d6, e, J/Hz
R
Yield, %
Molecular formula*
C18H13FN2O2
2ã
2e
2å
2g
H
55.7 125 – 126 (eth-
anol)
7.3 – 7.8 (10H, m, ArH, PyH), 8.7 – 8.8 (3H,
m, 2-H, 4-H, 6-H (Py))
H
70.2 99 – 100 (etha-
nol)
C19H15ClN2O3
C19H12Cl2N2O2
C19H11Cl3N2O2
5.00 (2H, s, CH2), 6.94 and 7.31 (4H, m,
O-C6H4-Cl), 7.51 (5H, m, ArH), 7.39 and
8.74 (4H, two m, PyH)
Cl
Cl
43.0
143 – 145
(ethyl acetate)
7.45 – 7.75 (9H, m, ArH, 5-H (Py)), 8.04
(1H, m, 4-H (Py)), 8.65 – 8.84 (2H, m, 2-H
and 6-H (Py))
50.5 129 – 130 (eth-
anol)
7.50 – 7.85 (8H, m, 2 ArH, 5-H (Py)),
7.90 – 8.02 (1H, m, 4-H (Py)), 8.70 – 8.82
(2H, m, 2-H and 6-H (Py))
2ç
2i
Cl
Cl
34.0
52.5
142 – 143
C18H12ClN3O2
7.25 – 7.60 and 7.75 (8H, two m, ArH, 4-H
and 5-H from two Py), 8.60 – 8.80 (3H, m,
2-H and 6-H from two Py), 8.80 – 8.90 (1H,
m, 2-H (Py))
(ethyl acetate)
141 – 142
C21H15ClN2O2
6.60 – 6.64 (1H, m, CH=), 7.36 – 7.77 (11H,
m and 2 sec, 2 ArH, CH=, 5-H (Py)), 7.91
(1H, m, 4-H (Py)), 8.62 – 8.76 (2H, m, 2-H
and 6-H (Py))
(ethyl acetate)
2j
F
F
34.0 137 – 139 (eth-
anol)
C19H12FClN2O2
7.30 – 8.01 (10H, m, ArH, 4-H, 5-H (Py)),
8.71 – 8.78 (2H, m, 2-H, 6-H (Py))
2k
77.1 125 – 127 (eth-
anol)
C19H11FCl2N2O2
7.37 – 7.82 (8H, m, ArH, 5-H (Py)),
7.90 – 8.02 (1H, m, 4-H (Py)), 8.70 – 8.82
(2H, m, 2-H-6-H (Py))
2l
F
49.7 124 – 126 (eth-
anol)
C21H15FN2O2
6.82 (1H, m, CH=), 7.35 – 8.11 (11H, m and
2 sec, ArH and CH=), 7.90 (1H, m, 4-H
(Py)), 8.62 – 8.79 (2H, m, 2-H and 6-H (Py))
*
Compounds 1a-h were prepared as oxalates and compounds 2a-l as bases.
survival of the animals to 50% (p < 0.12). Reference agent Convulsofin (100 mg/kg) eliminated tonic extension of the limbs and
death in 89% of animals in the MES antagonism test (Table 2).
Thus, compounds 1a, 1c, 1d, and 1g produced statistically significant protection of animals from developing tonic extension
and dying as a result of MES with a linear dose-effect plot over the dose range 0.5 – 150 mg/kg. Compound 1f was effective
only at low doses (1.5 – 3 mg/kg). Compound 2a showed a bell-shaped dose-effect curve with peak efficacy at 20 mg/kg. The
activities of compounds 1a, 1c, and 1d in the MES antagonism test were comparable with the actions of the anticonvulsant agent
Convulsofin, used as reference drug.
S.c. administration of corasol (100 mg/kg) produced first convulsive generalized seizures with a latent period of 32.8 sec
and killed 100% of the mice. Studies using the corasol antagonism test showed that compound 1a at doses of 20 and 60 mg/kg
produced statistically significant increases in the latent period of the first generalized seizure (LP) by 148 and 59 sec respec-
tively, while compounds 1c (50 mg/kg) and 1d (100 mg/kg) gave increases by 56 and 64 sec respectively as compared with the
control group, but did not prevent the development of corasol-induced convulsions or death (Table 2). Compound 1f at doses of
6 and 12.5 mg/kg and compound 2c at doses of 12.5 and 50 mg/kg produced statistically significant increases in the latent period
of the first convulsive seizure and protected 50 – 66.7% of animals from death (Table 2). Compounds 1e, 2b, 2f, 2g, 2k, and 2l
had no effect on the development of convulsions or death among the animals at doses of 0.5 – 60 mg/kg (Table 2). Reference

Synthesis and Anticonvulsive Activity
49
TABLE 2. Anticonvulsant Activity of 3- and 4-Benzoylpyridine Oxime Derivatives in the MES Test and the Corasol-Induced Primary Gener-
alized Convulsions Model
MES
Corasol
Compound
dose, mg/kg
% survivors
dose, mg/kg
LP 1-st seizure
% survivors
Control
–
10
25
–
0
32.8 ± 7.2
1a
0.5; 1.5
20
13
20
20
180.3 ± 37.4*
91.4 ± 10.1*
10
50
60
20; 40
67#
100#
0
100
60, 80, 100, 150
1b
25
50
13
5
17
0
21.3 ± 11.2
33
100
11
25
50
13
25
50
0
28.8 ± 10.6
17.5 ± 8.7
0
1c
1
3
13
38
0
0
40.5 ± 10.2
89.1 ± 7.8*
5
63#
75#
88#
17
17
20
40
1d
2.5; 5
10
5
0
0
65 ± 29
33
100
96 ± 18*
100
150
12.5
25, 50
1.5; 3
6.25
12.5
5
75#
100#
0
1e
1f
12.5, 25, 50
0
33
67#
6
40
50#
10
0
49.0 ± 11.3*
71.7 ± 16.5*
53.9 ± 17.1
50
12.5
20
43
1g
0
12.5
20
10
17
17
20, 40
67#
1i
10, 20
5
33
0
2a
5
10
25
38
63#
50
33
33
0
28.5 ± 11.5
44.5 ± 14.3
20
33
20
40
2b
5
5
0
20
20
33
40
60
67#
2c
5
0
12.5
20
67#
33
56#
0
85.3 ± 28.3*
48.6 ± 15.3
67.8 ± 17.6*
20
13
0
50
50
2f
12.5
25
17
33
17
37
50
38
25
25
10
25
17
0
50
50
2g
0.5
1.25; 2.5
5
12.5
25, 50
0
17
10
50

50
L. A. Zhmurenko et al.
TABLE 2. Continued
MES
Corasol
Compound
dose, mg/kg
% survivors
dose, mg/kg
LP 1-st seizure
% survivors
2k
0.12
0.25
0.5, 5
10, 30
5
33
50
17
13
38
50
25
89#
0.12 – 5
0
17
0
25
50
100
5
17
0
2l
10
20
Valproic acid
(Convulsofin)
100
100
78#
64.6 ± 14.7*
Note: regime 500/300 V/mA: 144 mA, t = 0.3 secretary.
#
* Significance of differences from control group, p £ 0.05 (Mann-Whitney test); significance of differences from control group, p £ 0.05
(Fisher’s exact test).
agent Convulsofin (100 mg/kg) increased the latent period of onset of the first convulsive seizure and protected 78% of animals
from death (Table 2).
Thus, studies using the corasol antagonism test showed that only compounds 1f and 2c produced effects in terms of survival.
Compounds 1a, 1c, 1d, and 1f had moderate anticonvulsant effects in terms of increases in the latent period of the onset of
corasol-induced convulsive seizures.
Acute toxicity (mice, i.p.) was studied for the most active compounds with efficacies comparable to that of Convulsofin in
the MES antagonism test, i.e., 1a, 1c, 1d, and 1f, which were effective in both the MES antagonism test and the corasol test.
ED and LD vales were determined by probit analysis (Finney method). TI was calculated as TI = LD /ED .
50
50
50
50
Studies of the acute toxicity of compounds containing a morpholinoethyl group (1a, 1d) showed that 10% of animals died by
24 h after administration of compound 1a at a dose of 22 mg/kg (i.e., 1 in 10), with no change in survival during the subsequent
two weeks. An increase in the dose of 420 mg/kg led to death of 100% of animals by 24 h. Administration of compound 1d at a
dose of 150 mg/kg did not cause death throughout the observation period, while a dose of 300 mg/kg produced death in 10% of
animals at 24 h and 83% by 14 days. Compound 1c, containing a dimethylaminopropyl group, produced death of 10% of the ani-
TABLE 3. Acute Toxicity of 3- and 4-Benzoylpyridine Oxime Derivatives in Mice (i.p.)
Survivors
Compound
Dose, mg/kg
24 h, abs.
9/10
6/10
5/10
0/10
9/10
7/10
2/10
1/10
6/6
24 h, %
90
14 days, abs.
9/10
6/10
5/10
0/10
6/10
2/10
1/10
0/10
6/6
14 days, %
1a
220
300
350
420
100
150
200
400
150
200
300
50
90
60
50
0
60
50
0
1c
90
60
20
10
0
70
20
10
1d
1f
100
100
83
100
67
17
100
90
67
50
6/6
4/6
5/6
1/6
6/6
100
90
6/6
100
200
400
9/10
4/6
9/10
4/6
67
3/6
50
3/6

Synthesis and Anticonvulsive Activity
51
TABLE 4. Calculated LD and ED Values for 3- and 4-Benzoylpyridine Oxime Derivatives
50
50
Compound
LD50, mg/kg
316
ED50, mg/kg
TI
21
16
34
4
1a
1c
1f
17
7
115
385
11
59
1g
242
mals by 24 h after a single dose of 100 mg/kg, lethality increasing to 40% by 14 days. An increase in the dose to 200 mg/kg led
to death of 80% of the animals by 24 h and 90% by 14 days, while a dose of 400 mg/kg of compound 1d led to death of 90% of
animals by 24 h and 100% by the end of the experiment. Administration of compound 1f at a dose of 100 mg/kg led to death of
10% of animals at 24 h, with no increase by two weeks of observation. Administration of compound 1f at a dose of 400 mg/kg
led to death of 50% of mice at 24 h, with no increase over the following two weeks (Table 3).
Calculation of lethal doses (LD) by probit analysis (Finney method) showed that the dose of compound 1a killing 50% of
mice (LD ) was 115 mg/kg, while values for 1d and 1f were 242 and 385 mg/kg respectively (Table 4).
50
Thus, the 3- and 4-benzoylpyridine oxime derivatives studied here - 1a, 1c, and 1f - are members of the class of moderately
toxic substances; their therapeutic indexes were greater than 10.
Analysis of the structure-action interaction in the series of compounds obtained here provided evidence that substance activ-
ity was significantly dependent on structure. The most active compounds were those containing morpholinoethyl (1a, 1d, 1g),
dimethylaminoethyl (1f), or dimethylaminopropyl (1c) groups, as well as the 3,4-dichlorobenzoyl (2a) group, which consists of
a single spatial isomer. At the same time, there was no clear correlation between the position of the nitrogen atom in the pyridine
heterocycle and the presence of absence of a halogen in the benzene ring and the activity of the compounds. Compounds 2l, 2g,
and 2f, with low anticonvulsant activity, had benzene radicals with two or one chlorine halogens, and substitution of the halogen
Cl by F in the pyridine heterocycle did not increase efficacy. Anticonvulsant activity in the MES antagonism test of compounds
with the morpholinoethyl radical was seen at intermediate and high doses (20 – 150 mg/kg) and was independent of substitu-
tions between Cl, F, and H in the Z position of the pyridine heterocycle. The anticonvulsant activity of compounds with the
aliphatic radical - 1c and 1f - was seen in the low dose range (1 – 5 mg/kg).
Thus, we present the synthesis of 3- and 4-benzoylpyridine oxime derivatives with potential anticonvulsant activity. The
most active compound in the maximum electric shock test was O-2,4-benzoylpyridine morpholinoethyloxime (oxalate 1a),
which at i.p. doses of 60 and 150 mg/kg increased survival in mice to 100%. The best effect in the corasol antagonism test was
obtained with 4-benzoylpyridine O-(isonicotinoyl)oxime (2c), which at an i.p. dose of 12.5 mg/kg increased the survival of mice
to 67% and the latent period of onset of generalized tonic-clonic convulsions by 52 sec. Compound 1a had low toxicity (LD
50
316 mg/kg, mice, i.p.) and a therapeutic index of 21.
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