Antiarrhythmic activity of diterpenoid alkaloids of the napelline type and their acylated derivatives

Full text of DOI:10.1023/A:1011917406301

Pharmaceutical Chemistry Journal
Vol. 35, No. 5, 2001
MEDICINAL PLANTS
ANTIARRHYTHMIC ACTIVITY OF DITERPENOID ALKALOIDS
OF THE NAPELLINE TYPE AND THEIR ACYLATED DERIVATIVES
N. Kh. Shakhidoyatova,1 F. N. Dzhakhangirov,1 and M. N. Sultankhodzhaev1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 5, pp. 31 – 32, May, 2001.
Original article submitted September 5, 2000.
Diterpenoid alkaloids possess a broad spectrum of phar-
macological properties [1 – 3]. The pronounced
EXPERIMENTAL CHEMICAL PART
antiarrhythmic activity of some compounds belonging to this
class and, in particular, the successful practical application of
allapinine [4] and aclezine [5] preparations justify the further
search for antiarrhythmic drugs among various structural
types of diterpenoid alkaloids and their synthetic analogs.
Below we present the results of investigation of the
antiarrhythmic activity of some alkaloids with the structural
skeleton of napelline (I), which were isolated from the plants
of Aconitum karakolicum Rapaics. In addition, we studied a
series of acylated derivatives of napelline and songorine con-
taining an acyl residue at C-1. These compounds were syn-
thesized by selective hydrolysis based on the difference in
the rates of hydrolysis of ester groups occurring in various
positions of the skeleton [6].
The group of substances studied in this work included al-
kaloids napelline (I), 12-O-acetylnapelline (II), 12-epinapel-
line (III), napelline N-oxide (IV), songorine (V),
dihydrosongorine (VI), and acylated derivatives of napelline
and songorine: 1-O-acetylnapelline (VIII), 1,15-O-tribenzo-
ylnapelline (IX), 1-O-benzoylnapelline (X), 1,15-O-diacetyl-
songorine (XI), 1-O-acetylsongorine (XIII), and 1-O-benzo-
ylsongorine (XIV). Some physicochemical properties of the
synthesized compounds are listed in Table 1.
Compounds VII and XI were synthesized as described in
[7] and [8], respectively.
1-O-Acetylnapelline (VIII).
A mixture of 1.0 g
(20 mmole) of 1,12,15-O-triacetylnapelline (VII) with 40 ml
of a 5% KOH solution in methanol was boiled with reflux for
35 min. Upon cooling, methanol was evaporated and the res-
idue dissolved in 50 ml water and extracted with chloroform.
The extract was dried over sodium sulfate, after which chlo-
roform was distilled off. The residue was treated with ace-
tone to isolate the target compound VIII (yield, 67%).
An analogous procedure was used for the synthesis of
1-O-acetylsongorine (XIII) from diacetylsongorine (XI).
1,12,15-O-Tribenzoylnapelline (IX). To a solution of
2.4 mg (6.7 mmole) napelline in 80 ml piperidine was added
dropwise 5.6 g (40.2 mmole) of benzoyl chloride, after
which the reaction mixture was allowed to stand at room
temperature for 40 h. Then piperidine and excess benzoyl
chloride were distilled off and the residue was dissolved in
2% sulfuric acid. The acid solution was triply washed with
benzene, alkalized on cooling with sodium carbonate, and
exhaustively extracted with chloroform. The extract was
dried over sodium sulfate, after which chloroform was dis-
tilled off. The residue was treated with methanol to isolate
the target compound IX (yield, 89%).
1
Institute of the Chemistry of Plant Substances, Academy of Sciences of
the Republic of Uzbekistan, Tashkent, Uzbekistan.
TABLE 1. Physicochemical Properties of the Synthesized Com-
pounds
Empirical
formula
Compound
M.p., °C
M+
Ref.
I
C22H33NO3
C24H35NO4
C22H33NO3
C22H33NO4
C22H31NO3
C22H33NO3
162 – 164
205 – 206
118 – 121
197 – 199
201 – 203
202 – 204
359
401
359
375
357
359
485
401
671
463
441
565
399
461
[9]
[7]
II
III
[10]
[11]
[9]
IV
V
VI
[12]
VII
VIII
IX
C28H39NO6 Amorphous
C24H35NO4
C43H45NO6
C29H37NO4
C26H35NO5
167 – 169
170 – 172
112 – 114
180 – 182
X
XI
An analogous procedure was used for the synthesis of
dibenzoylsongorine (XII) from songorine (V).
XII
XIII
XIV
C36H33NO5 Amorphous
C23H35NO4 101 – 103
C29H35NO4 Amorphous
1-O-Benzoylnapelline (X).
A
mixture of 2.1 g
(3.1 mmole) of 1,12,15-O-tribenzoylnapelline (IX) with
266
0091-150X/01/3505-0266$25.00 © 2001 Plenum Publishing Corporation

Antiarrhythmic Activity of Diterpenoid Alkaloids
267
TABLE 2. Antiarrhythmic Activity of the Synthesized Compounds
on the Aconitine-Induced Arrhythmia Model in Rats
70 ml of a 5% KOH solution in methanol was boiled with re-
flux for 45 min. Upon cooling, methanol was evaporated and
the residue dissolved in 100 ml water and extracted with
chloroform. The extract was dried over sodium sulfate, after
which chloroform was distilled off. The residue was treated
with methanol to crystallize the target compound X (yield,
72%).
An analogous procedure was used for the synthesis of
1-O-benzoylsongorine (XIV) from dibenzoylsongorine
(XII).
Compound
LD50, mg/kg
ED50, mg/kg AAI = ED50/LD50
I
88.0
101.0
82.0
10.0
15.0
80.0
28.0
7.3
8.8
6.7
II
III
IV
V
10.0
25.8
19.0
10.0
6.7
725.0
142.0
120.0
100.0
175.0
30.0
VI
12.0
15.0
20.0
0.24
18.0
15.0
VIII
OR2
IX
8.8
OH
X
133.3
7.3
OR1
CH2
12
OH
N
CH2
16
15
XI
131.0
150.0
41.0
14
XIII
10.0
107.9
1
N
4
10
8
OR3
XIV
0.38
OH
6
Novocainamide
Quinidine
Lidocaine
110.0
66.9
40.0
20.0
10.0
2.75
CH3
CH3
3.3
3.9
III
OH
39.0
I: R1 = R2 = R3 = H;
II: R1 = R3 = H, R2 = Ac;
VII: R1 = R2 = R3 = Ac;
VIII: R1 = Ac, R2 = R3 = H;
IX: R1 = R2 = R3 = Bz;
X: R1 = Bz, R2 = R3 = H.
OH
CH2
O
It was established that most of the studied compounds
produce a more or less pronounced antiarrhythmic effect (Ta-
ble 2). The maximum activity was observed for 1-O-benzo-
ylnapelline (X), the effect of which markedly exceeded that
of the initial napelline and the reference class I antiarrhyth-
mic drugs novocainamide, quinidine, and lidocaine.
N
OH
CH3
IV
O
O
CH3
OR1
N
CH2
OH
N
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OR2
OH
CH3
CH3
VI
V: R1 = R2 = H;
XI: R1 = R2 =Ac;
XII: R2 = R2 = Bz;
XIII: R1 = Ac, R2 = H;
XIV: R1 = Bz, R2 = H.
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The acute toxicity was determined by intravenous injec-
tions in a group of 340 white mice weighing 18 – 22 g. The
antiarrhythmic activity was studied on an aconitine-induced
arrhythmia model in a group of rats weighing 200 – 250 g.
The animals were narcotized by ethaminal sodium
(40 mg/kg, i.p.), aconitine was intraperitoneally injected in a
dose of 12 mg/kg, and EEG were measured in a second stan-
dard lead. The synthesized compounds were intravenously
injected in increasing (3 – 4 steps) doses 3 – 5 min before
aconitine injections. The effect of each dose was studied in a
group of 5 – 6 animals.
The LD50 and ED50 were calculated by the Litch-
field – Wilcoxon method. The therapeutic breadth was evalu-
ated by the antiarrhythmic index (AAI) calculated as the ra-
tio of lethal and effective doses (LD50/ED50).
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