Novel bicyclic derivatives of 1,3-selenazine

Article abstract of DOI:10.1007/s11172-013-0021-5

Bicyclic isoselenoureas (1-selena-3-azaspiro[5.5]undec-2-en-2-ylamines and 3-selena-1-azabicyclo[3.3.1]non-2-ylideneamines) were obtained by intramolecular cyclization of selenoureas leading to 1,3-selenazine ring formation and tested for antioxidant acti

Full text of DOI:10.1007/s11172-013-0021-5

Russian Chemical Bulletin, International Edition, Vol. 62, No. 1, pp. 142—146, January, 2013
142
Novel bicyclic derivatives of 1,3ꢀselenazine
A. N. Proshin,a I. V. Serkov,a A. S. Lermontov,b E. F. Shevtsova,a M. E. Neganova,a and S. O. Bachurina
aInstitute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi pr., 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: proshin@ipac.ac.ru
bN. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
31 Leninsky prosp., 119991 Moscow, Russian Federation
Bicyclic isoselenoureas (1ꢀselenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines and 3ꢀselenaꢀ1ꢀ
azabicyclo[3.3.1]nonꢀ2ꢀylideneamines) were obtained by intramolecular cyclization of selenoꢀ
ureas leading to 1,3ꢀselenazine ring formation and tested for antioxidant activity.
Key words: aryl isoselenocyanates, selenoureas, isoselenoureas, 1,3ꢀselenazine, 1ꢀselenaꢀ
3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamine, 3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylideneamine, antiꢀ
oxidant activity.
In the last few years, organoselenium (including selenoꢀ
presence of triethylamine6 to give the starting aryl isoꢀ
selenocyanates 3.
urea) chemistry has been an extensively developed area of
bioorganic and medicinal chemistry. Organoselenium
compounds attract constantly growing attention because
of their chemical properties and wide spectrum of biologiꢀ
cal activity.1 Their antioxidant,2 antiinflammatory,3 and
antiviral4 properties have been reported.
We developed a method for the synthesis of bicyclic
selenium derivatives, viz., 1ꢀselenaꢀ3ꢀazaspiro[5.5]undecꢀ
2ꢀenꢀ2ꢀylamines and 3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀ
ylideneamines. The starting aryl isoselenocyanates were
prepared from appropriate anilines 1 (Scheme 1). Comꢀ
pounds 1 were transformed into the corresponding formꢀ
amides 2 by reactions with formic acid5 and then refluxed
with phosgene and powdered selenium in toluene in the
A synthetic approach to spiro derivatives of 1,3ꢀselenꢀ
azine is based on intramolecular cyclization of selenoureas
5a—d containing a ,ꢀunsaturated fragment (Scheme 2).
Reactions of isoselenocyanates 3a—d with 2ꢀ(cyclohexꢀ
1ꢀenyl)ethylamine 4 (a ,ꢀunsaturated amine) afford
1ꢀarylꢀ3ꢀ(2ꢀcyclohexꢀ1ꢀenylethyl)selenoureas 5a—d. They
were hydrobrominated at the double bond of the cycloꢀ
hexene ring in boiling 48% aqueous HBr to give 1ꢀarylꢀ3ꢀ
[2ꢀ(1ꢀbromocyclohexyl)ethyl]selenoureas 6a—d, which
promptly undergo intramolecular Seꢀalkylation and cyclꢀ
ization into the corresponding Nꢀsubstituted 1ꢀselenaꢀ3ꢀ
azaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines 7a—d in total yields
of 60—80%.
The acidꢀcatalyzed alkylation followed by intramolecꢀ
ular cyclization of selenoureas 6a—d occurs at the Se atom,
producing the selenazine (pathway a) rather than pyrimiꢀ
dine ring (pathway b), which was confirmed by Xꢀray difꢀ
fraction data for the spiroselenazines obtained (Fig. 1).
Selenoureas 10a—c undergo similar intramolecular cyꢀ
clization to give 3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylꢀ
ideneamines 11a—c.7 The synthesis of the starting selenoꢀ
ureas 10a—c involves condensation of aryl isoselenocyanꢀ
ates 3a—c with 3ꢀbromomethylpiperidine 9 prepared in
quantitative yield by refluxing 3ꢀhydroxymethylpiperidꢀ
ine 8 in HBr. The condensation of compounds 9 and 3a—c
was carried out in methanol in the presence of NaHCO3.
The resulting selenoureas 10a—c undergo rapid intraꢀ
molecular Seꢀalkylation leading to the formation of the
selenazine ring. The overall reaction products are Nꢀarylꢀ
(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylidene)amines 11a—c
(bicyclic isoselenoureas).
Scheme 1
R = H (a), 3ꢀClꢀ4ꢀMe (b), 4ꢀF (c), 4ꢀPri (d)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0144—0148, January, 2013.
1066ꢀ5285/13/6201ꢀ142 © 2013 Springer Science+Business Media, Inc.

Novel bicyclic derivatives of 1,3ꢀselenazine
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
143
Scheme 2
Scheme 3
R = H (a), 3ꢀClꢀ4ꢀMe (b), 4ꢀF (c)
As in the case of the spiro derivatives, the alkylation
followed by the cyclization occurs at the Se atom (pathꢀ
way a), which was proved by Xꢀray diffraction study of
compounds 11a and 11c (Figs 2, 3). The geometrical paraꢀ
meters of their molecules are typical of this class of organꢀ
ic compounds.
The compounds obtained were tested for antioxidant
activity. It turned out that selenoureas 5a—d, which are
precursors to spiro derivatives 7a—d, exhibit radicalꢀtrapꢀ
ping properties and are efficient antioxidants. In contrast,
С(5)
С(4)
С(12)
С(6)
С(11)
С(3)
С(7)
С(12)
N(2)
N(1)
Se
С(7)
С(2)
С(14)
С(13)
С(6)
С(5)
С(10)
С(9)
С(10)
С(9)
N(1)
С(11)
С(2)
С(1)
С(1)
Se
С(13)
С(15)
С(3)
С(8)
Br–
N(2)
С(4)
С(8)
Fig. 1. Structure 7a in the crystal.
Fig. 2. Structure 11a in the crystal.

144
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
Proshin et al.
С(4)
ysis of the compounds obtained was performed on a CHN anaꢀ
lyzer (Carlo Erba).
С(3)
F
С(5)
Synthesis of 1ꢀarylꢀ3ꢀ(2ꢀcyclohexꢀ1ꢀenylethyl)selenoureas
5a—d. A solution of substituted aryl isoselenocyanate 3a—d
(0.01 mol) in diethyl ether (20 mL) was added dropwise to
a stirred solution of amine 4 (1.25 g, 0.01 mol) in diethyl ether
(20 mL). The reaction mixture was stirred at room temperaꢀ
ture for 2—5 h until a precipitate formed. The precipitate
was filtered off and dried to give analytically pure selenoꢀ
ureas 5a—d.
1ꢀ(2ꢀCyclohexꢀ1ꢀenylethyl)ꢀ3ꢀphenylselenourea (5a). Yield
83%, light brown crystals, m.p. 110—112 C. Found (%): C, 58.63;
H, 6.56; N, 9.12. C15H20N2Se. Calculated (%): C, 58.47; H, 6.62;
N, 9.24. 1H NMR, : 1.55 (m, 4 H, CH2CH2); 1.87 (m, 4 H,
CH2C=CHCH2); 2.23 (t, 2 H, NHCH2CH2, J = 6.3 Hz); 3.75
(q, 2 H, NHCH2CH2, J = 6.3 Hz); 5.31 (s, 1 H, C=CH); 6.34
(br.s, 1 H, NHCH2); 7.20 (m, 2 H, Harom); 7.43 (m, 3 H, Harom);
8.12 (br.s, 1 H, NH).
1ꢀ(3ꢀChloroꢀ4ꢀmethylphenyl)ꢀ3ꢀ(2ꢀcyclohexꢀ1ꢀenylethyl)seꢀ
lenourea (5b). Yield 82%, light brown crystals, m.p. 147—149 C.
Found (%): C, 54.02; H, 5.95; N, 7.87. C16H21N2ClSe. Calcuꢀ
lated (%): C, 53.82; H, 6.03; N, 7.99. 1H NMR, : 1.49 (m, 4 H,
CH2CH2); 1.83 (m, 4 H, CH2C=CHCH2); 2.19 (t, 2 H,
NHCH2CH2, J = 6.3 Hz); 2.36 (s, 3 H, Me); 3.71 (q, 2 H,
NHCH2CH2, J = 6.3 Hz); 5.30 (s, 1 H, C=CH); 6.24 (br.s, 1 H,
NHCH2); 6.98 (dd, 1 H, Harom, J = 2.0 Hz, J = 8.2 Hz); 7.19
(d, 1 H, Harom, J = 8.2 Hz); 7.25 (d, 1 H, Harom, J = 2.0 Hz);
8.04 (br.s, 1 H, NH).
С(12)
N(1)
N(2)
С(2)
С(1)
С(6)
С(7)
С(11)
С(10)
С(8)
Se
С(9)
С(13)
Fig. 3. Structure 11c in the crystal.
Table 1. Effects of compounds 5a—d on the antiradical activity
and Fe3+ꢀinitiated peroxide oxidation of lipids (POL) in rat brain
homogenates
b
Comꢀ
pound
I (%)a
IC50
AA (%)c
/mol L–1
5a
5b
5c
5d
87.27 6.22
81.35 7.09
86.02 6.99
77.04 12.28
1.93 1.63
2.12 0.69
2.20 0.93
3.77 1.19c
45.5 0.38
23.2 0.99
20.38 1.20
29.94 0.86
1ꢀ(2ꢀCyclohexꢀ1ꢀenylethyl)ꢀ3ꢀ(4ꢀfluorophenyl)selenourea (5c).
Yield 85%, light brown crystals, m.p. 157—159 C. Found (%):
C, 55.39; H, 5.89; N, 8.61. C15H19N2FSe. Calculated (%):
C, 55.55; H, 5.78; N, 8.71. 1H NMR, : 1.48 (m, 4 H, CH2CH2);
1.81 (m, 4 H, CH2C=CHCH2); 2.17 (t, 2 H, NHCH2CH2,
J = 6.3 Hz); 3.69 (q, 2 H, NHCH2CH2, J = 6.3 Hz); 5.24
(s, 1 H, C=CH); 6.10 (br.s, 1 H, NHCH2); 7.15 (m, 4 H, Harom);
8.10 (br.s, 1 H, NH).
a I is the POL inhibition (% of that in the control group).
b Compounds 7a—d and 11a—c show themselves inactive under
these experimental conditions.
c Antiradical activity (DPPH assay) (% of that in the control
group).
bicyclic isoselenoureas 7a—d and 11a—c can neither scavꢀ
enge radicals nor affect the peroxide oxidation of lipids
(POL) in rat brain homogenates (Table 1). Selenoureas
10a—c were not tested for biological activity because of
their in situ rearrangement into isoselenoureas 11a—c that
preclude them from being isolated.
To sum up, we developed a synthetic approach to biꢀ
cyclic isoselenoureas containing the 1,3ꢀselenazine ring,
namely, 1ꢀselenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines 7
and 3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylideneamines 11.
We demonstrated that intramolecular Seꢀalkylation of
selenoureas gives cyclic isoselenoureas, with dramatic
changes in their biological redox activity. Note that the
starting selenoureas 5a—d are comparable in antioxidant
activity with the wellꢀknown antioxidants trolox and ionol.8
1ꢀ(2ꢀCyclohexꢀ1ꢀenylethyl)ꢀ3ꢀ(4ꢀisopropylphenyl)selenoꢀ
urea (5d). Yield 80%, light brown crystals, m.p. 87—89 C.
Found (%): C, 61.88; H, 7.50; N, 8.02. C18H26N2Se. Calculatꢀ
1
ed (%): C, 61.99; H, 7.44; N, 7.93. H NMR, : 1.25 (d, 6 H,
CH(CH3)2, J = 6.8 Hz); 1.47 (m, 4 H, CH2CH2); 1.80 (m, 4 H,
CH2C=CHCH2); 2.16 (t, 2 H, NHCH2CH2, J = 6.3 Hz); 2.90
(m, 1 H, CHMe2); 3.69 (q, 2 H, NHCH2CH2, J = 6.3 Hz); 5.24
(s, 1 H, C=CH); 6.25 (br.s, 1 H, NHCH2); 7.15 (m, 4 H, Harom);
7.99 (br.s, 1 H, NH).
Synthesis of Nꢀsubstituted 1ꢀselenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀ
enꢀ2ꢀylamines 7a—d. Selenourea 5a—d was suspended in 48%
aqueous HBr (10 mL). The resulting suspension was refluxed for
5 h. After completion of the reaction, the mixture was cooled
and diluted with water (20 mL). The product was extracted with
CH2Cl2 (3×15 mL). The combined organic extracts were washed
with water and brine, dried with anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was recrystallized from
propanꢀ2ꢀol to give Nꢀsubstituted 1ꢀselenaꢀ3ꢀazaspiro[5.5]ꢀ
undecꢀ2ꢀenꢀ2ꢀylamine hydrobromide 7a—d.
Experimental
Nꢀ(1ꢀSelenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)aniline hydroꢀ
bromide (7a). Yield 79%, light brown crystals, m.p. 147—149 C.
Found (%): C, 46.41; H, 5.45; N, 7.22. C15H21N2SeBr. Calcuꢀ
lated (%): C, 46.22; H, 5.33; N, 7.31. 1H NMR, : 1.37 (m, 3 H,
C(9)H2, C(10)HH); 1.69 (m, 5 H, C(11)HH, C(10)HH, C(8)H2,
C(7)HH); 2.14 (m, 4 H, C(11)HH, C(7)HH, C(5)H2); 3.71
1
H NMR spectra were recorded on a Bruker CXPꢀ200 inꢀ
strument (Germany) in CDCl3. Chemical shifts  are referenced
to Me4Si. Melting points were determined on a Boetius hot stage
and are given uncorrected. Solutions were concentrated on
a rotary evaporator in a water aspirator vacuum. Elemental analꢀ

Novel bicyclic derivatives of 1,3ꢀselenazine
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
145
(m, 2 H, C(4)H2); 7.28 (m, 2 H, Harom); 7.40 (m, 3 H, Harom);
10.92 (s, 1 H, NH); 11.26 (s, 1 H, NH).
J = 8.6 Hz); 7.26 (d, 2 H, Harom, J = 8.6 Hz); 10.83 (s, 1 H, NH);
11.09 (s, 1 H, NH).
Nꢀ(1ꢀSelenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)ꢀ3ꢀchloroꢀ4ꢀ
methylaniline hydrobromide (7b). Yield 79%, light brown crysꢀ
tals, m.p. 198—200 C. Found (%): C, 44.01; H, 5.08; N, 6.42.
C16H21N2ClSeBr. Calculated (%): C, 44.11; H, 5.18; N, 6.22.
1H NMR, : 1.30 (m, 3 H, C(9)H2, C(10)HH); 1.62 (m, 5 H,
C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.04 (m, 4 H, C(11)HH,
C(7)HH, C(5)H2); 2.31 (s, 3 H, Me); 3.65 (m, 2 H, C(4)H2);
7.03 (dd, 1 H, Harom, J = 2.2 Hz, J = 8.6 Hz); 7.19 (d, 1 H,
Harom, J = 8.6 Hz); 7.20 (d, 1 H, Harom, J = 2.2 Hz); 9.29 (br.s,
2 H, 2 NH).
Nꢀ(1ꢀSelenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)ꢀ4ꢀfluoroanilꢀ
ine hydrobromide (7c). Yield 80%, light creamꢀcolored crystals,
m.p. 197—199 C. Found (%): C, 44.35; H, 4.96; N, 6.90.
C15H20N2FSeBr. Calculated (%): C, 44.51; H, 4.82; N, 6.81.
1H NMR, : 1.32 (m, 3 H, C(9)H2, C(10)HH); 1.62 (m, 5 H,
C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.06 (m, 4 H, C(11)HH,
C(7)HH, C(5)H2); 3.63 (m, 2 H, C(4)H2); 7.04 (m, 2 H, Harom);
7.20 (m, 2 H, Harom); 10.88 (s, 1 H, NH); 11.17 (s, 1 H, NH).
Nꢀ(1ꢀSelenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)ꢀ4ꢀisopropylꢀ
aniline hydrobromide (7d). Yield 75%, light creamꢀcolored crysꢀ
tals, m.p. 118—120 C. Found (%): C, 50.24; H, 6.32; N, 6.51.
C18H27N2SeBr. Calculated (%): C, 50.02; H, 6.22; N, 6.64.
1H NMR, : 1.25 (d, 6 H, CH(CH3)2, J = 6.8 Hz); 1.43 (m, 3 H,
C(9)H2, C(10)HH); 1.68 (m, 5 H, C(11)HH, C(10)HH, C(8)H2,
C(7)HH); 2.08 (m, 4 H, C(11)HH, C(7)HH, C(5)H2); 2.93
Synthesis of Nꢀaryl(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀ
ylidene)amines 11a—c. Aryl isoselenocyanate 3a—c (0.01 mol)
and 3ꢀbromomethylpiperidine 9 (1.78 g, 0.01 mol) were disꢀ
solved in methanol (30 mL). Then a saturated aqueous solution
of NaHCO3 (1.85 g, 0.022 mol) was added dropwise. The reacꢀ
tion mixture was stirred at room temperature for 1 h, diluted
with water (20 mL), and concentrated. The product was extractꢀ
ed with chloroform (3×10 mL). The combined organic extracts
were washed with water and brine, dried with anhydrous Na2SO4,
filtered, and concentrated in vacuo to give analytically pure comꢀ
pounds 11a—c.
Nꢀ(3ꢀSelenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylidene)aniline (11a).
Yield 95.2%, colorless crystals, m.p. 90—92 C. Found (%):
C, 55.92; H, 5.78; N, 10.03. C13H16N2Se. Calculated (%): C,
55.61; H, 5.62; N, 9.88. 1H NMR, : 1.51 (m, 1 H, C(6)Ha);
1.82 (m, 3 H, C(6)He, C(7)H2); 2.33 (dd, 1 H, C(5)H, J = 2.8 Hz,
J = 10.9 Hz); 2.87 (ddd, 1 H, C(4)Ha, J = 0.5 Hz, J = 3.0 Hz,
J = 11.6 Hz); 3.26 (m, 3 H, C(4)He, C(8)Ha, C(9)Ha); 3.69 (dq,
1 H, C(8)He, J = 2.1 Hz, J = 13.7 Hz); 4.28 (dm, 1 H, C(9)He,
J = 13.3 Hz); 6.88 (m, 2 H, Harom); 7.12 (tt, 1 H, Harom
J = 1.3 Hz, J = 7.3 Hz); 7.35 (m, 2 H, Harom).
,
Nꢀ(3ꢀChloroꢀ4ꢀmethylphenyl)(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]ꢀ
nonꢀ2ꢀylidene)amine (11b). Yield 88.4%, brown oil. Found (%):
C, 51.31; H, 5.23; N, 8.55. C14H17N2ClSe. Calculated (%):
C, 51.51; H, 5.32; N, 8.66. 1H NMR, : 1.47 (m, 1 H, C(6)Ha);
1.81 (m, 3 H, C(6)He, C(7)H2); 2.30 (dd, 1 H, C(5)H, J = 2.8 Hz,
(m, 1 H, CHMe2); 3.69 (m, 2 H, C(4)H2); 7.17 (d, 2 H, Harom
,
Table 2. Crystallographic parameters and the data collection and refinement statistics for structures 7a, 11a, and 11c
Parameter
7a
11a
11c
Molecular formula
M
Crystal dimensions/mm
Crystal system
Space group
a/Å
b/Å
c/Å
C15H21N2Se1Br1
388.21
0.150.090.09
Triclinic
P–1
C13H16N2Se1
279.24
0.120.110.08
Monoclinic
P21/n
C13H15F1N2Se1
297.23
0.190.140.12
Monoclinic
P21/c
6.486(3)
8.873(4)
13.608(6)
87.876(6)
80.834(6)
85.469(6)
770.5(6)
2
6.453(2)
10.710(3)
17.351(5)
90
91.489(5)
90
1198.7(6)
4
1.547
7.721(2)
10.021(3)
16.293(5)
90
92.525(4)
90
1259.4(6)
4
1.568
/deg
/deg
/deg
3
V/Å
Z
dcalc/g cm–3
1.673
5.019
/mm–1
3.106
2.973
F(000)
388
568
600
T/K
 scan range
173(2)
2.30—26.99
7383
2936
0.0270
180
0.0244
0.0604
1.075
173(2)
2.23—27.00
9851
2318
0.0342
145
0.0255
0.0608
1.045
173(2)
2.50—27.00
10325
2734
0.0242
255
0.0265
0.0617
1.076
Number of measured reflections
Number of unique reflections
Rint
Number of parameters refined
R1 (I  2I))
wR2 (for all reflections)
GOOF on F2
Residual electron density
–3
(max/min)/e Å
0.454/–0.457
0.385/–0.309
0.323/–0.443

146
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
Proshin et al.
J = 10.9 Hz); 2.33 (s, 3 H, Me); 2.84 (dd, 1 H, C(4)Ha, J = 2.8 Hz,
J = 11.6 Hz); 3.21 (m, 3 H, C(4)He, C(8)Ha, C(9)Ha); 3.63 (dq,
1 H, C(8)He, J = 1.9 Hz, J = 13.7 Hz); 4.21 (dm, 1 H, C(9)He,
J = 12.2 Hz); 6.64 (dd, 1 H, Harom, J = 2.0 Hz, J = 8.0 Hz); 6.80
(d, 1 H, Harom, J = 2.0 Hz); 7.14 (d, 1 H, Harom, J = 8.0 Hz).
Nꢀ(4ꢀFluorophenyl)(3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylidꢀ
ene)amine (11c). Yield 93.5%, colorless crystals, m.p. 106—108 C.
Found (%): C, 52.53; H, 5.09; N, 9.42. C13H15N2FSe. Calculatꢀ
radiation,  = 0.71073 Å, graphite monochromator). The strucꢀ
tures were solved by the direct methods12 and refined anisotropiꢀ
cally by the fullꢀmatrix leastꢀsquares method on F2 for all nonꢀ
hydrogen atoms. All the hydrogen atoms were located geometriꢀ
cally and refined using a riding model. The parameters of strucꢀ
tures 7a, 11a, and 11c have been deposited with the Cambridge
Structural Database (CCDC Nos 910290—910292).
1
This work was financially supported in part by the
Ministry of Education and Science (State Contract
No. 14.740.11.0810) and the Russian Foundation for Basic
Research (Project Nos 10ꢀ03ꢀ01137a, 11ꢀ03ꢀ00863ꢀa, and
12ꢀ04ꢀ00713ꢀa).
ed (%): C, 52.53; H, 5.17; N, 9.17. H NMR, : 1.51 (m, 1 H,
C(6)Ha); 1.89 (m, 3 H, C(6)He, C(7)H2); 2.33 (dd, 1 H, C(5)H,
J = 2.8 Hz, J = 10.8 Hz); 2.88 (dd, 1 H, C(4)Ha, J = 2.7 Hz,
J = 11.5 Hz); 3.26 (m, 3 H, C(4)He, C(8)Ha, C(9)Ha); 3.67 (dd, 1 H,
C(8)He, J = 2.3 Hz, J = 13.7 Hz); 4.25 (dd, 1 H, C(9)He, J = 2.3 Hz,
J = 12.8 Hz); 6.82 (m, 2 H, Harom); 7.03 (m, 2 H, Harom).
Effect on the peroxide oxidation of lipids in rat brain homoꢀ
genates. Outbred white male rats (300—400 g in weight) were
employed for tests. All manipulations with the animals were perꢀ
formed in compliance with the resolutions adopted by the Comꢀ
mission on Bioethics at the Institute of Physiologically Active
Compounds of the Russian Academy of Sciences. Subcell fracꢀ
tions were obtained by homogenization of rat brain followed by
centrifuging at 1500g. The homogenization solution consisted of
KCl (120.0 mmol L–1) and HEPES (20.0 mmol L–1), pH 7.4.
The protein content of rat brain homogenates was determined
using the biuret method.9 The POL intensity of rat brain homoꢀ
genates was determined from the amounts of products reacting
with thiobarbituric acid (TBA assay), with Fe3+ ions as an inducꢀ
tor (0.5•10–3 M Fe(NH4)(SO4)2).10 The amount of TBAꢀreacꢀ
tive POL products formed in control experiments in the presꢀ
ence of the POL inductor alone was taken to be 100%.
References
1. C. W. Nogueira, G. Zeni, J. B. T. Rocha, Chem. Rev., 2004,
104, 6255.
2. S. U. Hossain, A. K. Sharma, S. Ghosh, S. Bhattacharya,
Eur. J. Med. Chem., 2010, 45, 3265.
3. S. H. AbdelꢀHafez, Eur. J. Med. Chem., 2008, 43, 1971.
4. L. S. Jeong, Y. N. Choi, D. K. Tosh, W. J. Choi, H. O. Kim,
J. Choi, Bioorg. Med. Chem., 2008, 16, 9891.
5. A. R. Katritzky, R. L. Parris, E. S. Ignatchenko, S. M. Allin,
M. Siskin, J. Prakt. Chem., 1997, 339, 59.
6. D. H. R. Barton, S. I. Parekh, M. Tajbakhsh, E. A. Theoꢀ
dorakis, C.ꢀL. Tse, Tetrahedron, 1994, 50, 639.
7. A. N. Proshin, I. V. Serkov, S. O. Bachurin, Dokl. Akad.
Nauk, 2012, 443, 189 [Dokl. Chem. (Engl. Transl.), 2012].
8. Horáková, O. Ondrejièková, K. Bachratá, M. Vajdová, Gen.
Physiol. Biophys., 2000, 19, 195.
Radicalꢀtrapping activity was estimated with diphenylpicrylꢀ
hydrazyl (DPPH) as a model stable radical according to a known
procedure.11 The antiradical activity on a percentage basis (I (%))
was calculated by the formula
9. G. Gornall, C. J. Bardawill, M. M. David, J. Biol. Chem.,
1949, 177, 751.
10. J. K. Callaway, P. M. Beart, B. Jarrott, J. Pharmacol. Toxiꢀ
col. Methods, 1998, 39, 155.
I (%) = [(A0 – A1)/A0)•100,
11. W. BrandꢀWilliams, M. E. Cuvelier, C. Berset, Food Sci.
Technol., 1995, 28, 25.
12. G. M. Sheldrick, Acta Crystallogr., 2008, A64, 112.
where A0 is the optical density of a blank solution of DPPH and
A1 is the optical density of a solution with a test compound.
Xꢀray diffraction study. Selected crystallographic parameters
and the data collection and refinement statistics for structures 7a,
11a, and 11c are given in Table 2.
An experimental set of reflection intensities was collected on
a Bruker SMART APEX II automatic diffractometer (MoꢀK
Received November 16, 2012;
in revised form December 21, 2012