Synthesis and Antibacterial Activity of Novel Substituted Purine Derivatives

Article abstract of DOI:10.1002/jhet.2527

A series of novel N-substituted-2-(6-morpholino-9H-purin-9-yl)acetamide and 4-(9-((5-substituted-1,3,4-oxadiazole/thiadiazole-2-yl)methyl)-9H-purin-6-yl)-morpholine derivatives were synthesized and evaluated their antibacterial activities against rice bacterial leaf blight and tobacco bacterial wilt caused by Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (R. solanacearum) via the turbidimeter test in vitro. Antibacterial bioassay indicated that most compounds demonstrated good inhibitory effect against Xoo and R. solanacearum. Especially, compound 6a demonstrated the best inhibitory effect against Xoo with half-maximal effective concentration (EC₅₀) value of 8.39 μg/mL, which was even better than those of commercial agents Bismerthiazol and Thiodiazole copper. The synthesized purine derivatives containing amide and 1,3,4-oxadiazole/thiadiazole moieties exhibited excellent antibacterial activities against Xanthomonas oryzae pv. oryzae and R. solanacearum in vitro.

Full text of DOI:10.1002/jhet.2527

Month 2015
Synthesis and Antibacterial Activity of Novel Substituted
Purine Derivatives
Wen-Neng Wu, Man-Ni Gao, Hong Tu, and Gui-Ping Ouyang *
a,b
a
a
a
a
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry of Education, Center for Research and Development of Fine
Chemicals, Guizhou University, Guiyang 550025, People’s Republic of China
b
Food and Pharmaceutical Engineering Institute, Guiyang College, Guiyang 550003, People’s Republic of China
*
E-mail: oygp710@163.com
Received June 23, 2015
DOI 10.1002/jhet.2527
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel N-substituted-2-(6-morpholino-9H-purin-9-yl)acetamide and 4-(9-((5-substituted-1,3,4-
oxadiazole/thiadiazole-2-yl)methyl)-9H-purin-6-yl)-morpholine derivatives were synthesized and evaluated
their antibacterial activities against rice bacterial leaf blight and tobacco bacterial wilt caused by
Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (R. solanacearum) via the turbidimeter
test in vitro. Antibacterial bioassay indicated that most compounds demonstrated good inhibitory effect
against Xoo and R. solanacearum. Especially, compound 6a demonstrated the best inhibitory effect against
Xoo with half-maximal effective concentration (EC50) value of 8.39 μg/mL, which was even better than
those of commercial agents Bismerthiazol and Thiodiazole copper. The synthesized purine derivatives con-
taining amide and 1,3,4-oxadiazole/thiadiazole moieties exhibited excellent antibacterial activities against
Xanthomonas oryzae pv. oryzae and R. solanacearum in vitro.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
active compounds with a wide range of biological activity
including antibacterial [25], antifungal [26], insecticidal
Purines are the most ubiquitous components containing
nitrogen heterocycle in nature [1]. They are constituted for
DNA and RNA and consequently of fundamental impor-
tance in life processes [2–4]. The biological importance of
naturally occurring purines has led to an interest in studies
of the biological activities of synthetically modified purines
[
27], antiviral [28], herbicidal [29], anticancer [30], anti-
HIV-1 [31], antihepatitis [32], antitumor [33], and anti-
inflammatory [34] properties. In recent years, our research
group designed and synthesized a series of 2-substituted
1
1
,3,4-oxadiazole/thiadiazole derivatives and 2-substituted
,3,4-oxadiazole/thiadiazole sulfone derivatives which
[5]. A wide range of purine derivatives, such as purine, pu-
showed excellent antibacterial activities [35,36].
The union of active group is a versatile technology for
searching for new broad-spectrum and high-performance
bactericide. Herein, we attempt to design and synthesize
a series of purine derivatives via union of active group
based on taking into account the above findings, and eval-
uated their antibacterial activities. It is believed that these
purine derivatives have a very promising prospect in
bactericide.
rines nucleosides, and their analogs, have been developed,
and have exhibited potential activity as enzyme inhibitors
[
6], cytotoxic [7], antiviral [8], antihyperglycemic [9],
immunostimulator [10], anticonvulsant [11], antimalarial
12], anticancer [13], anti-inflammatory [14], anti-lipid per-
[
oxidation [15], antifungal [16], and antibacterial [17]
activities.
1
,3,4-Oxadiazole/thiadiazole, a privileged structure, rep-
resents a key motif in heterocyclic chemistry and has
shown excellent performances in antibacterial [18], antivi-
ral [19,20],antifungal [21], anti-inflammatory [22], anti-
anxiety [23], and antitubercular [24] activities.
Meanwhile, sulfone derivatives are also known to exhibit
a wide spectrum biological activities because the sulfone
group is an important core found in many biologically
RESULTS AND DISCUSSION
Chemistry.
The detailed synthetic route for the
preparation of N-substituted-2-(6-morpholino-9H-purin-9-yl)
acetamide and 4-(9-((5-substituted-1,3,4-oxadiazole/thiadiazole-
©
2015 HeteroCorporation

W. Wu, M. Gao, H. Tu, and G. Ouyang
Vol 000
2
-yl)methyl)-9H-purin-6-yl)-morpholine derivatives is
tested in vitro antibacterial activities against Xanthomonas
oryzae pv. oryzae (Xoo) and Ralstonia solanacearum
(R. solanacearum) by the turbidimeter test [25,37,38],
and the commercial agricultural antibacterial agents
Bismerthiazol and Thiodiazole copper were used as the
references. As shown in Table 1, compounds 6a, 7a, 7b,
summarized in Scheme 1. Ethyl 2-(6-morpholino-9H-
purin-9-yl)acetate (2) was prepared by 6-chloro-9H-purine
(1) on reaction with ethyl 2-chloroacetate in the presence of
potassium carbonate in the DMF. The key intermediate
ethyl 2-(6-morpholino-9H-purin-9-yl)acetate (3) was
synthesized from ethyl 2-(6-morpholino-9H-purin-9-yl)-
acetate (2) reacting with morpholine in the presence of
ethanol. Compounds 4a–4i were prepared by the ethyl
Table 1
Antibacterial activity of the synthesized compounds against Xanthomonas
oryzae pv. oryzae and Ralstonia solanacearum in vitro.
2
-(6-morpholino-9H-purin-9-yl)acetate
(3)
and
arylalkylamine in ethanol under reflux conditions.
Compounds 5–8 were synthesized from ethyl 2-(6-
morpholino-9H-purin-9-yl)-acetate (3) through sequential
a
Inhibition rate (%)
Xanthomonas oryzae
Ralstonia
reactions
including
hydrazidation,
cyclization,
pv. oryzae
solanacearum
thioetherification, and oxidation [19,20,25]. The structures
1
of the synthesized compounds were confirmed by IR, H
100
200
(mg/L) 100 (mg/L)
13
Compds.
200 (mg/L) (mg/L)
NMR, C NMR, MS, and elemental analysis.
The structures of compounds 4a–4h and 5–8 were confirmed
by spectral method. The IR spectrum of 4a–4h and 5–8 displayed
3
25 ± 1.01
30 ± 0.94
32 ± 1.48
35 ± 2.41
38 ± 1.22
61 ± 2.40
45 ± 0.72
40 ± 1.94
67 ± 1.45
52 ± 3.46
12 ± 0.61 32 ± 1.33 19 ± 1.57
16 ± 2.13 37 ± 0.73 21 ± 1.85
18 ± 1.50 40 ± 0.63 26 ± 3.01
21 ± 2.15 42 ± 0.78 26 ± 1.37
25 ± 3.03 46 ± 0.96 29 ± 1.81
35 ± 1.33 58 ± 2.06 36 ± 0.85
27 ± 1.69 50 ± 0.62 32 ± 2.56
26 ± 3.32 48 ± 2.71 30 ± 2.05
39 ± 2.26 61 ± 0.68 39 ± 2.71
31 ± 0.94 51 ± 1.76 33 ± 3.09
4a
ꢀ
1
absorption bands between 1680.4 and 1473.4cm corresponding
4b
1
4
4
4
c
d
e
to C¼C and C¼N. The H NMR spectrum of 7b in DMSO-d
6
displayed a triplet at δ 1.35 ppm and a quartet at δ 3.31ppm that
corresponds to ―S―CH CH functionality, a triplet at δ
2
3
4f
4g
3.73 ppm and a multiplet at δ 4.21 ppm that corresponds to
4
5
6
h
morpholine functionality, and a singlet at δ 5.74 ppm integrating
for two protons was assigned to ―CH ― protons of Imidazole–
2
a
100 ± 1.24 100 ± 1.08 79 ± 0.67 52 ± 1.60
100 ± 0.49 87 ± 1.73 63 ± 1.18 33 ± 1.24
CH . A singlet that appeared at δ 8.27ppm was observed because
2
6′a
of the protons of Imidazole. It was noteworthy that the pyrimidine
7a
100 ± 0.51 100 ± 1.72 76 ± 2.11 50 ± 1.50
100 ± 1.06 100 ± 1.17 70 ± 0.97 46 ± 1.28
100 ± 1.55 100 ± 0.84 54 ± 1.36 30 ± 2.15
7
7
7
b
′a
′b
proton appeared down-filed (δ 8.32 ppm) in DMSO-d solvent.
6
The structure of 7b was also confirmed by its mass spectral data.
100 ± 0.98
85 ± 1.25
77 ± 1.20
73 ± 3.43
66 ± 2.51
72 ± 0.65
64 ± 2.76
78 ± 1.21 47 ± 2.31 26 ± 1.40
51 ± 2.13 63 ± 3.41 43 ± 1.82
45 ± 1.93 51 ± 1.37 25 ± 1.80
42 ± 3.33 54 ± 1.63 43 ± 1.45
37 ± 1.39 42 ± 1.16 26 ± 1.07
54 ± 1.23 50 ± 2.11 30 ± 5.41
In its mass spectrum, the molecular ion peak was noticed m/z at
8a
8b
+
+
3
48.1 ([M + H] ), 370.1 ([M + Na] ) corresponding to its molecu-
8
8
′a
′b
lar weight.
Antibacterial activity of the synthesized compounds.
A
Bismerthiazol
Thiodiazole
copper
43 ± 3.15
/
/
series of N-substituted-2-(6-morpholino-9H-purin-9-yl)-
acetamide and 4-(9-((5-substituted-1,3,4-oxadiazole/
thiadiazole-2-yl)methyl)-9H-purin-6-yl)-morpholine were
a
The experiments were repeated three times.
Scheme 1. Synthetic route to compounds 2–8.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Purine Derivatives with Antibacterial Activities
Table 2
EXPERIMENTAL
Unless otherwise noted, all
Antibacterial activity of the test compounds against Xanthomonas oryzae
pv. oryzae.
General procedure.
common reagents and solvents were used as obtained
from commercial supplies without further purifications.
The melting points of the products were determined on a
XT-4 binocular microscope (Beijing Tech Instrument
Toxic regression
Compds.
EC50 (μg/mL)
equation
R
6
6
7
7
7
7
8
8
8
a
′a
a
8.39 ± 1.56
32.28 ± 1.87
10.29 ± 2.34
15.38 ± 0.68
19.61 ± 1.98
37.66 ± 2.91
67.80 ± 2.76
73.52 ± 2.48
79.84 ± 2.13
91.54 ± 2.14
124.68 ± 3.32
y = 1.558x + 4.410
y = 2.351x + 1.177
y = 1.674x + 3.756
y = 1.409x + 4.538
y = 1.327x + 3.285
y = 1.723x + 2.281
y = 1.336x + 3.285
y = 1.845x + 1.372
y = 1.950x + 1.298
y = 1.499x + 2.051
y = 1.540x + 1.790
0.98
0.98
0.96
0.97
0.99
0.97
0.99
0.99
0.99
0.98
0.98
1
13
Co., China) and were not corrected. H and C NMR
solvent DMSO-d ) spectra were recorded on a JEOL-
(
6
b
ECX 500 NMR spectrometer at room temperature using
TMS as an internal standard. Elemental analysis was
performed on an Elementar Vario-III CHN analyzer.
Infrared spectra were recorded in KBr on a Bruker
VECTOR 22 spectrometer. Mass spectral studies were
conducted on an Agilent 5973 organic mass spectrometer.
TLC was performed on silica gel GF254. All anhydrous
solvents were dried and purified according to standard
techniques before use.
′a
′b
a
b
′a
Bismerthiazol
Thiodiazole
copper
and 7′a possessed excellent antibacterial activity against
Xoo, with an inhibition rate of 100% at 200 and 100 μg/mL,
respectively, which was even better than those of
Bismerthiazol (72% and 54%, respectively) and Thiodiazole
copper (64% and 43%, respectively). Meanwhile, Table 1
showed that compounds 6a, 6′a, 7a, 7b, 8a, and 8′a
showed excellent antibacterial activity against R.
solanacearum at 200 μg/mL, with inhibition rates of 79%,
General procedure for synthesis of ethyl 2-(6-chloro-9H-
purin-9-yl)acetate (2).
Ethyl 2-chloroacetate (1.47 g,
2mmol) was added dropwise to a solution of 6-chloro-
H-purine (1) (1.54g, 10mmol) and potassium carbonate
1
9
(
2.76 g, 20mmol) in DMF (10 mL), then the reaction
mixture was stirred at room temperature. After stirring for
h, the mixture was evaporated under the reduced
pressure, and subsequently diluted with water. The
mixture was filtered and the obtained solids were
recrystallized from ethanol to give ethyl 2-(6-chloro-9H-
5
63%, 76%, 70%, 63%, and 54%, respectively, which were
better compared with standard drug Bismerthiazol (50%).
As illustrated in the previous bioassays, the half-
purin-9-yl)acetate (2).
maximal effective concentration (EC ) values of some
5
0
Ethyl 2-(6-chloro-9H-purin-9-yl)acetate (2). White solid;
1
of the synthesized compounds as well as for
Bismerthiazol and Thiodiazole copper were presented in
Table 2. Table 2 showed that all of the test compounds
showed moderate to excellent activity against Xoo, with
EC50 values of 8.39–79.84 μg/mL. Excitingly, compounds
yield 76.2%; m.p. 206–207°С; H NMR (DMSO-d6,
5
00MHz) δ: 8.65 (s, 1H, Pyrimidine–H), 8.19 (s, 1H,
Imidazole–H), 5.11 (s, 2H), 4.22–4.25 (m, 2H), 1.25 (t, 3H,
13
J=6.85Hz); C NMR (DMSO-d , 125MHz) δ: 168.60,
6
153.78, 152.64, 151.40, 141.14, 119.20, 61.90, 45.62,
+
+
6
a, 7a, 7b, and 7′a showed prominent activity against Xoo
in vitro, with EC50 values of 8.39, 10.29, 15.38, and
9.61 μg/mL, respectively, which were even better than
that of the commercial bactericide Bismerthiazol
1
4.53; MS (ESI) m/z: 240.1 ([M+H] ), 362.1([M+Na] ).
General procedure for synthesis of ethyl 2-(6-morpholino-
1
9H-purin-9-yl)-acetate (3). To an ice-bath cool solution
of ethyl 2-(6-chloro-9H-purin-9-yl)acetate (2) (2.40g,
10mmol) in ethanol (20 mL) was added dropwise
morpholine (1.05 g, 12mmol). After heating and stirring
for 6 h, the reaction mixture was cooled, poured into ice-
water, and the precipitated solid was filtered, washed
with water and recrystallized from ethanol and DMF to
give ethyl 2-(6-morpholino-9H-purin-9-yl)-acetate (3).
(92.61 μg/mL).
CONCLUSIONS
A series of purine derivatives containing amide and
,3,4-oxadiazole/thiadiazole moieties were synthesized
1
Ethyl 2-(6-morpholino-9H-purin-9-yl)acetate (3).
solid; yield 70.1%; m.p. 223–225°С; IR (KBr, cm ): ν
White
ꢀ
1
and evaluated their antibacterial activities against Xoo
and R. solanacearum by the turbidimeter test in vitro.
The bioassays result demonstrated that some of the synthe-
sized compounds exhibited excellent antibacterial activity
against Xoo. Among these compounds, compound 6a
against Xoo, with EC50 value of 8.39 μg/mL, which was
better than those of Bismerthiazol and Thiediazole copper.
This work demonstrated that the compound 6a can be used
to develop potential bactericides for plants.
3519.2, 3373.6, 2993.5, 2851.4, 1654.0, 1628.9, 1673.9,
1
1486.2, 1240.2, 1115.9, 1041.6, 817.8, 650.1; H NMR
(DMSO-d
(s, 1H, Imidazole–H), 5.09 (s, 2H), 4.20–4.25 (m, 5H),
, 500MHz) δ: 8.25 (s, 1H, Pyrimidine–H), 8.19
6
13
3.73 (t, 5H, J= 5.15 Hz), 1.23 (t, 3H, J=6.85Hz);
C
NMR (DMSO-d6, 125MHz) δ: 168.40, 153.73, 152.53,
151.37, 141.11, 119.13, 66.71, 61.92, 45.52, 14.54; MS
+
+
(ESI) m/z: 292.1 ([M+H] ), 314.1([M+Na] ).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Wu, M. Gao, H. Tu, and G. Ouyang
Vol 000
General procedure for synthesis of N-substituted-2-(6-
morpholino-9H-purin-9-yl)acetamide 4a–4h.
J = 5.15Hz), 3.05 (q, 2H, J = 6.85Hz), 1.45–1.47 (m,
To
solution of ethyl 2-(6-morpholino-9H-purin-9-yl)-acetate
0.59g, 2 mmol) in ethanol (20 mL) was added dropwise
arylalkylamine (10 mmol). After heating and stirring for
0h, the mixture was evaporated under the reduced
a
13
2
1
1
H), 0.85 (t, 3H, J= 7.45 Hz); C NMR (DMSO-d6,
25 MHz) δ: 166.58, 153.69, 152.28, 151.43, 141.69,
19.21, 66.75, 45.52, 41.08, 22.78, 11.90; MS (ESI)
(
+
+
m/z: 305.2 ([M + H] ), 327.1([M +Na] ); Anal. Calcd. for
1
C H N O : C 55.25, H 6.62, N 27.61; found C 55.24,
14 20 6 2
pressure, subsequently diluted with water, and was
filtered and the solid obtained and recrystallized from
H 6.63, N 27.59.
N-(2-aminoethyl)-2-(6-morpholino-9H-purin-9-yl)acetamide
ethanol to give compounds 4a–4h.
(4e).
Yellow solid; yield 68.5%; m.p. 184–185°С;
ꢀ
1
N-methyl-2-(6-morpholino-9H-purin-9-yl)acetamide (4a). White
IR (KBr, cm ): ν 3326.3, 2997.4, 2961.1, 1675.2,
ꢀ
1
solid; yield 71.3%; m.p. 221–222°С; IR (KBr, cm ): ν
1
8
1
588.4, 1569.1, 1476.5, 1285.6, 1248.9, 1112.0, 1004.9,
68.9, 642.3; H NMR (DMSO-d , 500MHz) δ: 8.27 (s,
H, CONH), 8.23 (s, 1H, Pyrimidine–H), 8.13
1
3
292.6, 2993.5, 1658.8, 1586.5, 1481.3, 1327.0,
6
1
1
263.4, 1114.9, 996.2, 794.7, 648.1;
H
NMR
(
DMSO-d , 500 MHz) δ: 8.23 (s, 1H, Pyrimidine–H),
6
(s, 1H, Imidazole–H), 4.85 (s, 2H), 4.19–4.22 (m, 3H),
.73 (t, 5H, J = 5.15Hz), 3.34 (s, 2H, NH ), 3.08 (t, 2H,
8
.19 (s, 1H, CONH), 8.13 (s, 1H, Imidazole–H), 4.84
3
2
(
s, 2H), 4.19–4.23 (m, 3H), 3.73 (t, 5H, J = 5.15 Hz),
J=6.3Hz), 3.41 (t, 2H, J=5.7Hz), 2.59 (t, 2H, J=6.3Hz);
1
3
13
2
1
1
.62 (d, 3H, J = 4.6 Hz);
C
NMR (DMSO-d6,
C NMR (DMSO-d6, 125MHz) δ: 166.77, 153.71,
25 MHz) δ: 167.18, 153.69, 152.30, 151.42, 141.64,
1
4
52.28, 151.44, 141.70, 119.21, 66.75, 45.59, 43.13,
1.74; MS (ESI) m/z: 306.2 ([M + H] ), 328.1([M +Na] );
+
+
19.21, 66.75, 45.53, 26.17; MS (ESI) m/z: 277.1
+
+
(
[M + H] ), 299.1([M + Na] ); Anal. Calcd. for
Anal. Calcd. for C H N O : C 51.14, H 6.27, N 32.11;
found C 51.11, H 6.30, N 32.13.
13 19 7 2
C H N O : C 52.16, H 5.84, N 30.42; found C 52.19,
1
2
16
6
2
H 5.82, N 30.40.
N-ethyl-2-(6-morpholino-9H-purin-9-yl)acetamide (4b). White
solid; yield 78.2%; m.p. 215–216°С; IR (KBr, cm ): ν
2-(6-Morpholino-9H-purin-9-yl)-1-(pyrrolidin-1-yl)ethanone
(4f). white solid; yield 75.6%; m.p. 232–234°С; IR (KBr,
ꢀ
1
ꢀ1
cm ): ν 2997.4, 2961.1, 2912.3, 1672.3, 1585.5, 1573.0,
3
289.7, 2993.5, 2943.1, 1676.2, 1654.0, 1591.3, 1570.1,
1450.3, 1334.8, 1301.0, 1248.9, 1105.2, 1021.3, 788.9,
687.6, 644.2; H NMR (DMSO-d , 500MHz) δ: 8.24 (s,
1H, Pyrimidine–H), 8.09 (s, 1H, Imidazole–H), 5.06
(s, 2H), 4.19–4.22 (m, 3H), 3.73 (t, 5H, J = 5.15Hz), 3.59
(t, 2H, J= 6.9 Hz), 3.34 (t, 2H, J = 5.75Hz), 1.63–1.66
1
1
1
480.4, 1250.8, 1112.9, 1004.9, 791.8, 647.1; H NMR
6
(
DMSO-d , 500MHz) δ: 8.28 (s, 1H, CONH), 8.23 (s,
6
1
H, Pyrimidine–H), 8.13 (s, 1H, Imidazole–H), 4.83 (s,
2
H), 4.19–4.22 (m, 3H), 3.72 (t, 5H, J = 5.15Hz), 3.24
13
13
(q, 2H, J= 7.4Hz), 1.05 (t, 2H, J =6.3 Hz); C NMR
(m, 4H), 1.45–1.47 (m, 2H); C NMR (DMSO-d6,
(
1
DMSO-d 125MHz) δ: 166.38, 153.69, 152.28, 151.43,
125 MHz) δ: 164.84, 153.71, 152.24, 151.58, 141.66,
6,
41.69, 119.21, 66.75, 45.51, 34.21, 15.12; MS (ESI)
119.11, 66.74, 46.35, 45.68, 45.19, 26.18, 24.24; MS
+
+
+
+
m/z: 291.2 ([M +H] ), 313.1([M+ Na] ); Anal. Calcd. for
(ESI) m/z: 317.2 ([M + H] ), 339.1([M +Na] ); Anal.
C H N O : C 53.78, H 6.25, N 28.95; found C 53.75,
Calcd. for C H N O : C 56.95, H 6.37, N 26.56; found
13
18
6
2
15 20 6 2
H 6.23, N 28.94.
N-isopropyl-2-(6-morpholino-9H-purin-9-yl)acetamide
C 56.95, H 6.37, N 26.56.
2-(6-Morpholino-9H-purin-9-yl)-1-(piperidin-1-yl)ethanone
(
(
4c).
White solid; yield 80.2%; m.p. 139–140°С; IR
(4g).
White solid; yield 80.2%; m.p. 193–195°С; IR
ꢀ
1
ꢀ1
KBr, cm ): ν 3275.2, 2995.2, 2971.3, 2850.4, 1653.0,
(KBr, cm ): ν 2996.9, 2953.4, 2853.8, 1648.2, 1585.5,
1
6
590.3, 1558.5, 1457.2, 1222.9, 1121.6, 1007.8, 793.4,
1569.1, 1559.5, 1473.6, 1447.6, 1326.1, 1253.7,
1122.6, 1016.5, 814.0, 789.8, 651.0; H NMR (DMSO-
1
1
47.1;
H
NMR (DMSO-d6, 500MHz) δ: 8.25
(
s, 1H, CONH), 8.23 (s, 1H, Pyrimidine–H), 8.19 (s, 1H,
d6, 500MHz) δ: 8.23 (s, 1H, Pyrimidine–H), 8.09 (s,
1H, Imidazole–H), 5.13 (s, 2H), 4.19–4.23 (m, 3H),
3.73 (t, 5H, J = 5.15Hz), 3.51 (t, 2H, J = 4.3 Hz), 3.41
(t, 2H, J= 5.7 Hz), 1.61–1.65 (m, 4H), 1.45–1.47 (m,
Imidazole–H), 5.09 (s, 2H), 4.20–4.25 (m, 4H), 3.72
13
(t, 5H, J = 4.55Hz), 1.05 (t, 6H, J= 7.45 Hz); C NMR
(
1
DMSO-d 125MHz) δ: 168.40, 153.74, 152.53, 151.37,
6,
13
41.12, 119.13, 66.70, 61.92, 44.52, 22.85, 34.21, 14.54;
2H);
C NMR (DMSO-d6, 125MHz) δ: 164.87,
+
+
MS (ESI) m/z: 305.2 ([M +H] ), 327.1([M +Na] ); Anal.
Calcd. for C H N O : C 55.25, H 6.62, N 27.61; found
C 55.28, H 6.61, N 27.63.
-(6-Morpholino-9H-purin-9-yl)-N-propylacetamide (4d). Yellow
solid; yield 80.2%; m.p. 207–208°С; IR (KBr, cm ): ν
153.71, 152.21, 151.64, 141.85, 119.14, 66.75, 45.63,
44.61, 40.54, 26.41, 25.67, 24.39; MS (ESI) m/z: 331.2
14 20 6 2
+
+
([M + H] ), 353.1([M +Na] );
Anal. Calcd.
for
2
C H N O : C 58.17, H 6.71, N 25.44; found C
16 22 6 2
ꢀ
1
5
8.15, H 6.74, N 25.42.
1-Morpholino-2-(6-morpholino-9H-purin-9-yl)ethanone
3
285.8, 2997.5, 2963.1, 2963.1, 1659.8, 1585.5, 1572.0,
1
557.5, 1453.4, 1248.9, 1124.5, 1010.7, 796.6, 648.1;
(4h).
White solid; yield 80.2%; m.p. 208–209°С; IR
1
ꢀ1
H NMR (DMSO-d , 500MHz) δ: 8.27 (s, 1H, CONH),
(KBr, cm ): ν 3526.9, 3373.6, 2978.9, 2903.4, 2855.7,
6
8
4
.23 (s, 1H, Pyrimidine–H), 8.13 (s, 1H, Imidazole–H),
.84 (s, 2H), 4.18–4.22 (m, 3H), 3.73 (t, 5H,
1652.1, 1589.4, 1575.9, 1569.1, 1486.2, 1426.4, 1240.2,
1115.8, 1041.6, 995.3, 816.8, 650.0, 575.7; H NMR
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Purine Derivatives with Antibacterial Activities
General procedure for synthesis of 5-((6-morpholino-9H-
purin-9-yl)methyl)-1,3,4-thiadiazole-2-thiol (6′).
(
DMSO-d , 500MHz) δ: 8.24 (s, 1H, Pyrimidine–H),
.09 (s, 1H, Imidazole–H), 5.18 (s, 2H), 4.19–4.21 (m,
6
2-(6-
8
3
2
1
6
Morpholino-9H-purin-9-yl)acetohydrazide (5) (20 mmol),
potassium hydroxide (20 mmol), and 400mL ethanol
were added in round-bottom flask equipped for 20 min.
Then carbon disulfide (24 mmol) was added dropwise to
the above precooled reaction mixture, which resulted in
formation of a white precipitate. The white precipitate
was filtered and repeatedly washed with cold ethanol
H), 3.73 (t, 5H, J = 4.6Hz), 3.57–3.62 (m, 6H), 3.44 (t,
1
3
H, J= 4.55 Hz); C NMR (DMSO-d6, 125MHz) δ:
65.59, 153.71, 152.25, 151.64, 141.75, 119.13, 66.74,
6.50, 66.45, 45.16, 45.54, 40.37; MS (ESI) m/z: 333.2
+
+
([M + H] ), 355.1([M+ Na] );
Anal. Calcd. for
C H N O : C 54.21, H 6.07, N 25.29; found C 54.19,
H 6.06, N 25.32.
15 20 6 3
(3 × 30mL) and dried in an oven. The dried salt was
General procedure for synthesis of 2-(6-morpholino-9H-
purin-9-yl)aceto hydrazide (5).
To an ice-bath cool
solution of ethyl 2-(6-chloro-9H-purin-9-yl)acetate
5.86g, 20mmol) in ethanol (40 mL), was added
dropwise 80% hydrazine hydrate (5 mL) in ethanol
8 mL). After the addition, the reaction mixture was
added in very small portion to cooled concentrated
sulfuric acid (30 mL, 0°С) taken in a round-bottomed
flask and stirred till the solution became homogenous.
The mixture was poured into crushed ice (1000 g). The
mixture was neutralized with sodium bicarbonate, and the
precipitated solid was filtered, washed with water, and
recrystallized from ethanol and DMF to give the
(
(
stirred 2 h at room temperature. The reaction mixture was
cooled and collected on filter.
2-(6-Morpholino-9H-purin-9-yl)acetohydrazide (5). White
compound 6′.
ꢀ
1
solid; yield 90.6%; m.p. 234–235°С; IR (KBr, cm ): ν
5-((6-Morpholino-9H-purin-9-yl)methyl)-1,3,4-thiadiazole-2-
thiol (6′). White solid; yield 88.3%; m.p. 244–246°С;
3
312.8, 2995.7, 2863.4, 1653.0, 1594.2, 1570.1, 1550.8,
ꢀ
1
1
IR (KBr, cm ): ν 3480.7, 2989.5, 2940.1, 2847.2,
1
477.3, 1262.4, 1111.0, 1010.7, 641.3; H NMR (DMSO-
1
7
8
5
594.6, 1573.0, 1475.6, 1326.0, 1249.9, 1065.7, 994.3,
d6, 500MHz) δ: 9.41 (s, 1H, CONH), 8.19 (s, 1H,
Pyrimidine–H), 8.11 (s, 1H, Imidazole–H), 5.13 (s, 2H),
1
89.8, 645.2;
H NMR (DMSO-d6, 500 MHz) δ:
.28 (s, 1H, Pyrimidine–H), 8.27 (s, 1H, Imidazole–H),
.61 (s, 2H), 4.19–4.22 (m, 3H), 3.72 (t, 5H,
4
.27 (s, 2H), 4.17–4.20 (m, 3H), 3.69 (t, 5H, J = 4.6 Hz);
C NMR (DMSO-d6, 125MHz) δ: 166.30, 153.69,
52.30, 151.37, 141.59, 119.23, 66.75, 44.33; MS (ESI)
13
13
J = 5.15Hz); C NMR (DMSO-d , 125MHz) δ: 159.53,
1
6
+
+
1
53.74, 152.70, 151.00, 140.58, 119.29, 66.68, 42.17; MS
m/z: 278.1 ([M + H] ), 300.1 ([M+ Na] ); Anal. Calcd. for
+
(ESI) m/z: 336.1 ([M + H] ); Anal. Calcd. for
C H N O : C 47.65, H 5.45, N 35.36; found C 47.67, H
11 15 7 2
C H N OS : C 42.97, H 3.91, N 29.23; found C 42.96,
5
.44, N 35.38.
12 13
7
2
General procedure for synthesis of 5-((6-morpholino-9H-
H 3.90, N 29.25.
purin-9-yl)methyl)-1,3,4-oxadiazole-2-thiol
(6).
2-(6-
General procedure for synthesis of 4-(9-((5-substituted-
Morpholino-9H-purin-9-yl)acetohydrazide (5) (20 mmol),
potassium hydroxide (20 mmol), and 100 mL of ethanol
were added into a round-bottom flask and stirred for
1,3,4-oxadiazole/thiadiazole-2-yl)-methyl)-9H-purin-
6-yl)morpholine.
To a solution of 5-((6-morpholino-
9H-purin-9-yl)methyl)-1,3,4-oxadiazole/thiadiazole-2-thiol
(4mmol) and sodium hydroxide (4.2mmol) in water
(25mL). The mixture was stirred at room temperature
for 20min, and then dimethyl sulfate (4.2mmol) and
diethyl sulfate (4.2mmol) were added to the reaction
mixture and stirred at room temperature for 2 h. The
mixture was filtered, and the solid was obtained and
recrystallized from DMF and ethanol to give compounds
7 and 7′.
1
0min, followed by addition of carbon disulfide
(24 mmol) to the mixture. The resulting mixture was
refluxed for 4h and monitored by TLC until completion.
The mixture was evaporated under the reduced pressure
and subsequently diluted with water. The mixture was
neutralized with concentrated hydrochloric acid and the
precipitated solid was filtered, washed with water, and
recrystallized from ethanol and DMF to give the
compound 6.
4
-(9-((5-(Methylthio)-1,3,4-oxadiazole-2-yl)methyl)-
9
H-purin-6-yl)morpholine (7a).
White solid; yield
5
-((6-Morpholino-9H-purin-9-yl)methyl)-1,3,4-oxadiazole-2-
ꢀ
1
thiol (6). White solid; yield 83.5%; m.p. 153–155°С; IR
89.6%; m.p. 137–138°С; IR (KBr, cm ): ν 3230.7,
ꢀ
1
(
KBr, cm ): ν 3372.6, 2994.2, 2962.4, 2859.8, 1592.3,
2992.2, 2855.8, 1582.6 1575.9, 1558.5, 1476.5, 1255.7,
1
1
570.1, 1506.4, 1476.5, 1256.6, 1004.9, 942.2, 633.6;
1163.1, 1112.0, 1003.0, 789.8, 645.2; H NMR (DMSO-
1
H NMR (DMSO-d , 500MHz) δ: 8.31 (s, 1H,
d , 500 MHz) δ: 8.32 (s, 1H, Pyrimidine–H), 8.26 (s, 1H,
6
6
Pyrimidine–H), 8.28 (s, 1H, Imidazole–H), 5.62 (s, 2H),
Imidazole–H), 5.73 (s, 2H), 4.19–4.22 (m, 3H), 3.72 (t,
5H, J = 5.15Hz), 2.67 (s, 3H); C NMR (DMSO-d6,
13
13
4
.19–4.22 (m, 3H), 3.72 (t, 5H, J = 5.15Hz); C NMR
(
DMSO-d 125MHz) δ: 178.44, 159.63, 153.75, 152.79,
125 MHz) δ: 165.90, 163.59, 153.74, 152.75, 151.11,
6,
1
3
51.12, 140.65, 119.18, 66.68, 38.27; MS (ESI) m/z:
20.1 ([M + H] ), 342.1([M + Na] ); Anal. Calcd. for
140.64, 119.20, 66.69, 38.09, 14.83; MS (ESI) m/z:
+
+
+
+
334.2 ([M + H] ), 366.1([M+ Na] ); Anal. Calcd. for
S: C 46.84, H 4.54, N 29.41; found C 46.85,
H 4.56, N 29.40.
C H N O S: C 45.13, H 4.10, N 30.70; found C
C H N O
13 15 7 2
12 13 7 2
4
5.10, H 4.11, N 30.70.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Wu, M. Gao, H. Tu, and G. Ouyang
Vol 000
4
-(9-((5-(Ethylthio)-1,3,4-oxadiazole-2-yl)methyl)-9H-purin-
(
8
3
DMSO-d , 500 MHz) δ: 8.32 (s, 1H, Pyrimidine–H),
6
6
1
1
6
-yl)morpholine (7b).
31–132°С; IR (KBr, cm ): ν 3237.3, 2995.7, 2871.4,
589.3 1574.5, 1558.5, 1476.1, 1250.7, 1112.7, 786.9,
47.5; H NMR (DMSO-d , 500 MHz) δ: 8.32 (s, 1H,
Pyrimidine–H), 8.27 (s, 1H, Imidazole–H), 5.74 (s, 2H),
.19–4.22 (m, 3H), 3.73 (t, 5H, J = 5.15Hz), 3.31 (q, 2H,
J =7.4 Hz), 1.35 (t, 2H, J = 7.15Hz); C NMR (DMSO-
d6, 125MHz) δ: 164.96, 163.62, 153.75, 152.73, 151.13,
Yellow solid; yield 88.5%; m.p.
.26 (s, 1H, Imidazole–H), 5.73 (s, 2H), 4.19–4.22 (m,
ꢀ
1
13
H), 3.72 (t, 5H, J= 5.15Hz), 3.53 (s, 3H); C NMR
(DMSO-d 125MHz) δ: 165.90, 163.59, 153.74, 152.75,
6,
1
6
151.11, 140.64, 119.20, 66.69, 38.09, 31.23; MS (ESI)
m/z: 366.1 ([M+ H] ), 388.1 ([M + Na] ); Anal. Calcd.
for C H N O S: C 42.73, H 4.14, N 26.84; found C
4
+
+
4
13 15 7 4
1
3
2.70, H 4.11, N 26.83.
4-(9-((5-(Ethylsulfonyl)-1,3,4-oxadiazole-2-yl)methyl)-9H-purin-
1
41.66, 119.23, 66.70, 38.11, 27.18, 15.27; MS (ESI)
6-yl)morpholine (8b).
127–129°С; IR (KBr, cm ): ν 3435.5, 2994.8, 2951.1,
Yellow solid; yield 62.4%; m.p.
+
+
ꢀ1
m/z: 348.1 ([M +H] ), 370.1([M+ Na] ); Anal. Calcd. for
C H N O S: C 45.13, H 4.10, N 30.70; found C 45.10,
2856.6, 1594.2, 1565.3, 1559.5, 1473.4, 1456.3, 1330.9,
1
4 17 7 2
H 4.11, N 30.70.
1292.3, 1259.5, 1146.7, 1004.9, 776.3, 730.0, 637.5,
1
4
-(9-((5-(Methylthio)-1,3,4-thiadiazole-2-yl)methyl)-9H-purin-
484.1; H NMR (DMSO-d , 500MHz) δ: 8.32 (s, 1H,
6
6
2
1
7
1
2
3
1
1
-yl)morpholine (7′a). White solid; yield 85.2%; m.p. 203–
04°С; IR (KBr, cm ): ν 3430.5, 2997.3, 2963.1, 2853.1,
Pyrimidine–H), 8.27 (s, 1H, Imidazole–H), 5.74 (s, 2H),
ꢀ
1
4
2
.19–4.22 (s, 3H), 3.73 (t, 5H, J= 5.15Hz), 3.60–3.63 (m,
H), 1.35 (t, 2H, J= 7.15 Hz); C NMR (DMSO-d6,
13
593.2, 1570.1, 1472.7, 1329.9, 1249.9, 1111.0, 1004.9,
1
91.8, 638.4; H NMR (DMSO-d , 500MHz) δ: 8.36 (s,
6
125 MHz) δ: 164.96, 163.62, 153.75, 152.73, 151.13,
H, Pyrimidine–H), 8.29 (s, 1H, Imidazole–H), 5.86 (s,
1
3
41.66, 119.23, 66.70, 38.11, 30.68, 7.58; MS (ESI) m/z:
80.1 ([M + H] ), 402.1([M+ Na] ); Anal. Calcd. for
+
+
H), 4.18–4.21 (m, 3H), 3.72 (t, 5H, J =5.15 Hz), 2.71 (s,
13
H); C NMR (DMSO-d 125MHz) δ: 169.48, 165.19,
6
,
C H N O S: C 44.32, H 4.52, N 25.84; found C 44.35,
15 17 7 4
53.75, 152.69, 150.91, 140.54, 119.38, 66.69, 41.84,
6.99; MS (ESI) m/z: 350.1 ([M + H] ), 372.1([M+ Na] );
H 4.51, N 25.84.
+
+
4-(9-((5-(Methylsulfonyl)-1,3,4-thiadiazole-2-yl)methyl)-9H-
Anal. Calcd. for C H N OS : C 44.68, H 4.33, N 28.06;
found C 44.71, H 4.35, N 28.04.
purin-6-yl)morpholine (8′a).
m.p. 150–151°С; IR (KBr, cm ): ν 3445.5, 2995.6,
Yellow solid; yield 64.3%;
1
3
15
7
2
ꢀ
1
4
-(9-((5-(Ethylthio)-1,3,4-thiadiazole-2-yl)methyl)-9H-purin-
2961.4, 2851.0, 1590.3, 1565.1, 1558.5, 1476.6, 1329.9,
1254.7, 1157.3, 1006.8, 763.8, 643.2, 531.4; H NMR
1
6
-yl)morpholine (7′b).
55–156°С; IR (KBr, cm ): ν 3430.6, 2999.6, 2963.7,
857.1, 1591.3, 1575.9, 1479.4, 1470.7, 1327.0, 1248.9,
111.0, 1001.1, 790.8, 639.4; H NMR (DMSO-d6,
00MHz) δ: 8.36 (s, 1H, Pyrimidine–H), 8.29 (s, 1H,
Imidazole–H), 5.87 (s, 2H), 4.19–4.23 (m, 3H), 3.73
t, 5H, J = 5.15Hz), 3.24 (q, 2H, J= 7.4Hz), 1.35 (t, 2H,
J =7.45 Hz); C NMR (DMSO-d6, 125MHz) δ: 167.81,
Yellow solid; yield 87.3%; m.p.
ꢀ
1
1
2
1
5
(DMSO-d , 500 MHz) δ: 8.36 (s, 1H, Pyrimidine–H),
6
8.29 (s, 1H, Imidazole–H), 5.86 (s, 2H), 4.19–4.22 (m,
1
13
3H), 3.72 (t, 5H, J= 5.15Hz), 3.53 (s, 3H); C NMR
(DMSO-d 125MHz) δ: 169.48, 165.19, 153.75, 152.69,
6,
150.91, 140.54, 119.38, 66.69, 49.68, 41.84; MS (ESI)
+
+
(
m/z: 382.1 ([M+ H] ), 404.1 ([M + Na] ); Anal. Calcd.
13
for C H N O S : C 40.93, H 3.96, N 25.70; found C
13
15 7 3 2
1
4
3
65.42, 153.74, 152.68, 150.93, 140.56, 119.38, 66.69,
40,91, H 3.97, N 25.72.
4-(9-((5-(Ethylsulfonyl)-1,3,4-thiadiazole-2-yl)methyl)-9H-
purin-6-yl)morpholine (8′b). Yellow solid; yield 67.2%;
+
1.83, 28.76, 14.93; MS (ESI) m/z: 364.1 ([M + H] ),
+
86.1([M + Na] ); Anal. Calcd. for C H N OS :
1
4
17
7
2
ꢀ
1
m.p. 136–137°С; IR (KBr, cm ): ν 3444.8, 2995.3,
C 46.26, H 4.71, N 26.98; found C 46.24, H 4.73, N 27.01.
2
951.9, 2854.3, 1593.2, 1568.1, 1564.3, 1558.5, 1474.6,
General procedure for synthesis of 4-(9-((5-(substituted-
1
331.9, 1292.3, 1259.5, 1146.7, 1005.9, 776.3, 637.5,
sulfonyl)-1,3,4-oxadiazole/thiadiazole-2-yl)methyl)-9H-purin-
1
6
-yl)morpholine.
A solution of 4-(9-((5-substituted-
533.34, 483.1; H NMR (DMSO-d
6
, 500MHz) δ: 8.38
1
,3,4-oxadiazole/thiadiazole-2-yl)-methyl)-9H-purin-6-
(s, 1H, Pyrimidine–H), 8.29 (s, 1H, Imidazole–H), 6.05
(s, 2H), 4.19–4.22 (m, 3H), 3.72 (t, 7H, J =6.85Hz),
yl)morpholine (3 mmol) in glacial acetic acid was treated
dropwise at 10°С with potassium permanganate as a 5%
aqueous solution over 30min. The reactions were reacted
for 20–35min at room temperature. Then, the redundant
potassium permanganate of the mixture was deoxidized
by 10% sodium bisulfite solution and distilled water,
dried under vacuum, and recrystallized from ethanol to
give pure products 8 and 8′.
13
1.32 (t, 3H, J =7.45Hz);
C
NMR (DMSO-d6,
125MHz) δ: 171.29, 169.58, 153.76, 152.71, 150.95,
140.62, 119.35, 66.69, 50.04, 42.09, 7.34; MS (ESI)
+
m/z: 396.1 ([M+ H] ); Anal. Calcd. for C14
H
N
17
O
7
S :
3 2
C 42.52, H 4.33, N 24.79; found C 42.53, H 4.33, N 24.81.
The antibacterial activities
Antibacterial activity.
of some title compounds against Xoo and R.
solanacearum were evaluated by the turbidimeter test.
Dimethylsulfoxide in sterile distilled water served as a
blank control; Bismerthiazol and Thiodiazole copper
served as positive controls. Approximately 40 μL of
solvent M210 (8.0 g of casein enzymatic hydrolysate,
4
-(9-((5-(Methylsulfonyl)-1,3,4-oxadiazole-2-yl)methyl)-9H-
purin-6-yl)morpholine (8a). Yellow needle; yield 60.5%;
m.p. 132–134°С; IR (KBr cm ): ν 3430.5, 2994.2,
ꢀ
1
2
971.1, 2851.6, 1589.4, 1569.1, 1558.5, 1479.4, 1457.2,
1
1
349.2, 1262.4, 1112.9, 1003.9, 743.5, 645.2; H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Purine Derivatives with Antibacterial Activities
[
13] Liu, H. X.; Li, L. B.; Qurat-ul-ain, S.; Jiang, T. J Heterocyclic
5
0
.0g of sucrose, 4.0g of yeast powder, 3.0g of K HPO ,
2 4
Chem 2015, 52, 473.
.3g of MgSO ·7H O, and 1000 mL of distilled water;
4
2
[14] Bordon-Pallier, F.; Jullian, N.; Ferrari, P.; Girard, A. M.;
pH =7.0) containing Xoo and R. solanacearum was
added to 5 mL of solvent M210 containing the test
compounds and positive controls. The inoculated test
tubes were incubated at 28±1°C and continuously shaken
at 180rpm for 24h. The growth of the cultures was
monitored on a microplate reader by measuring the optical
Bocquel, M. T.; Biton J.; Bouquin, N.; Haesslein, J. L. Biochim Biophys
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[
15] Thalassitis, A. N.; Hadjipavloulitina, D. J.; Litinas, K.
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[
[
density at 595nm (OD595) given by turbiditycorrected
[18]
Galge, R.; Raju, A.; Degani, M. S.; Torat, B. N. J Heterocyclic
=
ODbacterial
ꢀ OD
wilt, and then the
Chem 2015, 52, 352.
values
wilt
no bacterial
[
19] Wu, W. N.; Chen, Q.; Tai, A. Q.; Jiang, G. Q.; Ouyang, G. P.
Bioorg Med Chem Lett 2015, 25, 2243.
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inhibition rate I was calculated by I (%)=(C ꢀ T )/
tur
tur
Ctur ×100. Ctur is the corrected turbidity values of bacterial
growth on untreated M210 (blank control), and Ttur is the
corrected turbidity values of bacterial growth on treated
M210. Some of the title compounds were tested against at
five double declining concentrations method were
expressed by EC . The average EC was computed from
[
Chem 2015, DOI: 10.1002/jhet.2435
[21] Shelke, S. H.; Mhaske, P. C.; Kasm, S. K.; Bobade, V. D.
J Heterocyclic Chem 2014, 51, 1893.
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Biotechnol 2001, 76, 1154.
[23] Palaska, E.; Sahin, G.; Kelicen, P.; Durlu, N. T.; Altinok, G.
Farmaco 2002, 57, 101.
5
0
50
at least three separate analyses for growth inhibition using
the basic EC50 program version SPSS 17.0.
[
24] Harfenist, M.; Heuser, D. J.; Joyner, C. T.; Batchelor, J. F.;
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[
Acknowledgments. We gratefully acknowledge the Project
Enterprises and Business (H110039) for providing the financial
support.
[
[
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet