Synthesis and calming activity of helicid derivatives containing the 3,4-dihydropyrimidin-2(H)-one and 3,4-dihydropyrimidine-2(H)-thione moiety

Article abstract of DOI:10.1007/s10600-010-9630-5

A series of novel helicid derivatives containing 3,4-dihydropyrimidin-2(1H) -one and 3,4-dihydropyrimidine2(1H)-thione moiety (3a-3f and 4a-4f) were synthesized starting from helicid. The structure of the new compounds were characterized by ¹H

Full text of DOI:10.1007/s10600-010-9630-5

Chemistry of Natural Compounds, Vol. 46, No. 3, 2010
SYNTHESIS AND CALMING ACTIVITY OF HELICID DERIVATIVES
CONTAINING THE 3,4-DIHYDROPYRIMIDIN-2(H)-ONE
AND 3,4-DIHYDROPYRIMIDINE-2(H)-THIONE MOIETY
Hua Ling Luo, Wei Yang, Ying Li, and Shu Fan Yin*
UDC 547.772
A series of novel helicid derivatives containing 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidine-
2(1H)-thione moiety (3a–3f and 4a–4f) were synthesized starting from helicid. The structure of the new
1
compounds were characterized by H NMR, IR and HR-MS spectra. The sedative-hypnotic activities of the
target compounds were evaluated using the test of spontaneous locomotor activity in mice. All of the derivatives
produced moderate to high activities; in particular, compound 4a presented the most potent sedative-hypnotic
effect in comparison to the other derivatives, and derivatives 3a, 3c, 3d, 3e and 3f also showed potent
activities.
Keywords: helicid, 3,4-dihydropyrimidine, Biginelli reaction, sedative-hypnotic activity.
Helicid (1), a pure compound extracted from the fruit of Helicia nilagirica Beed [1], is distributed widely in Yunnan
Province of China. It is a major active ingredient of Chinese herbal medicine that has been reported to possess a variety of
biological effects on the central nervous system, including sedative, hypnotic, and anticonvulsant activities; moreover, no
obvious side effect has been reported [2]. However, the drug also has some disadvantages, such as the large dose required and
low bioavailability. Recently it has been demonstrated that epigenetic modifications at the aldehyde group of helicid play a key
role in improving its pharmacological and therapeutic activities [3–6].
3,4-Dihydropyrimidines (DHPMs) and their derivatives are very important compounds in the realm of synthetic
organic chemistry because they exhibit a wide range of biological and pharmacological properties, including antitumor and
anti-inflammatory actions [7–11]. It has been observed that in compounds containing the DHPM moiety, the absolute
configuration of the stereogenic center influences the biological effects [12]. In order to obtain novel helicid derivatives
possessing better biological effects, we synthesized a series of novel helicid derivatives containing the 3,4-dihydropyrimidin-
2(1H)-one and thioxo-3,4-dihydropyrimidine-2(1H)-thione moiety (3a–3f, 4a–4f) by modifying helicid at the aldehyde group
and hydroxyl groups (described in Scheme 1). The sedative-hypnotic activities of the target compounds were evaluated, and
the result showed that derivatives 3a, 3c, 3d, 3e, 3f, and 4a possess good activities.
In the present study, six novel helicid derivatives 3a–3f have been successfully synthesized by the one-pot Biginelli
reaction using easily and cheaply available sulfamic acid as a catalyst. This synthesis was carried out by ultrasonic radiation at
a power of 120 W for 40–60 min for a variety of compounds, and this approach was used to prepare a series of helicid
derivatives with good purities and good yields (85–95%). In this study, we did some comparative experiments using different
catalysts, and we found that sulfamic acid was the best catalyst. Six novel helicid derivatives 4a–4f have been synthesized by
reacting compounds 3a–3f with sodium methoxide in methanol at room temperature to give good yields (89–95%).
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China, e-mail: chuandayouji217@163.com.
Published in Khimiya Prirodnykh Soedinenii, No. 3, pp. 349–352, May–June, 2010. Original article submitted November 27,
2008.
412
0009-3130/10/4603-0412 02010 Springer Science+Business Media, Inc.

TABLE 1 Sedative-Hypnotic Activities of the Target Compounds Evaluated Using the Spontaneous Locomotor Activity Test
Number of movements per minute (movements/min)
Compound
Dose, mg·kg–1
0 min
after 30 min
after 60 min
after 90 min
A
B
1
2
–
20
204.33ꢂ35.76
200.17ꢂ24.44
168.50ꢂ50.75
0.00ꢂ0.00***
153.33ꢂ57.67
14.00ꢂ31.45**
157.83ꢂ57.96
0.00ꢂ0.00***
200
200
200
200
200
200
200
200
200
200
200
200
200
200
ꢂ
ꢂ
ꢂ
ꢂ
192.33 38.53
159.17 20.80
171.00 24.22
172.33 29.23
193.17ꢂ45.96
197.67ꢂ46.80
193.67ꢂ12.52
128.30ꢂ62.82
53.00ꢂ54.86*
113.00ꢂ69.84
148.50ꢂ64.11
61.67ꢂ62.84
123.00ꢂ61.41
153.50ꢂ57.51
32.33ꢂ15.33**
87.33ꢂ83.85
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
ꢂ
ꢂ
ꢂ
ꢂ
197.33 36.31
82.17 48.46*
117.33 50.57
111.50 55.71
190.33ꢂ20.72
188.83ꢂ42.36
87.50ꢂ49.29*
72.83ꢂ42.30**
147.67ꢂ51.02
96.00ꢂ66.48*
96.00ꢂ50.04
95.50ꢂ31.89
ꢂ
ꢂ
ꢂ
ꢂ
205.00 32.01
88.50 40.40*
91.33 58.91*
114.17 47.74
197.67ꢂ9.07
197.50ꢂ22.90
192.67ꢂ26.16
32.83ꢂ52.34**
108.50ꢂ63.98
92.00ꢂ73.65
58.67ꢂ74.19
109.17ꢂ73.55
85.50ꢂ84.80
18.50ꢂ27.52***
131.17ꢂ73.96
91.83ꢂ69.01
ꢂ
ꢂ
ꢂ
ꢂ
200.33 24.94
136.67 49.82
123.00 54.60
85.83 31.38
198.17ꢂ44.48
200.67ꢂ40.48
130.17ꢂ87.17
145.67ꢂ82.15
110.50ꢂ67.15
163.17ꢂ51.97
132.50ꢂ58.63
164.33ꢂ46.41
______
Values are means ꢂS. *P<0.05, **P<0.01, ***P<0.001 compared with A, A: saline, B: diazepam, 1: helicid,
2: 4-formylphenyl-(2,3,4,6-tetra-O-acetyl)-ꢀ-D-allopyranoside.
OH
OAc
CHO
CHO
O
O
O
O
a
HO
AcO
OH
O
OAc
O
OH
O
OAc
1
2
ROC
OR
1
X
b, c
O
NH
X
+
+
2
H N
2
NH
2
R
HN
R O
1
OR
1
OR
1
3a - f, 4a - f
3a, 4a: R = Me, X = O; 3b,4b: R = Me; X = S; 3c, 4c: R = OMe, X = O; 3d, 4d: R = OMe, X = S
3e, 4e: R = OEt, X = O; 3f, 4f: R = OEt, X = S; 3a - f: R = Ac; 4a - f: R = H
1
1
a. Ac O, DMF, triethylamine; b. sulfamic acid, ultrasonic radiation, 60ꢁC, EtOH; c. NaOMe, MeOH, room temperature
2
Scheme 1
In summary, twelve novel helicid derivatives were successfully synthesized, characterized, and tested for sedative-
hypnotic activity in our study, which suggested that these helicid derivatives might serve as lead compounds for designing new
compounds possessing potential sedative-hypnotic activity with high selectivity, low toxicity and additional pharmaceutical
effects. Further study is now in progress.
EXPERIMENTAL
4-Formylphenyl-(2,3,4,6-tetra-O-acetyl)-ꢀ-D-allopyranoside (2). Acetic anhydride (2.5 g, 25 mmol) was added
dropwise to a solution of helicid (1) (1.0 g, 3.5 mmol) in 2 mL of DMF and 3 mL of triethylamine in an ice bath. The mixture
was stirred vigorously at room temperature for 5 h and then poured into 20 mL of ice water. The precipitate was filtered,
washed with ice water, and recrystallized to get a white powder (2); yield 94%, mp 140–142ꢁC (lit.[13], 135–136ꢁC).
413

General Procedure for the Preparation of Compounds 3a–3f. A mixture of compound 2 (2 mmol), the
1,3-dicarbonyl compound (3 mmol), urea or thiourea (3 mmol), and sulfamic acid (0.6 g) was exposed to ultrasonic radiation
at a power of 120 W for 40–60 min; the temperature at the end of the reaction was 60ꢁC. The progress of the reaction was
monitored by TLC.After completion of the reaction, the mixture was cooled and poured into ice water and stirred for 5 to 10 min.
The solid was filtered, washed with ice water, and then recrystallized from ethanol to afford pure products 3a–3f.
5-Acetyl-6-methyl-4-[4-(2,3,4,6-tetra-O-acetyl-ꢀ-D-allopyranosyloxy)benzylidene]-3,4-dihydropyrimidin-2(1H)-
one (3a). This compound was prepared from 2, acetylacetone, and urea; yield 93%, white powder, mp 182–184ꢁC. IR (KBr, ꢃ,
–1
1
cm ): 3434, 3291, 2991, 1618, 1508, 1215, 1084, 1010, 847, 804. H NMR (400 MHz, DMSO-d , ꢄ, ppm): 1.99 (3H, s,
6
CH ), 2.03–2.50 (15H, m, 5CH CO), 4.15–4.36 (3H, m), 4.95–5.00 (2H, m, OCHO, CH), 5.22–5.61 (3H, m), 7.03–7.53 (4H,
3
3
+
m, ArH), 7.79 (1H, s, NH), 9.15(1H, s, NH). HR-MS(ESI) calcd for C H N Na O [M + Na] 599.1847, found 599.1819.
27 32
2
1 12
5-Acetyl-6-methyl-4-[4-(2,3,4,6-tetra-O-acetyl-ꢀ-D-allopyranosyloxy)benzylidene]-3,4-dihydropyrimidine-
2(1H)-thione (3b). This compound was prepared from 2, acetylacetone, and thiourea; yield 85%, white powder, mp 160–161ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3288, 3181, 2994, 1754, 1614, 1453, 1223, 1089, 1044, 852, 777. H NMR (400 MHz, DMSO-d , ꢄ, ppm):
6
1.98 (3H, s, CH ), 1.99–2.32 (15H, m, 5CH CO), 4.23–4.39 (3H, m), 4.78–5.00 (2H, m, OCHO, CH), 5.25–5.79 (3H, m), 7.03–
3
3
+
7.51 (4H, m, ArH), 9.73 (1H, s, NH), 10.28 (1H, s, NH). HR-MS (ESI) calcd for C H N Na O S [M + Na] 615.1619,
27 32
2
1 11 1
found 615.1616.
5-Methoxycarbonyl-6-methyl-4-[4-(2,3,4,6-tetra-O-acetyl-ꢀ-D-allopyranosyloxy)benzylidene]-3,4-
dihydropyrimidin-2(1H)-one (3c). This compound was prepared from 2, methyl acetoacetate, and urea; yield 95%, white
–1
1
powder, mp 140–142ꢁC. IR (KBr, ꢃ, cm ): 3321, 3231, 3115, 2953, 1750, 1667, 1508, 1222, 1091, 1038, 754, 717. H NMR
(400 MHz, DMSO-d , ꢄ, ppm): 2.00 (3H, s, CH ), 1.98–2.24 (12H, m, 4CH CO), 3.53 (3H, s, OCH ), 4.18–4.36 (3H, m),
6
3
3
3
4.95–5.00 (2H, m, OCHO, CH), 5.11–5.61 (3H, m), 7.01–7.19 (4H, m, ArH), 7.73 (1H, s, NH), 9.21 (1H, s, NH).
+
HR-MS(ESI) calcd for C H N Na O [M + Na] 615.1797, found 615.1810.
27 32
2
1 13
5-Methoxycarbonyl-6-methyl-4-[4-(2,3,4,6-tetra-O-acetyl-ꢀ-D-allopyranosyloxy)benzylidene]-3,4-
dihydropyrimidine-2(1H)-thione (3d). This compound was prepared from 2, methyl acetoacetate, and thiourea; yield 90%,
–1
1
white powder, mp 118–120ꢁC. IR (KBr, ꢃ, cm ): 3323, 2954, 1754, 1608, 1564, 1434, 1223, 1095, 1045, 854, 719. H NMR
(400 MHz, DMSO-d , ꢄ, ppm): 1.97 (3H, s, CH ), 1.98–2.27 (12H, m, 4CH CO), 3.54 (3H, s, OCH ), 4.16–4.35 (3H, m),
6
3
3
3
4.93–5.00 (2H, m, OCHO, CH), 5.12–5.60 (3H, m), 7.01–7.19 (4H, m, ArH), 9.64 (1H, s, NH), 10.35 (1H, s, NH).
+
HR-MS(ESI) calcd for C H N Na O S [M + Na] 631.1568, found 631.1589.
27 32
2
1 12 1
5-Ethoxycarbonyl-6-methyl-4-[4-(2,3,4,6-tetra-O-acetyl-ꢀ-D-allopyranosyloxy)benzylidene]-3,4-
dihydropyrimidin-2(1H)-one (3e). This compound was prepared from 2, ethyl acetoacetate, and urea; yield 94%, white
–1
1
powder, mp 104–106ꢁC. IR (KBr, ꢃ, cm ): 3340, 3244, 3119, 2979, 1755, 1698, 1508, 1444, 1091, 1044, 758, 711. H NMR
(400 MHz, DMSO-d , ꢄ, ppm, J/Hz): 1.17 (3H, t, J = 7.2, OCH CH ), 2.00 (3H, s, CH ), 1.98–2.24 (12H, m, 4CH CO), 4.01
6
2
3
3
3
(2H, q, J = 7.2, OCH CH ), 4.15–4.36 (3H, m), 4.95–4.98 (2H, m, OCHO, CH), 5.11–5.61 (3H, m), 7.07–7.20 (4H, m, ArH),
2
3
+
7.71 (1H, s, NH), 9.19 (1H, s, NH). HR-MS(ESI) calcd for C H N Na O [M + Na] 629.1953, found 629.1930.
28 34
2
1 13
5-Ethoxycarbonyl-6-methyl-4-[4-(2,3,4,6-tetra-O-acetyl-ꢀ-D-allopyranosyloxy)benzylidene]-3,4-
dihydropyrimidine-2(1H)-thione (3f). This compound was prepared from 2, ethyl acetoacetate, and thiourea; yield 88%,
–1
white powder, mp 100–102ꢁC. IR (KBr, ꢃ, cm ): 3321, 3202, 2982, 1756, 1710, 1652, 1608, 1451, 1219, 1094, 854, 712.
1
H NMR (400 MHz, DMSO-d , ꢄ, ppm, J/Hz): 1.13 (3H, t, J = 4.8, OCH CH ), 2.00 (3H, s, CH ), 2.01–2.31 (12H, m,
6
2
3
3
4CH CO), 4.02 (2H, q, J = 7.2, OCH CH ), 4.15–4.36 (3H, m), 4.95–4.98 (2H, m, OCHO, CH), 5.11–5.61 (3H, m, CH),
3
2
3
+
7.07–7.20 (4H, m, ArH), 9.65 (1H, s, NH), 10.36 (1H, s, NH). HR-MS(ESI) calcd for C H N Na O S [M + Na] 645.1725,
28 34
2
1 12 1
found 645.1738.
General Procedure for the Synthesis of Compounds 4a–4f. To a solution of compounds 3a–3f (2 mmol) in 20 mL
of methanol, 20 mL of methanol solution of 0.2 mol/L sodium methoxide was added. The mixture was stirred for 5 h at room
temperature. The solution was concentrated by evaporation in vacuo in methanol, and the residue was purified by chromatography
(MeOH–CH Cl , 1:10, v/v) to give pure compounds 4a–4f.
2
2
5-Acetyl-6-methyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4a). This compound was
–1
prepared from 3a; yield 95%, white powder, mp 178–179ꢁC. IR (KBr, ꢃ, cm ): 3306, 2923, 2344, 1688, 1508, 1451, 1081,
1
1037, 763, 720. H NMR (400 MHz, DMSO-d , ꢄ, ppm): 2.09 (3H, s, CH ), 2.26 (3H, s, CH CO), 3.42–3.93 (6H, m),
6
3
3
4.48–5.20 (4H, br, 4-OH), 5.05–5.09 (2H, m, OCHO, CH), 6.95–7.16 (4H, m, ArH), 7.77 (1H, s, NH), 9.15 (1H, s, NH).
+
HR-MS(ESI) calcd for C H N Na O [M + Na] 431.1425, found 431.1412.
19 24
2
1 8
414

5-Acetyl-6-methyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-3,4-dihydropyrimidine-2(1H)-thione (4b). This compound
was prepared from 3b; yield 93%, white powder, mp 199–200ꢁC.
–1
1
IR (KBr, ꢃ, cm ): 3288, 2925, 2847, 1692, 1574, 1508, 1463, 1085, 1033, 841, 769. H NMR (400 MHz, DMSO-d ,
6
ꢄ, ppm): 2.09 (3H, s, CH ), 2.26 (1H, s, CH CO), 3.42–3.93 (6H, m), 4.47–5.10 (4H, br, 4-OH), 5.05–5.09 (2H, m, OCHO,
3
3
+
CH), 6.96–7.15 (4H, m, ArH), 9.70 (1H, s, NH), 10.24 (1H, s, NH). HR-MS(ESI) calcd for C H N Na O S [M + Na]
19 24
2
1 7 1
447.1196, found 447.1175.
5-Methoxycarbonyl-6-methyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-3,4-dihydropyrimidin-2(1H)-one (4c). This
–1
compound was prepared from 3c; yield 89%, white powder, mp 200–202ꢁC. IR (KBr, ꢃ, cm ): 3348, 2903, 2877, 1671, 1433,
1
1273, 1086, 937 810, 759. H NMR (400 MHz, DMSO-d , ꢄ, ppm): 2.24 (3H, s, CH ), 3.53 (3H, s, OCH ), 3.32–3.92 (6H,
6
3
3
m), 4.45–5.09 (4H, br, 4-OH), 5.04–5.09 (2H, m, OCHO, CH), 6.94–7.15 (4H, m, ArH), 7.69 (1H, s, NH), 9.18 (1H, s, NH).
+
HR-MS(ESI) calcd for C H N Na O [M + Na] 447.1374, found 447.1361.
19 24
2
1 9
5-Methoxycarbonyl-6-methyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-3,4-dihydropyrimidine-2(1H)-thione (4d). This
–1
compound was prepared from 3d; yield 92%, white powder, mp 174–176ꢁC. IR (KBr, ꢃ, cm ): 3390, 2927, 2340, 1696, 1434,
1
1320, 1230, 1180, 1103, 1078, 1036, 847, 605. H NMR (400 MHz, DMSO-d , ꢄ, ppm): 2.29 (3H, s, CH ), 3.45 (3H, s,
6
3
OCH ), 3.33–4.03 (6H, m), 4.51–5.13 (4H, br, 4-OH), 5.05–5.09 (2H, m, OCHO, CH), 6.96–7.13 (4H, m, ArH), 9.61 (1H, s,
3
+
NH), 10.29 (1H, s, NH). HR-MS(ESI) calcd for C H N Na O S [M + Na] 463.1146, found 463.1136.
19 24
2
1 8 1
5-Ethoxycarbonyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4e). This
–1
compound was prepared from 3e; yield 91%, white powder, mp 180–182ꢁC. IR (KBr, ꢃ, cm ): 3361, 2978, 2931, 1694, 1508,
1
1226, 1089, 1038, 844, 759. H NMR (400 MHz, DMSO-d , ꢄ, ppm): 1.09 (3H, t, J = 7.2, OCH CH ), 2.24 (3H, s, CH ), 3.98
6
2
3
3
(2H, q, J = 7.2, OCH CH ), 3.33–3.91 (6H, m), 4.62–5.10 (4H, br, 4-OH), 5.04–5.09 (2H, m, OCHO, CH), 6.94–7.15 (4H, m,
2
3
+
ArH), 7.67 (1H, s, NH), 9.14 (1H, s, NH). HR-MS(ESI) calcd for C H N Na O [M + Na] 461.1531, found 461.1508.
20 26
2
1 9
5-Ethoxycarbonyl-4-(4-ꢀ-D-allopyranosyloxyphenyl)-6-methyl-3,4-dihydropyrimidine-2(1H)-thione (4f). This
–1
compound was prepared from 3f; yield 93%, white powder, mp 182–184ꢁC. IR (KBr, ꢃ, cm ): 3307, 2971, 2925, 1692, 1608,
1
1508, 1086, 1035, 841, 768. H NMR (400 MHz, DMSO-d , ꢄ, ppm, J/Hz): 1.10 (3H, t, J = 7.2, OCH CH ), 2.29 (3H, s, CH ),
6
2
3
3
4.02 (2H, q, J = 7.2, OCH CH ), 3.42–3.91 (6H, m), 4.45–5.10 (4H, br, 4-OH), 5.04–5.12 (2H, m, OCHO, CH), 6.94–7.13
2
3
+
(4H, m, ArH), 9.61 (1H, s, NH), 10.29 (1H, s, NH). HR-MS(ESI) calcd for C H N Na O S [M + Na] 477.1302, found
20 26
2
1 8 1
477.1288.
Mice (Kunming strain) weighting 18–22 g were obtained from West China School of Pharmacy, Sichuan University
(Chengdu, China). Diazepam was purchased from Huayin Jinqiancheng Pharmaceutical Co. Ltd. (China). All samples were
dissolved in 0.05% CMC to form different concentrations of solutions for later use.
The sedative-hypnotic activities of the compounds were investigated by recording the number of spontaneous
locomotions in mice using an actophotometer [14, 15]. Ninety-six mice were randomized into 16 groups of 6 mice each
(3 male and 3 female). When testing, basal activity score was taken, and then a solution of the drugs in 0.05% CMC and saline
–1
was injected into the mouse stomach with a syringe in a volume of 0.2 mL 10 g body weight. Scores were recorded at 0, 30,
60, and 90 min after the drugs and saline injection, respectively. The data were expressed as number of movements per minute,
averaged over 5 min.
The results of the spontaneous locomotor activity test are shown in Table 1. According to the data, helicid (1) and
4-formylphenyl-(2,3,4,6-tetra-O-acetyl)-ꢀ-D-allopyranoside (2) exhibited mild sedative-hypnotic activities. The sedative-
hypnotic activities of compounds 3a, 3c, 3d, 3e, 3f, and 4a were better than that of helicid (1). Except for compound 3b, the
higher sedative-hypnotic activities of derivatives 3a, 3c, 3d, 3e, and 3f suggested that the introduction of the acetyl group in
the sugar moiety led to an increase in the sedative-hypnotic effect. So, further modification of helicid should be worthwhile.
ACKNOWLEDGMENT
Thanks are due to the Analytical & Testing Center, Sichuan University, P. R. China for assistance in obtaining analytical
data, and to Mr. Bao (Department of Pharmacy, Sichuan University) who finished the sedative-hypnotic test.
415

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