Structure-activity relationships of chalcone analogs as potential inhibitors of ADP- and collagen-induced platelet aggregation

Article abstract of DOI:10.1016/j.bmc.2011.08.004

In an effort to develop potent antiplatelet agents, 12 O-prenylated (2-13) and 10 O-allylated (14-23) chalcones were synthesized and screened for in vitro inhibitory effects on aggregation of washed rabbit platelets induced by ADP (20 μM) and collagen (10

Full text of DOI:10.1016/j.bmc.2011.08.004

Bioorganic & Medicinal Chemistry 19 (2011) 7711–7719
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Structure–activity relationships of chalcone analogs as potential inhibitors
of ADP- and collagen-induced platelet aggregation
M. Vijaya Bhaskar Reddy a, Wei-Jern Tsai b, Keduo Qian c, Kuo-Hsiung Lee c,e, Tian-Shung Wu c,d,e,
⇑
a Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC
b National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC
c Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
d Department of Pharmacy, China Medical University, Taichung 404, Taiwan, ROC
e Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 404, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
In an effort to develop potent antiplatelet agents, 12 O-prenylated (2–13) and 10 O-allylated (14–23)
Received 26 April 2011
Revised 26 July 2011
Accepted 2 August 2011
Available online 6 August 2011
chalcones were synthesized and screened for in vitro inhibitory effects on aggregation of washed rabbit
platelets induced by ADP (20 lM) and collagen (10 lg/mL). In addition, the platelet aggregation activity
of previously synthesized Mannich bases of heterocyclic chalcones (MBHC) (24–62) was evaluated. The
preliminary structure–activity relationships suggested that the antiplatelet activity was governed to a
great extent by the presence of a pyridyl ring-B and a hydroxy group at position C-30 in ring-A of the
MBHC templates.
Keywords:
Oxyprenylated and oxyallylated chalcones
Mannich bases of heterocyclic chalcone
analogs
Ó 2011 Published by Elsevier Ltd.
Antiplatelet aggregation activity
1. Introduction
in evaluating the pharmaceutically important biological activities
of chalcones and their derivatives, presuming their role in the pre-
Platelet aggregation plays a central role in thrombosis (clot for-
mation). Platelet-mediated thrombus formation in the coronary ar-
vention of various degenerative diseases and other human ail-
ments. Many pharmacological activities have been reported for
these compounds: anticancer, anti-inflammatory, immunomodu-
latory, antibacterial, antioxidant and immunosuppressive, as well
as antiprotozoan activity, including trypanocidal, leishmanicidal,
and antimalarial.9–17 Lin et al.18 also reported that 20,50-dihydroxy-
chalcones exhibited good selective inhibitory effects on AA-in-
duced platelet aggregation. Therefore, in the present study, we
synthesized a series of 40-O-prenylated (2–13) and 40-O-allylated
chalcones (14–23) with various B-ring substituents, and screened
the compounds for inhibitory effects on aggregation of washed
rabbit platelets induced by ADP and collagen at concentrations of
tery is
a primary factor in the development of thrombotic
disorders, such as unstable angina, myocardial infarction, stroke1,2
and peripheral vascular diseases.3 Normally, the blood is not aggre-
gated in the blood vessels, but when bleeding occurs, blood aggre-
gation is generated as a physiological defense reaction. Platelet
aggregation is also caused by physiological substances, such as
thrombin and prostaglandin endoperoxide, and can lead to an arte-
rial thrombosis.4 Platelet aggregation is induced by the action of
endogenous agonists, such as arachidonic acid (AA), adenosine
diphosphate (ADP), platelet-activating factor (PAF), thrombin and
collagen.5 The inhibition of platelet function represents a promis-
ing approach for the treatment of thrombotic diseases. Many anti-
platelet drugs have been used clinically, but have certain
disadvantages such as notable side effects and inefficient ther-
apy.6,7 Therefore, pursuit of new antiplatelet drugs that are more
effective and safer with fewer side effects is very important.
Chalcones, which are classified as polyphenolic compounds, are
basically flavonoids and are ubiquitously present in plants, espe-
cially in fruits and vegetables.8 The literature cited in relation to
chalcones in recent years indicates that there is a growing interest
20 lM and 10 lg/mL, respectively. Moreover, we also evaluated
39 previously synthesized19 Mannich bases of heterocyclic chal-
cones (MBHC) (24–62) in these assays. Preliminary structure–
activity relationship (SAR) correlations are also discussed.
2. Results and discussion
We evaluated 2–23 for inhibitory effects on ADP- and collagen-
induced washed rabbit platelet aggregation (Table 1). Compound
20 showed potent inhibitory effects (70.4%) on ADP-induced
aggregation, while 15, 17, 19 and 20 with 2,3-dimethoxy, 2,5-
dimethoxy, 2,4-dimethoxy, and 3,4,5-trimethoxy benzene ring-B
moieties, respectively, showed potent inhibition (44.7%, 57.2%,
⇑
Corresponding author at: Department of Chemistry, National Cheng Kung
University, Tainan 701, Taiwan, ROC. Tel.: +886 6 2747538; fax: +886 2 2740552.
E-mail address: tswu@mail.ncku.edu.tw (T.-S. Wu).
0968-0896/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2011.08.004

7712
M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
Table 1
Inhibitory percentages of 2–62 (50 lg/mL) on platelet aggregation induced by ADP (20 lM) and collagen (10 lg/mL).
Compound
ADP (n = 3)
Collagen (n = 3)
Compound
ADP (n = 3)
Collagen (n = 3)
2
3
4
5
6
7
8
9
21.4
23.0
15.7
42.7
16.4
21.3
22.8
20.7
20.0
25.7
24.3
27.1
26.4
30.8
21.4
33.6
24.9
35.2
70.4
21.6
30.8
25.6
100.0
100.0
29.0
14.2
100.0
22.5
16.5
100.0
39.3
12.6
13.4
4.0
39.2
6.3
19.7
14.9
8.7
17.3
17.3
10.3
7.9
14.9
44.7
7.9
57.2
5.5
53.4
43.2
0.0
13.4
6.3
12.5
93.7
3.2
11.1
46.9
0.0
0.0
43.0
2.3
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
32.3
100.0
97.2
36.7
26.4
17.2
23.4
99.3
100.0
100.0
34.2
18.4
23.4
21.4
12.8
100.0
24.9
100.0
100.0
100.0
100.0
100.0
79.1
100.0
100.0
100.0
99.3
0.0
96.1
29.2
7.1
11.1
19.7
0.0
63.5
56.4
79.4
20.3
4.7
25.0
12.5
0.0
78.6
50.0
98.4
95.3
100.0
60.8
83.5
65.5
89.8
100.0
78.0
57.6
95.2
93.7
98.4
3.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
100.0
100.0
100.0
85.2
Clopidogrel (9.6 lg/mL)
The antiplatelet aggregation (%) was calculated by the following equation: Antiplatelet aggregation (%) = [1 ꢀ (platelet aggregation potency of sample/platelet aggregation
potency of vehicle)] ꢁ 100%.
53.4% and 43.2%, respectively) on collagen-induced platelet aggre-
gation, as compared with the reference compound clopidogrel
(3.5% inhibition at 30 lM).
of either ADP- or collagen-induced platelet aggregation. These re-
sults clearly indicated that a heteroaromatic pyridine ring-B moi-
ety was required for maximal inhibition of platelet aggregation
with these compounds.
Thirty-nine previously synthesized MBHC analogs (24–62)
(Scheme 3) were also evaluated on the platelet aggregation in-
In compounds 40–42, ring-A is substituted at C-30 with a mor-
pholine Mannich base and at C-40 with a hydroxy group, while
the B-ring is 2-pyridine, 3-pyridine and 4-pyridine, respectively.
These three compounds exhibited significant inhibitory effects on
ADP-induced platelet aggregation (99.3%, 100% and 100%) and
moderate effects (63.5%, 56.4% and 79.4%) on collagen-induced
platelet aggregation. Following the similar trend with compounds
28 versus 29–33 and 34 versus 35–38, when the pyridine moieties
of 40–42 were replaced with phenyl (43), furan (44), thiophene
(45), 3-methyl-2-thiophene (46) or 5-methyl-2-furan (47), de-
creased inhibitory effects were observed on both ADP- and colla-
gen-induced platelet aggregations.
Analogs 50, 51 and 52 have hydroxy and morpholine Mannich
base groups at positions C-30 and C-40, respectively, in ring-A,
and thus, are positional isomers of 40, 41 and 42. Compounds
50–52 exhibited potent inhibitory effects on both ADP- (100%)
and collagen- (95.3–100%) induced platelet aggregation. The latter
inhibitory effects were greater than those of 40–42. Compounds 48
and 57 are also positional isomers in ring-A, with the hydroxy
group at C-40 in the former and C-30 in the latter compound. Com-
pound 48 exhibited 100% inhibition of ADP- and 78.6% inhibition of
collagen-induced platelet aggregation, while 57 exhibited 100%
inhibition of both ADP- and collagen-induced aggregation. Based
on these results, a hydroxy group at position C-30 resulted in great-
er inhibition of platelet aggregation induced by collagen in this
compound series (50–52 and 57). Compounds 53–56, which have
hydroxy and morpholine Mannich base groups at positions C-30
and C-20, respectively, were more potent inhibitors of both
duced by ADP and collagen at concentrations of 20
10 g/mL, respectively (Table 1).
Compound 24 was a potent inhibitor (100%) of ADP-induced
lM and
l
platelet aggregation, but only a weak inhibitor (12.5%) of colla-
gen-induced aggregation. However, when the C-40 hydroxyl in 24
was replaced with a methoxy group as in 25, the potency increased
to 93.7% inhibition in the collagen-induced assay, and remained at
100% in the ADP-induced assay.
Compounds 28 and 31 with 3-pyridyl and 4-pyridyl ring-B moi-
eties, respectively, showed potent inhibition (100%) of ADP-in-
duced platelet aggregation and moderate inhibition (46.9% and
43%, respectively) of collagen-induced aggregation. When the pyr-
idine ring-B was replaced with 2-furan (29), 5-methylfuran (30),
phenyl (32) or 3-methyl-2-thiophene (33), the resulting com-
pounds showed drastically decreased inhibitory effects on ADP in-
duced platelet aggregation and no inhibition on collagen induced
platelet aggregation. Compound 34, which differs structurally from
28 only by having a methoxy rather than ethoxy group at position
C-40, potently inhibited both ADP- and collagen-induced platelet
aggregations by 100% and 96.1%, respectively. Replacement of the
3-pyridyl moiety in 34 with a phenyl moiety in 35 resulted in
essentially equipotent inhibition (97.2%) of ADP-induced platelet
aggregation and weak inhibition of collagen-induced platelet
aggregation. With the addition of a 4-methoxy group on the phenyl
ring of 35, the inhibitory effects decreased in both assays (see 36,
Table 1). In addition, analogs 37 and 38, which have 2-thiophene
and 2-furan ring-B moieties, respectively, exhibited no inhibition

M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
7713
ADP- and collagen-induced platelet aggregation than the positional
3. Conclusion
isomers 44–46 and 43, respectively, which have the hydroxy and
morpholine Mannich base groups at positions C-40 and C-30.
Compounds 58–62, which have 2-(N-morpholinylmethyl or N-
piperidylmethyl)-3-hydroxy-4-methoxyphenyl B-ring groups,
showed potent inhibition (100%) of ADP-induced platelet aggrega-
tion and moderate to potent inhibition (57.6–98.4%) of collagen-
induced platelet aggregation.
In conclusion, MBHC showed good inhibitory effects on both
ADP- and collagen-induced platelet aggregations. Among the 61
compounds tested, 19 showed full inhibitory activity at 50 lg/mL
in the ADP-induced model, while 9 compounds (25, 34, 50–52,
57, 60–62) showed >90% to full inhibitory activity in both models.
The preliminary SAR suggested that, among compounds 2–62, the
antiplatelet activity was governed to a greater extent by a pyridyl
group substituent as ring-B and hydroxy group at position C-30 in
ring-A of the MBHC templates. The SAR of the active compounds
merits further investigation to find the optimal lead structure with
maximum inhibitory activity. Because some MBHC were full inhib-
itors of platelet aggregation, additional potential evaluation should
be carried out with lower concentrations of compounds, and the
anti-platelet action mechanisms of potential leads also need fur-
ther analysis.
5
6
O
a
b
4
1
3
2
HO
OH
1a
O
OH
O
4. Experimental section
5
O
6
1
4
1
Melting points were measured using a Buchi melting point
apparatus B-540 and are uncorrected. IR spectra were determined
on a Shimadzu FT-IR Prestige 21 spectrophotometer. 1H and 13C
NMR spectra were recorded on a Bruker Avance 300 spectrometer,
using tetramethylsilane (TMS) as internal standard; all chemical
shifts were reported in parts per million (ppm, d). EIMS and HRE-
IMS spectra were obtained on a VG-70-250S mass spectrometer.
3
2
OH
O
1b
Scheme 1. Reagents and conditions: (a) K2CO3, Me2CO, prenyl bromide, reflux at
80 °C, 8 h (b) K2CO3, Me2CO, allyl bromide, reflux at 80 °C, 8 h
R4
R4
2"
5
5'
5"
3"
4"
4'
O
R5
R3
6
O
50% KOH
solution
in MeOH
R5
R3
R2
4
6'
1'
1"
1
3R' 2
7
3
+
8
2'
2
9
OHC
OH
O
R1
OH
1a
O
R1
2. R1 = R2 = R3 = OMe, R4 = R5 = H
3. R1 = R4 = R5 = H, R2 = OH, R3 = OMe
4. R2 = R5 = H, R1 = R3 = R4 = OMe
5. R2 = R4 = R5 = H, R1 = R3 = OMe
6. R1 = R2 = R3 = R4 = R5 = H
7. R3 = R4 = R5 = H, R1 = R2 =OMe
8. R2 = R3 = R5 = H, R1 = R4 =OMe
9. R1 = R3 = R5 = H, R2 = R4 = OMe
10. R1 = R4 = R5 = H, R2 = R3 = OCH2O
11. R1 = R2 = R4 = R5 = H, R3 = OMe
12. R1 = R4 = R5 = H, R2 = R3 = OMe
13. R1 = R5 = H, R2 = R3 = R4 = OMe
R4
R4
2"
5
5'
O
4'
50% KOH
solution
in MeOH
O
R5
R3
R5
R3
R2
3"
6
4
6'
1'
1"
+
1
3R' 2
7
3
8
OHC
2'
2
9
OH
1b
O
OH
O
R1
R1
14. R1 = R2 = R3 = OMe, R4 = R5 = H
15. R1 = R2 = OMe, R3 = R4 = R5 = H
16. R1 = R4 = R5 = H, R2 = R3 = OCH2O
17. R2 = R3 = R5 = H,R1 = R4 = OMe
18. R1 = R2 = R4 = R5 = H, R3 = OMe
19. R2 = R4 = R5 = H, R1 = R3 = OMe
20. R1 = R5 = H, R2 = R3 = R4 = OMe
21. R2 = R5 = H, R1 = R3 = R4 = OMe
22. R1 = R3 = R5 = H, R2 = R4 = OMe
23. R1 = R2 = R3 = R4 = R5 = H
Scheme 2.

7714
M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
Elemental analyses were determined by Elementer Vario EL III and
gave combustion values for C, H, N and S. Column chromatography
was performed on silica gel (70–230 mesh, 230–400 mesh). TLC
was conducted on precoated Kieselgel 60 F254 plates (Merck),
and the spots were detected by examination under a UV lamp.
4.1. 1-(2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl)ethanone
(1a)
To
a solution of 2,4-dihydroxyacetophenone (1, 15.2 g,
100 mmol) in dry acetone (100 mL) at room temperature was
O
N
RO
RO
B ring
B ring
N
O
OH
O
OH
O
R
B-ring
R
B-ring
28. ethyl
3-pyridyl
29. ethyl
2-furan
24. H
2-pyridyl
2-pyridyl
2-thiophene
3-methyl-2-thiophene
25. Me
30. ethyl
5-methyl-2-furan
2-pyridyl
26. isopropyl
27. prenyl
31. ethyl
32. ethyl
phenyl
33. ethyl
3-methyl-2-thiophene
3-pyridyl
34. methyl
35. methyl
36. methyl
37. methyl
38. methyl
39. isopropyl
phenyl
4-CH3OC6H4
2-thiophene
2-furan
2-thiophene
O
N
OH
HO
HO
N
B ring
B ring
B ring
O
O
N
O
O
N
O
O
B-ring
50. 2-pyridyl
51. 3-pyridyl
52. 4-pyridyl
B-ring
B-ring
40. 2-pyridyl
48. 2-pyridyl
41. 3-pyridyl
49. 3-methyl-2-thiophene
42. 4-pyridyl
43. phenyl
44. 2-furan
45. 2-thiophene
46. 3-methyl-2-thiophene
47. 5-methyl-2-furan
O
O
OH
N
OH
N
O
N
O
B ring
N
O
57.
B-ring
53. 2-furan
54. 2-thiophene
55. 3-methyl-2-thiophene
56. phenyl
OMe
OMe
OH
A ring
A ring
OH
N
O
O
N
O
A-ring
A-ring
58. 3-Me-C6H4
59. 4-Me-C6H4
60. 2-thiophene
61. 2-furan
62. 3-pyridyl
Scheme 3.

M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
7715
added freshly ignited K2CO3 (6.0 g), followed by prenyl bromide
1510, 1458, 1440, 1266, 1210, 1130, 1028, 977, 854, 796 cmꢀ1
.
(11.8 mL, 100 mmol). The reaction mixture was refluxed for 8 h
at 80 °C. The reaction progress was monitored by TLC. Upon reac-
tion completion, the mixture was filtered, and the solvent evapo-
rated under reduced pressure. The resulting crude product was
purified by column chromatography over a silica gel column, elut-
ing with 9:1 (hexane:EtOAc) to give 2-hydroxy-4-O-prenylace-
tophenone (1a) as a colorless solid (19.5 g) in 89% yield (Scheme
1). 1H NMR (300 MHz, CDCl3): d 12.74 (1H, s, 2-OH), 7.60 (1H d,
J = 8.0 Hz, H-6), 6.44 (1H, dd, J = 8.0, 2.0 Hz, H-5), 6.40 (1H, d,
J = 2.0, H-3). 13C NMR (75 MHz, CDCl3): d 202.3, 165.2, 164.9,
138.7, 132.0, 118.5, 113.5, 107.8, 101.2, 64.9, 25.8, 25.5, 17.9.
1H NMR (300 MHz, CDCl3): d 13.60 (1H, s, 2-OH), 7.80 (1H, d,
J = 15.3 Hz, H-9), 7.79 (1H, d, J = 9.0 Hz, H-6), 7.43 (1H, d,
J = 15.3 Hz, H-8), 7.26 (1H, d, J = 9.0 Hz, H-60), 7.14 (1H, d,
J = 2.5 Hz, H-20), 6.87 (1H, d, J = 9.0 Hz, H-50), 6.48 (2H, m,
J = 9.0 Hz, H-3,5), 5.48 (1H, t, J = 6.0 Hz, H-200), 4.57 (2H, d,
J = 6.0 Hz, H-100), 3.95 (3H, s, 40-OMe), 1.81 (3H, s, 400-Me), 1.76
(3H, s, 500-Me).13C NMR (75 MHz, CDCl3): d 191.7, 166.5, 165.4,
148.9, 145.9, 144.2, 139.1, 131.1, 128.4, 122.9 118.7, 118.4, 114.0,
113.0, 110.5, 108.1, 101.7, 65.1, 56.0, 25.8, 18.2. EIMS m/z (% rel
intensity): 354 (43) [M]+, 286 (100), 285 (53), 269 (14), 163 (17),
150 (27), 137 (71), 69 (43); HREIMS m/z Calcd for C21H22O5,
354.1467. Found 354.1465. Elemental Analysis: Calcd C, 71.17; H,
6.26. Found 71.46; H, 6.58.
4.2. 1-(4-(Allyloxy)-2-hydroxyphenyl)ethanone (1b)
To
a
solution of 2,4-dihydroxyacetophenone (1, 15.2 g,
5.3. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy) phenyl]-3-
100 mmol) in dry acetone (100 mL) was added freshly ignited
K2CO3 (6.0 g), followed by allyl bromide (8.6 mL, 100 mmol). The
reaction mixture was treated as described for the above procedure
to yield 2-hydroxy-4-O-allylacetophenone (1b) as yellow oil
(14.8 g) in 77% yield (Scheme 1).1H NMR (300 MHz, CDCl3): d
12.68 (1H, s, 2-OH), 7.56 (1H, d, J = 9.0 Hz, H-6), 6.39 (1H, d,
J = 3.0 Hz, H-3), 6.35 (1H, dd, J = 9.0, 3.0 Hz, H-5), 5.96 (1H, m, H-
20), 5.35 (2H, m, H-30), 4.50 (1H, d, J = 6.3 Hz, H-10), 2.50 (3H, s, Me).
(2,4,5-trimethoxyphenyl)prop-2-en-1-one (4)
The compound was isolated as a yellow solid (1.01 g) in 50%
yield, mp 102–103 °C. IR (neat) 2935, 2836, 1628 (C@O), 1554
(C@C), 1510, 1466, 1376, 1287, 1256, 1208, 1125, 1028, 850, 744,
630 cmꢀ1 1H NMR (300 MHz, CDCl3): d 13.69 (1H, s, 2-OH), 8.17
.
(1H, d, J = 15.3 Hz, H-9), 7.83 (1H, d, J = 9.0 Hz, H-6), 7.54 (1H, d,
J = 15.3 Hz, H-8), 7.13 (1H, s, H-60), 6.54 (3H, m, H-5,3,30), 6.50
(1H, t, J = 6.0 Hz, H-200), 4.57 (2H, d, J = 6.0 Hz, H-20), 3.98 (3H, s,
OMe), 3.93 (6H, s, 2xOMe), 1.81 (3H, s, H-400), 1.76 (3H, s, H-500).
13C NMR (75 MHz, CDCl3): d 192.1, 166.4, 165.1, 154.8, 152.6,
143.2, 139.6, 139.0, 130.9, 118.6, 118.0, 115.3, 114.1, 111.6,
107.9, 101.5, 96.7, 65.0, 56.5, 56.2, 56.0, 25.7, 18.1. EIMS m/z (%
rel intensity): 398 (52) [M]+, 367 (10), 330 (15), 299 (100), 181
(22), 137 (7), 69 (16); HREIMS m/z Calcd for C23H26O6, 398.1729.
Found, 398.1730. Elemental Analysis: Calcd C, 69.33; H, 6.58.
Found C, 69.34; H, 6.55.
5. General procedure for the synthesis of chalcones (2–23)
A solution of 50% KOH (50 mL) was added drop wise to a well-
stirred mixture of 2-hydroxy-4-O-prenylacetophenone 1a
(5 mmol) and different substituted aldehydes (5 mmol) in MeOH
at room temperature. After 24–36 h, the solvent was removed un-
der reduced pressure and acidified with 5% HCl (30–60 mL). The
aqueous layer was extracted with EtOAc, washed with brine, dried
(Na2SO4), and then concentrated in vacuo. The residue was purified
by column chromatography on silica gel, eluting with hex-
ane:EtOAc mixtures to afford oxyprenylated chalcones 2–13 in
high yield (Scheme 2). A similar procedure applied for the synthe-
sis of oxyallylated chalcones (14–23) from 1a,b (10 mmol) and dif-
ferent substituted aldehydes (10 mmol) (Scheme 2)
5.4. (E)-3-(2,4-Dimethoxyphenyl)-1-[2-hydroxy-4-(3-
methylbut-2-enyloxy)phenyl]prop-2-en-1-one (5)
The compound was isolated as a yellow solid (1.42 g) in 77%
yield, mp 72–73 °C. IR (neat) 2937, 2838, 1629(C@O), 1608(C@C),
1555, 1505, 1438, 1418, 1361, 1315, 1295, 1215, 1160, 1026,
1001, 942, 835 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.71 (1H, s, 2-
OH), 8.11 (1H, d, J = 15.0 Hz, H-9), 7.79 (1H, d, J = 9.0 Hz, H-6),
7.61 (1H, d, J = 9.0 Hz, H-60), 7.59 (1H, d, J = 15.0 Hz, H-8), 6.52
(4H, m, H-3, 5, 30, 50), 5.47 (1H, t, J = 6.0 Hz, H-200), 4.54 (2H, d,
J = 6.0 Hz, H-100), 3.89 (3H, s, OMe), 3.83 (3H, s, OMe), 1.79 (3H, s,
H-400), 1.74 (3H, s, H-500).13C NMR (75 MHz, CDCl3): d 192.3,
166.4, 165.1, 163.2, 160.5, 140.0, 138.9, 131.1, 131.1, 118.8,
118.1, 116.9, 114.2, 107.8, 105.5, 101.6, 98.3, 65.1, 55.5, 55.4,
25.8, 18.2. EIMS m/z (% rel intensity): 368 (56) [M]+, 300 (51),
269 (100), 191 (8), 164 (29), 151 (63), 137 (16), 69 (35); HREIMS
m/z Calcd for C22H24O5, 368.1624. Found, 368.1621. Elemental
Analysis: Calcd C, 71.71; H, 6.57. Found C, 71.77; H, 6.61.
5.1. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl]-3-
(2,3,4-trimethoxyphenyl)prop-2-en-1-one (2)
The compound was isolated as a yellow solid (1.5 g) in 75%
yield, mp 83–84 °C. IR (neat) 2938, 2840, 1632 (C@O), 1565
(C@C), 1495, 1465, 1435, 1415, 1359, 1303, 1282, 1256, 1211,
1133, 1096, 1045, 1009, 946, 859 cmꢀ1.1H NMR (300 MHz, CDCl3):
d 13.47 (1H, s, 2-OH), 8.01 (1H, d, J = 15.6 Hz, H-9), 7.77 (1H, d,
J = 9.0 Hz, H-6), 7.58 (1H, d, J = 15.6, H-8), 7.33 (1H, d, J = 9.0 Hz,
H-60), 6.67 (1H, dd, J = 9.0, 3.0 Hz, H-5), 6.44 (1H, d, J = 9.0 Hz, H-
50), 5.43 (1H, t, J = 6.3 Hz, H-200), 4.52 (2H, d, J = 6.3 Hz, H-100),
3.93, 3.88 (9H, m, 3ꢁ OMe), 1.77 (3H, s, H-400), 1.72 (3H, s, H-
500).13C NMR (75 MHz, CDCl3): d 192.2, 166.5, 165.3, 155.9, 153.9,
142.4, 139.7, 139.1, 131.1, 124.2, 121.9, 119.4, 118.7, 114.1,
108.1, 107.6, 101.6, 65.1, 61.4, 60.9, 56.1, 25.8, 18.2. EIMS m/z (%
rel intensity): 398 (24) [M]+, 367 (22), 330 (8), 300 (31), 299
(100), 181 (9), 137 (8), 69 (20); HREIMS m/z Calcd for C23H26O6,
398.1729. Found 398.1729. Elemental Analysis: Calcd C, 69.33; H,
6.58. Found C, 69.12; H, 6.51.
5.5. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl]-3-
phenylprop-2-en-1-one (6)
The compound was isolated as a yellow solid (1.08 g) in 70%
yield, mp 113–114 °C. IR (neat) 2926, 1631 (C@C), 1609 (C@O),
1578, 1500, 1415, 1358, 1275, 1217, 1138, 990, 875, 828, 763,
729 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.45 (1H, s, 2-OH), 7.89
(1H, d, J = 15.3 Hz, H-9), 7.82 (1H, d, J = 9.0 Hz, H-6), 7.63 (2H, m,
H-20, 60), 7.60 (1H, d, J = 15.3 Hz, H-8), 7.43 (3H, m, H-30, 40, 50),
6.49 (2H, m, H-3, 5), 5.47 (1H, t, J = 6.0 Hz, H-200), 4.56 (2H, d,
J = 6.0 Hz, H-100), 1.81 (3H, s, H-400), 1.76 (3H, s, H-500).13C NMR
(75 MHz, CDCl3): d 191.2, 166.1, 165.0, 143.7, 138.6, 134.2, 130.7,
5.2. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl]-3-(3-
hydroxy-4-methoxyphenyl) prop-2-en-1-one (3)
The compound was isolated as a yellow solid (1.08 g) in 61%
yield, mp 138–139 °C. IR (neat) 2932, 1633 (C@O), 1569 (C@C),

7716
M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
130.1, 128.4, 128.4, 128.0, 128.0, 119.8, 118.1, 113.4, 107.7, 101.2,
64.6, 25.3, 17.7. EIMS m/z (% rel intensity): 308 (19) [M]+, 240
(100), 239 (72), 223 (8), 163 (58), 137 (13) 103 (8), 69
(39); HREIMS m/z Calcd for C20H20O3, 308.1412. Found, 308.1411.
Elemental Analysis: Calcd C, 77.90; H, 6.54. Found C, 77.84; H,
6.50.
5.9. (E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-[2-hydroxy-4-(3-
methylbut-2-enyloxy)phenyl]prop-2-en-1-one (10)
The compound was isolated as a bright yellow solid (1.23 g) in
69% yield, mp 125–126 °C. IR (neat) 2911, 1634 (C@O), 1571 (C@C
C@C), 1503, 1489, 1447, 1375, 1248, 1215, 1038, 971, 933, 794 cm
ꢀ1
.
1H NMR (300 MHz, CDCl3): d 13.45 (1H, s, 2-OH), 7.79 (2H, m,
H-6, 60), 7.40 (1H, d, J = 15.3 Hz, H-9), 7.15 (1H, d, J = 15.3 Hz, H-
8), 7.10 (1H, d, J = 2.5 Hz, H-20), 6.84 (1H, d, J = 7.5 Hz, H-50), 6.48
(2H, m, J = 8.1 Hz, H-3, 5), 6.02 (2H, s, -OCH2O-), 5.48 (1H, t,
J = 6.6 Hz, H-200), 4.56 (2H, d, J = 6.6 Hz, H-100), 1.81 (3H, s, H-400),
1.75 (3H, s, H-500).13C NMR (75 MHz, CDCl3): d 191.6, 166.5,
165.4, 149.9, 148.4, 144.1, 139.1, 131.0, 129.2, 125.3, 118.6,
118.2, 113.9, 108.6, 108.1, 106.6, 101.6, 101.6, 65.1, 25.7, 18.2.
EIMS m/z (% rel intensity): 352 (41) [M]+, 385 (18) 284 (100), 283
(45), 267 (9), 163 (13), 148 (42), 135 (60), 69 (46); HREIMS m/z
Calcd for C21H20O5, 352.1311. Found, 352.1311. Elemental Analy-
sis: Calcd C, 71.58; H, 5.72. Found C, 71.49; H, 5.74.
5.6. (E)-3-(2,3-Dimethoxyphenyl)-1-[2-hydroxy-4-(3-
methylbut-2-enyloxy)phenyl]prop-2-en-1-one (7)
The compound was isolated as a pale yellow solid (1.2 g) in
65% yield, 108–109 °C. IR (neat) 2932, 2836, 1640 (C@O), 1613
(C@C), 1577, 1478, 1454, 1360, 1273, 1229, 1141, 1073, 1001,
974, 827, 742 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.47 (1H, s,
2-OH), 8.16 (1H, d, J = 15.6 Hz, H-9), 7.82 (1H, d, J = 9.0 Hz, H-
6), 7.67 (1H, d, J = 15.6 Hz, H-8), 7.29 (1H, d, J = 9 Hz, H-60),
7.10 (1H, t, J = 9, 2.4 Hz, H-5), 6.98 (1H, d, J = 8.1 Hz, H-40),
6.49 (2H, m, H-3, 50), 5.49 (1H, t, J = 6.6 Hz, H-200), 4.57 (2H, d,
J = 6.6 Hz, H-100), 3.90 (6H, s, 2xOMe), 1.81 (3H, s, H-400), 1.76
(H, s, H-500).13C NMR (75 MHz, CDCl3): d 192.1, 166.6, 165.5,
153.2, 149.0, 139.2, 139.1, 131.2, 129.0, 124.2, 121.9, 119.7,
118.6, 118.4, 114.2, 114.1, 108.2, 101.7, 65.1, 61.3, 55.9, 25.8,
18.2. EIMS m/z (% rel intensity): 368 (16) [M]+, 300 (17), 270
(17), 269 (100), 163 (3), 137 (6), 69 (17); HREIMS m/z Calcd
for C22H24O5, 368.1624. Found, 368.1623. Elemental Analysis:
Calcd C, 71.72; H, 6.57. Found C, 71.63; H, 6.50.
5.10. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl]-3-(4-
methoxyphenyl)prop-2-en-1-one (11)
The compound was isolated as a yellow solid (1.35 g) in 79%
yield, mp 97–98 °C. IR (neat) 2957, 294, 1624 (C@O), 1558 (C@C),
1505, 1415, 1362, 1277, 1215, 1169, 1130, 1007, 968, 627 cm
ꢀ1.1H NMR (300 MHz, CDCl3): d 13.55 (1H, s, 2-OH), 7.86 (1H, d,
J = 15.3 Hz, H-9), 7.81 (1H, d, J = 9.0 Hz, H-6), 7.62 (2H, d,
J = 9.0 Hz, H-20, 60), 7.46 (1H, d, J = 15.3 Hz, H-8), 6.94 (2H, d,
J = 9.0 Hz, H-30, 50), 6.51 (1H, d, J = 2.1 Hz, H-3), 6.49 (1H, dd,
J = 9.0, 2.1 Hz, H-5), 5.49 (1H, t, J = 6.0 Hz, H-200), 4.57 (2H, d,
J = 6.0 Hz, H-100), 3.87 (3H, s, H-40), 1.81 (3H, s, H-400), 1.76 (3H, s,
H-500).13C NMR (75 MHz, CDCl3): d 191.8, 166.5, 165.3, 161.7,
144.1, 139.1, 131.0, 130.3, 130.3, 127.5, 118.6, 117.8, 114.4,
114.4, 114.0, 108.1, 101.6, 65.1, 55.4, 25.7, 18.2. EIMS m/z (% rel
intensity): 338 (41) [M]+, 270 (100), 269 (56), 253 (9), 121 (51),
5.7. (E)-3-(2,5-Dimethoxyphenyl)-1-[2-hydroxy-4-(3-
methylbut-2-enyloxy)phenyl]prop-2-en-1-one (8)
The compound was isolated as a yellow solid (1.35 g) in 73%
yield, mp 125–126 °C. IR (neat) 2937, 1632(C@O), 1572 (C@C),
1498, 1464, 1424, 1360, 1284, 1253, 1224, 1135, 1047, 1002,
857, 807 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.52 (1H, s, 2-OH),
8.14 (1H, d, J = 15.6 Hz, H-9), 7.81 (1H, d, J = 8.7 Hz, H-6), 7.64
(1H, d, J = 15.6 Hz, H-8), 7.15 (1H, d, J = 2.7 Hz, H-60), 6.94 (1H,
dd, J = 9.0, 3.0 Hz, H-5), 6.85 (1H, d, J = 9.0 Hz, H-30), 6.48 (2H, m,
H-3, 40), 5.48 (1H, t, J = 6.6 Hz, H-200), 4.56 (2H, d, J = 6.6 Hz, H-100),
3.88 (3H, s, OMe), 3.82 (3H, s, OMe), 1.80 (3H, s, H-400), 1.75 (3H,
s, H-500).13C NMR (75 MHz, CDCl3): d 192.2, 166.5, 165.3, 153.4,
153.4, 139.7, 139.1, 131.2, 124.3, 121.2, 118.6, 117.2, 114.1,
114.0, 112.4, 108.1, 101.6, 65.1, 56.0, 55.8, 25.7, 18.2. EIMS m/z
(% rel intensity): 368 (24) [M]+, 300 (20), 269 (100), 164 (5), 137
(7), 69 (17); HREIMS m/z Calcd for C22H24O5, 368.1624. Found,
368.1621. Elemental Analysis: Calcd C, 71.72; H, 6.57. Found C,
71.72; H, 6.55.
69 (43); HREIMS m/z Calcd for
C21H22O4, 338.1518. Found,
338.1516. Elemental Analysis: Calcd C, 74.54; H, 6.55. Found C,
74.48; H, 6.58.
5.11. (E)-3-(3,4-Dimethoxyphenyl)-1-[2-hydroxy-4-(3-
methylbut-2-enyloxy)phenyl]prop-2-en-1-one (12)
The compound was isolated as a yellow solid (1.2 g) in 65%
yield, mp 108–109 °C. IR (neat) 2938, 2840, 1630 (C@O), 1566
(C@C), 1495, 1465, 1414, 1359, 1282, 1256, 1235, 1211, 1132,
1096, 1045, 1008, 796 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.58
(1H, s, 2-OH), 7.86 (1H, d, J = 15.0 Hz, H-9) 7.85 (1H, d, J = 9.0 Hz,
H-6), 7.46 (1H, d, J = 15.0 Hz, H-8), 7.29 (1H, dd, J = 9, 3.0 Hz, H-
60), 7.19 (1H, br s, H-20), 6.93 (1H, d, J = 9.0 Hz, H-50), 6.55 (1H, d,
J = 3.0, H-3), 6.52 (1H, dd, J = 9.0, 3.0 Hz, H-5), 5.51 (1H, t,
J = 6.0 Hz, H-200), 4.59 (2H, d, J = 6.0 Hz, H-100), 3.96–3.99 (6H, s,
2ꢁ OMe), 1.84 (3H, s, H-400), 1.79 (3H, s, H-500).13C NMR (75 MHz,
CDCl3): d 191.6, 166.5, 165.3, 151.5, 149.2, 144.4, 139.1, 131.0,
127.7, 123.2, 118.6, 118.0, 113.9, 111.1, 110.1, 108.1, 101.6, 65.1,
55.9, 55.9, 25.7, 18.2. EIMS m/z (% rel intensity): 368 (64) [M]+,
300 (100), 299 (42), 285 (12), 164 (44), 151 (81), 69 (48); HREIMS
m/z Calcd for C22H24O5, 368.1624. Found, 368.1621. Elemental
Analysis: Calcd C, 71.72; H, 6.57. Found C, 71.51; H, 6.61.
5.8. (E)-3-(3,5-Dimethoxyphenyl)-1-[2-hydroxy-4-(3-
methylbut-2-enyloxy)phenyl]prop-2-en-1-one (9)
The compound was isolated as a yellow solid (1.15 g) in 62%
yield, mp 142–143 °C. IR (neat) 2938, 1642 (C@O), 1600 (C@C),
1570, 1502, 1466, 1450, 1427, 1371, 1275, 1257, 1216, 1194,
1156, 1057, 967, 866, 835 cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
13.41 (1H, s, 2-OH), 7.81 (1H, d, J = 7.2 Hz, H-6), 7.79 (1H, d,
J = 15.6 Hz, H-9), 7.54 (1H, d, J = 15.6 Hz, H-8), 6.78 (2H, s, H-20,
60), 6.50 (3H, m, H-3, 5, 40), 5.48 (1H, t, J = 6.6 Hz, H-200), 4.57 (2H,
d, J = 6.6 Hz, H-100), 3.84 (3H, s, OMe), 3.82 (3H, s, OMe), 1.81 (3H,
s, 400-Me), 1.76 (3H, s, H-500).13C NMR (75 MHz, CDCl3): d 191.6,
166.6, 165.6, 161.0, 161.0, 144.3, 13.2, 136.7, 131.2, 120.8, 118.6,
113.9, 108.3, 106.4, 106.4, 102.7, 101.7, 65.2, 55.4, 55.4, 25.8,
18.2. EIMS m/z (% rel intensity): 368 (32) [M]+, 299 (31), 300
(100), 269 (27), 191 (8), 163 (27), 137 (10), 69 (46); HREIMS m/z
Calcd for C22H24O5, 368.1624. Found, 368.1624. Elemental Analy-
sis: Calcd C, 71.72; H, 6.57. Found C, 71.78; H, 6.56.
5.12. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl]-3-
(3,4,5-trimethoxyphenyl)prop-2-en-1-one (13)
The compound was isolated as a yellow solid (1.2 g) in 60%
yield, mp 143–144 °C. IR (neat) 2942, 1641 (C@O), 1571 (C@C),
1503, 1465, 1451, 1420, 1371, 1333, 1268, 1249, 1214, 1123,
970, 836, 800 cmꢀ1 1H NMR (300 MHz, CDCl3): d 13.47 (1H, s,
.

M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
7717
2-OH), 7.83 (1H, d, J = 9.0 Hz, H-6), 7.77 (1H, d, J = 15.0 Hz, H-9),
7.43 (1H, d, J = 15.0 Hz, H-8), 6.84 (2H, s, H-20, 60), 6.49 (1H, d,
J = 2.4 Hz, H-3), 6.47 (1H, dd, J = 9.0 Hz, 2.4 Hz, H-5), 5.45 (1H, t,
J = 6.0 Hz, H-200), 4.54 (2H, d, J = 6.0 Hz, H-100), 3.91 (9H, s, 3xOMe),
1.79 (3H, s, H-400), 1.74 (3H, s, H-500).13C NMR (75 MHz, CDCl3): d
191.5, 166.6, 165.5, 153.4, 144.4, 140.5, 139.1, 131.1, 130.2,
119.4, 118.6, 113.9, 108.2, 105.7, 105.3, 101.6, 65.2, 60.9, 56.2,
56.2, 25.8, 18.2. EIMS m/z (% rel intensity): 398 (76) [M]+, 330
(100), 329 (20), 299 (14), 287 (9), 194 (30), 181 (72), 163 (14),
137 (8), 69 (44); HREIMS m/z Calcd for C23H26O6, 398.1729. Found,
398.1731. Elemental Analysis: Calcd C, 69.33; H, 6.58. Found C,
69.20; H, 6.57.
148.4, 144.2, 132.2, 131.1, 129.2, 125.3, 118.3, 118.2, 114.2,
108,.6, 108.0, 106.6, 101.9, 101.6, 68.9; EIMS, m/z (% rel intensity):
324 (100), [M]+, 323 (32), 283 (21), 255 (10), 203 (15), 148 (69),
135 (44); HREIMS m/z Calcd for C19H16O5, 324.0998. Found,
324.0997. Elemental Analysis: Calcd C, 70.36; H, 4.97. Found C,
70.38; H, 5.01.
5.16. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-(2,5-
dimethoxyphenyl)prop-2-en-1-one (17)
The compound was isolated as a yellow solid (2.2 g) in 64%
yield, mp 101–102 °C. IR (neat) 2941, 2835, 1632 (C@O), 1496
(C@C), 1464, 1425, 1361, 1287, 1255, 1179, 1133, 1047, 1016,
984, 856 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.51 (1H, s, 2-OH),
8.15 (1H, d, J = 15.3 Hz, H-9), 7.82 (1H, d, J = 9.0 Hz, H-6), 7.66
(1H, d, J = 15.3 Hz, H-8), 7.16 (1H, d, J = 2.4 Hz, H-60), 6.95 (1H,
dd, J = 9.0, 2.4 Hz, H-5), 6.88 (1H, d, J = 9.0 Hz, H-30), 6.52 (1H, dd,
J = 9.0, 2.1 Hz, H-40), 6.47 (1H, d, J = 2.1 Hz, H-3), 6.05 (1H, m, H-
200), 5.38 (2H, m, H-300), 4.59 (2H, d, J = 6.0 Hz, H-100), 3.89 (3H, s,
OMe), 3.83 (3H, s, OMe).13C NMR (75 MHz, CDCl3): d 192.3,
166.5, 164.9, 153.4, 153.4, 139.8, 132.2, 131.3, 124.3, 121.2,
118.3, 117.3, 114.3, 114.0, 112.4, 107.9, 101.8, 68.9, 56.1, 55.8.
EIMS m/z (% rel intensity): 340 (40) [M]+, 310 (21), 309 (100),
268 (11), 203 (6), 164 (8); HREIMS m/z Calcd for C20H20O5,
340.1311. Found, 340.1308. Elemental Analysis: Calcd C, 70.57;
H, 5.92. Found C, 70.42; H, 5.84.
5.13. (E)-1-(4-[Allyloxy)-2-hydroxyphenyl]-3-(2,3,4-
trimethoxyphenyl)prop-2-en-1-one (14)
The compound was isolated as a yellow solid (2.5 g) in 67%
yield, mp 122–123 °C. IR (neat) 2945, 2828, 1629 (C@O), 1575
(C@C), 1505, 1465, 1435, 1413, 1363, 1283, 1257, 1217, 1194,
1132, 1094, 1041, 1003, 986, 969, 938, 906, 862, 835, 799 cm
ꢀ1.1H NMR (300 MHz, CDCl3): d 13.57 (1H, s, 2-OH), 8.06 (1H, d,
J = 15.6 Hz, H-9), 7.82 (1H, d, J = 9.0 Hz, H-6), 7.63 (1H, d,
J = 15.6 Hz, H-8), 7.37 (1H, d, J = 9.0 Hz, H-60), 6.72 (1H, d,
J = 9.0 Hz, H-50), 6.51 (1H, d, J = 3.0 Hz, H-3), 6.48 (1H, dd, J = 9.0,
3.0 Hz, H-5), 5.44 (1H, m, H-200), 5.37 (2H, m, H-300), 4.58 (2H, d,
J = 6.0 Hz, H-100), 3.97 (3H, s, OMe), 3.92 (3H, s, OMe), 3.90 (3H, s,
OMe).13C NMR (75 MHz, CDCl3): d 192.2, 166.4, 164.8, 155.9,
153.9, 142.4, 139.8, 132.2, 131.1, 124.2, 121.8, 119.4, 118.3,
114.3, 107.9, 107.5, 101.8, 68.9, 61.3, 60.9, 56.0. EIMS m/z (% rel
intensity): 370 (15) [M]+, 339 (100), 298 (8), 270 (2); HREIMS m/
z Calcd for C21H22O6, 370.1416. Found, 370.1419. Elemental Analy-
sis: Calcd C, 68.10; H, 5.99. Found C, 68.13; H, 6.03.
5.17. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-(4-
methoxyphenyl)prop-2-en-1-one (18)
The compound was isolated as a yellow solid (2.6 g) in 83%
yield, mp 126–127 °C. IR (neat) 2914, 2841, 1626 (C@O), 1562
(C@C), 1505, 1416, 1370, 1279, 1219, 1139, 1006, 975, 885,
810 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.82 (1H, s, 2-OH),
7.86 (1H, d, J = 15.3 Hz, H-9), 7.83 (1H, d, J = 9.0 Hz, H-6), 7.61
(2H, d, J = 9.0 Hz, H-20, 60), 7.45 (1H, d, J = 15.3 Hz, H-8), 6.94
(2H, d, J = 9.0 Hz, H-30, 50), 6.52 (1H, d, J = 3.0 Hz, H-3), 6.50
(1H, dd, J = 9.0, 3.0 Hz, H-5), 6.05 (1H, m, H-200), 5.41 (2H, m,
H-300), 4.59 (2H, d, J = 6.0 Hz, H-100), 3.86 (3H, s, OMe).13C NMR
5.14. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-(2,3-
dimethoxyphenyl)prop-2-en-1-one (15)
The compound was isolated as a pale yellow solid (2.7 g) in 79%
yield, mp 129–130 °C. IR (neat) 2941, 2835, 1632, 1572, 1497,
1464, 1425, 1361, 1254, 1224, 1133, 1046, 1015, 856, 806 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 13.51 (1H, s, 2-OH), 8.15 (1H, d,
J = 15.6 Hz, H-9), 7.82 (1H, d, J = 9.0 Hz, H-6), 7.66 (1H, d,
J = 15.6 Hz, H-8), 7.15 (1H, dd, J = 9.0, 3.0 Hz, H-60), 6.88 (1H, d,
J = 9. Hz, H-50), 6.50 (2H, m, H-3, 40), 6.05 (1H, m, H-200), 5.38 (2H,
m, H-300), 4.59 (2H, d, J = 5.1 Hz, H-100), 3.88 (3H, s, OMe), 3.82
(3H, s, OMe). 13C NMR (75 MHz, CDCl3): d 192.3, 166.5, 164.9,
153.4, 153.4, 139.8, 132.2 131.3, 124.3, 121.2, 118.3, 117.3, 114.3,
114.0, 112.4, 107.9, 101.8, 68.9, 56.1, 55.8. EIMS m/z (% rel inten-
sity): 340 (52) [M]+, 310 (26), 309 (100), 268 (13), 240 (5), 203
(8), 164 (10), 69 (1); HREIMS m/z Calcd for C20H20O5, 340.1311.
Found, 340.1308. Elemental Analysis: Calcd C, 70.57; H, 5.92.
Found C, 70.37; H, 5.92.
(75 MHz, CDCl3): d 191.8, 166.5, 164.9, 161.8, 144.2, 132.2,
131.1, 130.3, 130.3, 127.5, 118.3, 117.8, 114.4, 114.4, 114.2,
108.0, 101.9, 68.9, 55.4. EIMS m/z (% rel intensity): 310 (100)
[M]+, 309 (54), 269 (39), 241 (22), 203 (20), 161 (21), 134
(100), 121 (56). HREIMS m/z Calcd for
C19H18O4, 310.1205.
Found, 310.1204. Elemental Analysis: Calcd C, 73.53; H, 5.85.
Found C, 73.46; H, 5.88.
5.18. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-(2,4-
dimethoxyphenyl)prop-2-en-1-one (19)
The compound was isolated as a yellow solid (2.0 g) in 58%
yield, mp 129–130 °C. IR (neat) 2945, 1627 (C@O), 1550 (C@C),
1501, 1413, 1360, 1295, 1253, 1216, 1138, 991, 833 cmꢀ1.1H
5.15. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-
(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one (16)
NMR (300 MHz, CDCl3): d 13.70 (1H, s, 2OH), 8.11 (1H, d,
J = 15.3 Hz, H-9), 7.80 (1H, d, J = 9.0 Hz, H-6), 7.58 (1H, d,
J = 15.3 Hz, H-8), 7.53 (1H, dd, J = 9.0, 2.4 Hz, H-6), 6.49 (4H, m,
H-3, 5, 30, 50), 6.02 (1H, m, H-200), 5.36 (2H, m, H-300), 4.56 (2H, d,
J = 6.0 Hz, H-100), 3.90 (3H, s, OMe), 3.84 (3H,s, OMe).13C NMR
(75 MHz, CDCl3): d 192.4, 166.3, 164.6, 163.1, 160.4, 140.1, 132.2,
131.1, 131.1, 118.2, 118.1, 116.9, 114.3, 107.6, 105.4, 101.7, 98.3,
68.8, 55.4, 55.4. EIMS m/z (% rel intensity): 341 (19), 340 (90)
[M]+, 339 (17), 309 (100), 299 (19), 164 (50), 151 (66), 149 (24),
121 (10), 69 (3); HREIMS m/z Calcd for C20H20O5, 340.1311. Found,
340.1312. Elemental Analysis: Calcd C, 70.57; H, 5.92. Found C,
70.33; H, 5.86.
The compound was isolated as a yellow solid (2.4 g) in 74%
yield, mp 152–153 °C. IR (neat) 2909, 1627 (C@O), 1564 (C@C),
1490, 1446, 1377, 1290, 1252, 1218, 1123, 1103, 1039, 931,
799 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.47 (1H, s, 2-OH), 7.80
(1H, d, J = 15.0 Hz, H-9), 7.79 (1H, d, J = 9.0 Hz, H-6), 7.39 (1H, d,
J = 15.0 Hz, H-8), 7.16 (1H, d, J = 0.9 Hz, H-20), 7.13 (1H, br d,
J = 8.1 Hz, H-60), 6.85 (1H, d, J = 8.1 Hz, H-50), 6.52 (1H, d,
J = 2.4 Hz, H-3), 6.47 (1H, d, J = 9.0 Hz, H-5), 6.03 (1H, m, H-200),
6.02 (2H, s, –OCH2O–), 5.38 (2H, m, H-300), 4.58 (2H, d, J = 5.1 Hz,
H-100).13C NMR (75 MHz, CDCl3): d 191.6, 166.5, 165.0, 150.0,

7718
M. Vijaya Bhaskar Reddy et al. / Bioorg. Med. Chem. 19 (2011) 7711–7719
5.19. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-(3,4,5-
trimethoxyphenyl)prop-2-en-1-one (20)
(3H, m, H-30, 4, 50), 6.53 (1H, d, J = 1.5 Hz, H-3), 6.51 (1H, br d,
J = 9.0 Hz, H-5), 6.03 (1H, m, H-200), 5.38 (2H, m, H-300), 4.58 (2H,
d, J = 4.5 Hz, H-100).13C NMR (75 MHz, CDCl3): d 191.7, 166.5,
165.1, 144.3, 134.7, 132.2, 131.2, 130.6, 128.9, 128.4, 120.2,
118.3, 114.1, 108.0, 101.8, 68.9. EIMS m/z (% rel intensity): 280
(97), [M]+, 279 (53), 239 (29), 203 (88), 192 (28), 177 (71), 165
(98), 137 (48), 131 (43), 103 (89), 77 (100). HREIMS m/z Calcd for
The compound was isolated as a light yellow solid (2.3 g) in 62%
yield, mp 171–172 °C. IR (neat) 2984, 2838, 1640, 1575, 1502,
1451, 1419, 1371, 1332, 1270, 1218, 1193, 1125, 1007, 971, 861,
837 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.68 (1H, s, 2-OH), 7.83
(1H, d, J = 9.0 Hz, H-6), 7.79 (1H, d, J = 15.0 Hz, H-9), 7.44 (1H, d,
J = 15.0 Hz, H-8), 6.86 (2H, s, H-20, 60), 6.51 (1H, dd, J = 9.0, 3.0 Hz,
H-5), 6.47 (1H, d, J = 3.0 Hz, H-3), 6.03 (1H, m, H-200), 5.39 (2H, m,
H-300), 4.58 (2H, d, J = 6.0 Hz, H-100), 3.90–3.93 (9H, s, 3xOMe).13C
NMR (75 MHz, CDCl3): d 191.5, 166.5, 165.0, 153.4, 153.4, 144.5,
140.5, 132.1, 131.1, 130.2, 119.3, 118.3, 114.1, 108.0, 105.7,
105.7, 101.8, 68.9, 60.9, 56.2, 56.2. EIMS m/z (% rel intensity):
370 (100) [M]+, 369 (18), 329 (16), 301 (9), 194 (38), 181 (82),
179 (18). HREIMS m/z Calcd for C21H22O6, 370.1416. Found,
370.1419. Elemental Analysis: Calcd C, 68.10; H, 5.99. Found C,
68.16; H, 6.00.
C18H16O3, 280.1099. Found 280.1101. Elemental Analysis: Calcd
C, 77.12; H, 5.75. Found 76.39; H, 5.77.
6. Preparation of the platelet suspension
Washed platelet suspension was prepared as previously de-
scribed with some modifications.20–22 In brief, blood was col-
lected from the marginal ear vein of New Zealand white rabbits
into tubes containing one-sixth volume of acid-citrate dextrose
as anticoagulant. The blood was centrifuged at 1000g for 8 min
at room temperature. The upper portion was kept as platelet-rich
plasma (PRP) after mixing with EDTA to a final concentration of
5 mM and re-centrifuged at 2000g for 12 min. The platelet pellet
was suspended in modified Ca2+-free Tyrode0s buffer (137 mM
NaCl, 2.8 mM KCl, 2 mM MgCl2, 0.33 mM NaH2PO4, 5 mM glucose,
10 mM HEPES) with 0.35% bovine serum albumin, heparin
(50 unit/mL), and apyrase (1 unit/mL) and then was incubated
at 37 °C for 20 min. After centrifugation at 2000g for 6 min, the
washed platelet pellet was resuspended in Tyrode’s buffer con-
taining 1 mM Ca2+. For the aggregation test, the platelet numbers
were counted by hemacytometer calculator and adjusted to
2.5 ꢁ 108 platelets/mL.
5.20. (E)-1-(4-[Allyloxy)-2-hydroxyphenyl]-3-(2,4,5-
trimethoxyphenyl)prop-2-en-1-one (21)
The compound was isolated as a bright yellow solid (2.5 g) in
67% yield, mp 116–117 °C. IR (neat) 2936, 2836, 1628 (C@O),
1556 (C@C), 1510, 1466, 1410, 1375, 1342, 1208, 1126, 1028,
985, 850, 745, 649 cmꢀ1.1H NMR (300 MHz,CDCl3): d 13.68 (1H,
s, 2-OH), 8.18 (1H, d, J = 15.6 Hz, H-9), 7.83 (1H, d, J = 9.0 Hz, H-
6), 7.54 (1H, d, J = 15.6 Hz, H-8), 7.12 (1H, s, H-60), 6.50 (3H, m,
H-3, 5, 30), 6.08 (1H, m, H-200), 5.41 (2H, m, H-300), 4.59 (2H, d,
J = 6.0 Hz, H-100), 3.92–3.96 (9H, s, 3 ꢁ OMe). 13C NMR (75 MHz,
CDCl3): d 192.3, 166.4, 164.7, 154.8, 152.7, 143.3, 139.8, 132.2,
131.1, 118.3, 118.1, 115.4, 114.4, 111.7, 107.8, 101.8, 96.8, 68.9,
56.6, 56.3, 56.0. EIMS m/z (% rel intensity): 370 (75) [M]+, 340
(29), 339 (100), 301 (10), 298 (20), 214 (27), 194 (22), 181 (34).
HREIMS m/z Calcd for C21H22O6, 370.1416. Found 370.1416. Ele-
mental Analysis: Calcd C, 68.10; H, 5.99. Found 68.21; H, 5.85.
6.1. Measurement of Platelet Aggregation
Platelet aggregation was measured turbid metrically with a
light-transmission Platelet Aggregation Chromogenic Kinetic Sys-
tem PACK4 (Helena Laboratories, Beaumont TX) with some modi-
fications20-22. The platelet suspension was stirred at 900 rpm and
incubated with an appropriate amount of vehicle (dimethyl sulfox-
5.21. (E)-1-(4-[Allyloxy)-2-hydroxyphenyl]-3-(3,5-
dimethoxyphenyl)prop-2-en-1-one (22)
ide, DMSO), 50
control (30 M of clopidogrel) at 37 °C for 2 min. Aggregation
was induced with ADP (20 M) or collagen (10 g/mL). The trans-
lg/mL of test compounds in DMSO, and positive
l
l
l
The compound was isolated as a yellow solid (2.69 g) in 79%
yield, mp 142–143 °C. IR (neat) 2937, 2841, 1639 (C@O), 1600
(C@C), 1573, 1502, 1460, 1428, 1369, 1276, 1256, 1193, 1156,
mission of washed platelet suspension was assigned 0% aggrega-
tion while transmission through Tyrode0s buffer was assigned
100% aggregation. The extent of platelet aggregation was measured
as the maximal increase in light transmission within 4 min after
the addition of an inducer. To eliminate or minimize any possible
effects of the solvent, the final concentration of DMSO in the plate-
let suspension was fixed at 0.5%.
1060, 971, 927, 861, 836 cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
13.39 (1H, s, 2-OH), 7.82 (1H, d, J = 9.0 Hz, H-6), 7.78 (1H, d,
J = 15.0 Hz, H-9), 7.51 (1H, d, J = 15.0 Hz, H-8), 6.78 (2H, s, H-20,
60), 6.49 (3H, m, H-3,5,40), 6.04 (1H, m, H-200), 5.38 (2H, m, H-300),
4.59 (2H, d, J = 3.6 Hz, H-100), 3.84 (6H, s, 2ꢁ OMe). 13C NMR
(75 MHz, CDCl3): d 191.7, 166.6, 165.2, 161.0, 144.4, 136.6, 132.1,
131.3, 120.8, 118.4, 114.1, 108.1, 106.4, 102.8, 101.9, 69.0, 55.4.
EIMS m/z (% rel intensity): 340 (100) [M]+, 339 (31), 299 (62),
271 (27), 257 (16), 243 (18), 203 (78), 191 (26), 164 (46), 148
(35), 91 (28), 77 (32). HREIMS m/z Calcd for C20H20O5, 340.1311.
Found, 340.1310. Elemental Analysis: Calcd C, 70.57; H, 5.72.
Found C, 70.43; H, 5.87.
Acknowledgments
This work was supported by a Grant of National Science Coun-
cil, Taiwan, Republic of China, and Grant No.(OUA 95-3-2-021)
from the National Cheng Kung University, Tainan, Taiwan R.O.C
awarded to T. S. Wu. This study is supported in part by Taiwan
Department of Health Clinical Trial and Research Center of Excel-
lence (DOH100-TD-B-111-004).
5.22. (E)-1-[4-(Allyloxy)-2-hydroxyphenyl]-3-phenylprop-2-en-
1-one (23)
References and notes
The compound was isolated as a pale yellow solid (1.8 g) in 64%
yield, mp 83–84 °C. IR (neat) 3024, 2895, 1647 (C@O), 1577 (C@C),
1504, 1450, 1369, 1298, 1276, 1217, 1194, 1175, 1106, 976, 920,
869, 03, 764, 732, 697 cmꢀ1.1H NMR (300 MHz, CDCl3): d 13.42
(1H, s, 2-OH), 7.88 (1H, d, J = 15.6 Hz, H-9), 7.83 (1H, d, J = 9.0 Hz,
H-6), 7.64 (2H, m, H-20, 60), 7.57 (1H, d, J = 15.6 Hz, H-8), 7.42
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