Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents

Article abstract of DOI:10.1016/j.bmc.2008.06.018

The chalcone skeleton (1,3-diphenyl-2-propen-1-one) is a unique template that is associated with various biological activities. We synthesized Mannich bases of heterocyclic chalcones (9-47) using a one-step Claisen-Schmidt condensation of heterocyclic aldehydes with Mannich bases of acetophenones, and tested the target compounds for cytotoxicity against three human cancer cell lines (prostate, PC-3; breast, MCF-7; nasopharynx, KB) and a multi-drug resistant subline (KB-VIN). Out of the 39 chalcones synthesized, 31 compounds showed potent activity against at least one cell line with IC₅₀ values ranging from 0.03 to 3.80 μg/mL. Structure-activity relationships (SAR) are also discussed.

Full text of DOI:10.1016/j.bmc.2008.06.018

Bioorganic & Medicinal Chemistry 16 (2008) 7358–7370
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis, and biological evaluation of Mannich bases
of heterocyclic chalcone analogs as cytotoxic agents
M. Vijaya Bhaskar Reddy a, Chung-Ren Su a, Wen-Fei Chiou b, Yi-Nan Liu c, Rosemary Yin-Hwa Chen c,
Kenneth F. Bastow c, Kuo-Hsiung Lee c, Tian-Shung Wu a,
*
a Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan
b National Research Institute of Chinese Medicine, Taipei 112, Taiwan
c Natural Products Research Laboratories, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The chalcone skeleton (1,3-diphenyl-2-propen-1-one) is a unique template that is associated with vari-
ous biological activities. We synthesized Mannich bases of heterocyclic chalcones (9–47) using a one-step
Claisen–Schmidt condensation of heterocyclic aldehydes with Mannich bases of acetophenones, and
tested the target compounds for cytotoxicity against three human cancer cell lines (prostate, PC-3; breast,
MCF-7; nasopharynx, KB) and a multi-drug resistant subline (KB-VIN). Out of the 39 chalcones synthe-
sized, 31 compounds showed potent activity against at least one cell line with IC50 values ranging from
Received 4 February 2008
Revised 10 June 2008
Accepted 11 June 2008
Available online 14 June 2008
Keywords:
0.03 to 3.80
l
g/mL. Structure–activity relationships (SAR) are also discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Mannich bases of heterocyclic chalcones
Cytotoxicity
1. Introduction
as well as several human tumor cell lines.24 Mannich bases have
been associated with increased bioactivity.25 The presence of a
Mannich base group in chalcones and other compound types
may increase biological potency due to the greater number of
molecular sites for electrophilic attack by cellular constituents, as
well as due to the cascade effect of preferential
chemosensitization.
Heterocyclic chalcones play important roles as anti-ulcer, herbi-
cidal, anti-bacterial, analgesic, sedative, anti-phlogistic and viru-
cidal agents.26 However, to the best of our knowledge, no
literature exists on the synthesis and biological evaluation of Man-
nich bases of heterocyclic chalcones. Aminoalkylation of aromatic
substrates by the Mannich reaction has considerable importance
for the synthesis and modification of biologically active com-
pounds. This technique provides convenient access to many useful
synthetic building blocks, because the resulting amino group can
be easily converted to various functionalities, particularly, to qua-
ternary ammonium salts to increase water solubility. Accordingly,
we synthesized 39 Mannich base derivatives of heterocyclic chal-
cones, based on the above pharmacological importance of the chal-
cone moiety.
Chalcones, which are considered to be precursors of flavonoids
and isoflavonoids, are abundant in edible plants. Chemically they
are open-chain flavonoids in which the two aromatic rings are
joined by a three-carbon a,b-unsaturated carbonyl system (1,3-di-
phenyl-2-propen-1-one). Chalcones exhibit many pharmacological
activities, including anti-leishmanial,1 anti-inflammatory,2–4 anti-
mitotic,5 anti-invasive,6,7 anti-tuberculosis,8 anti-fungal,9 CyLT1
(LTD4) receptor antagonist,10 anti-malarial,11,12 anti-plasmodial,
immunosupressive, cytotoxic, anti-tumor, and anti-oxidant prop-
erties,13 and modulation of P-glycoprotein-mediated multi-drug
resistance.14 Recent studies have shown that chalcones inhibit can-
cer cell proliferation, are effective agents in vivo against skin carci-
nogenesis15,16 and induce apoptosis in various cell types, including
breast cancers.17,18 Several oxygenated chalcones, bischalcones,
and some quinolinyl chalcone analogs reportedly show anti-malar-
ial activity.19,20
Amodiaquine, amopyroquine, tebuquine, and tert-butylamo-
diaquine, which are semi-synthetic Mannich base derivatives of
chloroquine,21 and artemisin derivatives bearing Mannich bases
showed potent in vitro and in vivo anti-malarial activity.22 Man-
nich bases of phenolic azobenzenes demonstrated cytotoxic activ-
ity,23 and various Mannich base analogs of chalcones exhibited
potent cytotoxicity against murine P338 and L1210 leukemia cells
Herein, we describe the synthesis and in vitro biological evalu-
ation of Mannich bases of heterocyclic chalcones with different
substitution patterns in the B-ring, together with a discussion of
structure–activity relationships. All new analogs were tested for
cytotoxic activity against PC-3 (prostate cancer), MCF-7 (human
breast cancer), KB (nasopharyngeal carcinoma), and KB-VIN
(vincristine-resistant KB subline) to obtain preliminary biological
* Corresponding author. 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.06.018

M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
7359
profiles of this compound series that will be useful in the further
design and development of Mannich bases of heterocyclic
chalcones.
Although there were no direct comparisons among analogs with
C-40 methoxy groups, compounds 19 and 20 (B-ring@3-pyridyl
and phenyl, respectively; C-30 Mannich base) were more active
than 10 (B-ring@2-pyridyl; C-50 Mannich base) against MCF-7
and PC-3 cells. These results indicate that a C-30 Mannich base is
preferable to a C-50 Mannich base.
2. Chemistry
Compounds 25–32 have the same Mannich base at C-30 and a
hydroxy group at C-40, but differ in the identity of the B-ring. Com-
pounds 25–28, which bear 2-, 3-, and 4-pyridyl and phenyl groups,
respectively, were more potent against all cell lines (EC50
As shown in Scheme 1, compound 1 underwent regioselective
reaction with an alkyl halide (ethyl iodide, methyl iodide, isopropyl
bromide, or prenyl bromide) at the non hydrogen-bonded phenol
in the presence of K2CO3 in dry acetone at 80 °C to yield 4-alk-
oxy-substituted acetophenones 2a, 3a, 4a, and 5a, respectively.
These four acetophenones and 1 were reacted with morpholine
and 37% formaldehyde in EtOH at 120 °C for 18–22 h to provide
C-3 or C-5 substituted Mannich base derivatives (1a, 2b/c, 3b/c,
4b/c, and 5b) (Scheme 1). Similar reactions of 4-hydroxyacetophe-
none 6 and 3-hydroxyacetophenone 7 gave mono- (6a, 7a, and 7b)
and di-substituted (6b and 7c) Mannich base derivatives. 3-Hydro-
xy-4-methoxybenzaldehyde 8 was reacted separately with piperi-
dine and morpholine to obtain C-2 Mannich base derivatives 8a
and 8b, respectively.
The designed target compounds (9–42) depicted in Scheme 2
were obtained by reacting 2b, 2c, 3b, 3c, 4b, 4c, 5b, 6a, 6b, 7a,
7b, and 7c (Mannich bases of acetophenones 2a–7) with various
heterocyclic aldehydes under Claisen–Schmidt conditions using
30% KOH in MeOH at room temperature. In addition, 8a and 8b
(Mannich bases of benzaldehyde 8) were condensed with
30-methyl- and 40-methylacetophenone, 2-acetylthiophene, 2-ace-
tylfuran, and 3-acetylpyridine under similar conditions to yield
43–47, respectively, in good yields.
0.10–2.11 lg/mL) than analogs with five-membered heterocycles
(2-furan 29, 2-thiophene 30, 3-methyl-2-thiophene 31, and 5-
methyl-2-furan 32). A similar comparison was found between 33
and 34, which have two Mannich base groups in the A-ring. Com-
pound 33, with a six-membered 2-pyridyl B-ring, showed higher
cytotoxicity against all four cell lines (EC50 1.72, 1.34, 2.31, and
2.27
lg/mL, respectively) than 34, which has a five-membered
3-methyl-2-thiophene group. These results indicate that
a
six-membered B-ring, particularly a pyridyl group, is important
for enhanced cytotoxic activity.
Notably, compound 25, with only one Mannich base group, was
significantly more potent against all cell lines (EC500.31, 0.12, 0.73
and 0.30
lg/mL) than 33, with two Mannich base groups (EC50
1.72, 1.34, 2.31 and 2.27
lg/mL). Compound 25 was also generally
more potent than 9, which is structurally identical except for an
added 20-OH group.
The positions of the Mannich base and hydroxy group also had
some effect on activity. Compounds 35–37 are positional isomers
of 25–27. In the former compounds, the Mannich base and hydro-
xyl are at C-30 and C-40, respectively, while in the latter com-
pounds, these groups are at C-40 and C-50, respectively. Both sets
of compounds were significantly active in all assays, but 25–27
3. Results and discussion
were generally more potent than 35–37 (e.g., EC50 0.12–0.73
l
g/
The 39 Mannich bases of heterocyclic chalcones were evaluated
for cytotoxic activity against four human cancer cell lines (PC-3,
MCF-7, KB, and KB-VIN). The results are shown in Table 1.
Among analogous compounds 9–12, analog 9 showed signifi-
cant cytotoxic activity against all four cell lines, with EC50 values
mL for 25, EC50 0.43–1.30
lg/mL for 35). In addition, compound
33, bearing two Mannich base groups at C-20 and C-50 and a hydro-
xy group at C-40 was less potent than 42, bearing two Mannich
base groups at C-20 and C-40 and a hydroxyl at C-30.
As previously found with analogs 29–31, compounds 38–40,
which have five-membered B-rings (2-furan, 2-thiophene and 3-
methyl-2-thiophene), showed little potency against the tested cell
lines. However, compound 41, which has a phenyl group as the B-
ring, showed significant cytotoxic activity against all cell lines,
with EC50 values of 0.33, 0.28, 0.83, and 0.36 lg/mL.
Compounds 43 and 45–47, which have a Mannich base in the A-
ring rather than B-ring, showed significant activity against MCF-7
of 0.95 (PC-3), 0.08 (MCF-7), 1.54 (KB), and 0.80 (KB-VIN)
Compounds 10 and 11 showed significant activity against MCF-7
and KB-VIN cell lines (EC50 0.25/0.66 and 1.13/1.45 g/mL, respec-
lg/mL.
l
tively) and moderate cytotoxicity against PC-3 (only 11) and KB
(only 10). Compound 12 showed moderate activity only against
the MCF-7 cell line. Compound 9 was more active than 10,
although they have only one structural difference. Both com-
pounds possess a 2-pyridyl B-ring but have a hydroxy and methoxy
group, respectively, at the A-ring C-40 position. Thus, from an SAR
viewpoint, the hydroxy functionality is responsible for enhancing
cytotoxic activity in 9.
cells with EC50values of 0.42, 0.36, 0.11, 0.47, and 0.30 lg/mL,
respectively, but showed varying potencies against the other three
cell lines. Overall, compound 43 with a 3-methylphenyl A-ring
showed greater cytotoxicity than 45–47 with 2-thiophenyl, 2-fura-
nyl, and 3-pyridyl A-rings.
The following general observations were made from the study
results. With the exception of 13–15, 17, 18, 31, and 34, all synthe-
sized heterocyclic chalcones showed cytotoxic activity
Analogs 13–18, with a C-40 ethyl group and various phenyl and
heterocyclic B-rings, showed weak activity or no activity against
the four cell lines with EC50 values ranging from 3.14 to
20.00
lg/mL. Interestingly, compounds 19 and 20 were much more
potent [EC50 0.84 and 0.78 (PC-3). 0.10 and 0.03 (MCF-7)
l
g/mL,
(EC50 < 4
lg/mL) against at least one cell line. Compounds 25, 27,
respectively] than the corresponding 13 and 17. The two pairs of
compounds are structurally identical, except for a C-40 methyl
group in 19 and 20 rather than a C-40 ethyl group in 13 and 17. This
difference clearly indicates that, among these compounds, the C-40
methoxy group in ring A is of great importance to the activity. Ana-
log 24, which has a C-40 isopropoxy group, showed significant po-
41, and 42 had EC50 values less than 1
l
g/mL against all four cell
lines, and 9, 26, 28, 35, and 43 against three cell lines. MCF-7
and PC-3 were generally more sensitive than KB and KB-VIN cell
lines to these heterocyclic chalcones.
4. Conclusions
tency only against MCF-7 cells (EC50 0.24
lg/mL); however, it was
more potent than 22 (EC50 3.12
l
g/mL), which has a C-40-methoxy
In summary, we designed and synthesized a series of Mannich
bases of heterocyclic chalcones, which were structurally confirmed
by IR, 1H, 13C NMR, EIMS, HREIMS and elemental analysis and evalu-
ated their cytotoxicity against four human cancer cell lines (PC-3,
group, against this cell line. In addition, compounds 11 and 24 dif-
fer only in the position of the Mannich base group: C-30 in the for-
mer and C-50 in the latter. Compound 24 was somewhat more
active than 11 against MCF-7 cells (EC50 0.24 vs 0.66 lg/mL).

7360
M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
HO
a
N
O
OH
O
1a
O
N
H3CH2CO
b
H3CH2CO
H3CH2CO
+
a
OH
O
OH
2b
O
N
O
OH O
2a
2c
O
N
HO
MeO
MeO
c
MeO
a
+
OH
O
N
O
OH
O
OH
O
OH
O
O
1
3a
3b
3c
N
a
O
O
d
O
+
N
O
OH
4c
O
OH
O
OH
4b
O
4a
O
O
a
e
N
O
OH
O
OH
O
5a
5b
O
N
HO
HO
HO
HO
a
a
O
N
O
O
O
N
O
O
6
6
6b
6a
O
O
OH
OH
OH
N
OH
N
a
N
N
+
+
O
O
7
O
7b
O
7a
7c
O
O
N
OH
f
OMe
OMe
OH
OHC
O
OMe
8a
OH
OHC
N
8
g
OHC
8b
Scheme 1. Reagents and conditions: (a) HCHO, morpholine, reflux at 120 °C in 18–22 h; (b) MeI, Me2CO, reflux at 80 °C in 6 h; (c) C2H5I, Me2CO, reflux at 80 °C in 6 h;
(d) isopropyl bromide, Me2CO, reflux at 80 °C in 8 h; (e) prenyl bromide, Me2CO, reflux at 80 °C in 6 h; (f) HCHO, piperidine, reflux at 120 °C in 18–22 h.

M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
7361
O
N
RO
RO
B ring
B ring
N
O
OH
O
OH
O
R
B-ring
R
B-ring
13. ethyl
3-pyridyl
14. ethyl
2-furan
9. H
2-pyridyl
10. Me
2-pyridyl
15. ethyl
5-methyl-2-furan
2-pyridyl
11. isopropyl
12. prenyl
2-thiophene
3-methyl-2-thiophene
16. ethyl
17. ethyl
phenyl
18. ethyl
3-methyl-2-thiophene
3-pyridyl
19. methyl
20. methyl
21. methyl
22. methyl
23. methyl
24. 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
B-ring
O
35. 2-pyridyl
36. 3-pyridyl
37. 4-pyridyl
B-ring
B-ring
25. 2-pyridyl
33. 2-pyridyl
26. 3-pyridyl
34. 3-methyl-2-thiophene
27. 4-pyridyl
28. phenyl
29. 2-furan
30. 2-thiophene
31. 3-methyl-2-thiophene
32. 5-methyl-2-thiophene
O
O
OH
N
OH
N
N
B ring
O
N
O
O
42.
B-ring
38. 2-furan
39. 2-thiophene
40. 3-methl-2-thiophene
41. phenyl
OMe
OMe
OH
A ring
A ring
OH
N
O
O
N
O
A-ring
A-ring
45. 2-thiophene
46. 2-furan
43. 3-Me-C6H4
44. 4-Me-C6H4
47. 3-pyridyl
Scheme 2.
MCF-7, KB, and KB-VIN).The results showed that out of the 39 chal-
cones tested, 35 compounds showed potent activity against at least
one cell line. The most active compounds are 9 and 20 with IC50 val-
gave combustion values for C, H, N, and S within 0.4% of the theo-
retical values. 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
UV. Concentration of the reaction solutions involved the use of ro-
tary evaporator under reduced pressure.
ues of 0.08 and 0.03 lg/mL, respectively, against the MCF-7 cell line.
5. Experimental
5.1. Chemistry
5.1.1. General procedure for the synthesis of 2a, 3a, 4a, and 5a
To a solution of 2,4-dihdroxyacetophenone (1) in acetone
(100 mL) was added freshly ignited K2CO3 (6.0 g) followed by ethyl
iodide, methyl iodide, isopropyl bromide, or prenyl bromide at
room temperature. Each reaction mixture was separately refluxed
for 8 h at 80 °C. The progress of the reaction was monitored by TLC.
On completion of the reaction, the solvent was removed by filtra-
tion and evaporated under reduced pressure and the residue was
purified by column chromatography (hexanes and EtOAc mixtures)
to yield the title compounds 2a, 3a, 4a, and 5a, respectively.
Melting points were determined 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 are reported in parts per million (ppm, d). EIMS and HREIMS
spectra were obtained on a VG-70-250S mass spectrometer. Ele-
mental analyses were determined by Elementer Vario EL III and

7362
M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
Table 1
yield 4a as a yellow syrup (7.6 g, 76%). IR (neat) 2980, 1633,
1583, 1426, 1371, 1330, 1273, 1256, 1175, 1136, 1066, 923, 834,
804 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 12.68 (1H, s, OH), 7.52
(1H, d, J = 9.0 Hz), 6.32 (2H, br s), 4.52 (1H, m), 2.45 (3H, s), 1.29
(6H, d, J = 6.0 Hz). EIMS, m/z (% rel. intensity): 194 (23) [M]+, 152
(17), 137 (100), 123 (2), 105 (1), 77 (2), 43 (9).
Cytotoxic activity data for compounds 9–47
.
Compound
EC50
MCF-7
(
l
g/mL)
PC-3
KB
KB-VIN
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
45
46
47
0.95
10.52
2.80
NAa
NA
NA
0.08
0.25
0.66
3.19
10.61
20.00
NA
4.13
5.24
NA
1.54
3.41
5.12
8.43
NA
NA
NA
5.72
NA
NA
0.80
1.13
1.45
7.21
NA
NA
NA
5.55
9.92
NA
5.1.5. 1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)phenyl]ethanone
(5a)
Compound 1 (7.6 g, 0.05 mol) and prenyl bromide (6 mL) were
treated as described above. The crude product was purified by col-
umn chromatography eluting with hexanes/EtOAc (9:1) to yield 5a
as a colorless crystalline solid (9.0 g, 82%), mp 42–43 °C. IR (neat)
2975, 2933, 1633, 1505, 1330, 1273, 1252, 1191, 1151, 1136,
NA
3.14
6.72
NA
0.84
0.78
8.11
6.60
16.79
4.04
0.31
0.68
0.10
0.18
7.43
6.49
11.79
6.61
1.72
12.09
0.83
0.90
1.87
3.80
1.09
2.73
0.33
0.44
0.66
2.02
3.07
6.77
0.10
0.03
2.74
3.12
1.51
0.24
0.12
0.29
0.15
0.15
4.87
5.62
4.80
5.67
1.34
16.22
0.43
0.67
1.23
4.70
1.66
1.12
0.28
0.46
0.42
0.11
0.47
0.30
NA
4.64
3.50
6.58
6.25
8.12
5.02
0.30
0.69
0.41
0.69
3.27
2.58
11.45
3.29
2.27
11.99
0.68
1.17
2.62
5.77
2.15
1.64
0.36
0.71
0.60
2.09
2.61
2.64
14.90
9.60
7.75
13.54
9.44
0.73
2.11
0.74
2.11
6.12
5.14
NA
5.93
2.31
9.92
1.30
2.17
1.95
5.63
2.84
5.70
0.83
0.82
1.12
2.93
5.18
6.14
1066, 952, 834 cmꢀ1 1H NMR (300 MHz, CDCl3): d 12.72 (1H, s,
.
OH), 7.60 (1H d, J = 9.0 Hz), 6.44 (1H, dd, J = 9.0, 2.0 Hz), 6.41 (1H,
d, J = 2.0 Hz). 5.45 (1H, t, J = 6.0 Hz), 4.52 (2H, d, J = 6.0 Hz), 2.53
(3H, s), 1.78 (3H, s), 1.73 (3H, s). EIMS, m/z (% rel. intensity): 220
(2) [M]+, 194 (22), 152 (24), 137 (100), 69 (7), 43 (9).
5.2. General procedure for the synthesis of Mannich bases of
acetophenones and aldehydes
To a solution of hydroxyl-substituted acetophenone or aldehyde
and formaldehyde (37% solution) in EtOH (75 mL) was added the
corresponding secondary amine (morpholine or piperidine) at
room temperature as reported in earlier literature.23,27–29 Then,
the resulting mixture was heated to reflux for 18–22 h at 120 °C.
On completion, the reaction mixture was concentrated under re-
duced pressure and the crude product was purified by column
chromatography to yield a mixture of ortho- and para-substituted
Mannich bases of acetophenones.
5.2.1. 1-[2,4-Dihydroxy-3-(morpholinomethyl)phenyl]ethanone
(1a)
Compound
1
(3.8 g, 0.025 mol), formaldehyde (2.1 mL,
a
0.025 mol), and morpholine (2.2 mL, 0.025 mol) were treated as
described above. The crude product was purified by column chro-
matography eluting with hexanes/EtOAc (6:4) to yield 1a as color-
less needles (4.2 g, 67%), mp 116–117 °C. IR (neat) 3016, 2949,
1612, 1494, 1445, 1307, 1270, 1215, 1169, 1118, 1066, 992, 905,
Not active.
5.1.2. 1-(4-Ethoxy-2-hydroxyphenyl)ethanone (2a)
Compound 1 (15.2 g, 0.1 mol) and ethyl iodide (8 mL) were
treated as described above. The crude product was purified by col-
umn chromatography eluting with hexanes/EtOAc (8:2) to yield 2a
as a colorless crystalline solid (17.5 g, 97%), mp 46–47 °C. IR (neat)
2983, 1635, 1506, 1476, 1426, 1371, 1331, 1255, 1037, 987,
854, 759, 663, 628 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 13.13 (1H,
.
s, OH), 8.85 (1H, s, OH), 7.56 (1H, d, J = 9.0 Hz), 6.34 (1H, d,
J = 9.0 Hz), 3.85 (2H, s), 3.76 (4H, s), 2.75 (4H, s), 2.57 (3H, s). EIMS,
m/z (% rel. intensity): 251 (76) [M]+, 222 (14), 206 (13), 204 (13),
193 (79), 178 (19), 166 (12), 165 (67), 164 (41), 149 (24), 147
(29), 86 (100), 65 (13), 57 (33), 43 (23).
803 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 12.71 (1H, s, OH), 7.58
.
(1H, d, J = 8.7 Hz), 6.40 (1H, d, J = 1.8 Hz) 6.38 (1H, dd, J = 8.7,
1.8 Hz), 4.02 (2H, m), 2.51 (3H, s), 1.39 (3H, t, J = 4.0 Hz). EIMS,
m/z (% rel. intensity): 180 (67) [M]+, 166 (12), 165 (100), 164
(13), 137 (93), 86 (20), 43 (34).
5.2.2. 1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
ethanone(2b) and 1-[4-ethoxy-2-hydroxy-3-(morpholinomethyl)-
phenyl]ethanone (2c)
5.1.3. 1-(2-Hydroxy-4-methoxyphenyl)ethanone (3a)
Compound 2a (10.0 g, 0.056 mol), formaldehyde (4.6 mL,
0.056 mol), and morpholine (5.0 mL, 0.056 mol) were treated as
described above. The crude product was purified by column chro-
matography eluting with hexanes/EtOAc (1:1) to yield 2b (13.0 g,
83%) and 2c (900 mg, 6%). 2b: colorless solid, mp 127–128 °C. IR
(neat) 2957, 2852, 1633, 1497, 1475, 1453, 1371, 1333, 1270,
Compound 1 (15.2 g, 0.1 mol) and methyl iodide (7 mL) were
treated as described above. The crude product was purified by col-
umn chromatography eluting with hexanes/EtOAc (9:1) to yield 3a
as a colorless crystalline solid (15.8 g, 95%), mp 52–53 °C. IR (neat)
2972, 2875, 1637, 1500, 1442, 1369, 1332, 1274, 1208, 1156, 1109,
1065, 1025, 956, 897 cmꢀ1. 1H NMR (CDCl3, 300 MHz): d 12.70 (1H,
s, OH), 7.56 (1H, d, J = 9.0 Hz), 6.37 (2H, m), 3.78 (3H, s), 2.50 (3H,
s). EIMS, m/z (% rel. intensity): 166 (48) [M]+, 151 (100), 123 (22),
108 (10), 100 (5), 77 (9), 65 (8) 43 (18).
1233, 1193, 1153, 1115, 1085, 1004, 906, 865 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d 12.68 (1H, s), 7.65 (1H, s), 6.33 (1H, s), 4.09
(2H, m), 3.65 (4H, m), 3.43 (2H, s), 2.58 (4H, s), 2.45 (3H, s), 1.41
(3H, t, J = 6.0 Hz). EIMS, m/z (% rel. intensity): 279 (11) [M]+, 221
(16), 194 (14), 193 (91), 165 (42), 149 (15), 147 (13), 137 (25),
100 (100), 86 (38), 56 (42). 2c: colorless oil. IR (neat) 2937, 2845,
5.1.4. 1-(2-Hydroxy-4-isopropoxyphenyl)ethanone (4a)
Compound 1 (7.6 g, 0.05 mol) and isopropyl bromide (5 mL)
were treated as described above. The crude product was purified
by column chromatography eluting with hexanes/CHCl3 (1:1) to
1624, 1485, 1472, 1370, 1333, 1271, 1228, 1080, 907, 865 cmꢀ1
.
1H NMR (CDCl3, 300 MHz): d 7.66 (1H, d, J = 9.0 Hz), 6.41 (H, d,
J = 9.0 Hz), 4.07 (2H, m), 3.65 (4H, m), 2.86 (2H, s), 2.53 (4H, s),

M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
7363
2.44 (3H, s), 1.40 (3H, t, J = 6.0 Hz). EIMS, m/z (% rel. intensity): 279
(27) [M]+, 264 (6), 221 (19), 206 (4), 186 (3), 165 (43), 149 (15), 100
(100), 86 (39), 42 (6).
2.39 (3H, s). EIMS, m/z (% rel. intensity): 235 (100) [M]+, 204 (16),
190 (5), 188 (35), 176 (11), 162 (18), 149 (76), 134 (11), 133
(15), 106 (9), 86 (38), 77 (16), 57 (19), 56 (18), 43 (17).
5.2.3. 1-[2-Hydroxy-4-methoxy-5-(morpholinomethyl)phenyl]-
ethanone (3b) and 1-[2-hydroxy-4-methoxy-3-(morpholino-
methyl)phenyl]ethanone (3c)
5.2.7. 1-[4-Hydroxy-3,5-bis(morpholinomethyl)phenyl]ethanone
(6b)
Compound
6
(3.4 g, 0.025 mol), formaldehyde (4.1 mL,
Compound 3a (10.0 g, 0.06 mol), formaldehyde (4.9 mL,
0.06 mol), and morpholine (5.2 mL, 0.06 mol) were treated as de-
scribed above. The crude product was purified by column chroma-
tography eluting with hexanes/EtOAc (6:4) to yield 3b (13.6 g,
86%) and 3c (810 mg, 5%). 3b: colorless solid, mp 130–131 °C. IR
(neat) 2947, 2848, 1625, 1499, 1453, 1418, 1273, 1237, 1157,
0.05 mol), and morpholine (4.3 mL, 0.05 mol) were treated as de-
scribed above. The crude product was purified by column chroma-
tography eluting with EtOAc/MeOH (9:1) to yield 6b as a colorless
solid (5.0 g, 60%), mp 71–72 °C. IR (neat) 2957, 2851, 1677, 1599,
1474, 1412, 1357, 1306, 1245, 1115, 1071, 1032, 904, 864,
803 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.69 (2H, s), 3.71 (8H, m),
.
1115, 1093, 1029, 895, 793 cmꢀ1
.
1H NMR (CDCl3, 300 MHz): d
3.63 (4H, s), 2.54 (11H, m). EIMS, m/z (% rel. intensity): 334 (4)
[M]+, 249 (5), 248 (6), 247 (13), 217 (3), 133 (6), 100 (100), 70
(4), 56 (15), 43 (5).
12.35 (1H, s, OH), 7.64 (1H, s), 6.42 (1H, s), 3.85 (5H, s), 3.65 (4H,
m), 2.52 (7H, m). EIMS, m/z (% rel. intensity): 265 (42) [M]+, 236
(11), 220 (12), 207 (46), 192 (10), 179 (100), 86 (68), 43 (15). 3c: col-
orless oil. IR (neat) 2845, 1620, 1499, 1445, 1368, 1307, 1270, 1169,
992, 807, 759 cmꢀ1. 1H NMR (CDCl3, 300 MHz): d 12.31 (1H, s, OH),
7.67 (1H, d, J = 9.0 Hz), 6.44 (1H, d, J = 9.0 Hz), 3.85 (5H, s), 3.65
(4H, m), 2.52 (7H, m). EIMS, m/z (% rel. intensity): 265 (38) [M]+,
264 (3), 220 (24), 179 (100), 165 (13), 163 (18), 149 (22), 86 (56),
43 (14).
5.2.8. 1-[3-Hydroxy-4-(morpholinomethyl)phenyl]ethanone (7a),
1-[3-hydroxy-2-(morpholinomethyl)phenyl]ethanone (7b) and 1-
[3-hydroxy-2,4-bis(morpholinomethyl)phenyl]ethanone (7c)
Compound 7 (13.6 g, 0.1 mol), formaldehyde (8.2 mL, 0.1 mol),
and morpholine (8.7 mL, 0.1 mol) were treated as described in Sec-
tion 5.2. The crude product was purified by column chromatogra-
phy eluting with hexanes/CHCl3 (1:1) to yield 7a (8.7 g, 37%) and
7c (2.35 g, 7%). 7a: colorless oil. IR (neat) 2961, 1652, 1583, 1471,
5.2.4. 1-[2-Hydroxy-4-isopropoxy-3-(morpholinomethyl)phenyl]-
ethanone (4b) and 1-[2-hydroxy-4-isopropoxy-5-(morpholino-
methyl)phenyl]ethanone (4c)
1349, 1291, 1242, 1070, 1028, 960, 891, 859, 826 cmꢀ1
.
1H NMR
(CDCl3, 300 MHz): 7.32 (1H, d, J = 1.2 Hz), 7.29 (1H, d,
d
Compound 4a (5.0 g, 0.026 mol), formaldehyde (2.1 mL,
0.026 mol), and morpholine (2.3 mL, 0.026 mol) were treated as de-
scribed above. The crude product was purified by column chroma-
tography eluting with hexanes/EtOAc (7:3) to yield 4b (725 mg,
10%) and 4c (4.8 g, 66%). 4b: pale yellow oil. IR (neat) 2958, 1630,
1560, 1428, 1367, 1252, 1168, 1112, 941, 837 cmꢀ1. 1H NMR (CDCl3,
300 MHz): d 12.70 (1H, s, OH), 7.66 (1H, d, J = 9.0 Hz), 6.45 (1H, d,
J = 9.0 Hz), 4.68 (1H, m), 3.70 (6H, m), 2.56 (7H, s), 1.35 (6H, d,
J = 6.0 Hz); EIMS, m/z (% rel. intensity): 293 (100) [M]+, 275 (17),
241 (2), 100 (15), 86 (19). 4c: Colorless oil. IR (neat) 2852, 1628,
1468, 1418, 1367, 1165, 1110, 938 cmꢀ1. 1H NMR (CDCl3,300 MHz):
d 12.68 (1H, s, OH), 7.69 (1H, s), 6.36 (1H, s), 4.64 (1H, m), 3.69 (6H,
m), 2.56 (7H, m), 1.33 (6H, d, J = 6.0 Hz). EIMS, m/z (% rel. intensity):
293 (32) [M]+, 149 (100), 110 (17), 86 (54).
J = 8.0 Hz), 7.01 (1H, d, J = 8.0 Hz), 3.64 (6H, m), 2.47 (7H, m). EIMS,
m/z (% rel. intensity): 235 (24) [M]+, 217 (14), 207 (31), 188 (17),
149 (100), 100 (18), 86 (21), 78 (17). 7b: pale yellow oil, (7.2 g,
31%). IR (neat) 2965, 1648, 1572, 1469, 1240, 1068, 952, 886,
813 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.18 (1H, d, J = 8.0 Hz),
.
7.10 (1H, dd, J = 8.0, 2.0 Hz), 6.92 (1H, dd, J = 8.0, 2.0 Hz), 3.67
(6H, m), 2.51 (7H, m); EIMS, m/z (% rel. intensity): 235 (20) [M]+,
149 (100), 100 (22), 86 (14). 7c: colorless oil. IR (neat) 2948,
1647, 1613, 1568, 1413, 1239, 1020, 958, 823 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d7.15 (1H, d, J = 9.0 Hz), 6.96 (1H, d, J = 9.0 Hz),
3.98 (2H, s), 3.73 (4H, m), 3.67 (4H, m), 3.66 (2H, s), 2.55 (11H,
m). EIMS, m/z (% rel. intensity): 334 (32) [M]+, 247 (12), 189 (7)
133 (12), 100 (100), 86 (9), 56 (16).
5.2.9. 3-Hydroxy-4-methoxy-2-(piperidin-1-ylmethyl)benzaldehyde
(8a)
5.2.5. 1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)-3-(morpholino-
methyl)phenyl]ethanone (5b)
Compound 8 (7.6 g, 0.05 mol), formaldehyde (4.1 mL, 0.05 mol),
and piperidine (4.9 mL, 0.05 mol) were treated as described above.
The crude product was purified by column chromatography eluting
with hexanes/CHCl3 (1:1) to yield 8a as a crystalline solid (10.2 g,
82%), mp 78–79 °C. IR (neat) 2938, 2853, 1683, 1572, 1476, 1440,
Compound 5a (4.0 g, 0.018 mol), formaldehyde (1.5 mL,
0.018 mol), and morpholine (1.6 mL, 0.018 mol) were treated as
described above. The crude product was purified by column chro-
matography eluting with hexanes/EtOAc (7:3) to yield 5b as a col-
orless solid (5.0 g, 86%), mp 64–65 °C. IR (neat) 2954, 2853, 2808,
1630, 1495, 1452, 1418, 1369, 1270, 1162, 1116, 1080, 1004,
1268, 1203, 1080, 1040, 987, 931, 859, 786 cmꢀ1 1H NMR
.
(CDCl3,300 MHz): d 11.86 (1H, s, OH), 9.85 (1H, s, CHO), 7.23 (1H,
d, J = 8.4 Hz), 6.90 (1H, d, J = 8.4 Hz), 4.34 (2H, s), 3.95 (3H, s),
2.59 (4H, s), 1.66 (4H, m), 1.50 (2H, s). EIMS, m/z (% rel. intensity):
249 (21) [M]+, 248 (4), 221 (15), 206 (7), 178 (4), 165 (16), 164 (43),
149 (10), 84 (100), 65 (9).
. d 7.68 (1H, d,
978, 864 cmꢀ1 1H NMR (CDCl3, 300 MHz):
J = 9.0 Hz), 6.46 (1H, d, J = 9.0 Hz), 5.44 (1H, t, J = 6.0 Hz), 4.59
(2H, d, J = 6.0 Hz), 3.72 (6H, s), 2.58 (7H, s), 1.79 (3H, s), 1.74 (3H,
s). EIMS, m/z (% rel. intensity): 319 (41) [M]+, 251 (8), 250 (30),
233 (10), 217 (13), 192 (15), 179 (6), 165 (100), 147 (15), 137
(19), 86 (67), 69 (40), 56 (11).
5.2.10. 3-Hydroxy-4-methoxy-2-(morpholinomethyl)benzaldehyde
(8b)
5.2.6. 1-[4-Hydroxy-3-(morpholinomethyl)phenyl]ethanone (6a)
Compound 6 (13.6 g, 0.1 mol), formaldehyde (8.2 mL, 0.1 mol),
and morpholine (8.7 mL, 0.1 mol) were treated as described above.
The crude product was purified by column chromatography eluting
with hexanes/EtOAc (8:2) to yield 6a as a colorless solid (19.0 g,
81%). 67–68 °C. IR (neat) 2961, 2851, 1673, 1592, 1497, 1453,
Compound 8 (7.6 g, 0.05 mol), formaldehyde (4.1 mL, 0.05 mol)
and morpholine (4.3 mL, 0.05 mol) were treated as described above.
The crude product was purified by column chromatography eluting
with hexanes/CHCl3 (1:1) to yield 8b as a crystalline solid (10.8 g,
86%), 81–82 °C. IR (neat) 2960, 2848, 1690, 1600, 1571, 1466,
1443, 1302, 1264, 1209, 1115, 1073, 1030, 937, 865, 803 cmꢀ1 1H
.
1358, 1292, 1245, 1174, 1073, 1030, 964, 893, 862, 769 cmꢀ1
.
1H
NMR (CDCl3, 300 MHz): d 9.81 (1H, s, CHO), 9.21 (1H, s, OH), 7.22
(1H, d, J = 8.4 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.33 (2H, s), 3.90 (3H, s),
3.68 (4H, s), 2.58 (4H, s). EIMS, m/z (% rel. intensity): 252 (14) [M]+,
NMR (CDCl3, 300 MHz): d 7.80 (1H, dd, J = 2.2, 9.0 Hz), 7.66 (1H,
d, J = 2.2 Hz), 6.83 (1H, d, J = 8.6 Hz), 3.62 (6H, m), 2.48 (4H, m),

7364
M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
223 (13), 193 (3), 192 (7), 178 (3), 166 (9), 165 (26), 164 (100), 149
(15), 137 (10), 136 (24), 135 (16), 86 (13).
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2) to yield 11 (yellow crystalline solid, 720 mg, 55%),
mp 97–98 °C. IR (neat) 2850, 1627, 1490, 1420, 1275, 1247,
5.3. General procedure for the synthesis of Mannich bases of
chalcones
1112, 1058, 1003, 966, 862, 793, 705 cmꢀ1 1H NMR (DMSO-d6,
.
300 MHz): d 8.09 (1H, d, J = 9.0 Hz), 7.96 (1H, d, J = 15.3 Hz), 7.80
(1H, d, J = 6.0 Hz), 7.69 (1H, d, J = 3.6 Hz), 7.65 (1H, d, J = 15.3 Hz),
7.19 (1H, dd, J = 3.6, 6.0 Hz), 6.68 (1H, d, J = 9.0 Hz), 4.78 (1H, m),
3.50 (6H, m), 2.41 (4H, m),1.29 (6H, d, J = 6.0 Hz). 13C NMR
(DMSO-d6, 75 MHz): d 191.1, 163.3, 162.4, 139.7, 136.3, 132.9,
131.7, 130.8, 128.7, 120.1, 114.1, 112.4, 104.4, 70.3, 66.2 (2ꢁ),
53.0 (2ꢁ), 49.4, 21.8 (2ꢁ). EIMS, m/z (% rel. intensity): 387 (59)
[M]+, 358 (5), 329 (20), 302 (21), 293 (9), 259 (17), 244 (58), 205
(12), 191 (14), 165 (23), 149 (100), 147 (12), 110 (17), 86 (54),
71 (32), 57 (43). HREIMS m/z calcd for C21H25NO4S, 387.1504;
found, 387.1504. Elemental analysis: calcd C, 65.09; H, 6.50; N,
3.61; S, 8.27; found, C, 65.06; H, 6.48; N, 3.61; S, 8.39.
The general synthetic strategy employed to prepare the Man-
nich bases of heterocyclic chalcone derivatives was based on the
Claisen–Schmidt condensation. As shown in Scheme 2, a series of
39 Mannich bases of heterocyclic chalcones (9–47) were prepared
by base-catalyzed condensation of substituted Mannich bases of
acetophenones with appropriate heterocyclic aldehydes in MeOH.
To a stirred reaction mixture at 0 °C was added a 30% solution of
KOH (40 mL) dropwise over 30 min. The reaction mixture was kept
at room temperature for 24 h, then diluted with water and ex-
tracted with EtOAc. Pure target compounds were obtained by silica
gel column chromatography (cc) of the residue eluting with vari-
ous solvent mixtures as indicated below. The structures of all the
39 Mannich bases of heterocyclic chalcones were established on
the basis of IR, 1H, 13C NMR, EIMS, HREIMS, and elemental analyses.
5.3.4. (E)-1-[2-Hydroxy-4-(3-methylbut-2-enyloxy)-3-(morpholi-
nomethyl)phenyl]-3-(3-methylthiophen-2-yl)prop-2-en-1-one
(12)
Compound 5b (1.0 g, 3.13 mmol) and 3-methyl-2-thiophene-
carboxaldehyde (400 mg, 3.17 mmol) were treated as described
above. The crude product was purified by cc eluting with diiso-
propylether/MeOH (7:3) to yield 12 (yellow solid, 1.1 g, 82%), mp
126–127 °C. IR (neat) 2937, 1623, 1564, 1492, 1417, 1278, 1224,
5.3.1. (E)-1-[2,4-Dihydroxy-3-(morpholinomethyl)phenyl]-3-
(pyridin-2-yl)prop-2-en-1-one (9)
Compound 1a (1.0 g, 3.77 mmol) and 2-pyridinecarboxalde-
hyde (405 mg, 3.78 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropylether/
MeOH (7:3) to yield 9 as a yellow crystalline solid (850 mg, 64%),
mp 176–177 °C. IR (neat) 2960, 2902, 1639, 1610, 1576, 1487,
1110, 1065, 969, 858, 791 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
.
8.07 (1H, d, J = 15.0 Hz), 8.32 (1H, d, J = 9.0 Hz), 7.34 (1H, d,
J = 15.0 Hz), 7.32 (1H, d, J = 5.1 Hz), 6.91 (1H, d, J = 5.1 Hz), 6.68
(1H, d, J = 9.0 Hz), 5.44 (1H, t, J = 6.6 Hz), 4.62 (2H, d, J = 6.6 Hz),
3.76 (2H, s), 3.73 (4H, s), 2.61 (4H, s), 2.41 (3H, s), 1.80 (3H, s),
1.75 (3H, s). 13C NMR (CDCl3, 75 MHz): d 191.3, 163.9, 163.4,
142.7, 138.2, 134.8, 134.5, 131.4, 130.7, 127.3, 119.2 (2ꢁ), 115.1,
112.5, 103.1, 66.9 (2ꢁ), 65.3, 53.2 (2ꢁ), 49.8, 25.7, 18.2, 14.2. EIMS,
m/z (% rel. intensity): 427 (52) [M]+, 358 (51), 320 (9), 319 (48), 297
(7), 274 (16), 273 (77), 250 (35), 232 (17), 192 (20), 165 (61), 149
(89), 124 (23), 86 (100), 69 (62), 56 (14). HREIMS m/z calcd for
1401, 1356, 1290, 1249, 1224, 1117, 907, 786, 595 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d 13.70 (1H, s, OH), 8.84 (1H, s, OH), 8.68 (1H,
d, J = 4.2 Hz), 8.17 (1H, d, J = 15.0 Hz), 7.88 (1H, d, J = 9.0 Hz), 7.79
(1H, d, J = 15.0 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.45 (1H, d, J = 7.5 Hz),
7.27 (1H, d, J = 4.2 Hz), 6.40 (1H, d, J = 9.0 Hz), 3.89 (2H, s), 3.77
(4H, s), 2.64 (4H, s). 13C NMR (CDCl3, 75 MHz): d 191.8, 166.3,
164.1, 153.0, 150.1, 141.8, 136.8, 131.3, 125.5, 124.3, 124.3,
113.0, 108.6, 106.7, 66.5 (2ꢁ), 53.7, 52.8 (2ꢁ). EIMS, m/z (% rel.
intensity): 340 (36) [M]+, 322 (9), 273 (7), 255 (100), 237 (22),
226 (12), 207 (33), 196 (9), 177 (8), 149 (21), 132 (33), 106 (34),
86 (16). HREIMS m/z calcd for C19H20N2O4, 340.1423; found,
340.1422. Elemental analysis: calcd C, 67.05; H, 5.92; N, 8.23;
found, C, 66.73; H, 6.01; N, 8.14.
C24H29NO4S, 427.1817; found, 427.1815. Elemental analysis: calcd
C, 67.42; H, 6.84; N, 3.28; S, 7.50; found, C, 67.41; H, 6.83; N, 3.24;
S, 7.57.
5.3.5. (E)-1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
3-(pyridin-3-yl)prop-2-en-1-one (13)
5.3.2. (E)-1-[2-Hydroxy-4-methoxy-3-(morpholinomethyl)phenyl]-
3-(pyridin-2-yl)prop-2-en-1-one (10)
Compound 2b (500 mg, 1.80 mmol) and 3-pyridinecarboxalde-
hyde (208 mg, 1.73 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2) to yield 13 (pale yellow solid, 495 mg, 75%), mp
152–153 °C. IR (neat) 2936, 1639, 1537, 1359, 1287, 1230, 1194,
Compound 3c (1.0 g, 3.78 mmol) and 2-pyridinecarboxaldehyde
(403 mg, 3.76 mmol) were treated as described above. The crude
product was purified by cc eluting with hexanes/EtOAc (7:3) to
yield 10 (yellow solid, 750 mg, 56%), mp 161–162 °C. IR (neat)
2948, 1639, 1582, 1495, 1432, 1352, 1318, 1288, 1232, 1113,
1112, 1011, 980, 864, 819 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d
.
13.31 (1H, s, OH), 9.04 (1H, s), 8.61 (1H, t, J = 3.0 Hz), 8.35 (1H, d,
J = 6 Hz), 8.12 (1H, s), 8.09 (1H, d, J = 15.0 Hz), 7.82 (1H, d,
J = 15.0 Hz), 7.50 (1H, dd, J = 3.0, 6.0 Hz), 6.53 (1H, s), 4.10 (2H,
q), 3.54 (4H, s), 3.44 (2H, s), 2.39 (4H, s), 1.34 (3H, t, J = 6.0 Hz).
13C NMR (DMSO-d6, 75 MHz): d 191.3, 165.2, 164.1, 151.1, 150.4,
140.5, 135.3, 133.2, 130.3, 123.9, 123.2, 117.5, 112.8, 99.8, 66.2
(2ꢁ), 64.0, 55.4, 52.9 (2ꢁ), 14.3. EIMS, m/z (% rel. intensity): 368
(23) [M]+, 353 (5), 283 (35), 282 (100), 177 (28), 149 (8), 133 (8),
1074, 978, 863 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 8.69 (1H,
.
d, J = 4.5 Hz), 8.24 (1H, d, J = 15.3 Hz), 8.11 (1H, d, J = 9.0 Hz), 7.94
(1H, d, J = 8.7 Hz), 7.90 (1H, s), 7.77 (1H, d, J = 15.3 Hz), 7.44 (1H,
dd, J = 4.5, 8.7 Hz), 3.89 (3H, s), 3.85 (2H, s), 3.53 (4H, t,
J = 4.2 Hz), 2.43 (4H, t, J = 4.2 Hz). 13C NMR (DMSO-d6, 75 MHz):
d194.8, 165.5, 164.2, 153.6, 150.2, 143.2, 136.6, 131.3, 125.5,
124.3, 124.2, 114.3, 108.6, 106.6, 66.5 (2ꢁ), 58.9, 53.8, 52.8 (2ꢁ).
EIMS, m/z (% rel. intensity): 354 (40), [M]+, 336 (11), 297 (12),
270 (20), 269 (100), 268 (35), 251 (26), 221 (51), 163 (30), 133
(19), 132 (59), 106 (29), 98 (18). HREIMS m/z calcd for
86 (6). HREIMS m/z calcd for
C21H24N2O4, 368.1736; found,
368.1737. Elemental analysis: calcd C, 68.46; H, 6.57; N, 7.60;
found, C, 68.48; H, 6.60; N, 7.60.
C20H22N2O4, 354.1580; found, 354.1581. Elemental analysis: calcd
C, 67.78; H, 6.26; N, 7.90; found, C, 67.58; H, 6.25; N, 7.87.
5.3.6. (E)-1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
3-(furan-2-yl)prop-2-en-1-one (14)
5.3.3. (E)-1-[2-Hydroxy-4-isopropoxy-3-(morpholinomethyl)phenyl]-
3-(thiophen-2-yl)prop-2-en-1-one (11)
Compound 4C (1.0 g, 3.41 mmol) and 2-thiophenecarboxalde-
hyde (400 mg, 3.57 mmol) were treated as described above. The
Compound 2b (500 mg, 1.80 mmol) and 2-furaldehyde (172 mg,
1.80 mmol) were treated as described above. The crude product
was purified by cc eluting with diisopropyl ether/MeOH (9:1 to
8:2) to yield 14 (yellow crystalline solid, 580 mg, 91%), mp 157–

M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
7365
158 °C. IR (neat) 2820, 1639, 1574, 1550, 1353, 1276, 1232, 1114,
1010, 966, 859 cmꢀ1 1H NMR (DMSO-d6,300 MHz): d 13.29 (1H,
66.2 (2ꢁ), 64.0, 55.3, 52.9 (2ꢁ), 14.3. EIMS, m/z (% rel. intensity):
367 (63) [M]+, 352 (5), 282 (34), 281 (100), 203 (6), 177 (70), 149
(9), 133 (13), 126 (10), 86 (9). HREIMS m/z calcd for C22H25NO4,
367.1784; found, 367.1786. Elemental analysis: calcd C, 71.91; H,
6.86; N, 3.81; found, C, 71.93; H, 6.89; N, 3.76.
.
s, OH), 7.94 (2H, s), 7.64 (1H, d, J = 15.3 Hz), 7.55 (1H, d,
J = 15.3 Hz), 7.12 (1H, d, J = 3.0 Hz), 6.70 (1H, dd, J = 3.0, 3.0 Hz),
6.51 (1H, s), 4.11 (2H, q), 3.55 (4H, m), 3.43 (2H, s), 2.39 (4H, s),
1.33 (3H, t, J = 6.0 Hz). 13C NMR (DMSO-d6,75 MHz): d 190.8,
172.9, 164.7, 163.7, 151.0, 146.5, 132.1, 130.2, 117.8, 117.6,
113.2, 112.9, 95.1, 66.2 (2ꢁ), 64.0, 55.0, 52.9 (2ꢁ), 14.3. EIMS, m/
z (% rel. intensity): 357 (39) [M]+, 342 (2), 272 (21), 271 (100),
177 (68), 149 (8), 133 (12), 121 (10), 86 (6), 69 (6). HREIMS m/z
calcd for C20H23NO5, 357.1576; found, 357.1579. Elemental analy-
sis: calcd C, 67.21; H, 6.49; N, 3.92; found, C, 67.31; H, 6.48; N, 3.92.
5.3.10. (E)-1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
3-(3-methylthiophen-2-yl)prop-2-en-1-one (18)
Compound 2b (500 mg, 1.80 mmol) and 3-methyl-2-thiophene-
caroxaldehyde (225 mg, 1.78 mmol) were treated as described
above. The crude product was purified by cc eluting with diisopropyl
ether/MeOH (9.5:0.5) to yield 18 (pale yellow solid, 550 mg, 79%),
mp 160–161 °C. IR (neat) 2848, 1630, 1559, 1494, 1469, 1273,
5.3.7. (E)-1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
3-(5-methylfuran-2-yl)prop-2-en-1-one (15)
1148, 1114, 966, 847 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 13.28
.
(1H, s, OH), 7.92 (1H, s), 7.97 (1H, d, J = 15.0 Hz), 7.71 (1H, d,
J = 5.0 Hz), 7.41 (1H, d, J = 15.0 Hz), 7.04 (1H, d, J = 5.0 Hz), 6.51
(1H, s), 4.09 (2H, q), 3.57 (4H, s), 3.43 (2H, s), 2.40 (4H, s), 2.37 (3H,
s), 1.34 (3H, t, J = 6.0 Hz). 13C NMR (DMSO-d6,75 MHz): d 190.7,
164.6, 163.5, 143.3, 134.6, 133.6, 131.6, 129.3, 118.5, 117.5, 112.8,
99.8, 66.3 (2ꢁ), 64.0, 55.0, 53.0 (2ꢁ), 14.3, 13.9. EIMS, m/z (% rel.
intensity): 387 (39) [M]+, 302 (23), 301 (100), 235 (8), 177 (64),
149 (6), 133 (12), 126 (7), 98 (7). HREIMS m/z calcd for C21H25NO4S,
387.1504; found, 387.1501. Elemental analysis: calcd C, 65.09; H,
6.50; N, 3.61; S, 8.27; found, C, 65.03; H, 6.47; N, 3.54; S, 8.45.
Compound2b (500 mg, 1.80 mmol)and 5-methyl-2-furaldehyde
(197 mg, 1.80 mmol) were treated as described above. The crude
product was purified by cc eluting with diisopropyl ether/MeOH
(9:1) to obtain 15 (pale yellow solid, 450 mg, 67%), mp 148–
149 °C. IR (neat) 2930, 1638, 1563, 1525, 1348, 1371, 1267, 1231,
1146, 1115, 1014 cmꢀ1 1H NMR (DMSO-d6,300 MHz): d13.40 (1H,
.
s, OH), 7.92 (1H, s), 7.57 (1H, d, J = 15.0 Hz), 7.42 (1H, d,
J = 15.0 Hz), 7.02 (1H, d, J = 3.0 Hz), 6.50 (1H, s), 6.35 (1H, d,
J = 3.0 Hz), 4.09 (2H, q), 3.55 (4H, m), 3.43 (2H, s), 2.39 (7H, s),1.33
(3H, t, J = 6.0 Hz). 13C NMR (DMSO-d6, 75 MHz): d 190.8, 164.7,
163.5, 156.5, 149.8, 131.9, 130.2, 119.7, 117.5, 115.9, 112.9, 110.0,
99.8, 66.2 (2ꢁ), 63.9, 55.0, 52.9 (2ꢁ), 14.3, 13.7. EIMS, m/z (% rel.
intensity): 371 (38) [M]+, 286 (22), 285 (100), 284 (15), 177 (52),
149 (7), 133 (13), 121 (12), 107 (6), 77 (6), 56 (9). HREIMS m/z calcd
forC21H25NO5, 371.1733;found, 371.1735. Elementalanalysis:calcd
C, 67.91; H, 6.78; N, 3.77; found, C, 67.86; H, 6.77; N, 3.79.
5.3.11. (E)-1-[2-Hydroxy-4-methoxy-5-(morpholinomethyl)phenyl]-
3-(pyridin-3-yl)prop-2-en-1-one (19)
Compound 3b (1.0 g, 3.78 mmol) and 3-pyridinecarboxalde-
hyde (425 mg, 3.97 mmol) were treated as described above. The
crude product was purified by cc eluting with hexanes/EtOAc
(7:3) to yield 19 (yellow solid, 1.15 g, 86%), mp 144–145 °C. IR
(neat) 2944, 1640, 1574, 1496, 1362, 1285, 1226, 1147, 1114,
5.3.8. (E)-1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
3-(pyridin-2-yl)prop-2-en-1-one (16)
991, 863, 831 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 13.29 (1H,
.
s, OH), 9.04 (1H, s), 8.62 (1H, d, J = 3.0 Hz), 8.35 (1H, d,
J = 6.0 Hz), 8.12 (1H, s), 8.09 (1H, d, J = 15.6 Hz), 7.82 (1H, d,
J = 15.6 Hz), 7.50 (1H, t, J = 6.0 Hz), 6.56 (1H, s), 3.86 (3H, s), 3.55
(4H, s), 3.36 (2H, s), 2.38 (4H, s). 13C NMR (DMSO-d6,75 MHz):
d191.4, 165.3, 164.8, 151.1, 150.4, 140.5, 135.3, 133.3, 130.3,
123.9, 123.1, 117.4, 112.9, 99.4, 66.2 (2ꢁ), 56.1, 56.1, 53.1 (2ꢁ).
EIMS, m/z (% rel. intensity): 354 (25) [M]+, 301 (7), 269 (39), 268
(100), 163 (45), 149 (6), 133 (13). HREIMS m/z calcd for
Compound 2b (500 mg, 1.80 mmol) and 2-pyridinecarboxalde-
hyde (191 mg, 1.78 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2) to yield 16 (pale yellow solid, 365 mg, 55%), mp
154–155 °C. IR (neat) 2933, 1643, 1580, 1497, 1433, 1358, 1286,
1230, 1114, 1037, 1010, 976, 864, 818 cmꢀ1 1H NMR (DMSO-d6,
.
300 MHz): d 13.14 (1H, s, OH), 8.69 (1H, d, J = 3.0 Hz), 8.18 (1H,
d, J = 15.0 Hz), 7.98 (1H, s), 7.89 (2H, t, J = 3.0 Hz), 7.77 (1H, d,
J = 15.0 Hz), 7.43 (1H, dd, J = 3.0, 3.0 Hz), 6.54 (1H, s), 4.11 (2H,
q), 3.55 (4H, m), 3.43 (2H, s), 2.39 (4H, s), 1.34 (3H, t, J = 6.0 Hz).
13C NMR (DMSO-d6, 75 MHz): d 191.5, 164.8, 163.9, 152.5, 150.1,
142.6, 137.2, 132.4, 125.4 (2ꢁ), 124.9, 124.4, 113.1, 99.8, 66.2
(2ꢁ), 64.0, 55.0, 52.9 (2ꢁ), 14.3. EIMS, m/z (% rel. intensity): 368
(13) [M]+, 326 (12), 294 (9), 283 (72), 282 (100), 268 (24), 239
(12), 210 (6), 177 (21), 149 (14), 132 (15), 106 (18), 78 (8), 57
C20H22N2O4, 354.1850; found, 354.1581. Elemental analysis: calcd
C, 67.78; H, 6.26; N, 7.90; found, C, 67.58; H, 6.35; N, 7.91.
5.3.12. (E)-1-[2-Hydroxy-4-methoxy-5-(morpholinomethyl)phenyl]-
3-phenylprop-2-en-1-one (20)
Compound 3b (1.0 g, 3.78 mmol) and benzaldehyde (402 mg,
3.78 mmol) were treated as described above. The crude product
was purified by cc eluting with hexanes/EtOAc (7:3 to 6:4) to yield
20 (yellow solid, 980 mg, 73%), mp 153–154 °C. IR (neat) 2953,
1637, 1571, 1495, 1448, 1361, 1278, 1147, 1115, 992, 863,
(9). HREIMS m/z calcd for
C21H24N2O4, 368.1736; found,
368.1735. Elemental analysis: calcd C, 68.46; H, 6.57; N, 7.60;
found, C, 68.14; H, 6.63; N, 7.49.
734 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 13.42 (1H, s, OH),
.
8.11 (1H, s), 7.95 (1H, d, J = 15.6 Hz), 7.89 (2H, m), 7.81 (1H,
d,J = 15.6 Hz), 7.47 (3H, m), 6.56 (1H, s), 3.85 (3H, s), 3.55 (4H, t,
J = 4.2 Hz), 3.44 (2H, s), 2.38 (4H, t, J = 4.2 Hz). 13C NMR (DMSO-
d6,75 MHz): d 191.8, 165.2, 164.6, 144.0, 134.5, 133.1, 130.8,
129.0 (2ꢁ), 128.9 (2ꢁ), 121.2, 117.3, 112.9, 99.4, 66.2 (2ꢁ), 56.0,
55.5, 53.0 (2ꢁ). EIMS, m/z (% rel. intensity): 353 (43) [M]+, 268
(23), 267 (100), 163 (78), 133 (22), 86 (8). HREIMS m/z calcd for
5.3.9. (E)-1-[4-Ethoxy-2-hydroxy-5-(morpholinomethyl)phenyl]-
3-phenylprop-2-en-1-one (17)
Compound 2b (500 mg, 1.80 mmol) and benzaldehyde (190 mg,
1.80 mmol) were treated as described above. The crude product
was purified by cc eluting with diisopropyl ether/MeOH (9.5:0.5)
to yield 17 (pale yellow solid, 425 mg, 65%), mp 160–161 °C. IR
(neat) 2981, 1639, 1573, 1496, 1449, 1360, 1279, 1230, 1193,
C21H23NO4, 353.1627; found, 353.1626. Elemental analysis: calcd
1115, 1035, 864, 731 cmꢀ1
.
1H NMR (DMSO-d6, 300 MHz): d
C, 71.37; H, 6.56; N, 3.96; found, C, 71.34; H, 6.57; N, 3.91.
13.40 (1H, s, OH), 8.11 (1H, s), 7.94 (1H, d, J = 15.0 Hz), 7.89 (2H,
m), 7.80 (1H, d, J = 15.0 Hz), 7.46 (3H, m), 6.52 (1H, s), 4.09 (2H,
q), 3.53 (4H, m), 3.44 (2H, s), 2.39 (4H, s), 1.33 (3H, t, J = 6.9 Hz).
13C NMR (DMSO-d6, 75 MHz): d 191.7, 165.1, 163.9, 143.9, 134.5,
133.0, 130.7, 129.0 (2ꢁ), 128.9 (2ꢁ), 121.2, 117.4, 112.8, 99.8,
5.3.13. (E)-1-[2-Hydroxy-4-methoxy-5-(morpholinomethyl)phenyl]-
3-(4-methoxyphenyl)prop-2-en-1-one (21)
Compound 3b (1.0 g, 3.78 mmol) and 4-methoxybenzaldehyde
(517 mg, 3.80 mmol) were treated as described above. The crude

7366
M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
product was purified by cc eluting with hexanes/EtOAc (7:3 to 6:4)
to yield 21 (yellow solid, 720 mg, 50%), mp 137–138 °C. IR (neat)
2955, 1633, 1563, 1510, 1364, 1282, 1246, 1220, 1172, 1146, 1115,
[M]+, 372 (7), 301 (100), 259 (50), 191 (17), 164 (9), 149 (95),
121 (10), 86 (13). HREIMS m/z calcd for C21H25NO4S, 387.1504;
found, 387.1506. Elemental analysis: calcd C, 65.09; H, 6.50; N,
3.61; S, 8.27; found, C, 65.10; H, 6.51; N, 3.55; S, 8.38.
994, 832 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 13.58 (1H, s, OH),
.
8.09 (1H, s), 7.86 (2H, d, J = 9.0 Hz), 7.85 (2H, d, J = 15.0 Hz), 7.03
(2H, d, J = 9.0 Hz), 6.54 (1H, s), 3.85 (3H, s), 3.82 (3H, s), 3.55 (4H,
s), 3.44 (2H, s), 2.39 (4H, s). 13C NMR (DMSO-d6,75 MHz): d 191.8,
165.2, 164.5, 161.5, 144.1, 132.9, 131.0 (2ꢁ), 127.1, 118.4, 117.1,
114.4 (2ꢁ), 112.9, 99.3, 66.2 (2ꢁ), 56.0, 55.5, 55.4, 53.0 (2ꢁ). EIMS,
m/z (% rel. intensity): 383 (36) [M]+, 314 (8), 298 (22), 297 (100),
179 (7), 163 (88), 133 (18), 100 (17), 86 (7). HREIMS m/z calcd for
5.3.17. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-(pyridin-
2-yl)prop-2-en-1-one (25)
Compound 6a (1.0 g, 4.26 mmol) and 2-pyridinecarboxalde-
hyde (550 mg, 5.14 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2) to yield 25 (yellow crystalline solid, 900 mg, 65%),
mp 143–144 °C. IR (neat) 2962, 1659, 1612, 1585, 1496, 1469,
1431, 1408, 1347, 1276, 1214, 1116, 1071, 1029, 1005, 988, 910,
C22H25NO5, 383.1733; found, 383.1780. Elemental analysis: calcd
C, 68.91; H, 6.57; N, 3.65; found, C, 68.74; H, 6.54; N, 3.46.
.
833, 782 cmꢀ1 1H NMR (CDCl3, 300 MHz): d8.65 (1H, d,
5.3.14. (E)-1-[2-Hydroxy-4-methoxy-3-(morpholinomethyl)phenyl]-
3-(thiophen-2-yl)prop-2-en-1-one (22)
J = 6.0 Hz), 8.09 (1H, d, J = 15.0 Hz), 7.99 (1H, dd, J = 8.7, 2.1 Hz),
7.81 (1H, d, J = 1.5 Hz), 7.72 (1H, d, J = 15.0 Hz), 7.66 (1H, d,
J = 1.5 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.26 (1H, ddd, J = 1.5, 1.5,
6.0 Hz), 6.87 (1H, d, J = 8.7 Hz), 3.76 (2H, s), 3.72 (4H, s), 2.56
(4H, s). 13C NMR (CDCl3,75 MHz): d188.1, 162.5, 153.1, 149.9,
141.6, 136.8, 130.6, 130.1, 129.5, 125.2, 125.1, 124.1, 120.4,
116.1, 66.4 (2ꢁ), 61.1, 52.6 (2ꢁ). EIMS, m/z (% rel. intensity): 324
(21) [M]+, 294 (35), 277 (13), 239 (100), 238 (38), 210 (11), 180
(9), 132 (11), 106 (9), 86 (12), 57 (8). HREIMS m/z calcd for
Compound 3b (1.0 g, 3.78 mmol) and 2-thiophenecarboxalde-
hyde (425 mg, 3.79 mmol) were treated as described above. The
crude product was purified by cc eluting with hexanes/EtOAc (7:3)
to yield 22 (yellow solid, 1.0 g, 74%), mp 142–143 °C. IR (neat)
2961, 1631, 1565, 1496, 1374, 1275, 1215, 1114, 993, 838,
703 cmꢀ1. 1H NMR (CDCl3, 300 MHz): d 13.44 (1H, s, OH), 7.86 (1H,
d, J = 15.9 Hz), 7.77 (1H, s), 7.45 (1H, d, J = 4.8 Hz), 7.39 (1H, s), 7.25
(1H, d, J = 15.9 Hz), 7.10 (1H, dd, J = 3.6, 4.8 Hz), 6.44 (1H, s), 3.94
(3H, s), 3.77 (4H, t, J = 4.5 Hz), 3.52 (2H, s), 2.88 (4H, t, J = 4.5 Hz).
13C NMR (CDCl3,100 MHz): d 191.3, 165.9, 164.4, 140.3, 136.7,
132.1, 131.7, 129.1, 128.4, 119.2, 113.3, 108.2, 99.3, 66.8 (2ꢁ),
55.7, 55.6, 53.3 (2ꢁ). EIMS, m/z (% rel. intensity): 359 (52) [M]+,
329 (3), 298 (4), 274 (24), 273 (100), 164 (13), 163 (86), 133 (17),
109 (7), 86 (11), 77 (6), 56 (7). HREIMS m/z calcd for C19H21NO4S,
359.1191; found, 359.1188. Elemental analysis: calcd C, 63.49; H,
5.89; N, 3.90; S, 8.92; found, 63.51; H, 5.87; N, 3.86; S, 9.09.
C19H20N2O3, 324.1474; found, 324.1476. Elemental analysis: calcd
C, 70.35; H, 6.21; N, 8.64; found, C, 70.32; H, 6.31; N, 8.66.
5.3.18. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-(pyridin-
3-yl)prop-2-en-1-one (26)
Compound 6a (1.0 g, 4.26 mmol) and 3-pyridinecarboxalde-
hyde (530 mg, 4.34 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2) to yield 26 (pale yellow solid, 1.0 g, 73%), mp 114–
115 °C. IR (neat) 2961, 1659, 1610, 1588, 1496, 1415, 1304, 1275,
5.3.15. (E)-3-(Furan-2-yl)-1-[2-hydroxy-4-methoxy-3-(morpholinom
ethyl)phenyl]prop-2-en-1-one (23)
1233, 1158, 1116, 1025, 985, 910, 864, 803, 695 cmꢀ1 1H NMR
.
(DMSO-d6, 300 MHz): d 8.98 (1H, d, J = 3.0 Hz), 8.57 (1H, t,
J = 3.0 Hz), 8.34 (1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 2.1 Hz), 8.02
(1H, d, J = 15.6 Hz), 7.68 (1H, d, J = 15.6 Hz), 7.45 (1H, dd, J = 4.5,
8.1 Hz), 6.88 (1H, d, J = 8.1 Hz), 3.67 (2H, s), 3.59 (4H, t,
J = 4.2 Hz), 2.46 (4H, t, J = 4.2 Hz). 13C NMR (DMSO-d6,75 MHz): d
186.8, 161.8, 150.7, 150.1, 139.2, 134.9, 131.0, 130.7, 130.1,
128.7, 123.9, 123.8, 122.5, 115.4, 66.0 (2ꢁ), 58.2, 52.6 (2ꢁ). EIMS,
m/z (% rel. intensity): 324 (100) [M]+, 294 (13), 293 (10), 277
(32), 239 (83), 238 (55), 210 (8), 180 (10), 167 (6), 149 (8), 132
(13), 108 (21), 86 (30), 80 (17), 57 (30). HREIMS m/z calcd for
Compound 3b (1.0 g, 3.78 mmol) and 2-furaldehyde (402 mg,
3.74 mmol) were treated as described above. The crude product
was purified by cc eluting with hexanes/EtOAc (7:3) to yield 23
(yellow solid, 800 mg, 62%), mp 156–157 °C. IR (neat) 2955,
1636, 1573, 1551, 1353, 1276, 1226, 1146, 1115, 993, 860 cmꢀ1
.
1H NMR (CDCl3, 300 MHz): d 13.51 (1H, s OH), 7.91 (1H, S), 7.66
(1H, d, J = 15.0 Hz), 7.58 (1H, S), 7.52 (1H, d, J = 15.0 Hz), 6.77
(1H, s), 6.55 (1H, s), 6.46 (1H, s), 3.88 (3H, s), 3.77 (4H, s), 3.66
(2H, s), 2.56 (4H, s). 13C NMR (CDCl3,100 MHz): d191.8, 166.3,
164.6, 151.9, 145.4, 132.6, 130.6, 118.1, 116.8, 113.8, 113.0,
108.0, 99.6, 66.8 (2ꢁ), 56.0, 55.8, 53.3 (2ꢁ). EIMS, m/z (% rel. inten-
sity): 343 (50) [M]+, 258 (20), 257 (100), 164 (9), 163 (83), 133 (14),
121 (4), 86 (7), 56 (5). HREIMS m/z calcd for C19H21NO5, 343.1420;
found, 343.1422. Elemental analysis: calcd C, 66.46; H, 6.16; N,
4.08; found, 66.28; H, 6.20; N, 4.00.
C19H20N2O3, 324.1474; found, 324.1473. Elemental analysis: calcd
C, 70.35; H, 6.21; N, 8.64; found, C, 69.70; H, 6.31; N, 8.55.
5.3.19. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-(pyridin-
4-yl)prop-2-en-1-one (27)
Compound 6a (1.0 g, 4.26 mmol) and 4-pyridinecarboxalde-
hyde (520 mg, 4.30 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2 to 7:3) to yield 27 (pale yellow solid, 850 mg, 62%),
mp 144–145 °C. IR (neat) 2960, 1660, 1614, 1592, 1495, 1413,
1344, 1302, 1276, 1231, 1158, 1116, 986, 911, 863, 810,
5.3.16. (E)-1-[2-Hydroxy-4-isopropoxy-5-(morpholinomethyl)-
phenyl]-3-(thiophen-2-yl)prop-2-en-1-one (24)
Compound 4c (1.0 g, 3.41 mmol) and 2-thiophenecarboxalde-
hyde (400 mg, 3.57 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (8:2 to 7:3) to yield 24 (pale yellow solid, 900 mg, 68%),
mp 121–122 °C. IR (neat) 2931, 1630, 1565, 1490, 1375, 1275,
753 cmꢀ1
.
1H NMR (DMSO-d6, 300 MHz:): d8.63 (2H, d,
J = 6.0 Hz), 8.09 (1H, d, J = 15.3 Hz), 8.02 (1H, d, J = 9.0 Hz), 7.99
(1H, s), 7.79 (2H, d, J = 6.0 Hz), 7.59 (1H, d, J = 15.3 Hz), 6.88 (1H,
d, J = 9.0 Hz), 3.67 (2H, s), 3.59 (4H, s), 2.46 (4H, s). 13C NMR
(DMSO-d6, 100 MHz): d 187.0, 162.0, 150.3 (2ꢁ), 142.0, 139.8,
131.1, 130.2, 128.5, 126.4, 122.6, 122.4 (2ꢁ), 115.5, 66.1 (2ꢁ),
58.1, 52.7 (2ꢁ). EIMS, m/z (% rel. intensity): 324 (100) [M]+, 277
(28), 239 (22), 238 (52), 86 (18). HREIMS m/z calcd for
1250, 1216, 1149, 1113, 943, 837, 707 cmꢀ1 1H NMR (DMSO-d6,
.
300 MHz): d13.28 (1H, s, OH), 7.99 (1H, s), 7.96 (1H, d,
J = 15.0 Hz), 7.80 (1H, d, J = 3.0 Hz), 7.69 (1H, d, J = 3.0 Hz), 7.56
(1H, d, J = 15.0 Hz), 7.19 (1H, t, J = 3.0 Hz), 6.53 (1H, s), 4.71 (1H,
m), 3.56 (6H, s), 2.40 (4H, s), 1.28 (6H, d, J = 6.0 Hz). 13C NMR
(DMSO-d6,75 MHz): d 190.8, 164.6, 162.7, 139.6, 136.5, 133.1,
132.3, 130.8, 128.8, 119.5, 118.1, 112.7, 100.4, 70.3, 66.3 (2ꢁ),
55.1, 52.9 (2ꢁ), 21.8 (2ꢁ). EIMS, m/z (% rel. intensity): 387 (48)
C19H20N2O3, 324.1474; found, 324.1471. Elemental analysis: calcd
C, 70.35; H, 6.21; N, 8.64; found, C, 70.35; H, 6.21; N, 8.64; found C,
69.05; 6.27; N, 8.62.

M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
7367
5.3.20. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-phenyl-
prop-2-en-1-one (28)
(2H, s), 3.59 (4H, s), 2.45 (4H, s), 2.36 (3H, s). 13C NMR (DMSO-
d6,75 MHz): d 186.5, 161.4, 155.6, 150.0, 135.4, 130.5, 129.4, 129.0,
122.5, 118.3, 117.0, 115.4, 109.7, 66.1 (2ꢁ), 58.1, 52.7 (2ꢁ), 13.7.
EIMS, m/z (% rel. intensity): 327 (94) [M]+, 280 (15), 254 (7), 241
(25), 240 (100), 225 (30), 197 (11), 169 (12), 141 (14), 135 (19),
106 (13), 86 (20), 77 (24), 56 (14). HREIMS m/z calcd for
Compound 6a (1.0 g, 4.26 mmol) and benzaldehyde (520 mg,
4.38 mmol) were treated as described above. The crude product
was purified by cc eluting with hexanes/EtOAc (7:3) to yield 28
(yellow solid, 940 mg, 74%), mp 124–125 °C. IR (neat) 2960,
1657, 1609, 1590, 1494, 1448, 1334, 1304, 1275, 1229, 1157,
C19H21NO4, 327.1471; found, 327.1472. Elemental analysis: calcd
1116, 863, 766 cmꢀ1
.
1H NMR (CDCl3, 300 MHz): d 7.94 (1H, dd,
C, 69.71; H, 6.47; N, 4.28; found, C, 69.61; H, 6.60; N, 4.11.
J = 8.2, 2.1 Hz), 7.82 (1H, s), 7.80 (1H, d, J = 15.6 Hz), 7.64 (2H, m),
7.55 (1H, d, J = 15.6 Hz), 7.38 (3H, m), 6.92 (1H, d, J = 8.2 Hz),
3.83 (2H, s), 3.78 (4H, s), 2.64 (4H, s). 13C NMR (CDCl3,75 MHz):
d188.4, 162.3, 143.7, 134.9, 130.4, 130.2, 130.1, 129.8, 128.8 (2ꢁ),
128.2 (2ꢁ), 121.6, 120.4, 116.0, 66.4 (2ꢁ), 61.1, 52.6 (2ꢁ). EIMS,
m/z (% rel. intensity): 323 (100) [M]+, 276 (24), 238 (15), 237
(26), 235 (12), 131 (9), 103 (10), 86 (27). HREIMS m/z calcd for
5.3.24. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-
(3-methylthiophen-2-yl)prop-2-en-1-one (32)
Compound 6a (1.0 g, 4.26 mmol) and 3-methyl-2-thiophene-
carboxaldehyde (540 mg, 4.28 mmol) were treated as described
above. The crude product was purified by cc eluting with hex-
anes/EtOAc (7:3) to yield 32 (yellow solid, 820 mg, 56%), mp
132–133 °C. IR (neat) 2959, 1651, 1592, 1494, 1453, 1293, 1273,
C20H21NO3, 323.1521; found, 323.1523. Elemental analysis: calcd
C, 74.28; H, 6.55; N, 4.33; found, C, 74.27; H, 6.56; N, 4.25.
1156, 1116, 967, 863, 829 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
.
8.01 (1H, d, J = 15.0 Hz), 7.91 (1H, d, J = 9.0 Hz), 7.78 (1H, s), 7.28
(1H, d, J = 15.0 Hz), 7.26 (1H, d, J = 9.0 Hz), 6.90 (2H, m), 3.83 (2H,
s), 3.79 (4H, s), 2.64 (4H, s), 2.39 (3H, s). 13C NMR (CDCl3,100 MHz):
d 187.8, 162.1, 142.4, 134.8, 134.6, 131.3, 1306, 130.5, 130.0, 127.0,
119.6, 119.3, 116.3, 66.1 (2ꢁ), 60.5, 52.5 (2ꢁ), 14.2. EIMS, m/z (%
rel. intensity): 343 (100) [M]+, 296 (21), 258 (26), 257 (12), 256
(17), 241 (10), 228 (9), 151 (8), 135 (6), 121 (6), 86 (20), 56 (5).
HREIMS m/z calcd for C19H21NO3S, 343.1242; found, 343.1241. Ele-
mental analysis: calcd C, 66.45; H, 6.16; N, 4.08; S, 9.34; found, C,
66.60; H, 6.20; N, 4.01; S, 9.42.
5.3.21. (E)-3-(Furan-2-yl)-1-[4-hydroxy-3-(morpholinomethyl)-
phenyl]prop-2-en-1-one (29)
Compound 6a (1.0 g, 4.26 mmol) and 2-furaldehyde (420 mg,
4.37 mmol) were treated as described above. The crude product
was purified by cc eluting with hexanes/EtOAc (7:3 to 6:4) to
yield 29 (yellow solid, 1.12 g, 84%), mp 115–116 °C. IR (neat)
2960, 1656, 1606, 1552, 1498, 1496, 1275, 1233, 1214, 1116,
1016, 864, 746 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.95 (1H, d,
.
J = 8.4 Hz), 7.82 (1H, s), 7.57 (1H, d, J = 15.3 Hz), 7.52 (1H, s),
7.45 (1H, d, J = 15.3 Hz), 6.93 (1H, d, J = 8.7 Hz), 6.70 (1H, s),
3.85 (2H, s), 3.80 (4H, s), 2.67 (4H, s). 13C NMR (CDCl3,
5.3.25. (E)-1-[4-Hydroxy-3,5-bis(morpholinomethyl)phenyl]-3-
(pyridin-2-yl)prop-2-en-1-one (33)
100 MHz):
d 187.8, 162.3, 151.8, 144.6, 130.4, 130.0, 129.9,
129.8, 120.4, 119.0, 116.1, 115.7, 112.5, 66.5 (2ꢁ), 61.3, 52.7
(2ꢁ). EIMS, m/z (% rel. intensity): 313 (100) [M]+, 266 (22), 228
(13), 227 (17), 226 (30), 133 (18), 121 (10), 100 (5), 86 (25), 57
Compound 6b (1.0 g, 3.09 mmol) and 2-pyridinecarboxalde-
hyde (380 mg, 3.55 mmol) were treated as described above. The
crude product was purified by cc eluting with CHCl3/MeOH (9:1)
to yield 33 (pale yellow solid, 940 mg, 74%), mp 152–153 °C. IR
(neat) 2957, 1658, 1612, 1592, 1432, 1326, 1162, 1116, 1070,
(10). HREIMS m/z calcd for
C18H19NO4, 313.1314; found,
313.1313. Elemental analysis: calcd C, 68.99; H, 6.11; N, 4.47;
found, C, 68.95; H, 6.08; N, 4.43.
984, 906, 863, 783 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 8.67 (1H,
.
d, J = 3.0 Hz), 8.12 (1H, d, J = 15.3 Hz), 7.94 (2H, s), 7.75 (1H, d,
J = 15.3 Hz), 7.72 (1H, dd, J = 1.5, 7.8 Hz), 7.53 (1H, d, J = 7.8 Hz),
7.29 (1H, dd, J = 1.5, 3.0 Hz), 3.76 (12H, m), 2.60 (8H, s). 13C NMR
(CDCl3, 75 MHz): d 188.3, 161.4, 153.3, 150.0, 142.0, 136.9, 131.0
(2ꢁ), 129.1, 125.3, 125.2, 124.2, 121.6, 66.4 (4ꢁ), 58.8 (2ꢁ), 52.9
(4ꢁ). EIMS, m/z (% rel. intensity): 423 (31) [M]+, 365 (7), 337
(36), 336 (100), 278 (14), 253 (50), 252 (46), 251 (46), 222 (20),
194 (18), 132 (16), 100 (28), 86 (15), 57 (14). HREIMS m/z calcd
for C24H29N3O4, 423.2158; found, 423.2160. Elemental analysis:
calcd C, 68.06; H, 6.90; N, 9.92; found, C, 68.03; H, 6.96; N, 9.90.
5.3.22. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-(thio-
phen-2-yl)prop-2-en-1-one (30)
Compound 6a (1.0 g, 4.26 mmol) and 2-thiophenecarboxalde-
hyde (480 mg, 4.29 mmol) were treated as described above. The
crude product was purified by cc eluting with diisopropyl ether/
MeOH (7:3) to yield 30 (yellow solid, 920 mg, 66%), mp 148–
149 °C. IR (neat) 2960, 1653, 1595, 1494, 1452, 1364, 1274, 1210,
1155, 1116, 909, 862, 820, 578 cmꢀ1 1H NMR (CDCl3, 300 MHz): d
.
7.92 (1H, d, J = 5.4 Hz), 7.88 (1H, s), 7.77 (1H, s), 7.38 (1H, d,
J = 3.6 Hz), 7.34 (1H, d, J = 15.3 Hz), 7.32 (1H, d, J = 15.3 Hz), 7.06
(1H, dd, J = 8.1, 3.6 Hz), 6.90 (1H, d, J = 8.1 Hz), 3.80 (2H, s), 3.77
(4H, s), 2.61 (4H, s). 13C NMR (CDCl3,75 MHz): d 187.7, 162.3,
140.4, 136.2, 131.6, 130.3, 129.9, 129.7, 128.3, 128.2, 120.4, 120.3,
116.0, 66.4 (2ꢁ), 61.2, 52.6 (2ꢁ). EIMS, m/z (% rel. intensity): 329
(100) [M]+, 298 (5), 282 (18), 244 (12), 243 (12), 86 (11). HREIMS
m/z calcd for C19H19NO3S, 329.1086; found, 329.1088. Elemental
analysis: calcd C, 65.63; H, 5.81; N, 4.25; S, 9.73; found, 65.62; H,
5.81; N, 4.23; S, 9.90.
5.3.26. (E)-1-[4-Hydroxy-3,5-bis(morpholinomethyl)phenyl]-3-
(3-methylthiophen-2-yl)prop-2-en-1-one (34)
Compound 6b (1.0 g, 3.04 mmol) and 3-methyl-2-thiophene-
carboxaldehyde (400 mg, 3.17 mmol) were treated as described
above. The crude product was purified by cc eluting with
CHCl3/MeOH (8:2) to yield 34 (yellow solid, 850 mg, 65%), mp
146–147 °C. IR (neat) 2957, 1631, 1601, 1553, 1473, 1454, 1412,
1370, 1348, 1266, 1160, 1115, 1015, 967, 864 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d 8.01 (1H, d, J = 15.3 Hz), 7.87 (2H, s), 7.31
(1H, d, J = 15.3 Hz), 7.29 (1H, d, J = 4.8 Hz), 6.90 (1H, d,
J = 4.8 Hz), 3.78 (12H, br s), 2.62 (8H, s), 2.40 (3H, s). 13C NMR
(CDCl3,75 MHz): d 187.9, 161.0, 142.3, 134.8, 134.7, 131.3 (2ꢁ),
130.7, 130.3, 129.5, 127.1, 119.5 (2ꢁ), 66.3 (4ꢁ), 58.7 (2ꢁ), 52.8
(4ꢁ), 14.2. EIMS, m/z (% rel. intensity): 442 (38) [M]+, 384 (9),
357 (27), 356 (35), 355 (100), 297 (13), 270 (14), 244 (13), 171
(11), 151 (20), 147 (12), 123 (11), 86 (16), 57 (18). HREIMS m/z
calcd for C24H30N2O4S, 442.1926; found, 442.1926. Elemental
analysis: calcd. 65.13; H, 6.83; N, 6.33; S, 7.25; found, C, 65.03;
H, 6.82; N, 6.26; S, 7.30.
5.3.23. (E)-1-[4-Hydroxy-3-(morpholinomethyl)phenyl]-3-(5-
methylfuran-2-yl)prop-2-en-1-one (31)
Compound 6a (1.0 g, 4.26 mmol) and 5-methyl-2-furaldehyde
(470 mg, 4.27 mmol) were treated as described above. The crude
product was purified by cc eluting with hexanes/EtOAc (6:4) to yield
31 (yellow solid, 980 mg, 70%), mp 72–73 °C. IR (neat) 2920, 1656,
1606, 1522, 1496, 1366, 1347, 1322, 1299, 1210, 1183, 1155, 1117,
1021, 970, 90, 864, 827 cmꢀ1. 1H NMR (DMSO-d6, 300 MHz): d 7.87
(2H, m), 7.43 (1H, d, J = 15.3 Hz), 7.36 (1H, d, J = 15.3 Hz), 6.92 (1H,
d, J = 3.0 Hz), 6.86 (1H, d, J = 9.0 Hz), 6.30 (1H, d, J = 3.0 Hz), 3.66

7368
M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
5.3.27. (E)-1-[3-Hydroxy-4-(morpholinomethyl)phenyl]-3-(pyridin-
2-yl)prop-2-en-1-one (35)
1660, 1581, 1549, 1497, 1455, 1305, 1284, 1269, 1166, 1117,
1070, 985, 865, 793 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.52 (1H,
.
Compound 7a (1.0 g, 4.26 mmol) and 2-pyridinecarboxalde-
hyde (520 mg, 4.86 mmol) were treated as described above. The
crude product was purified by cc eluting with hexanes/EtOAc
(7:3) to yield 35 (yellow solid, 850 mg, 62%), mp 114–115 °C. IR
(neat) 2958, 1661, 1612, 1574, 1442, 1385, 1320, 1280, 1195,
br s), 7.24 (2H, t, J = 9.0 Hz), 7.00 (1H, d, J = 9.0 Hz), 6.99 (H, d,
J = 15.0 Hz), 6.96 (1H, d, J = 15.0 Hz), 6.68 (1H, d, J = 2.1 Hz), 6.50
(1H, br s), 3.88 (2H, s), 3.74 (4H, s), 2.59 (4H, s). 13C NMR
(CDCl3,75 MHz): d 195.1, 158.8, 150.9, 145.4, 140.1, 132.1, 128.3,
123.8, 119.1, 118.8 (2ꢁ), 116.5, 112.7, 66.4 (2ꢁ), 57.6, 52.5 (2ꢁ).
EIMS, m/z (% rel. intensity): 313 (92) [M]+, 284 (11), 228 (18),
227 (30), 226 (100), 210 (12), 198 (12), 197 (34), 191 (12), 190
(22), 161 (14), 147 (44), 141 (15), 121 (12), 115 (14), 86 (56), 81
(30), 56 (17). HREIMS m/z calcd for C18H19NO4, 313.1314; found,
313.1313. Elemental analysis: calcd C, 68.21; H, 5.72; N, 4.68;
found, C, 68.73; H, 6.09; N, 4.50.
1116, 991, 865, 775 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 8.69 (1H,
.
d, J = 4.2 Hz), 8.05 (1H, d, J = 15.0 Hz), 7.76 (1H, d, J = 15.0 Hz),
7.75 (1H, d, J = 1.5 Hz), 7.56 (1H, s), 7.53 (1H, d, J = 1.2 Hz), 7.49
(1H, d, J = 7.8 Hz), 7.30 (1H, m), 7.18 (1H, d, J = 7.8 Hz), 3.84 (2H,
s), 3.81 (4H, s), 2.67 (4H, s). 13C NMR (CDCl3,75 MHz): d 190.0,
157.7, 153.2, 150.0, 142.6, 138.8, 136.8, 129.2, 125.6 (2ꢁ), 125.2,
124.3, 119.8, 116.2, 66.4 (2ꢁ), 61.2, 52.8 (2ꢁ). EIMS, m/z (% rel.
intensity): 324 (73) [M]+, 285 (20), 277 (29), 239 (100), 238 (81),
237 (68), 209 (27), 208 (53), 180 (19), 161 (16), 132 (14), 106
(14), 93 (47), 86 (21), 78 (15). HREIMS m/z calcd for C19H20N2O3,
324.1474; found, 324.1473. Elemental analysis: calcd C, 70.35; H,
6.21; N, 8.64; found, C, 69.28; H, 6.20; N, 8.33.
5.3.31. (E)-1-[3-Hydroxy-2-(morpholinomethyl)phenyl]-3-(thio-
phen-2-yl)prop-2-en-1-one (39)
Compound 7b (1.0 g, 4.26 mmol) and 2-thiophenecarboxalde-
hyde (480 mg, 4.28 mmol) were treated as described above. The
crude product was purified by cc eluting with hexanes/EtOAc
(7:3) to yield 39 as yellow oil (1.2 g, 86%). IR (neat) 2960, 1638,
5.3.28. (E)-1-[3-Hydroxy-4-(morpholinomethyl)phenyl]-3-(pyridin-
3-yl)prop-2-en-1-one (36)
1581, 1498, 1454, 1286, 1166, 1116, 984, 933, 863, 792 cmꢀ1 1H
.
NMR (CDCl3, 300 MHz): d 7.60 (1H, d, J = 15.6 Hz), 7.46 (1H, d,
J = 3.6 Hz), 7.31 (1H, d, J = 3.6 Hz), 7.23 (1H, d, J = 9.0 Hz), 7.08
(1H, d, J = 9.0 Hz), 7.02 (1H, m), 6.98 (1H, s), 6.91 (1H, d,
J = 15.6 Hz), 3.91 (2H, s), 3.77 (4H, s), 2.64 (4H, s). 13C NMR
(CDCl3,75 MHz): d 195.0, 158.8, 140.1, 139.7, 138.9, 132.3, 129.7,
128.9, 128.4, 125.1, 119.6 (2ꢁ), 118.2, 66.0 (2ꢁ), 56.8, 52.4 (2ꢁ).
EIMS, m/z (% rel. intensity): 329 (68) [M]+, 244 (32), 243 (35),
242 (100), 213 (24), 190 (22), 181 (10), 147 (42), 134 (13), 109
(13), 97 (40), 86 (70), 58 (42), 57 (19). HREIMS m/z calcd for
Compound 7a (1.0 g, 4.26 mmol) and 3-pyridinecarboxalde-
hyde (520 mg, 4.86 mmol) were treated as described above. The
crude product was purified by cc eluting with CHCl3/MeOH
(9.5:0.5) to yield 36 (yellow solid, 820 mg, 59%), mp 140–141 °C.
IR (neat) 2970, 1661, 1603, 1569, 1510, 1450, 1385, 1306, 1270,
1191, 1168, 1116, 985, 864, 764 cmꢀ1
.
1H NMR (CDCl3,
300 MHz): d 8.83 (1H, s), 8.62 (1H, d, J = 2.4 Hz), 7.94 (1H, d,
J = 7.8 Hz), 7.76 (1H, d, J = 15.6 Hz), 7.55 (1H, d, J = 15.6 Hz), 7.52
(2H, s), 7.34 (1H, m), 7.17 (1H, d, J = 8.1 Hz), 3.81 (6H, m), 2.63
(4H, s). 13C NMR (CDCl3,100 MHz): d 189.3, 157.8, 151.0, 149.9,
140.7, 138.7, 134.5, 130.7, 129.3, 125.8, 123.9, 123.7, 119.6,
116.1, 66.5 (2ꢁ), 61.4, 52.8 (2ꢁ). EIMS, m/z (% rel. intensity): 324
(100) [M]+, 293 (8), 277 (39), 271 (8), 239 (59), 238 (84), 210
(13), 208 (7), 180 (21), 167 (14), 165 (6), 132 (26), 104 (29), 86
(18), 78 (21), 77 (34), 56 (20). HREIMS m/z calcd for C19H20N2O3,
324.1474; found, 324.1474. Elemental analysis: calcd C, 70.35; H,
6.21; N, 8.64; found, C, 70.24; H, 6.21; N, 8.61.
C18H19NO3S, 329.1086; found, 329.1083. Elemental analysis: calcd
C, 66.45; H, 6.16; N, 4.08; S, 9.34; found, C, 66.49; H, 5.95; N, 4.12;
S, 9.79.
5.3.32. (E)-1-[3-Hydroxy-2-(morpholinomethyl)phenyl]-3-(3-
methylthiophen-2-yl)prop-2-en-1-one (40)
Compound 7b (1.0 g, 4.26 mmol) and 3-methyl-2-thiophene-
carboxaldehyde (540 mg, 4.28 mmol) were treated as described
above. The crude product was purified by cc eluting with diisprop-
ylether/MeOH (7:3) to yield 40 (yellow solid, 1.0 g, 66%), mp 101–
102 °C. IR (neat) 2959, 1655, 1603, 1576, 1499, 1454, 1286, 1166,
5.3.29. (E)-1-[3-Hydroxy-4-(morpholinomethyl)phenyl]-3-(pyridin-
4-yl)prop-2-en-1-one (37)
1116, 1069, 984, 864 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.75
.
Compound 7a (1.0 g, 4.26 mmol) and 4-pyridinecarboxalde-
hyde (530 mg, 4.95 mmol) were treated as described above. The
crude product was purified by cc eluting with disopropyl ether/
MeOH (7:3) to yield 37 (yellow solid, 900 mg, 65%), mp 174–
175 °C. IR (neat) 2948, 1660, 1610, 1573, 1511, 1393, 1301, 1272,
(1H, d, J = 15.6 Hz), 7.33 (1H, d, J = 5.1 Hz), 7.28 (1H, d,
J = 15.6 Hz), 7.04 (1H, d, J = 9.0 Hz), 6.98 (1H, d, J = 9.0 Hz), 6.90
(1H, d, J = 3.9 Hz), 6.82 (1H, d, J = 9.0 Hz), 3.93 (2H, s), 3.77 (4H,
s), 2.63 (4H, s), 2.32 (3H, s). 13C NMR (CDCl3, 75 MHz): d 194.6,
158.8, 143.1, 140.5, 136.9, 134.0, 131.5, 128.8, 128.2, 123.8, 119.5
(2ꢁ), 118.5, 66.2 (2ꢁ), 57.0, 52.5 (2ꢁ), 14.3. EIMS, m/z (% rel. inten-
sity): 343 (87) [M]+, 258 (30), 257 (34), 256 (100), 243 (16), 227
(18), 213 (17), 190 (37), 161 (21), 147 (24), 127 (46), 126 (61),
111 (83), 86 (51), 77 (25), 57 (16). HREIMS m/z calcd for
1171, 1115, 980, 866, 563 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d
.
8.66 (2H, d, J = 6.0 Hz), 8.08 (1H, d, J = 15.3 Hz), 7.82 (2H, d,
J = 6.0 Hz), 7.64 (1H, d, J = 15.3 Hz), 7.62 (1H, m), 7.49 (1H, s),
7.35 (1h, d, J = 9.0 Hz), 3.67 (2H, s), 3.61 (4H, s), 2.47 (4H, m). 13C
NMR (DMSO-d6,75 MHz): d 188.8, 158.9, 150.4 (2ꢁ), 141.9, 140.7,
137.2, 129.9, 128.8, 126.5, 122.5 (2ꢁ), 119.8, 114.8, 66.1 (2ꢁ),
58.1, 52.9 (2ꢁ). EIMS, m/z (% rel. intensity): 324 (60) [M]+, 293
(5), 284 (18), 277 (24), 271 (5), 239 (100), 238 (52), 210 (12),
180 (12), 167 (9), 153 (7), 132 (14), 104 (13), 97 (13), 77 (22), 71
C19H21NO3S, 343.1242; found, 343.1245. Elemental analysis: calcd
C, 65.63; H, 5.81; N, 4.25; S, 9.73; found, C, 66.23; H, 6.18; N, 3.96;
S, 9.72.
5.3.33. (E)-1-[3-Hydroxy-2-(morpholinomethyl)phenyl]-3-phenyl-
prop-2-en-1-one (41)
(22), 69 (22), 55 (19). HREIMS m/z calcd for
C19H20N2O3,
324.1474; found, 324.1472. Elemental analysis: calcd C, 70.35; H,
6.21; N, 8.64; found, C, 70.47; H, 6.23; N, 8.65.
Compound 7b (1.0 g, 4.26 mmol) and benzaldehyde (440 mg,
4.15 mmol) were treated as described above. The crude product
was purified by cc eluting with diisopropylether/MeOH (8:2) to
yield 41 (brown solid, 1.0 g, 73%), mp 71–72 °C. IR (neat) 2961,
1642, 1578, 1497, 1453, 1402, 1166, 1117, 1070, 986, 933, 797,
5.3.30. (E)-3-(Furan-2-yl)-1-[3-hydroxy-2-(morpholinomethyl)-
phenyl]prop-2-en-1-one (38)
Compound 7b (1.0 g, 4.26 mmol) and 2-furaldehyde (420 mg,
4.37 mmol) were treated as described above. The crude product
was purified by cc eluting with diisopropyleter/MeOH (7:3) to
yield 38 (yellow solid, 1.2 g, 90%), mp 82–83 °C. IR (neat) 2960,
762 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 7.55 (2H, m), 7.46 (1H, d,
.
J = 16.2 Hz), 7.40 (3H, m), 7.25 (1H, t, J = 7.8 Hz), 7.10 (1H, d,
J = 16.2 Hz), 6.99 (2H, t, J = 7.8 Hz), 3.87 (2H, s), 3.74 (4H, s), 2.57
(4H, m). 13C NMR (CDCl3,100 MHz): d 195.8, 158.8, 146.2, 140.1,

M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
7369
134.2, 130.8, 128.9 (2ꢁ), 128.4 (3ꢁ), 126.6, 119.1, 118.8 (2ꢁ), 66.4
(2ꢁ), 57.6, 52.5 (2ꢁ). EIMS, m/z (% rel. intensity): 323 (38) [M]+,
322 (11), 238 (37), 237 (39), 236 (85), 235 (61), 207 (20), 190
(21), 178 (15), 162 (23), 148 (100), 147 (42), 131 (19), 103 (21),
91 (30), 86 (74), 77 (29), 57 (19). HREIMS m/z calcd for
5.3.37. (E)-3-[3-Hydroxy-4-methoxy-2-(piperidin-1-ylmethyl)-
phenyl]-1-(thiophen-2-yl)prop-2-en-1-one (45)
Compound 8a (1.0 g, 4.01 mmol) and 2-acetylthiophene
(504 mg, 4.01 mmol) were treated as described above. The crude
product was purified by cc eluting with hexanes/EtOAc (8:2) to
yield 45 (pale yellow solid, 1.3 g, 91%), mp 123–124 °C. IR (neat)
2937, 1645, 1576, 1513, 1472, 1412, 1355, 1257, 1078, 751,
C20H21NO3, 323.1521; found, 323.1520. Elemental analysis: calcd
C, 74.28; H, 6.55; N, 4.33; found, 73.94; H, 6.63; N, 4.35.
664 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 8.05 (1H, d, J = 15.3 Hz),
.
5.3.34. (E)-1-[3-Hydroxy-2,4-bis(morpholinomethyl)phenyl]-3-
(pyridin-2-yl)prop-2-en-1-one (42)
7.83 (1H, d, J = 3.0 Hz), 7.71 (1H, d, J = 3.0 Hz), 7.22 (1H, d,
J = 15.3 Hz), 7.19 (1H, d, J = 9.0 Hz), 7.09 (1H, dd, J = 3.0, 3.0 Hz),
3.91 (2H, s), 3.90 (3H, s), 2.58 (4H, s), 1.64 (4H, s), 1.49 (2H, s).
13C NMR (CDCl3,75 MHz): d 182.3, 150.5, 148.9, 146.1, 141.5,
134.2, 132.1, 128.7, 127.0, 122.2, 121.4, 118.4, 111.1, 57.9, 56.3,
54.3, 26.1, 24.2. EIMS, m/z (% rel. intensity): 357 (35) [M]+, 274
(10), 246 (48), 229 (4), 190 (7), 163 (8), 162 (14), 147 (6), 111
Compound 7c (1.0 g, 3.09 mmol) and 2-pyridinecarboxaldehyde
(380 mg, 3.55 mmol) were treated as described above. The crude
product was purified by cc eluting with CHCl3/MeOH (9:1) to yield
42 (brown solid, 850 mg, 67%), mp 117–118 °C. IR (neat) 2957,
1649, 1613, 1573, 1503, 1435, 1306, 1116, 986, 863 cmꢀ1 1H
.
NMR (CDCl3, 300 MHz): d 8.61 (1H, d, J = 3.0 Hz), 7.70 (1H, t,
J = 7.5 Hz), 7.47 (1H, d, J = 15.3 Hz), 7.46 (1H, d, J = 7.5 Hz), 7.34
(1H, m), 7.25 (1H, d, J = 15.3 Hz), 7.12 (1H, d, J = 7.8 Hz), 3.75 (6H,
s), 3.68 (2H, s), 3.60 (4H, s), 2.57 (4H, s), 2.45 (4H, s). 13C NMR
(100), 97 (10), 84 (69). HREIMS m/z calcd for C20H23NO3S,
357.1399; found, 357.1402. Elemental analysis: calcd C, 67.20; H,
6.49; N, 3.92; S, 8.97; found, C, 67.11;, 6.46; N, 3.87; S, 9.20.
(CDCl3,100 MHz):
d
195.8, 156.5, 153.3, 150.1, 142.2, 139.9,
5.3.38. (E)-1-(Furan-2-yl)-3-[3-hydroxy-4-methoxy-2-(piperidin-
1-ylmethyl)phenyl]prop-2-en-1-one (46)
136.7, 130.7, 128.4, 124.1, 123.9 (2ꢁ), 121.4, 118.9, 66.5 (2ꢁ),
66.3 (2ꢁ), 59.2, 54.7, 53.0 (2ꢁ), 52.6 (2ꢁ). EIMS, m/z (% rel. inten-
sity): 423 (2) [M]+, 339 (7), 338 (31), 336 (62), 252 (21), 251 (100),
250 (30), 249 (31), 248 (60), 232 (20), 223 (20), 222 (19), 204 (10),
194 (12). HREIMS m/z calcd for C24H29N3O4, 423.2158; found,
423.2161. Elemental analysis: calcd C, 68.06; H, 6.90; N, 9.92;
found, C, 67.81; H, 6.88; N, 9.85.
Compound 8a (1.0 g, 4.01 mmol) and 2-acetylfuran (450 mg,
4.09 mmol) were treated as described above. The crude product
was purified by cc eluting with hexanes/EtOAc (8:2) to yield 46
(yellow solid, 1.1 g, 81%), mp 155–156 °C. IR (neat) 2937, 1654,
1581, 1465, 1403, 1263, 1081, 1050, 985, 927, 757 cmꢀ1 1H NMR
.
(CDCl3, 300 MHz): d 8.06 (1H, d, J = 15.3 Hz), 7.64 (1H, s), 7.31
(1H, d, J = 3.0 Hz), 7.29 (1H, d, J = 15.3 Hz), 7.26 (1H, d, J = 9.0 Hz),
6.84 (1H, d, J = 9.0 Hz), 6.58 (1H, t, J = 3.0 Hz), 4.00 (2H, s), 3.91
(3H, s), 2.66 (4H, s), 1.70 (4H, s), 1.51 (2H, s). 13C NMR
5.3.35. (E)-3-[3-Hydroxy-4-methoxy-2-(morpholinomethyl)-
phenyl]-1-m-tolylprop-2-en-1-one (43)
Compound 8b (1.90 g, 7.57 mmol) and 3-methylacetophenone
(1.02 g, 7.61 mmol) were treated as described above. The crude
product was purified by cc eluting with disopropylether/MeOH
(7:3) to yield 43 (yellow solid, 2.01 g, 75%), mp 114–115 °C. IR
(neat) 2957, 1656, 1604, 1581, 1462, 1403, 1257, 1181, 1116,
(CDCl3,100 MHz): d 177.7, 153.7, 150.3, 148.1, 146.5, 140.6,
126.7, 121.4, 120.6, 118.3, 117.4, 112.5, 110.8, 56.3, 55.8, 53.7,
25.1, 23.4. EIMS, m/z (% rel. intensity): 341 (61) [M]+, 258 (13),
256 (11), 246 (54), 227 (6), 190 (5), 177 (11), 162 (24), 161 (14),
95 (100), 84 (92), 81 (11). HREIMS m/z calcd for C20H23NO4,
341.1627; found, 341.1628. Elemental analysis: calcd C, 70.36; H,
6.79; N, 4.10; found, C, 70.31; H, 6.85; N, 4.09.
1075, 1040, 1004, 864, 800 cmꢀ1 1H NMR (DMSO-d6, 300 MHz):
.
d9.41 (1H, s, OH), 8.08 (1H, d, J = 15.3 Hz), 7.87 (2H, m), 7.58 (1H,
d, J = 15.3 Hz), 7.49 (1H, d, J = 9.0 Hz), 7.43 (2H, m), 6.95 (1H, d,
J = 9.0 Hz), 3.83 (3H, s), 3.73 (2H, s), 3.52 (4H, m), 2.43 (7H, m).
13C NMR (DMSO-d6,75 MHz): d 198.8, 148.3, 145.2, 141.6, 141.6,
137.2 (2ꢁ), 132.4, 127.9, 127.6, 126.5, 124.7, 122.0, 120.0, 117.,
109., 65.3 (2ꢁ), 54.8, 52.5, 51.7 (2ꢁ), 20.0. EIMS, m/z (% rel. inten-
sity): 367 (8) [M]+, 313 (92), 284 (11), 227 (30), 226 (100), 210 (13),
197 (34), 190 (22), 169 (16), 147 (44), 141 (15), 115 (14), 86 (56),
81 (30). HREIMS m/z calcd for C22H25NO4, 367.1784; found,
367.1785. Elemental analysis: calcd C, 71.91; H, 6.86; N, 3.81;
found, C, 71.53; H, 6.88; N, 3.86.
5.3.39. (E)-3-[3-Hydroxy-4-methoxy-2-(piperidin-1-ylmethyl)phenyl]-
1-(pyridin-3-yl)prop-2-en-1-one (47)
Compound 8a (1.0 g, 4.01 mmol) and 3-acetylpyridine (490 mg,
4.05 mmol) were treated as described above. The crude product
was purified by cc eluting with diisopropylether/MeOH (8:2) to
yield 47 (yellow solid, 920 mg, 65%), mp 112–113 °C. IR (neat)
2936, 1659, 1583, 1470, 1407, 1347, 1307, 1258, 1155, 1110,
1077, 982, 861 795, 753 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 9.24
.
(1H, s), 8.80 (1H, d, J = 4.2 Hz), 8.30 (1H, d, J = 7.8 Hz), 8.12 (1H,
d, J = 15.3 Hz), 7.46 (1H, t, J = 6.9 Hz), 7.35 (1H, d, J = 15.3 Hz),
7.31 (1H, d, J = 8.4 Hz), 6.87 (1H, d, J = 8.4 Hz), 3.99 (2H, s), 3.93
(3H, s), 2.65 (4H, s), 1.72 (4H, s), 1.52 (2H. s). 13C NMR (CDCl3,
75 MHz): d 188.4, 152.9, 150.2, 149.5, 148.4, 142.6, 135.7, 133.5,
126.1, 123.5, 121.0, 120.9, 118.0, 110.5, 57.3, 55.7, 53.7, 25.5,
23.6. EIMS, m/z (% rel. intensity): 352 (44) [M]+, 269 (20), 246
(79), 164 (24), 162 (16), 147 (15), 106 (77), 84 (100), 78 (56). HRE-
IMS m/z calcd for C21H24N2O3, 352.1787; found, 352.1790. Elemen-
tal analysis: calcd C, 71.57; H, 6.86; N, 7.95; found, C, 71.38; H,
6.93; N, 7.85.
5.3.36. (E)-3-[3-Hydroxy-4-methoxy-2-(morpholinomethyl)-
phenyl]-1-p-tolylprop-2-en-1-one (44)
Compound 8b (1.90 g, 7.57 mmol) and 4-methylacetophenone
(1.02 g, 7.61 mmol) were treated as described above. The crude
product was purified by cc eluting with disopropylether/MeOH
(7:3) to yield 44 (yellow solid, 2.3 g, 83%), mp 137–138 °C. IR (neat)
2957, 1657, 1579, 1463, 1400, 1258, 1162, 1117, 1002, 863,
796 cmꢀ1 1H NMR (DMSO-d6, 300 MHz): d 9.94 (1H, s, OH), 8.07
.
(1H, d, J = 15.6 Hz), 7.99 (2H, d, J = 8.1 Hz), 7.58 (1H, d, J = 15.6 Hz),
7.49 (1H, d, J = 8.7 Hz), 7.34 (2H, d, J = 8.1 Hz), 6.95 (1H, d,
J = 8.7 Hz), 3.85 (3H, s), 3.72 (2H, s), 3.53 (4H, s), 2.42 (4H, s), 2.38
(3H, s). 13C NMR (DMSO-d6,75 MHz): d 188.1, 148.2, 145.2, 142.2,
141.3, 134.5, 128.3 (2ꢁ), 127.6 (2ꢁ), 126.5, 121.9, 120.4, 117.8,
109.8, 65.3 (2ꢁ), 54.8, 52.5, 51.8 (2ꢁ), 20.2. EIMS, m/z (% rel. inten-
sity): 367 (18) [M]+, 282 (23), 280 (10), 248 (42), 190 (9), 162 (13),
119 (100), 105 (9), 91 (31), 86 (12). HREIMS m/z calcd for
5.4. Cytotoxic activity assay
All stock cultures were grown in T-25 flasks. Freshly trypsini-
zed cell suspensions were seeded in 96-well microtiter plates at
densities of 1500–7500 cells per well with compounds added
from DMSO-diluted stock. After 3 days in culture, attached cells
were fixed with cold 50% trichloroacetic acid and then stained
with 0.4% sulforhodamine B (SRB). The absorbance at 562 nm
C22H25NO4, 367.1784; found, 367.1786. Elemental analysis: calcd
C, 71.91; H, 6.86; N, 3.81; found, C, 71.90; H, 6.86; N, 3.69.

7370
M. V. B. Reddy et al. / Bioorg. Med. Chem. 16 (2008) 7358–7370
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was measured using a microplate reader after solubilizing the
bound dye. The mean EC50 is the concentration of agent that re-
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Acknowledgments
This work was supported by a grant from National Science
Council, Taiwan, Republic of China (NSC 96-2628-M-006-002)
and grant (OUA 95-3-2-021) from the National Cheng Kung Uni-
versity, Tainan, Taiwan, ROC, awarded to T.S. Wu. Partial support
was received from NIH Grant CA-17625 awarded to K.H. Lee.
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