Synthesis and biological evaluation of curcumin analogues having a piperidone core as potential antioxidant agents

Article abstract of DOI:10.3184/174751912X13274805259980

A series of new unsymmetrical curcumin derivatives were designed and synthesised to which the indole fragment was introduced according to the principle of association. These compounds were characterised by ¹H NMR, IR, ESIMS and elemental analys

Full text of DOI:10.3184/174751912X13274805259980

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 63
FEBRUARY, 63–65
Synthesis and biological evaluation of curcumin analogues having a
piperidone core as potential antioxidant agents
Jian Wang, Gangchun Sun*, Zhicheng Li*, Wenpeng Mai and Jingxi Xie
Chemistry and Chemical Engineering School, Henan University ofTechnology, Henan Province, Zhengzhou 450001, P. R. China
A series of new unsymmetrical curcumin derivatives were designed and synthesised to which the indole fragment
was introduced according to the principle of association. These compounds were characterised by 1H NMR, IR, ESI-
MS and elemental analysis and their antioxidant activity was investigated using the 1,1-diphenyl-2-picrylhydrazyl
method. The results indicated that curcumin analogues having a piperidone structure exhibit varying degrees of
antioxidant activity.
Keywords: unsymmetrical curcumin analogue, piperidone, antioxidant activity
Curcumin, which is extracted from Curcuma longa, a medici-
nal plant widely cultivated in tropical regions of Asia, has
antioxidant,1 anti-inflammatory,2 anticancer,3 antirheumatic,4
antibacteral,5 antihepatotoxic,6 anti-Alzheimer’s disease7–9 and
anti-HIV integrase activity.10 Efforts to improve the biological
activity of curcumin have led to the development of analogues
by appropriate structural modification of curcumin.11,12
In the past, large numbers of curcumin analogues, contain-
ing N-substituted piperidone groups have been synthesised as
potential antitumour agents.13,14 Subbagh synthesised a series
of curcumin analogues; compound 1 (Fig. 1) showed moderate
activity against human immunodeficiency virus-1 (HIV-1).15
The other synthetic curcumin analogues showed potent α-
glucosidase inhibitory effects with IC50 of 2.8, 2.6, 1.6, and
8.2 µM, respectively.16 EF24,17 which has lower toxicity than
curcumin can inhibit a variety of tumour cells, while anti-
tumour tests showed that the IC50 was 7.5% that of curcumin,
and is about to enter clinical trials. The interesting discovery of
the anti-tumour activity of N-substituted or N-unsubstituted
piperidone compounds as curcumin analogues prompted us to
study a series of curcumin analogues.
enhance the yield of 5g–i which contained hydroxyl groups.
However, when 3 was used for condensation, the reaction
proceeded with cleavage of the N-acyl group by piperidine
during the prolonged stirring process (15 h). In this way, the
intermediate 4 could be obtained easily with the yield up to
58%. The results showed that it was necessary to use 3 rather
than indole-3-carbaldehyde itself. According to the principle
of vinylogy, the electron-donating effect of the NH group in
the indole core can be transmitted through the conjugated
carbon–carbon double bond to the carbonyl group which
makes it less electrophilic. Decreasing the electron density of
the carbonyl group of 3 by use of the strong electron-drawing
N-benzoyl group makes the aldehyde 3 more reactive than 2.
The antioxidant properties of the new compounds were
determined by the free radical scavenging reaction with 1,1-
diphenyl-2-picrylhydrazyl (DPPH). The method is simple and
straightforward and does not require the use of any biological
media. In its radical form DPPH absorbs at 515 nm, but upon
reduction by an antioxidant or radical species its absorption
decreases. A volume of 2.0 mL of a 1.2 × 10−4 M solution
DPPH in methanol was used. The reaction was started by the
addition of 2.0 mL of 6.4 × 10−5 M methanol solutions of the
samples. The bleaching of DPPH was followed at 515 nm at
0 min, 5 min, and every 5 minutes thereafter until the reaction
reached a steady state. This plateau was attained within
60 minutes (Fig. 2).
Determination of the antioxidant activity revealed promis-
ing activity. Amongst the new compounds, 5h showed high
free radical scavenger activity with inhibition values of 58.87%.
This study suggested that curcumin analogues would be lead
compounds suitable for designing new free radical inhibitors
of this kind. Depending on the rate of the oxygen free radical
scavenger activity of the tested compounds, the following
structural requirements for high antioxidant activity were
identified: (a) a phenolic hydroxy group at the para-position is
the most essential component in the antioxidant structure; (b)
electron-donating substituents on the benzene ring ortho to the
phenolic hydroxy group effectively enhance the free radical
scavenging rate.
In the work described here, we designed and synthesised a
series of new compounds in order to introduce the indole group
to N-substituted piperidone analogues of curcumin via sequen-
tial Knoevenagel reactions (Scheme 1). It was hoped that these
novel curcumin analogues would exhibit improved physico-
chemical and biological properties. The study of their other
biological activity is in progress.
Results and discussion
As shown in Scheme 1, compounds 4 and 5a–i were obtained
via the Knoevenagel reaction between the appropriate alde-
hyde and 1-methyl-4-piperidone in the presence of piperidine,
sodium hydroxide or glacial acetic acid saturated with
anhydrous hydrogen chloride. From the reaction between the
N-unsubstituted indole-3-carbaldehyde 2 and 1-methyl-4-
piperidone, we could only isolate the starting materials and
the yield of 4 was very low even when using a stronger base,
such as sodium hydroxide in methanol. The intermediate 4
was easily converted to 5a–i, and Method B could efficiently
Fig. 1 The structures of curcumin, compound 1 and EF24.
* Correspondent. E-mail: sungangchun@163.com

64 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 1 Synthesis of curcumin analogues. Reagents and conditions: (a) Et3N, r.t., 4 h; (b) piperidine, 50 °C, 6 h;
(c) Method A (for 5a–f): NaOH (aq), 35–40 °C, 4 h; or method B (for 5g–i): AcOH, HCl (g), 25–30 °C, 24 h.
83.5 °C). 1H NMR (CDCl3, 400 MHz) δ: 10.07 (1H, s), 8.33 (2H, dd,
Experimental
J = 7.0 Hz, 2.0 Hz), 8.34 (2H, m), 7.96 (1H, s), 7.78 (2H, d, J = 7.2
DPPH was purchased from Sigma–Aldrich (USA). The other starting
materials came from commercial sources. The melting points are
uncorrected. UV-Vis spectra were obtained on a Shimadzu UV-2450
spectrophotometer. The IR spectra were obtained for KBr pellets
Hz), 7.44–7.72 (5H, m). IR (KBr) ν (cm−1): 1669 (CO). MS (m/z) 250
(M+). Anal. Calcd for C16H11NO2: C, 77.10; H, 4.45; N, 5.62. Found:
C, 76.81; H, 4.45; N, 5.62%.
(E)-3-[(1H-indol-3-yl)methylene]-1-methylpiperidin-4-one (4):19A
using a Prestige-21 Shimadzu IR spectrophotometer; νmax is expressed
in cm−1. The 1H NMR spectra, were recorded for solutions in CDCl3 or
DMSO-d6 with TMS as an internal standard, unless otherwise stated
on a Bruker-400 spectrometer. Chemical shifts are reported in δ (ppm)
and J in Hz. Multiplicities were recorded as s (singlet), brs (broad
singlet), d (doublet), t (triplet), q (quartet), m (multiplet). MS (ESI)
spectra were obtained using an Agilent LC-MS 6310 EV instrument.
Elemental analyses were carried out with a Flash EA 1112 elemental
analyser. The DPPH radical scavenging activity was evaluated as
reported previously.18
1-Benzoyl-1H-indole-3-carbaldehyde (3): Indole-3-carbaldehyde 2
(10 mmol) was dissolved in dry THF to which was added triethyl-
amine (10 mmol) and benzoyl chloride (15 mmol). The mixture was
stirred at room temperature for 4–5 h (TLC) and after removal of the
solvent under reduced pressure, adjusted to pH 8 (sat.aq.NaHCO3)
and then filtered. The crude product was recrystallised from dichloro-
methane to give 3 as a white solid (yield 95%). m.p. 84 °C (lit.20
solution of 3 (10 mmol) in methanol (100 mL) was treated with 1-
methyl-4-piperidinone (15 mmol) and piperidine (10 mmol). The
mixture was stirred for 6 h at 50 °C and for 15 h at room temperature.
After removal of the methanol under reduced pressure, the residue
was purified by column chromatography using ethyl acetate–methanol
(8:1) as eluent to afford 4 as a yellow solid (yield 58%). m.p. 147–
149 °C. 1H NMR (CDCl3, 400 MHz) δ: 8.97 (1H, s), 8.09 (1H, s), 7.89
(2H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.32–7.24
(2H, m), 3.66 (2H, s), 2.86 (2H, t, J = 6.2 Hz), 2.70 (2H, t, J = 6.0 Hz),
2.54 (3H, s). IR (KBr) ν (cm−1): 1652(CO). MS (m/z) 241 (M+). Anal.
Calcd for C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found: C, 74.85; H,
6.74; N, 11.61%.
Preparation of 5a–i; general procedure
Method A (for 5a–f): To a mechanically stirred solution of 4
(10 mmol) in methanol (100 mL) was added sodium hydroxide
(10 mL; 10%) keeping the temperature at 35–40 °C, followed by addi-
tion of the appropriate aldehyde (15 mmol). The mixture was stirred
for 4–5 h (TLC). After cooling the solvent was evaporated under
reduced pressure and the crude product was purified by column
chromatography using ethyl acetate-methanol (20:1) as eluent to
afford 5a–f.
Method B (for 5g–i): A mixture of the 2a and the appropriate alde-
hyde was dissolved in glacial acetic acid saturated with anhydrous
hydrogen chloride and warmed in a water bath at 25–30 °C for 2 h.
After standing for 2 days, the mixture was treated with cold water and
filtered. The solid obtained was then washed and dried. The crude
product was purified by column chromatography using ethyl acetate-
methanol (20:1) as eluent to afford 5g–i.
(3E,5E)-3-(Furan-2-ylmethylene)-5-[(1H-indol-3-yl)methylene])-
1-methylpiperidin-4-one (5a):Yield 65%; red solid; m.p. 223–226 °C.
1
UV-Vis: λmax(MeOH) 418.8 nm. H NMR (DMSO-d6, 400 MHz)
δ: 11.97 (1H, s), 7.96 (2H, d, J = 3.2 Hz), 7.79 (1H, d, J = 7.7 Hz),
7.72(1H, s), 7.50 (1H, d, J = 7.9 Hz), 7.35 (1H, s), 7.25–7.16 (2H, m),
6.95 (1H, d, J = 3.5 Hz), 6.70 (1H, dd, J = 2.9 Hz, 1.6 Hz), 3.81 (2H,
s), 3.70 (2H, s), 2.49 (3H, s). IR (KBr) ν (cm−1): 3182 (NH), 2935
(CH2), 2770 (CH2), 1655 (CO). MS (m/z) 319 (M+). Anal. Calcd for
C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.29; H, 5.72; N,
8.79%.
Fig. 2 Free radical scavenging rate of 5a–i.

JOURNAL OF CHEMICAL RESEARCH 2012 65
(3E,5E)-3-[(1H-Indol-3-yl)methylene]-1-methyl-5-(pyridin-
2-ylmethylene)piperidin-4-one (5b): Yield 72%; red solid; m.p.
177–179 °C. UV-Vis: λmax(MeOH) 420.0 nm. H NMR (DMSO-d6,
MS (m/z) 375 (M+). Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N,
7.48. Found: C, 73.27; H, 6.01; N, 7.56%.
1
(3E,5E)-3-(3-Hydroxy-4-methoxybenzylidene)-5-[(1H-indol-3-
yl)methylene]-1-methylpiperidin-4-one (5i): Yield 52%; yellow solid;
m.p. 207–208 °C. UV-Vis: λmax(MeOH) 415.6 nm. 1H NMR (DMSO-
d6, 400 MHz) δ: 11.96 (1H, s), 9.28 (1H, s), 7.94 (1H, s), 7.78 (1H,
d, J = 2.7 Hz), 7.71 (1H, d, J = 2.7 Hz), 7.49 (2H, d, J = 8.2 Hz),
7.25–7.16 (2H, m), 7.01 (1H, d, J = 8.6 Hz), 6.92 (2H, dd, J = 9.1 Hz,
1.7 Hz), 3.80 (3H, s), 3.69 (4H, s), 2.50 (3H, s). IR (KBr) ν (cm−1):
3429 (OH), 3296 (NH), 2949 (CH2), 2785 (CH2), 1651 (CO). MS
(m/z) 375.2 (M+). Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N,
7.48. Found: C, 73.57; H, 5.77; N, 7.63%.
400 MHz) δ: 12.01 (1H, s), 8.74 (1H, s), 7.98 (1H, s), 7.88 (1H, td,
J = 7.6 Hz, 2.0 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, s), 7.68 (1H,
d, J = 7.9 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 7.5 Hz,
4.8 Hz), 7.26–7.17 (2H, m), 3.70 (2H, d, J = 1.9 Hz), 3.18(2H, d, J =
4.9 Hz), 2.48 (3H, s). IR (KBr) ν (cm−1): 3264 (NH), 2937 (CH2), 2757
(CH2), 1653 (CO). MS (m/z) 330 (M+). Anal. Calcd for C21H19N3O: C,
76.57; H, 5.81; N, 12.76. Found: C, 76.12; H, 5.77; N, 12.81%.
(3E,5E)-3-Benzylidene-5-[(1H-indol-3-yl)methylene]-1-methylpi-
peridin-4-one (5c): Yield 71%; yellow solid; m.p. 100–104 °C.
1
UV-Vis: λmax(MeOH) 204.0 nm. H NMR (DMSO-d6, 400 MHz)
δ: 12.00 (1H, s), 7.98 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.74 (1H, s),
7.63 (1H, s), 7.45–7.51 (5H, m), 7.42 (1H, dd, J = 8.3 Hz, 4.0 Hz),
7.26–7.17 (2H, m), 3.71 (4H, s), 2.45 (3H, s). IR (KBr) ν (cm−1):3213
(NH), 2933 (CH2), 1622 (CO). MS (m/z) 329 (M+). Anal. Calcd for
C22H20N2O: C, 80.46; H, 6.14; N, 8.53. Found: C, 80.20; H, 6.17; N,
8.55%.
The financial support of Natural Science Foundation of Henan
Educational Commission (Grant No. 2010A1500007), Key
Scientific and Technological Project of Henan Province (Grant
No. 102102210027, 092102210007) is greatly appreciated.
Received 10 September 2011; accepted 13 January 2012
Paper 1100885 doi: 10.3184/174751912X13274805259980
Published online: 23 February 2012
(3E,5E)-3-(4-Chlorobenzylidene)-5-[(1H-indol-3-yl)methylene]-1-
methylpiperidin-4-one (5d): Yield 77%; yellow solid; m.p. 216–
217 °C. UV-Vis: λmax(MeOH) 222.0 nm. 1H NMR (DMSO-d6,
400 MHz) δ: 12.03 (1H, s), 7.98 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.74
(1H, s), 7.59 (1H, s), 7.49–7.54 (5H, m), 7.26–7.17 (2H, m), 3.69 (4H,
d, J = 4.16 Hz), 2.45 (3H, s). IR (KBr) ν (cm−1): 3242 (NH), 2941
(CH2), 1651 (CO). MS (m/z) 363 (M+). Anal. Calcd for C22H19ClN2O:
C, 72.82; H, 5.28; N, 7.72. Found: C, 72.50; H, 5.35; N, 7.68%.
(3E,5E)-3-[(1H-Indol-3-yl)methylene]-5-(4-methoxybenzylidene)-
1-methylpiperidin-4-one (5e): Yield 85%; yellow solid; m.p. 237–
239 °C. UV-Vis: λmax(MeOH) 412.0 nm. 1H NMR (DMSO-d6,
400 MHz) δ: 11.96 (1H, s), 7.95 (1H, s), 7.78 (1H, d, J = 7.8 Hz), 7.72
(1H, d, J = 2.7 Hz), 7.58 (1H, s), 7.49 (1H, d, J = 7.8 Hz), 7.44 (2H, d,
J = 8.7 Hz), 7.25–7.16 (2H, m), 7.03 (2H, d, J = 8.7 Hz), 3.80 (3H, s),
3.70 (4H, d, J = 4.8 Hz), 2.50 (3H, s). IR (KBr) ν (cm−1): 3177 (NH),
2931 (CH2), 1634 (CO). MS (m/z) 359 (M+). Anal. Calcd for
C23H22N2O2: C, 77.07; H, 6.19; N, 7.82. Found: C, 76.80; H, 6.17; N,
7.81%.
(3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-
1-methylpiperidin-4-one (5f): Yield 82%; yellow solid; m.p. 205–
208 °C. UV-Vis: λmax(MeOH) 422.0 nm. 1H NMR (DMSO-d6,
400 MHz) δ: 11.96 (1H, s), 7.96 (1H, s), 7.80 (1H, d, J = 7.8 Hz), 7.72
(1H, d, J = 2.7 Hz), 7.60 (1H, s), 7.50 (1H, d, J = 7.9 Hz), 7.25–7.16
(2H, m), 7.09 (1H, s), 7.05 (2H, s), 3.81 (3H, s), 3.80 (3H, s), 3.74
(2H, s), 3.70 (2H, s), 2.50 (3H, s). IR (KBr) ν (cm−1): 3172 (NH), 2938
(CH2), 1653 (CO). MS (m/z) 389.2 (M+). Anal. Calcd for C24H24N2O3:
C, 74.21; H, 6.23; N, 7.21. Found: C, 73.29; H, 6.31; N, 7.18%.
(3E,5E)-3-(4-Hydroxybenzylidene)-5-[(1H-indol-3-yl)methylene]-
1-methylpiperidin-4-one (5g): Yield 66%; yellow solid; m.p. 268–
270 °C. UV-Vis: λmax(MeOH) 371.0 nm. 1H NMR (DMSO-d6,
400 MHz) δ: 11.94 (1H, s), 9.98 (1H, s), 7.94 (1H, s), 7.78 (1H, d,
J = 7.8 Hz), 7.69 (1H, d, J = 2.7 Hz), 7.54 (1H, s), 7.48 (1H, d,
J = 8.0 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.25–7.16 (2H, m), 6.86 (2H, d,
J = 8.2 Hz), 3.70 (4H, s), 2.46 (3H, s). IR (KBr) ν (cm−1): 3401 (OH),
3169 (NH), 2936 (CH2), 1649 (CO). MS (m/z) 345.1 (M+). Anal.
Calcd for C22H20N2O2: C, 76.72; H, 5.85; N, 8.13. Found: C, 75.91; H,
5.69; N, 8.14%.
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