Synthesis of β-Ketoamide Curcumin Analogs for Anti-Diabetic and AGEs Inhibitory Activities

Article abstract of DOI:10.1002/cbdv.201800105

Two different series of novel β-ketoamide curcumin analogs enriched in biological activities have been synthesized. The synthesized compounds were screened for their in?vitro anti-diabetic and AGEs inhibitory activities and exhibited potent to good anti-diabetic and AGEs inhibitory activities. The molecular docking study was also performed with the α-amylase enzyme.

Full text of DOI:10.1002/cbdv.201800105

Article Type: Full Paper
Synthesis of β-Ketoamide Curcumin Analogues for Anti-Diabetic and
AGEs
Inhibitory Activities
Govindharasu Banuppriya, Rajendran Sribalan, Sulthan Alavudeen Rizwan Fathima, Vediappen
Padmini*
Abstract: Two different series of novel β-ketoamide curcumin analogues enriched in biological activities have been synthesized.
The synthesized compounds were screened for their in vitro anti-diabetic and AGEs inhibitory activities and exhibited potent to
good anti-diabetic and AGEs inhibitory activities. Further molecular docking study was also performed with the α-amylase
enzyme.
Introduction
Diabetes mellitus (DM) is a major global health issue because most of the people are afflicted in each and every year
nearly 300 million people as per the statistics [1-2]. Till now there are no curable drugs available in the market for
diabetes mellitus. In addition to that for hyperglycemic patients, the excessive production of glucose leads to AGEs
(advanced glycation end products) formation [3]. The formation of several AGE products leads to problems associated
with diabetic related health disorders. Thus the inhibition of AGEs formation could hold back the intensity of
complications in diabetic condition [4-7]. Several researchers have tried to develop a new drug candidate for diabetes
mellitus. Among the various strategies available for developing anti-diabetic lead molecules, use of herbal biomolecules
and derivatives of natural compounds draw a considerable interest because of their hypoglycemic effects.
Curcumin which is isolated from the root of Curcuma Longa Linn (turmeric plant) [8] has various biological applications
including anti-diabetic property [9]. Apart from curcumin, several synthetic curcumin derivatives are also proved to be a
better anti-diabetic agent as well as AGEs inhibitor [10-11]. Recently Sribalan et al. synthesized the water-soluble
curcumin derivatives which served as an AGEs inhibitor [12]
.
Even though curcumin/curcuminoids has several biomedical applications, they have some drawbacks such as instability
and poor metabolic property. The pharmacological studies proved that the presence of central β-diketone functionality
of curcumin may leads to rapid metabolism of curcumin [13-15]. To improve the metabolic stability of curcumin, several
structural modifications have been designed without the presence of β-diketone moieties of curcumin [16-19]. Mono
carbonyl analogues of curcumin have shown better stability and activity than curcumin.
G. Banuppriya, R. Sribalan, S. A. R. Fathima, Dr. V. Padmini
Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University, Madurai, Tamil Nadu, India.
E-mail id: padimini_tamilenthi@yahoo.co.in
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/cbdv.201800105
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[20]
Earlier studies also reported that the diarylidenyl-piperidone based mono carbonyl analogues of curcumin
and o-
fluoro substituted piperidone bis-benzylidine curcumin analogues [21] were potent anticancer agents. Similarly, Katsori et
al. [22] reported the piperidone ring incorporated in monocarbonyl curcumin exhibited in vivo anti-inflammatory activity.
Based on the above literature reports, we have planned to synthesis the mono carbonyl analogues of curcumin
derivatives (Fig 1).
Fig 1: Curcumin and synthesized derivatives of curcumin.
The unstable β-diketone of curcumin is replaced with stable β-ketoamide with various bioactive units (piperidone/aryl
amide core) in the α-carbon of the carbonyl group. The synthesized compounds were studied for an anti-diabetic
activity like α-amylase inhibitory activity, α-glucosidase activity and AGEs inhibitory activity.
In addition, the 3D structures of the synthesized compounds were studied for in silico molecular docking studies against
α-amylase enzyme to identify probable binding mode. Out of the several enzymes, α-amylase is an important enzyme
because it is responsible for carbohydrate digestion (gives glucose) which leads to diabetes. So inhibitors of α-amylase
can effectively retard the digestion as well as the assimilation at the early stages of starch digestion. This leads to the
significant delay of postprandial hyperglycemia and found to be effective on insulin resistance [23]. α-amylase is
considered to be one of the best targets for the development of type II diabetes therapeutic agents.
Results and Discussion
Chemistry
In the present work, two types of curcuminoids were synthesized. The precursor 1-(piperidine-1-yl)butane-1,3-dione (3)
was prepared by adding equimolar amounts of piperidine and ethyl acetoacetate under reflux condition. The precursor
(3) on reaction with different aromatic aldehydes afforded the expected curcuminoids (4a-j) in the presence of piperidine
as a base. Similarly, another precursor 3-oxo-N-phenylbutanamide(6) was synthesized by refluxing equimolar amount of
ethyl acetoacetate with various aromatic amines under toluene. The target (7a-j) compounds were prepared with vanillin
and corresponding N-phenylbutanamide using boron oxide, tri-n-butyl borate and n-butyl amine as reported earlier [24]
.
1
Piperidinylamide monocarbonyl analogues of curcumin (4a-j) were characterized by H NMR, 13C NMR and 1D-Dept
135 spectroscopy. The appearance of multiplets around 1.35 to 3.38 ppm in 1H NMR indicates the presence of
piperidine unit. In 13C NMR, the appearance of amide carbonyl peak around 165.48 ppm and the appearance of
carbonyl peak around 185.35 ppm confirmed the formation of an amide. In DEPT 135 the piperidine carbons appeared
in the negative region which clearly indicates the piperidine unit present in the compound. Another, hybrid compounds
1
of curcumin along with N-phenyl pentenamide (7a-j) were characterized by H NMR and 13C NMR spectroscopy. The
appearance of singlet around 3.62 ppm and 2.42 ppm indicates the presence of O-CH3 and CH2 group. Similarly, in 13
C
NMR also confirmed the carbonyl peak (194.83 ppm) and amide carbonyl peak (166.45 ppm) of the products. The
synthetic route for β-ketoamide curcumin derivatives was represented in Scheme 1. The lists of synthesized
compounds were represented in Fig 2 and Fig 3.
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Scheme 1: Synthetic route for β-ketoamide curcumin derivatives
Biological studies
In vitro α-amylase inhibition
All the synthesized compounds (4a-j and 7a-j), parent curcumin and standard drug were evaluated for in vitro α-
amylase inhibition at different concentrations (50-200 μg/mL). In the series of compounds (4a-j), most of the compounds
showed equal to better inhibition than the standard acarbose. The compounds 4a, 4e, 4f, 4g, and 4i showed better
activity than acarbose as well as parent curcumin. Among the compounds, 4e having the 4-hydroxy3-methoxy
substituents showed least inhibitory concentration. The IC50 of the compounds is 1.5 fold better activities than curcumin
and acarbose. The compounds 4b, 4c and 4d containing hydroxyl and methoxy substituents showed moderate activity
to standard. The thiophene substituted curcumin exhibited potent activity. The calculated inhibitory concentration is
25.07 µg/mL. But pyrrole substituents (4j) showed poor activity than standard as well as curcumin.
Similarly, in the second series, the compounds (7a-j) displayed a good to potent α-amylase inhibitory activity. The
compounds 7d, 7f, 7h and 7i containing p-fluoro, p-sulfonamide, p-acetyl and m-dichlorophenyl substituents showed
potent inhibitions. The calculated inhibitory concentration for 7i is 20.67 µg/mL. It is the least IC50 value than others. The
compounds 7c, 7e, 7g and 7j bearing naphthalene, p-chloro phenyl, m-acetyl phenyl and piperidine substituents
showed potent activity than standard and equal activity towards curcumin. The compounds 7a and 7b containing phenyl
and toluene substituents showed moderate activity than parent and standard. The IC50 values for all the compounds,
curcumin and acarbose is represented in Table 1 & 2.
Fig 2: List of synthesized compounds (4a-j)
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Fig 3: List of synthesized compounds (7a-j).
In vitro α-glucosidase inhibition
The synthesized compounds (4a-j and 7a-j), parent and standard drug were tested for in vitro α-glucosidase inhibition
studies at various concentrations (50-200 μg/mL) and the IC50 values were calculated and presented in Table 2. The α-
glucosidase studies gave the results similar to α-amylase inhibition. In the first series of compounds (4a-j), most of them
showed a better inhibition than standard and curcumin. The compounds 3,4,5-trimethoxy phenyl 4d, vanillin 4e, p-
chlorophenyl 4h and pyrrole 4j have shown better activity than acarbose as well as parent curcumin. Among the
compounds, 4h having the p-chlorophenyl substituents showed very good inhibition. The IC50 of the compounds is 1.5
fold better activities than curcumin and acarbose. The compound 4a, 4c containing phenyl and p-methoxyphenyl
substituents showed nearer activity to curcumin and less activity to acarbose. The compound 4b, 4f and 4g containing
p-hydroxyl phenyl, p-N,N-dimethylaminophenyl and o-chloro phenyl substituents showed less activity to parent and
standard. The thiophene substituted curcumin exhibited potent activity and the calculated IC50 values are approximately
1.5 fold higher than standard as well as a parent.
Similarly, the second series of compounds (7a-j) displayed a better α-glucosidase inhibitory activity. Compare to the first
series, the compounds 7a-j showed moderate activity. The compounds 7f, 7i, and 7j containing p-sulfonamido phenyl,
m-dichlorophenyl and piperidine substituents showed equal inhibition to standard and potent inhibition than the parent.
Within this series, the piperidine substituted curcumin exhibited the highest inhibition. The calculated inhibitory
concentration is 25.10 µg/mL. The compounds 7a, 7d, and 7e bearing phenyl, p-fluorophenyl, p-chlorophenyl
substituents showed moderate activity towards the standard and curcumin. The compounds 7b, 7g and 7h containing p-
toluene, m-acetyl phenyl, and p-acetyl phenyl substituents showed poor activity than parent and standard. The IC50
values of all the compounds, curcumin and acarbose against α-glucosidase are represented in Table 1 & 2.
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Table 1: α-amylase inhibition, α-glucosidase inhibition and AGEs inhibitory activity of compound 4a-j.
S.no
Compound
α-amylase inhibition
α-glucosidase inhibition
AGE inhibition
IC50(µg/mL)
130.24
60.24
IC50(µg/mL)
30.92
34.36
44.64
36.78
21.29
29.44
24.26
26.28
25.07
55.56
32.89
34.76
-
IC50(µg/mL)
39.63
47.50
34.97
25.42
24.89
50.28
44.15
22.54
26.43
24.56
31.76
26.34
-
1
2
4a
4b
3
4c
65.45
4
4d
67.80
5
4e
90.43
6
4f
85.9
7
4g
154.3
8
4h
4i
167.98
116.54
122.89
80.87
9
10
11
12
13
4j
Curcumin
Acarbose
phloroglucinol
-
128.9
AGEs Inhibitory activity
In vitro AGEs inhibitory activities were also studied for the synthesized curcumin analogues and their inhibitory
concentrations were calculated. Phloroglucinol and curcumin were used as a reference compounds to compare the
activity. In the series (4a-j), several compounds showed a better inhibition than standard phloroglucinol. The
compounds 4b, 4c, and 4d showed a better activity than phloroglucinol as well as parent curcumin. Among the
compounds, 4b having the p-hydroxy phenyl substituents showed better inhibitory concentration. The compounds 4e
and 4f containing vanillin and p-N,N-dimethyl phenyl substituents showed nearer activity to parent curcumin. The
compounds 4a, 4i and 4j having phenyl, thiophene and pyrrole substituents showed better activities than phloroglucinol.
The other compounds showed moderate AGEs inhibitory activity.
In second series(7a-j), all the compounds showed potent AGEs inhibitory activity. The compounds 7f and 7j containing
p-sulfonamide and piperidine substituents showed two-fold better inhibitions than curcumin and three-fold better
inhibitions than phloroglucinol. Their IC50 values are 46.23 and 48.9 µg/mL correspondingly. The compounds 7b, 7c, 7g
and 7h containing p-tolyl, naphthalene, m-acetylphenyl and p-acetylphenyl showed two-fold better inhibition than
standard phloroglucinol. Remaining all the compounds showed equal activity towards curcumin. The IC50 values for all
the compounds, curcumin and phloroglucinol is represented in Table 1 & 2.
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Table 2: α-amylase inhibition, α-glucosidase inhibition and AGE inhibitory activity of compound 7a-j.
S.no
Compound
α-amylase
α-glucosidase
AGE
inhibition
inhibition
inhibition
IC50(µg/mL)
37.49
45.07
32.50
22.08
32.47
25.24
32.46
25.10
20.67
32.15
32.89
34.76
-
IC50(µg/mL)
40.15
58.65
48.20
39.31
40.22
29.10
67.72
55.10
26.62
25.10
31.76
26.34
-
IC50(µg/mL)
78.15
65.73
68.90
76.89
80.10
46.23
66.65
66.40
72.34
48.90
80.87
-
1
2
7a
7b
3
7c
4
7d
5
7e
6
7f
7
7g
8
7h
7i
9
10
11
12
13
7j
Curcumin
Acarbose
phloroglucinol
128.9
Molecular docking studies
The molecular docking studies deals with the atomic-level interactions of ligand and target. The interactions of ligands
with enzymes are influenced by the hydrophilic and hydrophobic bonding contributions of amino acid residues. Among
different types of docking, protein-ligand docking is of special interest because of its application in pharmaceutical
industry. All the synthesized compounds were studied for their molecular docking studies against α-amylase (1HNY)
enzyme.
In the first series of compounds (4a-j), the ligand 4e showed the highest number of hydrogen bond interactions than
other derivatives. The hydrogen bonded amino acid residues were found to be GLY225, PHE229, SER3, TYR2 and
ARG291. And also it showed a very good binding energy (-310.4 KJ/mol). The compound 4h showed four hydrogen
bond interactions with the amino acid residues (TYR2, SER3, Lys227, and PRO228). Similarly, the compound 4i
showed four hydrogen bond interactions with amino acid residues (THR6, GLN7, ASP402, and ARG252). Their binding
energies were found to be -303.49 KJ/mol and -279.59 KJ/mol correspondingly. The molecular docking results
suggested that the compounds 4e, 4h and 4i could be better bioactive compounds against the docking of α-amylase
inhibition. The remaining compounds were moderate bio-active compounds against enzyme inhibition. The same
results were obtained in the experimental α-amylase inhibitory studies.
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Table3: Molecular docking interaction of synthesized compounds (4a-j) against α-amylase enzymes.
Entry
Compound
1HNY
Binding
energy
No.of
hydrogen
bonding
Amino acid residues
(KJ/mol)
-273.64
-285.6
1
2
4a
4b
1
4
ASP402
ARG219, PRO228,
SER3, TYR2
3
4
5
4c
4d
4e
-302.75
-332.36
-310.4
1
2
5
ASP147
HIS299, ASP300,
GLY225, PHE229,
SER3, TYR2, ARG291
6
7
8
4f
-297.34
-310.40
-303.49
-
-
4g
4h
1
4
ASP402
TYR2, SER3, Lys227,
PRO228
9
4i
4j
-279.59
-273.20
4
-
THR6, GLN7, ASP402,
ARG252
10
-
In the second series of compounds (7a-j), the ligand 7d showed the four number of hydrogen bond interactions with
amino acid residues (GLN390, LYS322, ARG343 and CYS378). The binding energy of the compound is -277.79 KJ/mol
correspondingly. The compound 7f showed three hydrogen bond interactions with ASP402, ARG398 and PRO223. And
also the binding energy of 7f compound is found be -276.93 KJ/mol. Similarly, the compound 7i showed three hydrogen
bond interactions with amino acid such as GLU390, ARG343 and CYS378. The binding energy of the compound is
found to be -295.73 KJ/mol. The remaining compounds showed a moderate number of hydrogen bonding interactions
and binding energies. In the second series, the molecular docking results suggested that the compounds 7d, 7f and 7i
could be better bioactive compounds against the docking of α-amylase inhibition. The remaining compounds were
moderate bioactive compounds against enzyme inhibition. Similar to the previous series of compounds, the same
results were obtained in the experimental α-amylase inhibitory studies.
From this study, it is clearly evidenced that the β-ketoamide curcuminoids could be used as inhibitors for α-amylase.
The molecular docking studies also proved the compounds have very good α-amylase inhibitory activity. The molecular
docking results for compounds 4a-j and 7a-j are represented in Table 3 & 4. The protein-ligand interaction for the
compounds 4e and 7d is represented in Fig 4 and 5.
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Table 4: Molecular docking interaction of synthesized compounds (7a-j) against α-amylase.
Entry
Compound
1HNY
Binding energy
(KJ/mol)
No.
hydrogen
bonding
of
Amino
residues
acid
1
2
3
4
7a
7b
7c
7d
-289.28
-272.67
-305.7
-
-
-
-
2
4
ASN5, LYS227,
-277.79
GLN390,LYS322,
ARG343,
CYS378
5
6
7e
7f
-275.72
-276.93
2
3
ASP300, GLN63
ASP402,
ARG398, PRO223
7
8
9
7g
7h
7i
-307.96
-299.68
-295.73
1
1
3
THR163
ALA310
GLU390,
ARG343, CYS378
10
7j
-254.86
2
ARG291, THR6
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Conclusion
The β-ketoamide curcumin derivatives were synthesized and in vitro biological applications were studied. As
expected, these compounds have enhanced anti-diabetic, AGEs inhibition activities than the parent and standard. The
molecular docking studies also proved that the curcuminoids could be a good α-amylase inhibitor.
Experimental section
Chemistry
All the solvents used were analytical grade and purchased from Spectrochem and Sigma-Aldrich. Reactions were
monitored by TLC analysis on precoated silica gel 60 F254 in TLC sheets (0.2mm thickness, Merck plate) and 60-120
mesh Merck silica gel used for column chromatography. Petroleum ether and ethyl acetate were used as the eluents. 1H
NMR and 13C NMR spectra were recorded on Bruker 300 MHz and 75 MHz instruments, CDCl3 and DMSO-d6 were
used as an internal solvent. Chemical shift values were represented in δ (ppm) and coupling constants are mentioned in
terms of Hz with the internal references TMS. Melting point was determined by open capillary tube using sigma melting
point apparatus.
General procedure for the synthesis of 1-(piperidine-1-yl) butane-1,3-dione (3):
The compound 3 was prepared by following the reported literature [25, 26]
.
General procedure for the synthesis of β-ketoamide curcumin analogues (4a-j):
A mixture of 1-(piperidine-1-yl) butane-1,3-dione 3 (0.3 g, 0.00118 mol) and corresponding aldehyde (0.46 g, 0.00236
mol) was dissolved in toluene. To that mixture, piperidine (0.00236 mol) and glacial acetic acid were added and the
reaction mixture was stirred at 80 ◦C. After the completion of the reaction, the mixture was extracted with ethyl acetate
(50 mL), washed with water (50 mL) and brine solution (50 mL). The organic layer was separated and dried over
anhydrous sodium sulfate. The crude product was purified by column chromatography using petroleum ether: ethyl
acetate to give the desired product.
(E)-2-((E)-benzylidene)-5-phenyl-1-(piperidine-1-yl) pent-4-ene-1,3-dione (4a):
Yield 75%. Pale yellow solid, Mp: 118-120 0C. 1H NMR (300 MHz CDCl3): δ 7.80 (d, 1H, J=15.6 Hz), 7.66 (s, 1H), 7.58-
7.63 (m, 5H), 7.38-7.46 (m, 5H), 7.19 (d, 1H, J=15.6 Hz), 3.23-3.83 (m, 4H), 1.55-1.68 (m, 2H), 1.25-1.42 (m, 4H). 13
C
NMR (75 MHz CDCl3): δ 186.89, 166.81, 145.10, 138.64, 136.65, 134.86, 133.75, 130.76, 130.46, 129.98, 129.03,
128.94, 128.69, 121.92, 47.64, 42.42, 26.08, 25.35, 24.51. ESI-MS calculated.m/z 345.47 found 346.10 [M+1]+.
E)-2-((E)-4-hydroxybenzylidene)-5-(4-hydroxyphenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione (4b):
Yield 67%. Yellow solid, Mp: 190-192 0C. 1H NMR (300 MHz CDCl3): δ 9.87 (bs, 2H), 7.58-7.63 (m, 2H), 7.52 (d, 2H, J=
7.5 Hz), 7.43 (d, 2H, J=8.7 Hz), 7.17 (d, 1H, J=15.6 Hz), 6.79-6.84 (m, 4H), 3.36-3.78(m, 4H), 1.36-2.00 (m, 6H). 13C
NMR (75 MHz CDCl3): δ 184.75, 165.48, 158.78, 158.60, 142.40, 136.82, 132.06, 130.66, 129.02, 124.24, 122.97,
116.48, 114.52, 114.45, 45.64, 40.24, 24.36, 23.65, 22.75. ESI-MS calculated.m/z 377.16 found 378.15 [M+1]+.
(E)-2-((E)-4-methoxybenzylidene)-5-(4-methoxyphenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione (4c):
Yield 78%. Yellow solid, Mp: 142-144 0C. 1H NMR (300 MHz CDCl3): δ 7.76 (d, 1H, J= 15.6 Hz), 7.62 (s, 1H), 7.53-7.58
(m, 4H), 7.05 (d, 1H, J=15.3 Hz), 6.89-6.93 (m, 4H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78-3.81 (m, 2H), 3.23-3.32 (m, 2H),
1.39-1.71 (m, 6H). 13C NMR (75 MHz CDCl3): δ 186.48, 167.49, 161.77, 161.49, 144.49, 138.37, 134.24, 132.06,
130.44, 127.56, 126.30, 119.51, 114.46, 114.41, 55.50, 55.45, 47.63, 42.37, 26.17, 25.45, 24.51. ESI-MS
calculated.m/z 405.19 found 428.18 [M+Na]+ .
(E)-1-(piperidin-1-yl)-2-((Z)-3,4,5-trimethoxybenzylidene)-5-(3,4,5-trimethoxyphenyl)pent-4-ene-1,3-dione (4d):
0
1
Yield 70%. Yellow solid. Mp: 140-142 C. H NMR (300 MHz CDCl3): δ 7.72 (d, 1H, J=15.6 Hz), 7.57 (s, 1H), 7.06 (d,
1H, J=15.3 Hz), 6.86 (s, 2H), 6.83 (s, 2H), 3.91 (bs, 6H), 3.90 (bs, 6H), 3.87 (bs, 6H), 3.16-3.60 (m, 4H), 1.42-1.70 (m,
6H). 13C NMR (75 MHz CDCl3): δ 186.55, 167.09, 153.52, 153.30, 145.25, 140.69, 140.10, 138.70, 135.72, 130.24,
129.04, 121.21, 107.12, 105.90, 61.08, 56.30, 56.22, 47.71, 42.36, 26.21, 25.56, 24.47. ESI-MS calculated.m/z 525.25
found 526.20 [M+1]+.
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(E)-2-((Z)-4-hydroxy-3-methoxybenzylidene)-5-(4-hydroxy-3-methoxyphenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione
(4e):
0
1
Yield 70%. Red solid. Mp: 106-108 C. H NMR (300 MHz CDCl3): δ 7.72 (d, 1H, J= 15.3 Hz), 7.59 (s, 1H), 7.13-7.19
(m, 3H), 7.06 (s, 1H), 6.90-6.95 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.17-3.41 (m, 4H), 1.28-1.42 (m, 6H). 13C NMR (75
MHz CDCl3): δ 186.58, 167.78, 148.79, 148.47, 147.12, 146.98, 145.09, 139.07, 138.83, 127.23, 125.86, 125.13,
123.51, 119.37, 114.95, 114.86, 111.62, 110.24, 55.02, 55.95, 47.66, 42.33, 26.14, 25.50, 24.44. ESI-MS
calculated.m/z 437.18 found 438.17 [M+1]+ .
(E)-2-((Z)-4-(dimethylamino)benzylidene)-5-(4-(dimethylamino)phenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione (4f):
Yield 67%. Red solid. Mp: 100-102 0C. 1H NMR (300 MHz CDCl3): δ 7.74 (d, 1H, J=15.3 Hz), 7.62 (s, 1H), 7.41-7.51 (m,
4H), 6.96 (d, 1H, J=15.3 Hz), 6.61-6.68 (m, 4H), 3.73-3.89 (m, 6H), 3.02 (s, 12H), 1.60-1.92 (m, 6H). 13C NMR (75 MHz
CDCl3): δ 183.70, 163.30, 151.82, 151.58, 144.69, 140.38, 138.97, 132.34, 132.26, 130.43, 124.27, 122.28, 111.75,
111.65, 47.48, 42.26, 40.13, 40.02, 26.14, 25.28, 24.56. ESI-MS calculated.m/z 431.26 found 432.10 [M+1]+.
(E)-2-((Z)-2-chlorobenzylidene)-5-(2-chlorophenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione (4g):
0
Yield 70%.Yellow solid. Mp: 148-150 C. 1H NMR (300 MHz CDCl3): δ 7.82 (s, 1H), 7.66 (d, 2H, J=7.8 Hz), 7.19-7.44
(m, 8H), 3.17-3.77 (m, 4H), 1.25-1.54 (m, 6H).13C NMR (75 MHz CDCl3): δ 195.66, 165.61, 141.14, 138.26, 138.23,
135.68, 135.11, 134.56, 134.55, 132.04, 131.45, 131.24, 130.34, 130.09, 129.70, 129.66, 127.17, 124.15, 47.48, 42.20,
25.88, 25.16, 24.34. ESI-MS calculated.m/z 413.09 found 414.20 [M+1]+.
(E)-2-((E)-4-chlorobenzylidene)-5-(4-chlorophenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione (4h):
Yield 68%. Yellow solid. Mp: 70-72 0C. 1H NMR (300 MHz CDCl3): δ 7.74 (d, 1H, J=15.6 Hz), 7.59 (s, 1H), 7.51-7.56 (m,
4H), 7.32-7.39 (m, 4H), 7.13 (d, 1H, J=15.6 Hz). 13C NMR (75 MHz CDCl3): δ 186.2, 166.35, 143.79, 137.26, 136.71,
136.69, 136.53, 133.07, 131.96, 131.14, 129.79, 129.25, 129.18, 121.84, 47.58, 42.38, 26.13, 25.33, 24.34. ESI-MS
calculated.m/z 413.09 found 414.20 [M+1]+.
(2Z,4E)-1-(piperidin-1-yl)-5-(thiophen-2-yl)-2-(thiophen-2-ylmethylene)pent-4-ene-1,3-dione (4i):
Yield 79%. Yellow solid. Mp: 142-144 0C. 1H NMR (300 MHz CDCl3): δ. 7.91 (d, 1H, J=15.3 Hz), 7.81 (s, 1H), 7.51 (d,
2H, 5.1 Hz), 7.41 (d, 2H, J=4.8 Hz), 7.07-7.10 (m, 2H), 6.91 (d, 1H, J=15.0 Hz), 3.25-3.41 (m, 4H), 1.25-1.46 (m, 6H).
13C NMR (75 MHz CDCl3): δ 185.31, 166.53, 140.31, 137.25, 137.18, 134.12, 133.34, 132.43, 131.67, 131.38, 129.23,
128.49, 128.06, 120.68, 47.58, 42.54, 26.26, 25.35, 24.59. ESI-MS calculated.m/z 357.09 found 356.23 [M-1]-.
(2E,4E)-2-((1H-pyrrol-2-yl)methylene)-1-(piperidin-1-yl)-5-(1H-pyrrol-2-yl)pent-4-ene-1,3-dione(4j):
Yield 55%. Yellow solid, Mp: 102-104 0C. 1H NMR (300 MHz CDCl3): δ 10.20 (bs, 2H), 7.77 (d, 1H, J=15.3 Hz), 7.72 (s,
1H), 7.10 (d, 1H, J=8.4 Hz), 6.94 (d, 1H, J=15.6 Hz), 6.73-6.89(m, 3H), 6.39-6.36 (m, 2H), 3.44-3.94 (m, 4H), 1.40-1.94
(m, 6H). 13C NMR (75MHz CDCl3): 186.25, 169.22, 134.23, 131.63, 129.91, 129.55, 129.09, 128.59, 127.39, 126.87,
125.39, 124.49, 119.20, 111.02, 48.29, 42.83, 26.28, 25.69, 24.44. ESI-MS calculated.m/z 323.16 found 322.15 [M-1]-.
General procedure for the synthesis of 3-oxo-N-phenylbutanamide (6):
A mixture of ethyl acetoacetate (1) (1.36 mL, 0.01097 mol) and corresponding aromatic amine (5) (0.978 mL, 0.01097
mol) in toluene was taken into a round bottom flask and refluxed under stirring for 2 h. After completion of the reaction,
the product was extracted with ethyl acetate (50 mL), washed with water (50 mL) and brine solution (50 mL). The
organic layer was separated and dried over anhydrous sodium sulfate and evaporated under reduced pressure to give
the desired product.
General procedure for the synthesis of (7a-j):
A mixture of boric anhydride (0.0825 g, 0.001185 mol) and corresponding phenyl butanamide (0.30 mL, 0.001693 mol)
was dissolved in ethyl acetate (5 mL) and stirred for 30 min at room temperature under nitrogen atmosphere. Then the
4-hydroxy 3-methoxybenzaldehyde (0.257 g, 0.001693 mol) and tri n-butyl borate (0.4 mL, 0.001693 mol) were added
to the reaction mixture and stirred for an hour. Then n-butylamine was added dropwise over 15 min and again stirred
for 3 hours at ambient temperature. After completion of the reaction, warmed hydrochloric acid (60 ˚C) (5 mL, 0.4 N)
was added to the reaction mixture and stirring was continued for an hour. Then the reaction mixture was diluted with
water and extracted with ethyl acetate (20 mL). The ethyl acetate layer was washed with water (20 mL) and brine
solution (20 mL). The organic layer was separated and dried over anhydrous sodium sulphate and evaporated under
reduced pressures to give desired product. The obtained product was purified by column chromatography.
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(E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxo-N-phenylpent-4-enamide (7a):
0
1
Yield 58%. White solid, Mp: 166-168 C. H NMR (300 MHz CDCl3): δ 7.76 (s, 1H), 7.54-7.59 (m, 3H), 7.31-7.37 (m,
2H), 7.08-7.14 (m, 3H), 6.88 (d, 1H, J=8.4 Hz), 3.62 (s, 3H), 2.46 (s, 2H). 13C NMR (75 MHz CDCl3): 194.83, 166.45,
149.18, 147.24, 139.65, 138.23, 133.94, 128.28, 125.70, 124.13, 123.64, 119.30, 115.04, 111.46, 55.06, 26.21. ESI-MS
calculated. m/z 311.12 found 312.01 [M+1]+ .
(E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxo-N-(p-tolyl)pent-4-enamide (7b):
Yield 45%. White solid, Mp: 194-196 0C. 1H NMR (300 MHz CDCl3): δ 9.19 (s, 1H), 7.50 (d, 2H, J=8.1 Hz), 7.44 (s, 1H),
7.31 (d, 1H, J=7.5 Hz), 7.15 (d, 1H, J=15.6 Hz), 7.05 (d, 2H, J=8.1 Hz), 6.99 (d, 1H, J=15.6 Hz), 6.79 (d, 1H, J=8.4 Hz),
3.57 (s, 3H), 2.38 (s, 2H), 2.27 (s, 3H). 13C NMR (75 MHz CDCl3): 186.39, 166.54, 149.25, 147.38, 140.30, 135.76,
134.33, 133.87, 129.31, 126.20, 124.78, 119.85, 115.19, 111.70, 55.64, 26.83, 20.75. ESI-MS calculated m/z 325.13
found 326.21 [M+1] +.
(E)-5-(4-hydroxy-3-methoxyphenyl)-N-(naphthalen-1-yl)-3-oxopent-4-enamide (7c):
0
1
Yield 58%. Brown solid, Mp: 112-114 C. H NMR (300 MHz CDCl3): δ 9.41 (s, 1H), 7.65-7.70 (m, 3H), 7.50 (s, 1H),
7.33 (d, 1H, J=8.1 Hz), 7.18 (d, 1H, J=8.4 Hz), 6.98- 7.08 (m, 5H), 6.86 (d, 1H, J =8.1 Hz), 3.62 (s, 3H), 2.44 (s, 2H). 13
C
NMR (75 MHz CDCl3): 195.69, 167.19, 149.28, 147.34, 140.98, 134.59, 133.85, 132.22, 128.00, 127.63, 125.82,
125.60, 125.20, 124.61, 121.87, 121.22, 115.21, 112.16, 55.38, 26.37. ESI-MS calculated/z 361.13 found 362.30
[M+1]+.
(E)-N-(4-fluorophenyl)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-4-enamide (7d):
0
1
Yield 65%. White solid, Mp: 160-162 C. H NMR (300 MHz CDCl3): δ 7.71 (s, 1H), 7.52-7.56 (m, 3H), 7.06-7.11 (m,
2H), 7.01 (d, 2H, J=9.0 Hz), 6.89 (d, 1H, J=8.4 Hz), 3.66 (s, 3H), 2.47 (s, 2H). 13C NMR (75 MHz CDCl3): 195.18,
166.66, 149.37, 147.40, 140.26, 134.57, 134.06, 126.08, 124.52, 121.36, 121.26, 115.34, 115.23, 115.06, 111.63,
55.43, 26.62. ESI-MS calculated.m/z 329.11 found 330.01 [M+1] +.
(E)-N-(4-chlorophenyl)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-4-enamide (7e):
Yield 72%. Yellow solid, Mp: 150-152 0C. 1H NMR (300 MHz CDCl3): δ 10.28 (s, 1H), 9.31(s, 1H), 8.11 (s, 1H), 7.74 (d,
2H, J=8.7 Hz), 7.44 (d, 2H, J=8.7 Hz), 7.28-7.24(m, 2H), 7.19-7.16(m, 2H), 3.71 (s, 3H), 3.61 (s, 2H). ESI-MS
calculated. m/z 345.08 found 346.17 [M+1]+.
(E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxo-N-(4-sulfamoylphenyl)pent-4-enamide (7f):
Yield 56%. White solid, Mp: 158-160 0C. 1H NMR (300 MHz CDCl3): δ 8.85 (s, 1H), 7.43-7.48 (m, 3H), 6.90 (s, 2H), 6.56
-6.71 (m, 6H), 3.73 (s, 3H), 2.50 (s, 2H). 13C NMR (75 MHz CDCl3): 196.67, 165.67, 151.84, 151.34, 147.58, 145.45,
130.11, 129.99, 127.37, 127.22, 119.65, 115.30, 112.48, 111.79, 111.12, 55.67, 45.93. ESI-MS calculated.m/z 390.09
found 391.38 [M+1]+.
(E)-N-(3-acetylphenyl)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-4-enamide (7g):
0
1
Yield 50%. White solid, Mp: 166-168 C. H NMR (300 MHz CDCl3): δ 10.12 (s, 1H,), 8.28 (s, 1H), 8.05 (d, 1H, J=8.1
Hz), 7.68 (d, 1H, J=7.5 Hz), 7.50 (s, 1H), 7.41-7.46 (m, 2H), 7.20 (d, 1H, J=8.4 Hz), 7.06 (d, 1H, J=8.4 Hz), 6.85 (d, 1H,
J=15.6 Hz), 3.61 (s, 3H), 2.60 (s, 2H), 2.44 (s, 3H). 13C NMR (75 MHz CDCl3): 197.46, 195.10, 166.94, 149.33, 147.32,
140.30, 138.86, 137.25, 133.80, 128.81, 125.77, 124.15, 123.90, 123.52, 119.02, 115.19, 111.50, 55.19, 26.33. ESI-MS
calculated.m/z 353.13 found 354.97 [M+1]+.
(E)-N-(4-acetylphenyl)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-4-enamide (7h):
0
1
Yield 67%. White solid, Mp: 192-194 C. H NMR (300 MHz CDCl3): δ 10.43 (s, 1H), 7.85-7.94 (m, 6H), 7.49 (s, 1H),
7.04 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=8.1 Hz), 3.59 (s, 3H), 2.58 (s, 2H), 2.44 (s, 3H). 13C NMR (75 MHz CDCl3):
195.61, 194.32, 166.50, 149.07, 146.96, 142.44, 139.64, 133.45, 131.69, 128.54, 125.19, 123.45, 118.08, 114.84,
111.19, 54.64, 25.63, 25.50. ESI-MS calculated.m/z 353.13 found 354.97 [M+1]+.
(E)-N-(3,5-dichlorophenyl)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-4-enamide (7i):
0
1
Yield 58%. Yellow solid, Mp: 198-200 C. H NMR (300 MHz CDCl3): δ 10.18 (s, 1H,), 8.60 (d, 1H, J=6.6 Hz), 7.74 (s,
2H), 7.48 (s, 1H), 7.03-7.12 (m, 3H), 6.85 (d, 1H, J=8.1 Hz), 3.67 (s, 3H), 2.42 (s, 2H). 13C NMR (75 MHz CDCl3):
195.02, 167.26, 149.55, 147.46, 140.71, 140.50, 134.76, 133.67, 125.97, 124.24, 123.65, 117.73, 115.36, 111.57,
55.44, 26.58. ESI-MS calculated.m/z 379.04 found 380.09 [M+1]+.
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(E)-5-(4-hydroxy-3-methoxyphenyl)-1-(piperidin-1-yl)pent-4-ene-1,3-dione (7j):
0
1
Yield 45%. Orange solid, Mp: 146-148 C. H NMR (300 MHz CDCl3): δ 7.43 (s, 1H), 7.04-7.11(m, 3H), 6.88 (d, 1H,
J=15.6 Hz), 4.08-4.15 (m, 2H), 3.86 (s, 3H), 3.64-3.79 (m, 2H), 2.40 (s, 2H), 1.23-1.31 (m, 6H). 13C NMR (75 MHz
CDCl3): 195.66, 167.26, 148.54, 146.98, 139.68, 133.79, 125.51, 125.29, 115.05, 111.70, 56.00, 47.56, 42.26, 26.53,
26.14, 25.34, 24.48. ESI-MS calculated. m/z 303.15 found 304.91[M+1]+.
α-Amylase inhibition activity:
The alpha amylase inhibition assay was carried out by following the reported literature[27]
.
α-Gluosidase inhibition activity:
Alpha-glucosidase activities were performed according to the literature reported[27]
.
AGEs inhibition activity:
The AGEs inhibitory study was performed by following the literature[12]
.
Molecular docking study
The rigid molecular docking studies were performed by using HEX 8.0 software[28].The three-dimensional structure
of synthesized compounds (4a-j and 7a-j) were constructed using ChemBio 3D ultra 13.0 software, and then they were
energetically minimized using MMFF94 with a maximum number of iteration of 5000 and minimum RMS gradient of
0.10[29]. The crystal structures of Protein (PDB ID: 1HNY) were taken from Protein Data bank (www.rcsb.org). The
docked complexes were visualized using discovery studio 4.1 client.
Supporting information
Supporting information contains spectra for the synthesized compounds.
Acknowledgements
The authors are grateful to UGC [39-693/2010(SR)] and DST (SR/FT/CS-59/2010), New Delhi for financial support,
DST-IRHPA program for providing high-resolution NMR facility, DST- PUESE, DST-FIST for providing the instrumental
facility.
Keywords: AGEs inhibitor, α-amylase inhibition, α-glucosidase inhibition, β-ketoamide curcumin.
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Two different series of novel β-
Govindharasu Banuppriya, Rajendran
Sribalan, Sulthan Alavudeen Rizwan
Fathima, Vediappen Padmini*
ketoamide
curcumin
analogues
enriched in biological activities have
been synthesized. The synthesized
compounds were screened for their in
vitro anti-diabetic and AGEs inhibitory
activities and exhibited potent to good
anti-diabetic and AGEs inhibitory
activities. Further molecular docking
study was also performed with the α-
amylase enzyme.
Page No. – Page No.
Synthesis of β-Ketoamide Curcumin Analogues
for Anti-Diabetic and AGEs Inhibitory Activities
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