Synthesis and Inhibitory Effect of Some Indole-Pyrimidine Based Hybrid Heterocycles on α-Glucosidase and α-Amylase as Potential Hypoglycemic Agents

Article abstract of DOI:10.1002/open.201900240

The Michael addition reaction of barbituric acid with chalcones incorporating the indole scaffold was achieved by using a highly efficient bimetallic Iron–palladium catalyst in the presence of acetylacetone (acac). This catalytic approach produced the desired products in a simple operation and low catalyst loading with acceptable yield of the new hybrids. All tested compounds were subjected for biological activity on α-glucosidase and α-amylase. The results revealed that all synthesized compounds exhibited very good activity against both enzymes when compared to positive control (acarbose). Moreover, compound 5o showed the best activity whereas its IC₅₀ (μM) are 13.02+0.01 and 21.71+0.82 for α-glucosidase and α-amylase respectively. Both compounds 5o and 5l exhibited high similarity in binding mode and pose with amylase protein (4UAC). The obtained data may be used for developing potential hypoglycemic agents.

Full text of DOI:10.1002/open.201900240

DOI: 10.1002/open.201900240
Full Papers
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Synthesis and Inhibitory Effect of Some Indole-Pyrimidine
Based Hybrid Heterocycles on α-Glucosidase and
α-Amylase as Potential Hypoglycemic Agents
Farid A. Badria,[a] Saleh Atef,[b] Abdullah Mohammed Al-Majid,[b] M. Ali,[b]
Yaseen A. M. M. Elshaier,[c] Hazem A. Ghabbour,[d] Mohammad Shahidul Islam,*[b] and
Assem Barakat*[b, e]
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The Michael addition reaction of barbituric acid with chalcones
incorporating the indole scaffold was achieved by using a
highly efficient bimetallic Iron–palladium catalyst in the pres-
ence of acetylacetone (acac). This catalytic approach produced
the desired products in a simple operation and low catalyst
loading with acceptable yield of the new hybrids. All tested
compounds were subjected for biological activity on α-
glucosidase and α-amylase. The results revealed that all
synthesized compounds exhibited very good activity against
both enzymes when compared to positive control (acarbose).
Moreover, compound 5o showed the best activity whereas its
IC50 (μM) are 13.02+0.01 and 21.71+0.82 for α-glucosidase
and α-amylase respectively. Both compounds 5o and 5l
exhibited high similarity in binding mode and pose with
amylase protein (4UAC). The obtained data may be used for
developing potential hypoglycemic agents.
1. Introduction
received significant attention due to their wide range of
biological activities including antimicrobial, anticancer, anti-HIV
antileishmanial and anti-inflammatory.[3] In recent past, several
nitrogen containing novel chemical entities emerged as drug
molecules, for example, Atevirdine (anti-HIV); Camptothecin
(CPT) (inhibitors of topoisomerase I);[4] Cryptolepine (inhibitors
topoisomerase II).[5] Synthetic analogues of Cryptolepine such as
IQDMA and benzo-pyrido-indole derivatives exhibited potent
anticancer activity via interaction of DNA[6]. We are engaged in
a research program for drug development as anti-diabetes
based on indole and pyrimdine scaffolds.[7] One example of our
invention the use of indole scaffold in the treatment and
prevention of diabetes has been described (Figure 1).[7–8]
Diabetes Mellitus (DM) is a growing global health concern.
In 2017, diabetes affected an estimated 426 million adults
people (20–79 years) world-wide; by 2045 this numbers are
expected to overrun 629 million.[9] The release of free glucose
from starch is mediated by two important enzymes: α-amylase
and α-glucosidase. α-Amylase is a metalloenzyme that cleaves
polysaccharide chains, semi-randomly creating shorter chains
rapidly, whereas α-glucosidase breaks these shorter chains into
free glucose. The inhibition of these two enzymes can delay
digestion, and absorption of carbohydrates, and hence, impair
Heterocyclic compounds are of immense chemical and bio-
logical significance. In particular, azaheterocycles (nitrogen
containing heterocycles) such as pyrimidines and indoles are
structural constituents of many natural as well as synthetic
bioactive drug-like molecules.[1] Substituted azaheterocycles
have been referred as “privileged structures” since they are
capable of binding to many receptors with high affinity and
hydrogen bonding capacity. Naturally occurring nitrogen-based
heterocycles such as reserpine, vinca alkaloids, bisindoles,
indoloquinolines, opioid analgesics, carbolines and cinchona
alkaloids are established source of lead molecules for diverse
therapeutic areas.[2] Among the nitrogen containing hetero-
cycles, indole is the parent core in a large number of bioactive
naturally occurring compounds. Indole and its derivatives have
[a] Prof. Dr. F. A. Badria
Department of Pharmacognosy, Faculty of pharmacy, Mansura University,
Mansura 35516 Egypt
[b] S. Atef, Prof. Dr. A. M. Al-Majid, M. Ali, M. S. Islam, Dr. A. Barakat
Department of Chemistry, College of Science, King Saud University, P. O.
Box 2455, Riyadh 11451, Saudi Arabia
E-mail: mislam@ksu.edu.sa
ambarakat@ksu.edu.sa
[c] Dr. Y. A. M. M. Elshaier
Department of Organic and Medicinal chemistry, Faculty of Pharmacy,
University of Sadat City, Menoufiya, Egypt
[d] Dr. H. A. Ghabbour
Department of Medicinal Chemistry, Faculty of Pharmacy, University of
Mansoura, Mansoura 35516, Egypt
[e] Dr. A. Barakat
Department of Chemistry, Faculty of Science; Alexandria University, P.O. Box
426, Ibrahimia, Alexandria 21321, Egypt
©2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Figure 1. Previous and current study.
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Table 1. Model example for investigation of the reaction parameters.
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#
Solvent
Metal Salts
Ligands
Ligand:Metal mol%
Yield
1.
2.
3.
4.
5.
6.
7.
Toluene
Toluene
Toluene/THF
THF
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
FeCl3/PdCl2
FeCl3/PdCl2
L1
L1
L1
L1
L1
L1
L2
10:11 mol%
10:11 mol%
10:11 mol%
10:11 mol%
10:11 mol%
10:10 mol%
10:10 mol%
No rxn[b]
No rxn
No rxn
No rxn
No rxn
No rxn
55%
ACN
MeOH
MeOH[a]
°
[a] The reaction carried out at 60 C. [b] No rxn: No reaction.
the postprandial hyperglycemia. Therefore, the aim of our work
was to synthesize, through a Michael addition to a series of
indole containing chalcones, new heterocycles that may act as
inhibitors of these two enzymes
ACN, or Toluene/THF mixture, the reaction did not occur. Other
metal salt as Zn(OTf)2 did not facilitate the reaction under the
same conditions. Additionally, one attempt with FeCl3/PdCl2
°
carried out in MeOH at 60 C, the reaction didnot occur at all.
Only, FeÀ Pd bimetallic system[11] in MeOH at 60 C provides
°
the desired product in moderate yield (55%) (Table 1). The
molecular structures of target compounds 5a were determined
by analysis of its spectroscopic data including 1H-, 13C-NMR,
Fourier-transform infra-red (FT-IR) spectroscopy and X-ray
crystal analysis.
To investigate the generality of this method, the reaction of
barbituric acid and different enones was examined under the
optimized reaction conditions (10 mol% of FeCl3, 10 mol% of
PdCl2 and 15 mol% Acac, 1.0 equiv. chalcone and 1.1 equiv.
2. Results and Discussion
2.1. Synthesis
The requisite compounds chalcones were prepared by reaction
of N-alkyl-3-acetylindole and aryl aldehyde derivatives stirring
in EtOH/H2O (1:1) with NaOH at room temperature for 24 h.
The product was produced in high yield (up to 90%), as
depicted in Scheme 1. The configuration of the chalcones
obtained exclusively with E-geometry. The E configuration of
these compounds was supposed in analogy with similar
compounds, previously prepared by us, whose configuration
was established through X-ray analysis.[14b]
Reaction of (E)-1-(1-methyl-1H-indol-3-yl)-3-phenylprop-2-
en-1-one 3a with barbituric acid 4 was chosen as a model
reaction to prepare 1,3-dimethyl-5-(3-(1-methyl-1H-indol-3-yl)-3-
oxo-1-phenylpropyl)pyrimidine-2,4,6(1H,3H,5H)-trione 5a. Ini-
tially, the reaction of 3a with barbituric acid 4 carried out in
°
barbituric acid in CH3OH at at 60 C. All of the results are
summarized in Table 2.
2.2. X-Ray Crystallography
The structure of 5g was further confirmed by X-Ray structural
study. The asymmetric unit contains one independent molecule
that is shown in Figure 2. It was found to crystallize in
Monoclinic Cc space group. The crystallographic data and
refinement information are summarized in Table 3 and bond
lengths are in normal ranges as shown in Table 4. The crystal
structure reveals that the title compound is found in three
planes, the angles between indole ring plane (C1À C8/N1) and
fluorophenyl ring (C12À C17) and pyrimidine moiety
°
toluene at 80 C in the presence of Cu(OTf)2/L1 (10:10 mol%)
did not work all.[10] However, upon using different solvents; THF,
°
°
(C20À C21À N2À C22À N3À C23) are 22.41 and 41.07 , respectively.
The angle between fluorophenyl ring and pyrimidine ring is
°
57.88 . The crystal structure is stabilized by many non-classical
hydrogen bonds along the b axis direction Figure 3, Table 5.
Scheme 1. Synthesis of the chalcones 3a–q.
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2.3. Biological Activity
Table 2. Substrate scope of desired compounds 5a–q.
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The present study seeks an alternative drug among series of
synthesized compounds that can regulate the hyperglycemia
by down-regulating alpha-glucosidase and alpha-amylase activ-
ity by using virtual and in vitro assays.
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#
Chlacones
3a–q
Ar
R
Products
5a–q
[%] Yield
5a–q
The data reported in Table 6 showed that the most active
compounds, both on α-glucosidase and on α-amylase, are
compounds 5o, 5k, and 5l. All other compounds were found to
have only good to moderate activity ranging from 28.05+0.41
to 77.05+0.04 μM in the case of α-glucosidase, but in the range
of 53.10+0.10 to 96.42+0.22 μM in the case of α-amylase.
Structure activity relationship indicates the importance of the
naphthyl moiety in 5o, of the p-CF3Ph propanone substituted
indole in 5k, and of a thiophene ring in 5l. The most active
compound is 5o, which showed an IC50 =13.02+0.01 μM and
21.71+0.82 μM, for α-glucosidase, and α - amylase respectively.
1.
2.
3.
4.
5.
6.
7.
8.
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
Ph
4-MePh
4-ClPh
2,4-Cl2Ph
4-OMePh
4-BrPh
4-FPh
3-FPh
3-MePh
3-BrPh
4-CF3Ph
Thiophinyl
Furanyl
3,4,5-OMe3Ph
2-Napthyl
2,4,6-Me3Ph
4-NO2Ph
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
55
44.9
60.2
55.1
53
39.3
47.6
46.8
46.6
36.7
39.7
53.7
54.6
35.5
37
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9.
10.
11.
12.
13.
14.
15.
16.
17.
2.4. Docking Studies
-
34.6
The compound 5o was selected for docking study with (4UAC)
because of its strongest inhibitory activity among these
derivatives. The X-ray crystal structure of (4UAC) was obtained
from protein data bank (PDB ID: 4UAC).[12] Protein-ligand
docking was operated by (OpenEye Scientific Software, Santa
Fe, NM 87508).[13] The binding site of the protein was prepared
by employing FRED RECEPTOR 2.2.5 (OpenEye Scientific Soft-
ware, Santa Fe, NM 87508).
In the figure 4, we can find that compound 5o formed
hydrogen bonds to ASN 191 AA through the oxygen of
carbonyl linked to indole moiety. Moreover, this compound
formed another HB with GLN 110 AA through the carbonyl of
barbiturate ring. These two interactions are similar to acrabose
standard with receptor in its cocrystalized from.[12]
Figure 2. ORTEP diagram of the titled compounds 5g. Displacement
ellipsoids are plotted at the 40% probability level for non-H atoms.
Compound 5o exhibited high similarity to the potent
derivative (compound 5l) in the specific receptor, figure 5.
Experimental Section
General Procedure for the Synthesis of Chalcones 3a–q
The chalcones were prepared followed by reported procedure.[14]
(E)-1-(1-Methyl-1H-indol-3-yl)-3-phenylprop-2-en-1-one (3a)
Yield 0.75 g (2.8 mmol, 53.8%); All other spectral data are consistent
with reported literature.[14c]
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(p–tolyl)prop-2-en-1-one (3b)
Yield 1.34 g (4.63 mol, 86.8%); m.p. 85–86 C; 1H-NMR (400 MHz,
°
DMSO-d6) δ: 1.47 (t, 3H, J=7.2 Hz, CH3), 2.29 (s, 3H, CH3) 4.12 (q, 2H,
J=7.2 Hz, CH2), 7.12 (d, 2H, J=7.6 Hz, ArÀ H), 7.22–7.28 (m, 4H,
ArÀ H & CH=CH), 7.45 (d, 2H, J=8.0 Hz, ArÀ H), 7.71 (d, 1H, J=
15.6 Hz, CH=CH), 7.81 (s, 1H, ArÀ H), 8.44–8.46 (m, 1H, ArÀ H); 13C-
NMR (100 MHz, DMSO-d6) δ: 15.1, 21.4, 41.8, 109.6, 117.7, 122.5,
Figure 3. Molecular packing of titled compounds 5g viewed hydrogen bonds
which are drawn as dashed lines along b axis.
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Table 3. Experimental details of 5g.
Crystal data 5g
Table 6. Results of the α-glucosidase and α-Amylase inhibitory activity of
the synthesized compounds 5a–q.
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#
Compounds
α-Glucosidase
IC50 (μM)*
α-Amylase
Chemical formula
Mr
Crystal system, space group
Temperature (K)
a, b, c (Å)
C25H24FN3O4
449.47
Monoclinic, Cc
293
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5q
65.14�0.17
53.15�0.12
49.75�0.01
58.21�0.09
61.42�0.78
53.15�0.12
69.75�0.01
61.10�0.42
73.15�0.12
77.05�0.04
20.49�0.44
22.28�0.48
64.35�0.08
53.15�0.12
13.02�0.01
31.12�0.11
2.35�0.13
93.25�0.10
80.17�0.05
71.24�0.20
96.42�0.22
88.45�0.32
78.25�0.10
86.42�0.22
89.45�0.44
95.25�0.10
86.42�0.22
47.11�0.09
35.42�0.60
82.15�0.50
93.25�0.10
21.71�0.82
63.00�0.61
0.75�0.07
12.128 (5), 28.221 (12), 8.718 (3)
°
β ( )
129.532 (9)
2301.4 (16)
4
Mo Kα radiation
0.09
V (Å3)
Z
Radiation type
μ (mmÀ 1
)
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11
12
13
14
15
16
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19
20
21
22
23
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Crystal size (mm)
0.33×0.20×0.09
9
10
11
12
13
14
15
16
STD
Data collection
Diffractometer
Absorption correction
θmax
No. of measured, independent
and observed [I>2σ(I)] reflec-
Bruker APEX-II D8 venture
Multi-scan, SADABS Bruker 2014
°
27.0
21063, 4914, 2093
Acarbose (μM)
tions
Rint
0.180
*α-Glucosidase and �-amylase are expressed with mean�SD of triplicates.
Refinement
R[F2 >2σ( F2)], wR( F2), S
No. of reflections
No. of parameters
No. of restraints
0.067, 0.184, 0.99
4914
302
122.9, 123.0, 123.4, 127.0, 128.0, 129.5, 132.6, 133.5, 136.6, 104.0,
140.9, 184.4; IR (KBr, cmÀ 1) νmax =3043, 2979, 1643, 1585, 1523,
1486, 1447, 1388, 1308, 1299, 1205, 1205, 1185, 1087; [Anal. Calcd.
for C20H19NO: C, 83.01; H, 6.62; N, 4.84; Found: C, 83.41; H, 6.12; N,
4.32]; LC/MS (ESI, m/z): [M+], found 290.32, C20H19NOfor 289.15.
2
H-atom treatment
H atoms treated by a mixture of
independent and constrained refine-
ment
Δ1max, Δ1min (e ÅÀ 3
)
0.22, À 0.15
CCDC
1877313
(E)-3-(4-Chlorophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one
(3c)
Yield 1.56 g (5.04 mmol, 94.5%); All other spectral data are
consistent with reported literature.[14d]
°
Table 4. Selected geometric parameters (Å, ) of 5g.
O9À C15
1.374 (16)
1.230 (10)
1.216 (9)
1.231 (11)
1.208 (9)
1.386 (11)
1.355 (10)
108.3 (6)
126.0 (7)
125.7 (7)
123.7 (7)
119.2 (7)
117.0 (8)
124.4 (6)
117.5 (7)
118.1 (6)
129.6 (7)
107.6 (7)
110.8 (7)
121.3 (8)
N1À C18
1.488 (10)
1.369 (12)
1.384 (11)
1.477 (14)
1.353 (11)
1.372 (11)
1.479 (10)
120.6 (7)
116.6 (10)
120.0 (13)
115.2 (9)
119.9 (7)
121.6 (8)
118.5 (7)
120.2 (9)
121.1 (8)
118.7 (8)
120.1 (7)
121.5 (8)
118.4 (7)
O1À C9
N2À C21
O2À C21
N2À C22
(E)-3-(2,4-Dichlorophenyl)-1-(1-ethyl-1H-indol-3-yl)
prop-2-en-1-one (3d)
O3À C22
N2À C24
O4À C23
N3À C22
N1À C1
N3À C23
1
°
Yield 1.70 g (4.9 mmol, 92.8%); m.p. 168–169 C; H-NMR (400 MHz,
N1À C8
N3À C25
DMSO-d6) δ: 148 (t, 3H, J=7.2 Hz, CH3), 4.14 (q, 2H, J=7.2 Hz, CH2),
7.15–7.19 (m, 1H, ArÀ H), 7.23–7.28 (m, 4H, ArÀ H & CH=CH), 7.35 (d,
1H, J=2.4 Hz, ArÀ H), 7.56 (d, 1H, J=8.0 Hz, ArÀ H), 7.80 (s, 1H,
ArÀ H), 7.98 (d, 1H, J=15.2 Hz, CH=CH), 8.42–8.43 (m, 1H, ArÀ H); 13C-
NMR (100 MHz, DMSO-d6) δ: 15.3, 42.1, 109.8, 117.7, 122.9, 123.2,
123.9, 127.1, 127.5, 128.4, 130.1, 132.4, 134.1, 135.8, 135.8, 136.7,
184.1; IR (KBr, cmÀ 1) νmax = 3046, 2971, 2926, 2872, 1653, 1595,
1582, 1527, 1464, 1392, 1238, 1200, 1124, 1098, 1057; [Anal. Calcd.
for C19H15Cl2NO: C, 66.29; H, 4.39; N, 4.07; Found: C, 66.42; H, 4.23; N,
4.36]; LC/MS (ESI, m/z): [M+], found 344.10, C19H15Cl2NO for 343.05.
C1À N1À C8
C1À N1À C18
C8À N1À C18
C21À N2À C22
C21À N2À C24
C22À N2À C24
C22À N3À C23
C22À N3À C25
C23À N3À C25
N1À C1À C2
N1À C1À C6
N1À C8À C7
O1À C9À C7
O1À C9À C10
O9À C15À C14
O9À C15À C16
N1À C18À C19
O2À C21À N2
O2À C21À C20
N2À C21À C20
O3À C22À N2
O3À C22À N3
N2À C22À N3
O4À C23À N3
O4À C23À C20
N3À C23À C20
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(4-methoxyphenyl)
prop-2-en-1-one (3e)
°
Table 5. Hydrogen-bond geometry (Å, ) of 5g.
Yield 1.60 g (5.2 mmol, 98.1%); All other spectrum data are
consistent with reported literature.[14d]
DÀ H···A
DÀ H
H···A
D···A
DÀ H···A
C10À H10B···O2
C14À H14A···O9i
C18À H18A···O4ii
C25À H25B···O3iii
0.9700
0.9300
0.9700
0.9600
2.3200
2.3400
2.4500
2.5400
2.975 (12)
3.170 (13)
3.364 (14)
3.388 (15)
124.00
148.00
156.00
148.00
(E)-3-(4-Bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one
(3f)
Yield 1.75 g (4.95 mmol, 92.8%); m.p. 139–140 C; 1H-NMR
°
Symmetry codes: (i) x, À y+1, z+1/2; (ii) x+1/2, À y+1/2, z+3/2; (iii) x,
À y+1, zÀ 1/2.
(400 MHz, DMSO-d6) δ: 1.49 (t, 3H, J=7.2 Hz, CH3), 4.17 (q, 3H, J=
7.2 Hz, CH2), 7.23–7.29 (m, 4H, ArÀ H & CH=CH), 7.41 (q, 4H, J=
6.8 Hz, ArÀ H), 7.64 (d, 1H, J=15.2 Hz, CH=CH), 7.82 (s, 1H, ArÀ H),
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Figure 4. Snap shot visualization of 5o docked with ID: 4AUC, showing formation of two HBs interaction as illustrated by Vida
Figure 5. Snap shot visualization of compound 5l overlays with 5o and shown same binding mode and pose with receptor.
8.42–8.45 (m, 1H, ArH); 13C-NMR (100 MHz, DMSO-d6) δ: 15.1, 41.8,
109.8, 117.6, 122.7, 123.0, 123.6, 123.8, 124.4, 126.9, 129.5, 131.9,
133.7, 133.3, 136.7, 139.5, 183.8; IR (KBr, cmÀ 1) νmax =3449, 3041,
2977, 1645, 1610, 1588, 1525, 1481, 1469, 1454, 1399, 1310, 1241,
1267, 1268, 1016; [Anal. Calcd. for C19H16BrNO: C, 64.42; H, 4.55; N,
3.95; Found: C, 64.31; H, 4.67; N, 4.15]; LC/MS (ESI, m/z): [M+], found
354.18, C19H16BrNO for 353.04.
7.54 (m, 2H, ArÀ H), 7.65-7.70 (m, 1H,CH=CH), 7.82 (s, 1H, ArÀ H),
8.41–8.45 (m, 1H, ArÀ H); 13C-NMR (100 MHz, DMSO-d6) δ: 15.1, 41.8,
109.8, 115.7, 115.9, 117.6, 122.6, 123.0, 123.5, 123.7, 126.8, 129.5,
131.6, 133.7, 136.7, 139.6, 164.8, 183.8; IR (KBr, cmÀ 1) νmax =3451,
3047, 2979, 1642, 1613, 1589, 1524, 1482, 1468, 1450, 1397, 1313,
1242, 1269, 1262, 1015; [Anal. Calcd. for C19H16FNO: C, 77.80; H, 5.50;
N, 4.77; Found: C, 78.05; H, 5.59; N, 4.61]; LC/MS (ESI, m/z): [M+],
found 294.280, C19H16FNO for 293.12.
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(4-fluorophenyl)prop-2-en-1-one
(3g)
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(3-fluorophenyl)prop-2-en-1-one
(3h)
1
°
Yield 1.40 g (4.77 mmol, 89.4%); m.p. 94–95 C; H-NMR (400 MHz,
1
°
DMSO-d6) δ: 1.44 (t, 3H, J=7.2 Hz, CH3), 4.12 (q, 2H, J=7.2 Hz, CH2),
7.96–7.02 (m, 2H, ArÀ H), 7.15–7.30 (m, 4H, ArÀ H & CH=CH), 7.49 –
Yield 1.40 g (4.77 mmol, 89.4%); m.p. 84–85 C; H-NMR (400 MHz,
DMSO-d6) δ: 1.47 (t, 3H, J=6.0 Hz, CH3), 4.15 (q, 2H, J=6.0 Hz, CH2),
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6.94–7.00 (m, 1H, ArÀ H), 7.24–7.29 (m, 7H, J=6.8 Hz, ArÀ H &
CH=CH), 7.67 (d, 1H, J=15.2 Hz, CH=CH), 7.83 (s, 1H, ArÀ H), 8.43–
8.45 (m, 1H, ArH); 13C-NMR (100 MHz, DMSO-d6) δ: 15.3, 42.0,109.9,
114.0 & 114.2, 116.6 & 116.8, 117.7, 122.9, 123.2, 123.7, 124.4, 125.0,
127.0, 130.4 & 130.5, 133.9, 136.8, 137.7 & 137.8, 139.6, 162.4, 164.1,
184.8; IR (KBr, cmÀ 1) νmax =3459, 3049, 2977, 1646, 1611, 1588, 1524,
1486, 1463, 1449, 1391, 1311, 1245, 1268, 1260, 1011; [Anal. Calcd.
for C19H16FNO: C, 77.80; H, 5.50; N, 4.77; Found: C, 77.95; H, 5.37; N,
4.48]; LC/MS (ESI, m/z): [M+], found 294.21, C19H16FNO for 293.12.
cmÀ 1) νmax =3474, 3106, 3073, 2970, 2928, 1632, 1560, 1522, 1486,
1447, 1388, 1360, 1207, 1103, 1085,; [Anal. Calcd. for C17H15NOS: C,
72.57; H, 5.37; N, 4.98; Found: C, 72.82; H, 5.15; N, 5.10]; LC/MS (ESI,
m/z): [M+], found 282.23, C17H15NOS for 281.09.
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(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(furan-2-yl)prop-2-en-1-one (3m)
1
°
Yield 1.35 g (5.09 mmol, 95.4%); m.p. 74–75 C; H-NMR (400 MHz,
DMSO-d6) δ: 1.54 (t, 3H, J=7.2 Hz, CH3), 4.23 (q, 2H, J=7.2 Hz, CH2),
7.32–7.37 (m, 3H, ArÀ H), 7.42 (d, 1H, J=15.6 Hz, CH=CH), 7.61 (d,
2H, J=8.0 Hz, ArÀ H), 7.69 (d, 2H, J=8.0 Hz, ArÀ H), 7.75 (d, 1H, J=
15.2 Hz, CH=CH), 7.92 (s, 1H, ArÀ H ), 8.49–8.51 (m, 1H, ArÀ H); 13C-
NMR (100 MHz, DMSO-d6) δ: 15.1, 41.7, 109.7, 112.3, 114.6, 117.7,
121.3, 123.0, 123.4, 126.9, 127.4, 133.8, 136.7, 144.0, 152.0, 183.7; IR
(KBr, cmÀ 1) νmax =3478, 3102, 3075, 2972, 2929, 1631, 1562, 1524,
1488, 1442, 1389, 1365, 1204, 1102, 1086; [Anal. Calcd. for
C17H15NO2: C, 76.96; H, 5.70; N, 5.28; Found: C, 76.55; H, 5.95; N,
5.10]; LC/MS (ESI, m/z): [M+], found 266.27, C17H15NO2 for 265.11.
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(m–tolyl)prop-2-en-1-one (3i)
Yield 1.28 g (4.42 mmol, 82.9%); m.p. 116–117 C; 1H-NMR
°
(400 MHz, DMSO-d6) δ: 1.54 (t, 3H, J=7.2 Hz, CH3), 2.38 (s, 3H, CH3),
4.22 (q, 2H, J=7.2 Hz, CH2), 7.17 (d, 1H, J=3.6 Hz, ArÀ H), 7.24–7.47
(m, 7H, ArÀ H & CH=CH), 7.78 (d, 1H, J=15.2 Hz, CH=CH), 7.9 (s, 1H,
ArÀ H), 8.50–8.53 (m, 1H, ArÀ H); 13C-NMR (100 MHz, DMSO-d6) δ:
15.1, 21.3, 41.8, 109.7, 117.7, 122.6, 123.1, 123.4, 123.6, 125.3, 127.0,
128.6, 130.6, 133.7, 135.3, 136.7, 138.4, 138.4, 141.2, 184.3; IR (KBr,
cmÀ 1) νmax =3046, 2977, 1644, 1589, 1525, 1482, 1449, 1389, 1304,
1297, 1206, 1204, 1188, 1088; [Anal. Calcd. for C20H19NO: C, 83.01; H,
6.62; N, 4.84; Found: C, 83.35; H, 6.51; N, 4.73]; LC/MS (ESI, m/z): [M+
], found 290.24, C20H19NO for 289.15.
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)
prop-2-en-1-one (3n)
1
°
Yield 1.1 g (3.01 mmol, 56.4%); m.p. 197–198 C; H-NMR (400 MHz,
DMSO-d6) δ: 1.53 (t, 3H, J=7.6 Hz, CH3), 3.87 (s, 3H, OCH3) 3.90 (s,
6H, OCH3), 4.23 (q, 2H, J=7.6 Hz, CH2), 6.83 (s, 2H, ArÀ H), 7.26 (d,
1H, J=15.2 Hz, CH=CH), 7.30–7.37 (m, 3H, ArÀ H), 7.71 (d, 1H, J=
15.2 Hz, CH=CH), 7.93 (s, 1H, ArÀ H), 8.49–8.51 (m, 1H, ArÀ H); 13C-
NMR (100 MHz, DMSO-d6) δ: 15.2, 41.8, 56.2, 60.9, 105.4, 109.7,
117.6, 122.6, 123.1, 123.2, 123.5, 127.0, 130.9, 133.8, 136.8, 141.3,
153.4, 184.1; IR (KBr, cmÀ 1) νmax =3452, 3103, 2977, 2942, 2831,
1639, 1581, 1566, 1522, 1463, 1447, 1419, 1392, 1337, 1250, 1147,
1121, 1002; [Anal. Calcd. for C22H23NO4: C, 72.31; H, 6.34; N, 3.83;
Found: C, 72.46; H, 6.12; N, 3.51]; LC/MS (ESI, m/z): [M+], found
366.20, C22H23NO4 for 365.16.
(E)-3-(3-Bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one
23 (3j)
24
Yield 1.60 g (4.53 mmol, 84.8%); m.p. 126–127 C; 1H-NMR
(400 MHz, DMSO-d6) δ: 1.54 (t, 3H, J=5.6 Hz, CH3)„ 4.22 (q, 2H, J=
5.6 Hz, CH2), 7.25–7.36 (m, 5H, ArÀ H & CH=CH), 7.49 (t, 2H, J=
8.8 Hz, ArÀ H), 7.68–7.78 (m, 2H, J=15.2 Hz, ArÀ H & CH=CH), 7.92 (s,
1H, ArÀ H), 8.50–8.53 (m, 1H, ArÀ H); 13C-NMR (100 MHz, DMSO-d6) δ:
15.3, 42.0, 109.9, 117.7, 122.9, 123.01, 123.2, 123.8, 125.1, 127.05,
127.3, 130.3, 130.4, 132.6, 134.03, 136.8, 137.6, 139.3, 183.7; IR (KBr,
cmÀ 1) νmax =3445, 3042, 2971, 1643, 1617, 1585, 1521, 1482, 1467,
1455, 1399, 1312, 1242, 1261, 1264, 1012; [Anal. Calcd. for
C19H16BrNO: C, 64.42; H, 4.55 N, 3.95; Found: C, 64.65; H, 4.38; N,
4.17]; LC/MS (ESI, m/z): [M+ found 354.19, C19H16BrNO for 353.04.
°
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(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(naphthalen-2-yl)prop-2-en-1-one
(3o)
1
°
Yield 0.9 g (2.7 mmol, 51.8%); m.p. 113–114 C; H-NMR (400 MHz,
DMSO-d6) δ: 1.46 (t, 3H, J=7.2 Hz, CH3), 4.14 (q, 2H, J=7.2 Hz, CH2),
7.23–7.28 (m, 3H, ArÀ H), 7.38 –7.42 (m, 3H, ArÀ H & CH=CH), 7.69 –
7.78 (m, 4H, ArÀ H), 7.89 (d, 3H, J=15.2 Hz, CH=CH & ArÀ H), 8.46–
8.48 (m, 1H, ArÀ H); 13C-NMR (100 MHz, DMSO-d6) δ: 15.1, 41.8,
109.7, 117.7, 122.6, 123.1, 123.5, 123.8, 123.9, 126.5, 126.9, 127.0,
127.7, 128.4, 129.8, 132.8, 133.4, 133.9, 134.0, 136.7, 141.1, 184.1; IR
(KBr, cmÀ 1) νmax =3478, 3105, 3049, 2968, 2926, 2879, 1642, 1578,
1505, 1468, 1388, 1294, 1208, 1141, 1085; [Anal. Calcd. for C23H19NO:
C, 84.89; H, 5.89; N, 4.30; Found: C, 84.96; H, 6.11; N, 4.62]; LC/MS
(ESI, m/z): [M+], found 326.10, C23H19NO for 325.15.
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)
prop-2-en-1-one (3k)
1
°
Yield 1.7 g (4.9 mmol, 92.7%); m.p. 150–151 C; H-NMR (400 MHz,
DMSO-d6) δ: 1.54 (t, 3H, J=7.2 Hz, CH3), 4.23 (q, 2H, J=7.2 Hz, CH2),
7.31–7.39 (m, 3H, ArÀ H), 7.44 (d, 1H, J=15.2 Hz, CH=CH), 7.61 (d,
2H, J=8.0 Hz, ArÀ H), 7.69 (d, 2H, J=8.0 Hz, ArÀ H), 7.80 (d, 1H, J=
15.2 Hz, CH=CH), 7.92 (s, 1H, ArÀ H), 8.49–8.51 (m, 1H, ArÀ H); 13C-
NMR (100 MHz, DMSO-d6) δ: 15.1, 41.7, 109.7, 112.3, 114.6, 117.7,
121.4, 122.6, 123.1, 123.4, 126.9, 127.4, 133.8, 136.7, 144.03, 152.0,
183.8; IR (KBr, cmÀ 1) νmax =3441, 3037, 2981, 1652, 1624, 1596, 1532,
1475, 1471, 1456, 1388, 1327, 1246, 1275, 1252, 1011; [Anal. Calcd.
for C20H16F3NO: C, 69.96; H, 4.70; N, 4.08; Found: C, 70.12; H, 4.92; N,
4.40]; LC/MS (ESI, m/z): [M+], found 344.24, C20H16F3NO for 343.12
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-mesitylprop-2-en-1-one (3p)
Yield 1.10 g (3.4 mmol, 64.9%); m.p. 83–84 C; 1H-NMR (400 MHz,
°
DMSO-d6) δ: 1.52 (t, 3H, J=7.6 Hz, CH3), 2.29 (s, 3H, CH3) 2.36 (s, 6H,
CH3), 4.22 (q, 2H, J=7.6 Hz, CH2), 6.91 (s, 2H, ArÀ H), 6.99 (d, 1H, J=
16.4 Hz, CH=CH), 7.30–7.38 (m, 3H, ArÀ H), 7.80 (s, 1H, ArÀ H), 7.93 (d,
1H, J=16.4 Hz, CH=CH), 8.50–8.53 (m, 1H, ArÀ H); 13C-NMR
(100 MHz, DMSO-d6) δ: 15.3, 21.1, 21.3,41.9, 109.8, 117.8, 122.7,
123.2, 123.6, 127.1, 129.1, 129.3, 132.3, 133.8, 136.8, 136.9, 137.9,
139.6, 184.5; IR (KBr, cmÀ 1) νmax =3041, 2974, 1641, 1584, 1525,
1483, 1447, 1385, 1302, 1294, 1206, 1188, 1089, 1062; [Anal. Calcd.
for C22H23NO: C, 83.24; H, 7.30; N, 4.41; Found: C, 83.52; H, 7.19; N,
4.61]; LC/MS (ESI, m/z): [M+], found 318.20; C22H23NO for 317.18.
(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(thiophen-2-yl)prop-2-en-1-one
(3l)
Yield 1.46 g (5.19 mmol, 97.2%); m.p. 119–120 C; 1H-NMR
°
(400 MHz, DMSO-d6) δ: 1.47 (t, 3H, J=7.6 Hz, CH3), 4.14 (q, 2H, J=
7.6 Hz, CH2), 6.98 (t, 1H, J=7.6 Hz, ArÀ H), 7.10 (d, 1H, J=15.6 Hz,
CH=CH), 7.24–7.30 (m, 5H, ArÀ H), 7.81 (s, 1H, ArÀ H), 7.86 (d, 1H, J=
15.6 Hz, CH=CH), 8.45–8.44 (m, 1H, ArÀ H); 13C-NMR (100 MHz,
DMSO-d6) δ: 15.1, 41.8, 109.7, 117.6, 122.6, 122.8, 123.1, 123.5,
126.9, 127.5, 128.1, 130.9, 133.6, 133.7, 136.7, 140.8, 183.6; IR (KBr,
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(E)-1-(1-Ethyl-1H-indol-3-yl)-3-(4-nitrophenyl)prop-2-en-1-one
(3q)
5-(1-(4-Chlorophenyl)-3-(1-ethyl-1H-indol-3-yl)-3-oxopropyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5c)
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1
Yield 0.95 g (2.9 mmol, 55.5%); m.p. 179–180 C; H-NMR (400 MHz,
Yield 280 mg (0.60 mmol, 60.2%); m.p. 166–167 C; 1H-NMR
°
°
DMSO-d6) δ: 1.45 (t, 3H, J=7.2 Hz, CH3), 4.1 (t, 2H, J=7.2 Hz, CH2),
7.24–7.30 (m, 5H, ArÀ H & CH=CH), 7.55 (d, 2H, J=8.8 Hz, ArÀ H),
8.13 (d, 2H, J=8.8 Hz, ArÀ H), 8.17 (d, 1H, J=15.2 Hz, CH=CH), 8.25 -
8.27 (m, 1H, ArÀ H); 13C-NMR (100 MHz, DMSO-d6) δ: 15.1, 41.9,
109.9, 116.2, 122.5, 123, 123.6, 126.5, 128.5, 134.3, 136.6, 137.9,
141.7, 147.2, 150.8, 194.1; IR (KBr, cmÀ 1) νmax =3472, 3116, 3069,
3049, 2973, 1744, 1679, 1638, 1529, 1462, 1423, 1378, 1285, 1205,
1129, 1110, 1052; [Anal. Calcd. for C19H16N2O3: C, 71.24; H, 5.03; N,
8.74; Found: C, 71.51; H, 5.19; N, 8.95]; LC/MS (ESI, m/z): [M+], found
321.19, C19H16N2O3 for 320.12.
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=4.2 Hz, NCH2CH3), 3.11 (s, 3H,
NCH3), 3.16 (s, 3H, NCH3), 3.35–3.37(dd, 1H, J=11.2 Hz, 5.0 Hz,
CH2(a)), 3.96 (t, 1H, J=6.4 Hz, CH2(e)), 3.98 (d, 1H, J=2.8 Hz, CH), 4.23
(q, 2H, J=4.8 Hz, NCH2CH3), 4.44–4.49 (m, 1H, CH), 7.12 (d, 2H, J=
5.6 Hz, ArÀ H), 7.24 (d, 2H, J=5.6 Hz, ArÀ H), 7.29–7.31 (m, 2H, ArÀ H),
7.37–7.39 (m, 1H, ArÀ H), 7.95 (s, 1H,ArÀ H), 8.33–8.37 (m, 1H, ArÀ H);
13C-NMR (150 MHz, CDCl3) δ: 15.2, 27.3, 28.4, 41.1, 41.9, 43.6, 53.1,
109.8, 116.5, 121.8, 122.7, 123.4, 126.5, 129.1, 129.2, 134.1, 135.2,
136.7, 137.8, 151.0, 167.3, 168.0, 192.3; IR (KBr, cmÀ 1) νmax =3443,
2983, 1745, 1692, 1685, 1651, 1531, 1466, 1428, 1375, 1289, 1205,
1109, 1057; [Anal. Calcd. for C25H24ClN3O4: C, 64.44; H, 5.19; Cl, 7.61;
N, 9.02; Found: C, 64.53; H, 5.32; N, 9.21]; LC/MS (ESI, m/z): [M+],
found 466.20, C25H24ClN3O4 for 465.15.
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General Procedure for the Preparation of 5a-q
FeCl3 (0.025 mmol), PdCl2 (0.025 mmol), and acetylacetone
(0.075 mmol) were added into a solution of enone (0.5 mmol) and
barbituric acid (0.55 mmol) in freshly distilled CH3OH (2 ml). After
stirring at room temperature for 24 h, the mixture was diluted with
H2O (10 ml) and extracted with EtOAc (3×15 ml). The combined
organic layers were dried (Na2SO4), concentrated in vacuo and
purified by column chromatography on silica gel (200–300 mesh,
gradient eluted with EtOAc–petroleum ether=1 : 10–1: 5) to gain
the pure product.
5-(1-(2,4-Dichlorophenyl)-3-(1-ethyl-1H-indol-3-yl)-3-oxoprop-
yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5d)
Yield 275 mg (0.55 mmol, 55.1%); m.p. 149–150 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.54 (t, 3H, J=4.8 Hz, NCH2CH3), 3.20 (s, 3H,
NCH3), 3.22 (s, 3H, NCH3), 3.37–3.39 (dd, 1H, J=10.8 Hz, 4.0 Hz,
CH2(a)), 3.38–3.71 (dd, 1H, J=10.8 Hz, 6.4 Hz, CH2(a)), 3.86 (d, 1H, J=
2.4 Hz, CH), 4.23 (q, 2H, J=4.8 Hz, NCH2CH3), 4.90–4.93 (m, 1H, CH),
7.20 & 7.23 (dd, 1H, J=5.6 Hz, 1.6 Hz, ArÀ H), 7.28–7.32 (m, 2H,
ArÀ H), 7.35–7.38 (m, 2H, ArÀ H), 7.40 (d, 1H, J=1.6 Hz, ArÀ H), 7.85 (s,
1H,ArÀ H), 7.28 (d, 1H, J=4.8 Hz, ArÀ H); 13C-NMR (150 MHz, CDCl3) δ:
15.2, 28.2, 29.5, 38.9, 41.0, 42.1, 52.9, 109.8, 114.9, 122.6, 122.9,
123.2, 123.5, 127.2, 128.4, 129.8, 130.0, 133.9, 134.9, 135.9, 137.0,
150.1, 167.9, 168.4, 192.1; IR (KBr, cmÀ 1) νmax =3449, 29.80, 17.47,
1694, 1681, 1653, 1530, 1461, 1427, 1379, 1288, 1201, 1104, 1052;
[Anal. Calcd. for C25H23Cl2N3O4: C, 60.01; H, 4.63; N, 8.40; Found: C,
69.89; H, 4.71; N, 8.32]; LC/MS (ESI, m/z): [M+], found 500.21,
C25H23Cl2N3O4 for 499.11.
1,3-Dimethyl-5-(3-(1-methyl-1H-indol-3-yl)-3-oxo-1-phenyl-
propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (5a)
1
°
Yield 230 mg (0.55 mmol, 55%); m.p. 185–186 C; H-NMR (600 MHz,
CDCl3) δ: 3.06 (s, 3H, NCH3), 3.11 (s, 3H, NCH3), 3.34–3.36 (dd, 1H, J=
11.2 Hz, 3.6 Hz, CH2(a)), 3.87 (s, 3H, NCH3), 3.96–4.00 (m, 2H, CH2(e)
&
CH), 4.49–4.46 (m, 1H, CH), 2.48–2.58 (m, 1H, CH2), 3.82–3.92 (m, 1H,
CHN), 7.11–7.13 (m, 2H, ArÀ H), 7.26–7.35 (m, 6H, ArÀ H), 7.93 (s,
1H,ArÀ H), 8.34–8.39 (m, 1H, ArÀ H); 13C-NMR (150 MHz, CDCl3) δ:
28.0, 28.1, 33.6, 41.0, 44.9, 53.2, 109.6, 116.5, 122.6, 122.7, 123.4,
126.2, 127.3, 128.2, 128.6, 135.7, 137.4, 138.4, 151.0, 167.9, 168.3,
192.2; IR (KBr, cmÀ 1) νmax =3439, 3111, 3108, 3056, 2951, 1679, 1637,
1536, 1530, 1442, 1425, 1375, 1335, 1223, 1145, 1081; [Anal. Calcd.
for C24H23N3O4: C, 69.05; H, 5.55; N, 10.07; Found: C, 69.23; H, 5.41; N,
9.95]; LC/MS (ESI, m/z): [M+], found 418.20, C24H23N3O4 for 417.17.
5-(3-(1-Ethyl-1H-indol-3-yl)-1-(4-methoxyphenyl)-3-oxopropyl)-
1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5e)
Yield 245 mg (0.53 mmol, 53.1%); m.p. 128–129 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=5.2 Hz, NCH2CH3), 3.09 (s, 3H,
NCH3), 3.12 (s, 3H, NCH3), 3.31–3.34 (dd, 1H, J=11.2 Hz, 3.6 Hz,
CH2(a)), 3.76 (s, 3H, OCH3), 3.93–3.98 (m, 2H, CH2(e)& CH), 4.23 (q, 2H,
J=4.8 Hz, NCH2CH3), 4.39–4.44 (m, 1H, CH), 6.85 (d, 2H, J=6.0 Hz,
ArÀ H), 7.50 (d, 2H, J=6.0 Hz, ArÀ H), 7.28–7.31 (m, 2H, ArÀ H), 7.36–
7.38 (m, 1H, ArÀ H), 7.97 (s, 1H,ArÀ H), 8.38–8.41 (m, 1H, ArÀ H); 13C-
NMR (150 MHz, CDCl3) δ: 15.2, 28.0, 28.2, 41.4, 41.8, 44.2, 53.4, 55.2,
109.7, 113.9, 116.6, 122.6, 122.7, 123.3, 126.5, 128.5, 130.4, 134.1,
136.5, 151.0, 159.2, 168.0, 168.5, 192.0; IR (KBr, cmÀ 1) νmax =3434,
3103, 2985, 2947, 2835, 1749, 1673, 1647, 1582, 1523, 1516, 1421,
1374, 1331, 1241, 1208, 1126, 1101, 1006; [Anal. Calcd. for
C26H27N3O5: C, C, 67.66; H, 5.90; N, 9.10; Found: C, 66.71; H, 5.97; N,
9.21]; LC/MS (ESI, m/z): [M+], found 462.30, C26H27N3O5 for 461.20.
1,3-Dimethyl-5-(3-(1-methyl-1H-indol-3-yl)-3-oxo-1-(p–tolyl)
propyl)pyrimidine-2,4,6(1H,3H,5H)-trione (5b)
Yield 200 mg (0.45 mmol, 44.9%); m.p. 155–156 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=4.2 Hz, NCH2CH3), 2.29 (s, 3H,
CH3), 3.07 (s, 3H, NCH3), 3.11 (s, 3H, NCH3), 3.32–3.34 (dd, 1H, J=
11.2 Hz, 3.6 Hz, CH2(a)), 3.95–3.99 (m, 2H, CH2(e)& CH), 4.23 (q, 2H, J=
4.8 Hz, NCH2CH3), 4.38–4.44 (m, 1H, CH), 7.01 (d, 2H, J=5.6 Hz,
ArÀ H), 7.06 (d, 2H, J=5.2 Hz, ArÀ H), 7.28–7.31 (m, 2H, ArÀ H), 7.36–
7.38 (m, 1H, ArÀ H), 7.97 (s, 1H,ArÀ H), 8.39–8.40 (m, 1H, ArÀ H); 13C-
NMR (150 MHz, CDCl3) δ: 15.2, 21.1, 28.0, 28.1, 41.2, 41.8, 44.6, 53.3,
109.7, 116.5, 122.6, 122.8, 123.3, 126.5, 127.2, 129.3, 134.1, 135.4,
136.4, 137.9, 151.1, 168.0, 148.4, 192.4; IR (KBr, cmÀ 1) νmax =3437,
3114, 3101, 3059, 2955, 1678, 1636, 1539, 1448, 1426, 1371, 1335,
1227, 1142, 1084; [Anal. Calcd. for C26H27N3O4: C, 70.09; H, 6.11; N,
9.43; Found: C, 69.87; H, 5.95; N, 9.63]; LC/MS (ESI, m/z): [M+], found
446.28, C26H27N3O4 for 445.20.
5-(1-(4-Bromophenyl)-3-(1-ethyl-1H-indol-3-yl)-3-oxopropyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5f)
Yield 200 mg (0.39 mmol, 39.3%); m.p. 159–160 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=5.2 Hz, NCH2CH3), 3.12 (s, 3H,
NCH3), 3.16 (s, 3H, NCH3), 3.34–3.37 (dd, 1H, J=11.2 Hz, 4.0 Hz,
CH2(a)), 3.96 & 3.98 (dd, 1H, J=11.2 Hz, 6.4 Hz, CH2(e)), 3.98 (d, 1H, J=
2.4 Hz, CH), 4.23 (q, 2H, J=4.8 Hz, NCH2CH3), 4.44–4.46 (m, 1H, CH),
7.06 (d, 2H, J=5.6 Hz, ArÀ H), 7.29–7.31 (m, 2H, ArÀ H), 7.37–7.39 (m,
1H, ArÀ H), 7.40 (d, 2H, J=5.6 Hz, ArÀ H), 7.94 (s, 1H,ArÀ H), 8.35–8.36
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Full Papers
(m, 1H, ArÀ H); 13C-NMR (150 MHz, CDCl3) δ: 15.2, 28.2, 28.3, 41.2,
5-(1-(3-Bromophenyl)-3-(1-ethyl-1H-indol-3-yl)-3-oxopropyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5j)
1
2
3
4
5
6
7
8
9
41.8, 43.6, 52.8, 109.8, 116.5, 122.0, 122.6, 122.7, 123.4, 126.4, 129.3,
131.8, 134.0, 134.5, 138.1, 150.9, 167.8, 168.0, 192.1; IR (KBr, cmÀ 1
)
Yield 187 mg (0.37 mmol, 36.7%); m.p. 130–131 C; 1H-NMR
°
ν
max =3452, 3116, 3043, 2974, 1744, 1679, 1638, 1526, 1462, 1423,
(600 MHz, CDCl3) δ: 1.56 (t, 3H, J=5.2 Hz, NCH2CH3), 3.11 (s, 3H,
NCH3), 3.16 (s, 3H, NCH3), 3.34–3.37 (dd, 1H, J=11.2 Hz, 4.0 Hz,
CH2(a)), 3.92–3.97 (m, 2H CH2(e)& CH), 4.24 (q, 2H, J=4.8 Hz,
NCH2CH3), 4.41–4.43 (m, 1H, CH), 7.10 (d, 1H, J=5.2 Hz, ArÀ H), 7.15
(t, 1H, J=5.2 Hz, ArÀ H), 7.29–7.32 (m, 2H, ArÀ H), 7.33 (d, 1H, J=
1.2 Hz, ArÀ H), 7.37–7.39 (m, 2H, ArÀ H), 7.97 (s, 1H,ArÀ H), 8.37–8.38
(m, 1H, ArÀ H); 13C-NMR (150 MHz, CDCl3) δ: 15.2, 28.1, 28.2, 40.9,
41.9, 44.2, 53.1, 109.8, 116.4, 122.7, 122.8, 123.4, 126.4, 130.2, 130.4,
131.2, 131.7, 134.1, 136.5, 138.2, 141.2, 150.9, 167.7, 168.0, 191.9; IR
(KBr, cmÀ 1) νmax =3453, 3119, 3047, 2975, 1748, 1674, 1633, 1528,
1464, 1426, 1371, 1282, 1204, 1118, 1059, 1001;[Anal. Calcd. for
C25H24BrN3O4: C, 58.83; H, 4.74; N, 8.23; Found: C, 58.69; H, 4.47; N,
8.45]; LC/MS (ESI, m/z): [M+], found 510.18, C25H24BrN3O4 for 509.10.
1378, 1285, 1205, 1110, 1052, 1009; [Anal. Calcd. for C25H24BrN3O4: C,
58.83; H, 4.74; N, 8.23; Found: C, 59.11; H, 4.59; N, 8.33]; LC/MS (ESI,
m/z): [M+], found 510.17, C25H24BrN3O4 for 509.10.
5-(3-(1-Ethyl-1H-indol-3-yl)-1-(4-fluorophenyl)-3-oxopropyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5g)
10
11
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13
14
15
16
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18
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22
23
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26
27
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41
42
43
44
45
46
47
48
49
50
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53
54
55
56
57
Yield 214 mg (0.48 mmol, 47.6%); m.p. 185–186 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=5.2 Hz, NCH2CH3), 3.10 (s, 3H,
NCH3), 3.14 (s, 3H, NCH3), 3.35–3.38 (dd, 1H, J=11.2 Hz, 3.6 Hz,
CH2(a)), 3.94–3.99 (m, 2H,CH2(e)& CH), 4.23 (q, 2H, J=4.8 Hz,
NCH2CH3), 4.45–4.59 (m, 1H, CH), 6.96 (t, 2H, J=4.0 Hz, ArÀ H), 7.15
(t, 2H, J=4.0 Hz, ArÀ H), 7.27–7.31 (m, 2H, ArÀ H), 7.37–7.39 (m, 1H,
ArÀ H), 7.96 (s, 1H,ArÀ H), 8.37–8.38 (m, 1H, ArÀ H); 13C-NMR
(150 MHz, CDCl3) δ: 15.2, 28.11, 28.3, 41.4, 41.7, 43.7, 53.2, 109.8,
115.5, 115.7, 121.9, 122.7, 123.4, 127.3, 129.1, 129.2, 134.1, 136.5,
139.1, 149.0, 167.0, 168.2, 191.2; IR (KBr, cmÀ 1) νmax =3471, 3118,
2951, 1745, 1682, 1639, 1614, 1588, 1528, 1463, 1445, 1420, 1375,
1273, 1206, 1114, 1053; [Anal. Calcd. for C25H24FN3O4: C, 66.80; H,
5.38; N, 9.35; Found: C, 67.02; H, 5.54; N, 9.47]; LC/MS (ESI, m/z): [M+
], found 450.20, C25H24FN3O4 for 449.18.
5-(3-(1-Ethyl-1H-indol-3-yl)-3-oxo-1-(4-(trifluoromethyl)phenyl)
propyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5k)
Yield 198 mg (0.40 mmol, 39.7%); m.p. 168–169 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=5.2 Hz, NCH2CH3), 3.11 (s, 3H,
NCH3), 3.17 (s, 3H, NCH3), 3.40 & 3.43 (dd, 1H, J=11.2 Hz, 4.0 Hz,
CH2(a)), 3.98 & 4.01 (dd, 1H, J=11.2 Hz, 4.0 Hz, CH2(e)), 4.03 (d, 1H, J=
0.8 Hz, CH), 4.24 (q, 2H, J=4.8 Hz, NCH2CH3), 4.55–4.57 (m, 1H, CH),
7.26–7.33 (m, 2H, ArÀ H), 7.35–7.38 (m, 3H, ArÀ H), 7.54 (d, 2H, J=
5.6 Hz, ArÀ H), 7.97 (s, 1H,ArÀ H), 8.33–8.35 (m, 1H, ArÀ H); 13C-NMR
(150 MHz, CDCl3) δ: 15.2, 28.6, 28.3, 41.1, 41.8, 43.4, 52.8, 109.8,
116.3, 122.6, 122.8, 123.4, 125.6, 1257, 126.7, 128.2, 134.0, 136.5,
143.7, 150.9, 167.7, 167.8, 192.0; IR (KBr, cmÀ 1) νmax =3423, 3119,
2982, 1749, 1688, 1636, 1525, 1461, 1421, 1380, 1326, 1207, 1159,
1116, 1070; [Anal. Calcd. for C26H24F3N3O4: C, 62.52; H, 4.84; N, 8.41;
Found: C, 62.33; H, 5.11; N, 8.63]; LC/MS (ESI, m/z): [M+], found
500.20, C26H24F3N3O4 for 499.17.
5-(3-(1-Ethyl-1H-indol-3-yl)-1-(3-fluorophenyl)-3-oxopropyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5h)
Yield 210 mg (0.47 mmol, 46.8%); m.p. 188–189 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=5.2 Hz, NCH2CH3), 3.11 (s, 3H,
NCH3), 3.15 (s, 3H, NCH3), 3.37–3.40 (dd, 1H, J=11.2 Hz, 3.6 Hz,
CH2(a)), 3.95–3.98 (m, 2H,CH2(e)& CH), 4.22–4.26 (m, 2H CH), 4.24 (q,
2H, J=4.8 Hz, NCH2CH3), 4.45–4.59 (m, 1H, CH), 6.89–6.92 (m,
1H,ArÀ H), 6.94–6.98 (m, 2H, ArÀ H), 7.23–7.25 (m, 1H, ArÀ H), 7.29–
7.31 (m, 2H, ArÀ H), 7.37–7.39 (m, 1H, ArÀ H), 7.96 (s, 1H,ArÀ H), 8.36–
8.38 (m, 1H, ArÀ H); 13C-NMR (150 MHz, CDCl3) δ: 15.3, 28.2, 28.4,
41.1, 41.9, 44.1, 35.1, 109.8, 115.1, 115.2, 121.0, 122.7, 122.9, 123.5,
127.0, 129.5, 130.3, 134.2, 136.6, 137.9, 138.7, 150.2, 167.9, 168.3,
191.1; IR (KBr, cmÀ 1) νmax =3471, 3118, 2951, 1745, 1682, 1639, 1614,
1588, 1528, 1463, 1445, 1420, 1375, 1273, 1206, 1114, 1053; [Anal.
Calcd. for C25H24FN3O4: C, 66.80; H, 5.38; N, 9.35; Found: C, 67.13; H,
5.61; N, 9.41]; LC/MS (ESI, m/z): [M+], found 450.24, C25H24FN3O4 for
449.18.
5-(3-(1-Ethyl-1H-indol-3-yl)-3-oxo-1-(thiophen-2-yl)
propyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5l)
Yield 224 mg (0.54 mmol, 53.7%); m.p. 154–155 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.56 (t, 3H, J=4.8 Hz, NCH2CH3), 3.15 (s, 3H,
NCH3), 3.17 (s, 3H, NCH3), 3.39–3.43 (m, 2H, CH2(a)), 3.98–4.01 (dd,
1H, J=11.2 Hz, 6.4 Hz, CH2(e)), 4.05 (d, 1H, J=2.4 Hz, CH), 4.24 (q,
2H, J=4.8 Hz, NCH2CH3), 4.82–4.83 (m, 1H, CH), 6.86 (d, 1H, J=
2.0 Hz, ArÀ H), 6.90 (t, 1H, J=2.8 Hz, ArÀ H), 7.16 (d, 1H, J=3.6 Hz,
ArÀ H), 7.29–7.37 (m, 2H, ArÀ H), 7.37–7.38 (m, 1H, ArÀ H), 7.96 (s,
1H,ArÀ H), 8.38–8.40 (m, 1H, ArÀ H);13C-NMR (150 MHz, CDCl3) δ: 15.2,
28.2, 28.4, 39.6, 41.8, 42.7, 53.0, 109.7, 116.4, 122.7, 123.3, 124.9,
125.7, 126.4, 126.9, 128.3, 134.2, 136.5, 141.5, 151.2, 167.6, 167.9,
191.9; IR (KBr, cmÀ 1) νmax =3458, 3104, 3051, 2974, 2928, 1748, 1662,
1563, 1530, 1460, 1425, 1381, 1317, 1273, 1200, 1148, 1128, 1051;
[Anal. Calcd. for C23H23N3O4S: C, 63.14; H, 5.30; N, 9.60; Found: C,
63.35; H, 5.41; N, 9.48]; LC/MS (ESI, m/z): [M+], found 438.10,
C23H23N3O4S for 437.14.
5-(3-(1-Ethyl-1H-indol-3-yl)-3-oxo-1-(m–tolyl)propyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5i)
Yield 194 mg (0.44 mmol, 46.6%); m.p. 125–126 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.56 (t, 3H, J=5.2 Hz, NCH2CH3), 2.29 (s, 3H,
CH3), 3.06 (s, 3H, NCH3), 3.10 (s, 3H, NCH3), 3.34–3.37 (dd, 1H, J=
11.2 Hz, 3.6 Hz, CH2(a)), 3.94–3.99 (m, 2H, CH2(e)& CH), 4.24 (q, 2H, J=
4.8 Hz, NCH2CH3), 4.37–4.49 (m, 1H, CH), 6.90 (d, 1H, J=5.2 Hz,
ArÀ H), 6.93 (s, 1H, ArÀ H), 7.06 (d, 1H, J=5.2 Hz, ArÀ H), 7.15 (t, 1H,
J=5.2 Hz, ArÀ H), 7.29–7.31 (m, 2H, ArÀ H), 7.36–7.38 (m, 1H, ArÀ H),
7.98 (s, 1H,ArÀ H), 8.39–8.41 (m, 1H, ArÀ H); 13C-NMR (150 MHz,
CDCl3) δ: 15.2, 21.3, 27.9, 28.1, 41.0, 41.8, 45.0, 53.4, 109.7, 116.6,
122.6, 122.7, 123.3, 124.3, 126.5, 128.1, 128.4, 128.9, 134.1, 136.5,
138.4, 151.0, 168.0, 168.5, 192.3; IR (KBr, cmÀ 1) νmax =3438, 3113,
3104, 3058, 2954, 1677, 1632, 1534, 1447, 1427, 1372, 1336, 1225,
1143, 1081; [Anal. Calcd. for C26H27N3O4: C, 70.09; H, 6.11; N, 9.43;
Found: C, 70.29; H, 6.33; N, 9.57]; LC/MS (ESI, m/z): [M+], found
446.31, C26H27N3O4 for 445.20.
5-(3-(1-Ethyl-1H-indol-3-yl)-1-(furan-2-yl)-3-oxopropyl)-1,3-dim-
ethylpyrimidine-2,4,6(1H,3H,5H)-trione (5m)
Yield 230 mg (0.55 mmol, 54.6%); m.p. 188–189 C; 1H-NMR
°
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=4.8 Hz, NCH2CH3), 3.18 (s, 3H,
NCH3), 3.21 (s, 3H, NCH3), 3.39–3.41 (dd, 1H, J=11.2 Hz, 6.4 Hz,
CH2(a)), 3.81 & 3.84 (dd, 1H, J=11.2 Hz, 6.0 Hz, CH2(e)), 3.96 (d, 1H, J=
2.4 Hz, CH), 4.24 (q, 2H, J=4.8 Hz, NCH2CH3), 4.57–4.59 (m, 1H, CH),
6.11 (d, 1H, J=2.4 Hz, ArÀ H), 6.26 (q, 1H, J=1.6 Hz, ArÀ H), 7.26–7.37
(m, 1H, ArÀ H), 7.29–7.32 (m, 2H, Arq-H), 7.37–7.38 (m, 1H, ArÀ H),
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Full Papers
7.95 (s, 1H,ArÀ H), 8.38–8.40 (m, 1H, ArÀ H); 13C-NMR (150 MHz,
CDCl3) δ: 15.2, 28.3, 28.4, 38.1, 39.7, 41.8, 51.5, 107.0, 109.7, 110.5,
116.4, 122.7, 123.4, 126.5, 129.9, 134.2, 136.5, 142.2, 151.4, 152.8,
167.6, 167.9, 191.8; IR (KBr, cmÀ 1) νmax =3427, 3116, 2978, 2932,
1744, 1642, 1655, 1530, 1460, 1422, 1394, 1272, 1202, 1145, 1114;
[Anal. Calcd. for C23H23N3O5: C, 65.55; H, 5.50; N, 9.97; Found: C,
65.73; H, 5.63; N, 10.09]; LC/MS (ESI, m/z): [M+], found 422.20,
C23H23N3O5 for 421.16.
Single Crystal X-ray Crystallography
1
2
3
4
5
6
7
8
9
The compound of 5g was obtained as single crystals by slow
evaporation from ethanol solution of the pure compound at room
temperature. Data were collected on a Bruker APEX-II D8 Venture
area diffractometer, equipped with graphite monochromatic Mo Kα
radiation, λ=0.71073 Å at 293 (2) K. Cell refinement and data
reduction were carried out by Bruker SAINT. SHELXT[15] was used to
solve structure. The final refinement was carried out by full-matrix
least-squares techniques with anisotropic thermal data for non-
hydrogen atoms on. CCDC 1877313 contains the supplementary
crystallographic data for this compound can be obtained free of
charge from the Cambridge Crystallographic Data Centre vi-
awww.ccdc.cam.ac.uk/data_request/cif.
5-(3-(1-Ethyl-1H-indol-3-yl)-3-oxo-1-(3,4,5-trimethoxyphenyl)
propyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5n)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
Yield 185 mg (0.35 mmol, 35.5%); m.p. 170–171 C; 1H-NMR
°
(600 MHz, CDl3) δ: 1.56 (t, 3H, J=4.8 Hz, NCH2CH3), 3.12 (s, 3H,
NCH3), 3.17 (s, 3H, NCH3), 3.34–3.36 (dd, 1H, J=10.8 Hz, 4.0 Hz,
CH2(a)), 3.80 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.95–
3.99 (m, 2H, CH2(e) & CH), 4.24 (q, 2H, J=4.8 Hz, NCH2CH3), 4.39–4.41
(m, 1H, CH), 6.39 (s, 2H,ArÀ H), 7.30–7.33 (m, 2H, ArÀ H), 7.37–7.39
(m, 1H, ArÀ H), 7.97 (s, 1H,ArÀ H), 8.38–8.40 (m, 1H, ArÀ H); 13C-NMR
(150 MHz, CDCl3) δ: 15.2, 28.2, 28.3, 41.4, 41.9, 44.7, 51.1, 53.0, 60.8,
60.9, 109.7, 115.1, 116.5, 122.7, 122.8, 123.3, 126.5, 132.6, 134.0,
Biological Activitiy Assays
Reagents
α-glucosidase type 1 from baker‘s yeast (G5003; Sigma-Aldrich, St.
Louis, MO, USA), p-nitrophenyl α-D-glucopyranoside (N1377, Sigma-
Aldrich), sodiumphosphatemonobasic (S3139, Sigma-Aldrich), so-
diumphosphatedibasic (S5136, Sigma-Aldrich), andacarbose (A8980,
Sigma-Aldrich), DMSO (Dimethylsulfoxide), α-amylase from Aspergil-
lus oryzae (Sigma Aldrich), starch, DNS (3, 5-dinitrosalicylic acid),
sodiumpotassiumtartratetetrahydrate.
134.7, 136.5, 151.0, 153.2, 168.1, 168.3, 192.4; IR (KBr, cmÀ 1) νmax
=
3435, 3105, 2983, 2946, 2839, 1748, 1677, 1646, 1589, 1526, 1512,
1423, 1376, 1331, 1243, 1209, 1127, 1104, 1003; [Anal. Calcd. for
C28H31N3O7: C, 64.48; H, 5.99; N, 8.06; Found: C, 64.31; H, 6.09; N,
8.24]; LC/MS (ESI, m/z): [M+], found 522.20, C28H31N3O7 for 521.22.
5-(3-(1-Ethyl-1H-indol-3-yl)-1-(naphthalen-2-yl)-3-oxopropyl)-1,
3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5o)
α-Glucosidase Inhibition Assay
Concentration of α-glucosidase and substrate. Sodium phosphate
buffer (0.1 M) was adjusted by 0.1 N HCl to pH 7.0 with a pH meter
(Thermo Fisher Scientific Inc., Waltham, MA, USA). p-Nitrophenyl α-
D-glucopyranoside (10 mM) and α-glucosidase solutions (1 U/ml)
were solubilized in 0.1 M sodium phosphate buffer (pH 7.0). All the
reagents were manufactured shortly before use and warmed to
1
°
Yield 178 mg (0.37 mmol, 37.0%); m.p. 85–86 C; H-NMR (600 MHz,
CDCl3) δ: 1.56 (t, 3H, J=4.8 Hz, NCH2CH3), 3.02 (s, 3H, NCH3), 3.09 (s,
3H, NCH3), 3.45–3.47 (dd, 1H, J=10.8 Hz, 3.6 Hz, CH2(a)), 4.08–4.15
(m, 2H, CH2(e) & CH), 4.24 (q, 2H, J=4.8 Hz, NCH2CH3), 4.60–4.64 (m,
1H, CH), 7.29–7.32 (m, 3H, ArÀ H), 7.36–7.39 (m, 1H, ArÀ H), 7.45–7.47
(m, 2H, ArÀ H), 7.63 (s, 1H,ArÀ H), 7.75–7.79 (m, 3H, ArÀ H), 8.00 (s,
1H,ArÀ H), 8.39–8.40 (m, 1H, ArÀ H); 13C-NMR (150 MHz, CDCl3) δ:
15.4, 28.4, 28.8, 41.2, 41.8, 44.2, 52.4, 108.9, 113.5, 116.5, 121.5,
121.9, 123.5, 125.3, 126.0, 126.2, 126.5, 127.1, 127.6, 128.2, 128.9,
°
37 C in a water bath. Sodium phosphate buffer (0.1 M, 158 μl per
well) was added to a 96-well plate. α-Glucosidase (20 μl) and 2 μl of
sample were added to 20 μl of p-nitrophenyl α-D-glucopyranoside.
In the 200-μl final reaction volume (0.02 U/well, 0.1 U/ml) the
substrate concentration was adjusted to 10 mM. The background
signal due to the sample color was measured at 405 nm with the
PerkinElmer Wallac Victor3 spectrophotometer (PerkinElmer, Wal-
tham, MA, USA) prior to adding the enzyme. Immediately following
α-glucosidase addition, absorbance was measured at 405 nm 8
times at 1-min intervals.[16]
130.7, 134.3, 137.2, 140.6, 158.2, 168.6, 169.4, 192.4; IR (KBr, cmÀ 1
max =3438, 3106, 2983, 2944, 2832, 1745, 1678, 1643, 1585, 1528,
)
ν
1516, 1424, 1370, 1332, 1243, 1205, 1128, 1103, 1005; [Anal. Calcd.
for C29H27N3O4: C, 72.33; H, 5.65; N, 8.73; Found: C, 72.49; H, 5.41; N,
8.85]; LC/MS (ESI, m/z): [M+], found 482.30, C29H27N3O4 for 481.20.
5-(3-(1-Ethyl-1H-indol-3-yl)-1-(4-nitrophenyl)-3-oxopropyl)-1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5q)
α Amylase Assay
Yield 165 mg (0.35 mmol, 34.6%); m.p. 198–199 C; 1H-NMR
°
Briefly, 250 μL (0.4 mg/mL) was preincubated with 250 μL of α-
°
amylase solution for 10 min at 25 C in one set of tubes. In another
(600 MHz, CDCl3) δ: 1.55 (t, 3H, J=4.8 Hz, NCH2CH3), 2.21 (s, 3H,
CH3), 3.23 (s, 3H, NCH3), 3.34–3.37 (dd, 1H, J=12.0 Hz, 4.4 Hz, CH2(a)),
3.93 & 3.96 (dd, 1H, J=12.0 Hz, 4.4 Hz, CH2(e)), 4.21–4.26 (m, 4H, CH
& NCH2CH3), 7.28–7.31 (m, 2H, ArÀ H), 7.38 (t, 3H, J=6.0 Hz, ArÀ H),
7.88 (s, 1H,ArÀ H), 8.17 (d, 2H, J=6.0 Hz, ArÀ H), 8.25–8.27 (m, 1H,
ArÀ H); 13C-NMR (150 MHz, CDCl3) δ: 15.2, 29.0, 29.3, 38.7, 41.9, 42.5,
50.2, 109.9, 116.2, 122.4, 122.9, 123.8, 125.9, 126.5, 127.1, 129.3,
set of tubes α-amylase was preincubated with 250 μL of phosphate
buffer (pH 6.9). 250 μL of starch solution at increasing concen-
trations (0.2–1% (w/v)) was added to both sets of reaction mixtures
to start the reaction. The mixture was then incubated for 10 min at
°
25 C and then boiled for 15 min after the addition of 250 μL of
DNS to stop the reaction. The amount of reducing sugars released
was determined spectrophotometrically using a maltose standard
curve and converted to reaction velocities.
133.6, 142.7, 144.8, 151.5, 167.8, 168.6, 192.1; IR (KBr, cmÀ 1) νmax
=
3379, 3125, 2980, 1761, 1690, 1634, 1532, 1517, 1460, 1381, 1215,
1078; [Anal. Calcd. for C25H24N4O6: C, 63.02; H, 5.08; N, 11.76; Found:
C, 62.84; H, 5.25; N, 12.01]; LC/MS (ESI, m/z): [M+], found 477.20,
C25H24N4O6 for 476.17
Calculation of Inhibition Efficiency
The inhibitory concentration 50% (IC50) values were determined
from the plots of percent inhibition versus log inhibitor concen-
ChemistryOpen 2019, 8, 1288–1297
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Full Papers
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Docking Studies
A virtual library of designed compounds was energy minimized
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in OpenEye software[13b] to generate a physical property (ΔG)
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3. Conclusion
The present study mainly focuses on the synthesis of novel
indole-pyrimidine based chemical entities for the improved
anti-diabetic activity. The new series of indole- pyrimidine
based compounds obtained via bimetallic catalytic system
which has a dramatic effect in promoting the Michael addition
reaction. The synthesized compounds screened against wide
range of α-glucosidase inhibition and
α -amylase assay
inhibitory activity. Docking study describes that both barbitu-
rate and acyl indole parts participate in HB while the aryl linker
occupy the receptor through lipophilic-lipophilic interactions.
Acknowledgments
The authors would like to extend their sincere appreciation to
Researchers Supporting Project Number (RSP-2019/64), King Saud
University, Riyadh, Saudi Arabia.
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Conflict of Interest
The authors report no declarations of interest.
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Keywords: bimetallic catalysis · Lewis acid · Michael addition ·
indoles · barbituric acid · α-amylase · α-glucosidase · docking
studies
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Springer, 2007, pp. 135–152.
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10274.
Manuscript received: July 18, 2019
Revised manuscript received: August 18, 2019
ChemistryOpen 2019, 8, 1288–1297
www.chemistryopen.org
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© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA