Novel indole-2-carboxylic acid linked 3-phenyl-2-alkoxy propanoic acids: Synthesis, molecular docking and in vivo antidiabetic studies

Article abstract of DOI:10.1007/s00044-017-1791-3

A series of indole-2-carboxylic acid linked 3-phenyl-2-alkoxy propanoic acids has been designed and synthesized employing Suzuki coupling reaction. All the six targeted compounds (7a–f) were evaluated for their in vivo antidiabetic activities using rat mo

Full text of DOI:10.1007/s00044-017-1791-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1791-3
ORIGINAL RESEARCH
Novel indole-2-carboxylic acid linked 3-phenyl-2-alkoxy propanoic
acids: Synthesis, molecular docking and in vivo antidiabetic studies
1 ●
1 ●
2 ●
3
Amanjot Singh Raman K. Verma Anurag Kuhad Rajiv Mall
Received: 19 September 2016 / Accepted: 13 January 2017
©
Springer Science+Business Media New York 2017
Abstract A series of indole-2-carboxylic acid linked 3-
phenyl-2-alkoxy propanoic acids has been designed and
synthesized employing Suzuki coupling reaction. All the six
targeted compounds (7a–f) were evaluated for their in vivo
antidiabetic activities using rat model while using rosigli-
tazone as standard drug and streptozotocin was used to
induce diabetes. After 4 weeks duration of the experiment,
it was shown that all the compounds exhibited significant
lowering of blood glucose level (mg/dl) and decrease in
body weight gain (g) as compared to the standard drug.
Furthermore, molecular docking study was carried out with
peroxisome proliferator-activated receptor γ (PPARγ) pro-
tein, which showed good affinity of the compounds at the
active site. Compound 7b was considered as promising
candidate of this series.
Introduction
Peroxisome proliferator-activated receptors (PPARs) are
transcription factors that belong to the nuclear receptor
family. The three PPAR subtypes PPARα, PPARδ, and
PPARγ play an important role in glucose and lipid home-
ostasis (Berger and Moller 2002; Epple et al. 2010; Matin
et al. 2009; Pirat et al. 2012). Agonists of the γ-subtype have
been studied extensively for their role in regulating glucose
metabolism and insulin sensitivity. PPARγ full agonists,
such as thiazolidinediones (TZDs) have been developed and
marketed for the treatment of non-insulin-dependent type 2
diabetes mellitus (Liu et al. 2011). However clinical use of
these TZDs, rosiglitazone and pioglitazone (Fig.1), as well
as several others have been associated with adverse effects
including weight gain, increased adipogenesis, renal fluid
retention, and plasma volume expansion and, more recently,
possible increased incidence of cardiovascular events (Seto
et al. 2010). Therefore, several PPARγ partial agonists or
selective modulators of PPARγ have been developed. The
concept of selective modulation involves targeting and
activating specific gene to minimize side effects while
maintaining therapeutic benefits (Bajare et al. 2012).
Recently, several reports in literature show that indoles were
among some of first partial agonist to be developed. Some
important indole-based partial agonists include nTZDpa,
MRL-24, SR145, and SR147 (Fig. 1) (Bruning et al. 2007;
Kroker and Bruning 2015). The present study include the
design of novel PPARγ selective modulators/partial ago-
nists by incorporating indole as core structure, directly
linked to central flat aromatic ring containing α-alkoxy
propanoic acid as hydrogen bonding part, while introducing
conformational constrains through meta-substitution for U-
shaped conformation required to fit into the active site of
PPARγ protein. The docking studies at the crystal structure
●
●
Keywords Indole derivatives Type II diabetes PPARγ
●
●
partial agonists Antidiabetics Molecular docking
Electronic supplementary material The online version of this article
(
doi:10.1007/s00044-017-1791-3) contains supplementary material,
which is available to authorized users.
*
Rajiv Mall
rajivmall@pbi.ac.in
1
Synthetic Organic and Medicinal Chemistry Laboratory,
Department of Chemistry, Punjabi University, Patiala, Punjab
1
47002, India
2
3
Pharmacology Research Laboratory, University Institute of
Pharmaceutical Sciences, UGC Centre for Advanced Studies
(
CAS), Panjab University, Chandigarh 160014, India
Department of Basic and Applied Sciences, Punjabi University,
Patiala 147002, India

Med Chem Res
Fig. 1 Representative examples
of full and partial PPARγ
agonists
S
CH3
N
O
S
H C
3
O
N
N
H
O
O
N
H
N
O
O
Rosiglitazone
Pioglitazone
S
S
S
N
Cl
Cl
Cl
COOH
COOH
COOH
N
N
Cl
nTZDpa
SR145
SR147
F3CO
O
COOH
CH3
H
N
H CO
3
O
MRL-24
of PPARγ using SYBYL 7.3 (SYBYL 2006, available in
our in silico Drug Design Laboratory) were carried out for
prediction of binding affinities and interactions of the pro-
posed new chemical entities (NCEs) as compared to the
standard rosiglitazone. Results of the in vivo studies carried
out indicated significant reduction in plasma glucose levels
which leads to antidiabetic effect of these novel agonists.
singlet; d, doublet; t, triplet; m, multiplet. Molecular
weights of the synthesized compounds were checked by
(liquid chromatography–mass spectrometry) Waters, Q-
TOF Micromass, UK in electrospray ionization mode. The
Infrared spectra of the reported compounds were recorded
on Perkin Elmer Spectrum RX FT-IR Spectrophotometer,
USA. Elemental analyses of these compounds were carried
out on Vario Micro V1 Elemental Analyzer. Compounds 1
and 2a were prepared following reported procedures
(Hopkins et al. 2006; Verma et al. 2015).
Materials and methods
Chemistry
Synthesis of ethyl 3-bromo-1H-indole-2-carboxylate (1)
All the chemicals used in the reported work were purchased
from Aldrich and SD Fine chemicals. The melting/boiling
points reported here were recorded using an open con-
centrated sulphuric acid bath and are uncorrected. Thin-
layer chromatography analysis was carried out on glass
plates coated with silica gel-GF254 (Loba Chemie), and
spots were visualized using a UV cabinet (Perfit India).
Column chromatography was performed using silica gel
To a solution of ethyl 1H-indole-2-carboxylate (2 mmol) in
dry DMF (10 mL) was added NBS (2 mmol). The resulting
mixture was stirred at room temperature under nitrogen gas
for 12 h. Crushed ice was added into the reaction mixture.
White precipitate appeared was collected under vacuum
suction, washed with cold water, dried, and re-crystallized
from ethanol to get pure product (1) (0.49 g, 90%); mp
−
1
146–148 °C; FTIR (KBr, cm ) νmax: 3377, 3297, 1686,
1
6
0–120 mesh (Loba Chemie), and taking ethyl acetate/
1573, 1515, 740, 642; H NMR (400 MHz, CDCl ): δ =
3
1
13
hexane in 1:2 ratio as solvent system. H, C, DEPT135,
HSQC, and COSY NMR spectra were recorded on a Bruker
AVANCE II 400 (400.13 MHz, 100.62 MHz) NMR spec-
trometer, BrukerBioSpin, Switzerland. Chemical shifts were
reported in ppm (δ) with reference to the internal standard
TMS. The signals were designated as follows: br, broad; s,
9.28 (s, 1H, NH), 7.67 (m, 1H, Ar–H), 7.40 (m, 2H, Ar–H),
7.25 (m, 1H, Ar–H), 4.49 (q, J = 7.12 Hz, 2H,
COOCH CH ), 1.47 (t, J = 7.08 Hz, 3H, COOCH CH );
2
3
2
3
1
3
C
NMR (100 MHz, CDCl3): δ = 161.16 (C,
COOCH CH ), 135.41 (C, C-2), 128.01 (C, C-7a), 126.57
2
3
(CH, C-4), 121.47 (CH, C-5), 121.33 (CH, C-6), 112.06

Med Chem Res
(
1
CH, C-7), 98.31 (C-Br, C-3), 61.54 (CH , COOCH CH ),
Synthesis of different derivatives of ethyl N-substituted-1H-
indole-2-carboxylate aldehyde
2
2
3
+
4.36 (CH , COOCH CH ); ESI–MS (m/z): [M+Na]
3
2
3
Calcd for C H BrNO : 266.98; Found: 289.98.
1
1
10
2
To
a
solution of (2a/2b) (1 mmol) and 3-
formylphenylboronic acid (1 mmol) in a mixture of diox-
ane and water (4:1) was added K CO (3 mmol). The
resulting mixture was degassed, stirred at ambient tem-
perature for 20 min and catalytic amount (0.005mmol) of Pd
Synthesis of different derivatives of N-substituted ethyl 3-
bromo-1H-indole-2-carboxylate
2
3
To a solution of (1) (1 mmol) and K CO (3 mmol) in dry
2
3
(
PPh ) was added. The mixture was degassed again and
3 4
dimethylformamide (DMF) (10 mL) was added benzyl
bromide or 4-chlorobenzyl bromide (1 mmol). The resulting
mixture was stirred at room temperature under nitrogen gas
for 24 h. Crushed ice was added and the white precipitate
was collected under vacuum suction, washed with cold
water, dried, and re-crystallized from ethanol to get pure
product.
then refluxed under nitrogen gas for 8 h. It was allowed to
cool, filtered through celite, and extracted using ethyl
acetate (3 × 20 mL). The organic layer was dried (Na SO ),
2
4
filtered, and concentrated under reduced pressure to give an
oil, which was subjected to column chromatography using a
mixture of ethyl acetate/hexane (2:8) to afford the desired
targeted compound.
Ethyl 1-benzyl-3-bromo-1H-indole-2-carboxylate (2a)
Ethyl 1-benzyl-3-(3-formylphenyl)-1H-indole-2-carboxylate
(
3a)
Product was obtained as white solid (0.17 g, 63%); mp
−
1
7
1
1
3–75 °C; FTIR (KBr, cm ) νmax: 3025, 2975, 2936, 1704,
Product was obtained as oil (0.32 g, 89%); FTIR (KBr,
cm ) νmax: 3060, 2982, 2936, 2826, 2727, 1701, 1702,
1
δ = 10.06 (s, 1H, CHO), 8.01 (t, 1H, Ar–H), 7.90 (m, 1H,
Ar–H), 7.75 (m, 1H, Ar–H), 7.61 (t, 1H, Ar–H), 7.54 (d,
1
(
7
1
497, 1450, 740; H NMR (400 MHz, CDCl ): δ = 7.71 (d,
−1
3
H, Ar–H), 7.35 (m, 2H, Ar–H), 7.25 (m, 4H, Ar–H), 7.02
1
582, 1535, 1474, 741, 699; H NMR (400 MHz, CDCl ):
3
(
m, 2H, Ar–H), 5.77 (s, 2H, N–CH –C H ), 4.39 (q, J =
2 6 5
7
.08 Hz, 2H, COOCH CH ), 1.38 (t, J = 7.12 Hz, 3H,
2 3
1
3
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 161.21
2
3
3
H, Ar–H), 7.41 (d, 1H, Ar–H), 7.35 (m, 1H, Ar–H), 7.28
m, 2H, Ar–H) 7.22 (m, 1H, Ar–H), 7.18 (m, 1H, Ar–H),
.11 (d, 2H, Ar–H), 5.83 (s, 2H, N–CH –C H ), 4.11 (q, J
7.08 Hz, 2H, COOCH CH ), 0.93 (t, J = 7.20 Hz, 3H,
2 3
(
C, COOCH CH ), 138.07 (C, C-2), 137.83 (C, C-1′),
2 3
1
7
28.67 (CH, C-3′, C-5′), 127.33 (CH, C-4′), 126.96 (C, C-
a), 126.45 (CH, C-4), 126.20 (CH, C-2′, C-6′), 125.34 (C,
2 6 5
=
C-3a), 121.62 (CH, C-5), 121.61 (CH, C-6), 110.88 (CH, C-
), 99.72 (C–Br, C-3), 61.28 (CH , COOCH CH ), 48.77
13
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 192.46
(
1
1
C-5′), 128.56 (CH, C-5″), 128.25 (CH, C-4″), 127.32 (CH,
C-4′), 126.66 (C, C-7a), 126.36 (CH, C-2′, C-6′), 125.90
(CH, C-6), 124.75 (C, C-3a), 123.61 (C, C-3″), 121.43 (CH,
C-5), 121.25 (CH, C-4), 110.92 (CH, C-7), 60.79 (CH2,
COOCH CH ), 48.32 (CH , N–CH –C H ), 13.64 (CH ,
2
3
3
7
2
2
3
CH, CHO), 162.09 (C, COOCH CH ), 138.41 (C, C-2),
38.12 (C, C-1′), 136.72 (CH, C-6″), 136.21 (C, C-1″),
35.96 (C,C-3), 132.15 (CH, C-2″), 128.70 (CH, C-3′,
2 3
(
CH2, N–CH –C H ), 14.20 (CH3, COOCH CH );
2 6 5 2 3
+
ESI–MS (m/z): [M+Na] Calcd for C H BrNO : 357.03;
1
8
16
2
Found: 380.01.
Ethyl 3-bromo-1-(4-chlorobenzyl)-1H-indole-2-carboxylate
2b)
(
2
3
2
2
6
5
3
+
Product was obtained as white solid (0.24 g, 89%); mp
COOCH CH ); ESI–MS (m/z): [M+Na] Calcd for
C H NO : 383.15; Found: 405.80.
25 21 3
2 3
7
1
9–81 °C; FTIR (KBr, cm− ) νmax: 3032, 2926, 2851, 1705,
1
1
613, 1454, 802, 742, 612; H NMR (400 MHz, CDCl ): δ
3
=
7.70 (d, 1H, Ar–H), 7.34 (m, 1H, Ar–H), 7.26 (m, 4H,
Ethyl 1-(4-chlorobenzyl)-3-(3-formylphenyl)-1H-indole-2-
Ar–H), 6.94 (d, 2H, Ar–H), 5.68 (s, 2H, N–CH –C H Cl),
carboxylate (3b)
2
6 4
4
.38 (q, J = 7.12 Hz, 2H, COOCH CH ), 1.38 (t, J = 7.12
2 3
1
3
Hz, 3H, COOCH CH ); C NMR (CDCl , 100 MHz): δ =
Product was obtained as oil (0.36 g, 87%); FTIR (KBr,
2
3
3
−
1
1
1
61.17 (C, COOCH CH ), 137.94 (C, C-2), 136.38 (C, C-
′), 133.31 (C-Cl, C-4′), 128.83 (CH, C-3′, C-5′), 127.66
cm ) νmax: 3055, 2982, 2934, 2826, 2726, 1701, 1702,
2
3
1
1604, 1534, 1457, 744, 699; H NMR (400 MHz, CDCl ):
3
(
1
1
CH, C-2′, C-6′), 127.00 (C, C-7a), 126.64 (CH, C-6),
25.12 (C, C-3a), 121.78 (CH, C-5), 121.75 (CH, C-4),
10.67 (CH, C-7), 100.02 (C–Br, C-3), 61.38 (CH2,
δ = 10.07 (s, 1H, CHO), 8.00 (t, 1H, Ar–H), 7.91 (m, 1H,
Ar–H), 7.75 (m, 1H, Ar–H), 7.62 (t, 1H, Ar–H), 7.54 (d,
1H, Ar–H), 7.38 (m, 2H, Ar–H), 7.25 (m, 2H, Ar–H), 7.19
(m, 1H, Ar–H), 7.06 (d, 2H, Ar–H), 5.79 (s, 2H,
N–CH –C H Cl), 4.12 (q, J = 7.20 Hz, 2H, COOCH CH ),
COOCH CH ), 48.16 (CH , N–CH –C H Cl), 14.24 (CH ,
COOCH CH ); ESI–MS (m/z): [M+Na] Calcd for
C H BrClNO : 390.99; Found: 413.40.
2
3
2
2
6
4
3
+
2
3
2
6
4
2
3
1
3
0.95 (t, J = 7.40 Hz, 3H, COOCH CH ); C NMR (100
2 3
1
8
15
2

Med Chem Res
MHz, CDCl ): δ = 192.42 (CH, CHO), 162.04 (C,
60.58 (CH , COOCH CH ), 48.12 and 48.07 (CH , N–
3
2
2
3
2
COOCH CH ), 138.28 (C, C-2), 136.68 (C, C-1′), 136.66
CH –C H ), 13.58 and 13.52 (CH , COOCH CH );
2 6 5 3 2 3
2
3
+
(
CH, C-6″), 136.63 (C, C-1″), 135.80 (C, C-3), 133.08 (C-
Cl, C-4′), 132.05 (CH, C-2″), 128.85 (CH, C-3′, C-5′),
28.55 (CH, C-5″), 128.37 (CH, C-4″), 127.80 (CH, C-2′,
C-6′), 126.71 (C, C-7a), 126.07 (CH, C-6), 124.50 (C, C-
ESI–MS (m/z): [M+Na] Calcd for C H NO : 411.18;
27 25 3
Found: 434.00.
1
Ethyl 1-(4-chlorobenzyl)-3-[3-(2-methoxyvinyl)phenyl]-1H-
3
1
a), 123.88 (C, C-3″), 121.56 (CH, C-5), 121.38 (CH, C-4),
indole-2-carboxylate (4b)
10.66 (CH, C-7), 60.84 (CH , COOCH CH ), 47.75 (CH ,
2
2
3
2
N–CH –C H Cl), 13.61 (CH , COOCH CH ); ESI–MS (m/
Product was obtained as oil (0.18 g, 82%); FTIR (KBr,
2
6
4
+
3
2
3
−1
z): [M+Na] Calcd for C H ClNO : 417.11; Found:
cm ) νmax: 3052, 1698, 1651, 1605, 1533, 1456, 1245,
2
5
20
3
1
4
40.20.
910, 802, 743, 704; H NMR (CDCl , 400 MHz): δ = 7.65
3
(m, 2H, Ar–H), 7.36 (m, 3H, Ar–H), 7.24 (m, 3H, Ar–H),
Synthesis of different derivatives of vinyl ether of ethyl N-
subtituted-1H-indole-2-carboxylate
7.16 (m, 1H, Ar–H), 7.09 (m, 1H, Ar–H), 7.05 (m, 2H,
Ar–H), 6.14 (d, J = 7.04 Hz, 1H, cis isomer of
CH=CH–OCH ), 5.87 (d, J = 13.00 Hz, 1H, trans isomer
3
To a slurry of (methoxymethyl)triphenylphosphonium
chloride (1 mmol) and diisopropylamine (0.75 mmol) in
tetrahydrofuran (THF) (20 mL) was added a 1.6 M n-
butyllithium solution in hexane (0.75 mmol), at −10 °C.
After 1 h, at −10 °C, a solution of (3a/b) (0.50 mmol) in
THF (4 mL) was added. The mixture was allowed to warm
to room temperature over 2 h, then poured into water
of CH=CH–OCH ), 5.75 (s, 2H, N–CH –C H Cl), 5.26 (d,
3
2
6 4
J = 7.04 Hz, 1H, cis isomer of CH=CH–OCH ), 4.12 (dq,
3
J = 7.16, 7.16 Hz, 2H, COOCH CH ), 3.74 (s, 3H, trans
2
3
isomer of O–CH ), 3.67 (s, 3H, cis isomer of O–CH ), 0.99
3
3
1
3
(t, J = 7.12 Hz, 3H, COOCH CH ); C NMR (100 MHz,
2
3
CDCl ): δ = 162.68 and 162.54 (C, COOCH CH ), 148.92
3
2
3
and 148.04 (CH, C H –CH=CH–OCH ), 138.25 (C, C-2),
6
4
3
(
20 mL), and extracted with ether (3 × 20 mL). The com-
136.91 and 136.85 (C, C-1′), 135.85 and 135.47 (C, C-1″),
134.81 and 134.24 (C, C-3), 133.00 and 132.96 (C-Cl, C-
4′), 130.40 (CH, C-2″), 128.80 (CH, C-3′, C-5′), 128.10 and
127.96 (CH, C-6″), 127.87 and 127.86 (CH, C-2′, C-6′),
127.66 and 127.29 (CH, C-4″), 127.07 and 127.00 (C, C-
bined extracts were washed with brine, dried over sodium
sulfate, and concentrated. The required product (1:1 mixture
of geometrical isomers) was isolated by column chroma-
tography (ethyl acetate/hexane, 1:4) as oil.
7a), 126.93 (CH, C-5″), 125.71 and 125.50 (C, C-3a),
Ethyl 1-benzyl-3-[3-(2-methoxyvinyl)phenyl]-1H-indole-2-
124.45 (C, C-3″), 123.81 (CH, C-6), 122.07 and 121.90
carboxylate (4a)
(CH, C-4), 121.14 and 121.04 (CH, C-5), 110.44 and
1
10.37 (CH, C-7), 105.70 and 105.10 (CH,C H –
6 4
Product was obtained as oil (0.16 g, 77%); FTIR (KBr,
CH=CH–OCH3), 60.73 and 56.60 (CH ,C H –CH=
CH–OCH ), 60.69 (CH , COOCH CH ), 47.63 and 47.59
3 2 2 3
3 6 4
−1
cm ) νmax: 3031, 1700, 1651, 1605, 1535, 1453, 1245,
1
8
2
62, 743, 699; H NMR (400 MHz, CDCl ): δ = 7.65 (m,
(CH2, N–CH –C H Cl), 13.63 and 13.57 (CH3,
2 6 4
3
+
H, Ar–H), 7.37 (m, 8H, Ar–H), 7.15 (m, 3H, Ar–H), 6.13
COOCH CH ); ESI–MS (m/z): [M+Na] Calcd for
2 3
(
d, J = 7.00 Hz, 1H, cis isomer of CH=CH–OCH ), 5.87
C H ClNO : 445.14; Found: 468.20.
27 24 3
3
(
d, J = 13.00 Hz, 1H, trans isomer of CH=CH–OCH3),
5
.80 (s, 2H, N–CH –C H ), 5.26 (d, J = 7.04 Hz, 1H, cis
Synthesis of different derivatives of acetal formation of ethyl
2
6 5
isomer of CH=CH–OCH ), 4.12 (dq, J = 7.12, 7.12 Hz,
N-substituted-1H-indole-2-carboxylate
3
2
H, COOCH CH ), 3.73 (s, 3H, trans isomer of O–CH ),
2 3 3
3
.66 (s, 3H, cis isomer of O–CH ), 0.98 (t, J = 7.12 Hz, 3H,
A solution of (4a/4b) (2.0 mmol) and p-toluenesulfonic acid
monohydrate (0.21 mmol) in various type of alcohols
(methanol, ethanol, and isobutanol) (7 mL) was heated to
reflux overnight. The solvent was removed, the residue was
taken up in ethyl acetate, and the solution was washed with
5% sodium bicarbonate and brine, dried over sodium sul-
fate, and concentrated to an oil of series (5a–f).
3
1
3
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 162.67
and 162.52 (C, COOCH CH ), 148.82 and 147.95 (CH,
C H –CH=CH–OCH ), 138.29 and 138.25 (C, C-2, C-1′),
2
3
3
2
3
6
4
3
1
1
1
35.76 and 135.39 (C, C-1″), 134.90 and 134.33 (C, C-3),
30.36 (CH, C-2″), 128.57 (CH, C-3′,C-5′), 127.86 and
27.59 (CH, C-4″), 127.24 (CH, C-6″), 127.15 and 127.12
(
CH, C-4′), 126.93 and 126.86 (C, C-7a), 126.78 (CH, C-
″), 126.37 and 126.34 (CH, C-2′, C-6′), 125.31 and 125.12
C, C-3a), 124.61 (C, C-3″), 123.68 (CH, C-6), 121.86 and
21.69 (CH, C-4), 120.92 and 120.83 (CH, C-5), 110.62
and 110.55 (CH, C-7), 105.67 and 105.06 (CH,C H –CH=
5
(
1
Ethyl 1-benzyl-3-[3-(2,2-dimethoxyethyl)phenyl]-1H-
indole-2-carboxylate (5a)
Product was obtained as oil (0.58 g, 65%); FTIR (KBr,
6
4
−1
CH–OCH ), 60.65 and 56.52 (CH ,C H –CH=CH–OCH ),
cm ) νmax: 3032, 1701, 1606, 1535, 1453, 1245, 1073,
3
3
6
4
3

Med Chem Res
1
7
43, 707; H NMR (400 MHz, CDCl ): δ = 7.60 (d, 1H,
(s, 2H, N–CH –C H ), 4.72 (t, J = 5.68 Hz, 1H,
2 6 5
3
Ar–H), 7.38 (m, 5H, Ar–H), 7.28 (m, 4H, Ar–H), 7.16 (m,
C H –CH CH(OCH CH ) ), 4.12 (q, J = 7.16 Hz, 2H,
6 4 2 2 3 2
3
1
H, Ar–H), 5.81 (s, 2H, N–CH –C H ), 4.62 (t, J = 5.68 Hz,
COOCH CH ), 3.71 (m, 2H, C H –CH CH(OCH CH ) ),
2 3 6 4 2 2 3 2
2
6
5
H, C H –CH CH(OCH ) ), 4.12 (q, J = 7.12 Hz, 2H,
3.50 (m, 2H, C H –CH CH(OCH CH ) ), 2.99 (d, J =
6
4
2
3 2
6 4 2 2 3 2
COOCH CH ), 3.36 (s, 6H, C H –CH CH(OCH ) ), 2.98
5.64 Hz, 2H, C H –CH CH(OCH CH ) ), 1.19 (t, J = 7.08
6 4 2 2 3 2
2
3
6
4
2
3 2
(
7
d, J = 5.68 Hz, 2H, C H -CH CH(OCH ) ) 0.98 (t, J =
Hz, 6H, C H –CH CH(OCH CH ) ), 0.98 (t, J = 7.16 Hz,
3H, COOCH CH ); C NMR (100 MHz, CDCl ): δ =
2 3 3
6
4
2
3 2
6 4 2 2 3 2
13
1
3
.12 Hz, 3H, COOCH CH ); C NMR (100 MHz, CDCl3):
2
3
δ = 162.56 (C, COOCH CH ), 138.33 (C, C-2), 138.28 (C,
162.56 (C, COOCH CH ), 138.32 (C, C-2), 138.29 (C, C-
2
3
2 3
C-1′), 136.44 (C, C-1″), 134.63 (C, C-3), 131.49 (CH, C-2″),
1′), 136.73 (C, C-1″), 134.48 (C, C-3), 131.52 (CH, C-2″),
128.66 (CH, C-6″), 128.59 (CH, C-3′, C-5′), 128.14 (CH,
C-5″), 127.64 (C, C-3a), 127.16 (CH, C-4″, C-4′), 126.97
(C, C-7a), 126.36 (CH, C-2′, C-6′), 125.47 (C, C-6), 125.22
(C, C-3″), 121.73 (C, C-4), 120.87 (CH, C-5), 110.62 (CH,
C-7), 103.93 (CH, C H –CH CH(OCH CH ) ), 61.87
1
28.62 (CH, C-3′, C-5′, C-6″), 128.00 (CH, C-5″), 127.78
(CH, C-4″), 127.19 (CH, C-4′), 126.98 (C, C-7a), 126.39
(CH, C-2′, C-6′), 125.51 (C, C-6), 125.15 (C, C-3″), 124.67
(C, C-3a), 121.72 (CH, C-4), 120.93 (CH, C-5), 110.65 (CH,
C-7), 105.42 (CH, C H –CH CH(OCH ) ), 60.57 (CH ,
6
4
2
3 2
2
6
4
2
2
3 2
COOCH CH ), 53.34 (CH , C H –CH CH(OCH ) ), 48.19
(CH2,
C H –CH CH(OCH CH ) ),
60.55
(CH2,
2
3
3
6
4
2
3 2
6
4
2
2
3 2
(
1
CH , N–CH –C H ), 39.66 (CH , C H –CH CH(OCH ) ),
2 2 6 5 2 6 4 2 3 2
COOCH CH ), 48.18 (CH , N–CH –C H ), 40.86 (CH ,
C H –CH CH(OCH CH ) ), 15.29 (CH , C H –CH CH
6 4 2 2 3 2 3 6 4 2
2
3
2
2
6
5
2
+
3.61 (CH , COOCH CH ); ESI–MS (m/z): [M+Na]
3
2
3
Calcd for C H NO : 443.20; Found: 465.80.
(OCH CH ) ), 13.61 (CH , COOCH CH ); ESI–MS (m/z):
2 3 2 3 2 3
2
8
29
4
+
[
M+Na] Calcd for C H NO : 471.24; Found: 494.10.
30 33 4
Ethyl 1-(4-chlorobenzyl)-3-[3-(2,2-dimethoxyethyl)phenyl]-
H-indole-2-carboxylate (5b)
1
Ethyl 1-(4-chlorobenzyl)-3-[3-(2,2-diethoxyethyl)phenyl]-
H-indole-2-carboxylate (5d)
1
Product was obtained as oil (0.54 g, 57%); FTIR (KBr,
−
1
cm ) νmax: 3032, 1700, 1607, 1536, 1456, 1245, 1085,
Product was obtained as oil (0.47 g, 47%); FTIR (KBr,
1
−1
7
98, 743, 707; H NMR (400 MHz, CDCl ): δ = 7.59 (d,
H, Ar–H), 7.38 (m, 5H, Ar–H), 7.26 (m, 3H, Ar–H), 7.17
cm ) ν : 3052, 1700, 1607, 1535, 1455, 1245, 1015, 799,
3
max
1
1
744, 708; H NMR (400 MHz, CDCl ): δ = 7.59 (d, 1H,
3
(
m, 1H, Ar–H), 7.06 (m, 2H, Ar–H), 5.76 (s, 2H,
Ar–H), 7.36 (m, 4H, Ar–H), 7.30 (m, 4H, Ar–H), 7.16 (m,
1H, Ar–H), 7.06 (m, 2H, Ar–H), 5.76 (s, 2H,
N–CH –C H Cl), 4.71 (t, J = 5.64 Hz, 1H, C H -CH CH
N–CH –C H Cl), 4.62 (t, J = 5.64 Hz, 1H, C H –CH CH
2
6
4
6
4
2
(
(
OCH ) ), 4.12 (q, J = 7.08 Hz, 2H, COOCH CH ), 3.36
3 2 2 3
2
6
4
6
4
2
s, 6H, C H –CH CH(OCH ) ), 2.98 (d, J = 5.64 Hz, 2H,
(OCH CH ) ), 4.12 (q, J = 7.12 Hz, 2H, COOCH CH ),
6
4
2
3 2
2 3 2 2 3
C H –CH CH(OCH ) ), 0.98 (t, J = 7.16 Hz, 3H,
3.73 (m, 2H, C H –CH CH(OCH CH ) ), 3.52 (m, 2H,
6 4 2 2 3 2
C H –CH CH(OCH CH ) ), 2.99 (d, J = 5.64 Hz, 2H,
6 4 2 2 3 2
6
4
2
3 2
1
3
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 162.50
2
3
3
(
C, COOCH CH ), 138.21 (C, C-2), 136.81 (C, C-1′),
C H –CH CH(OCH CH ) ), 1.19 (t, J = 7.08 Hz, 6H,
6 4 2 2 3 2
2
3
1
1
36.46 (C, C-1″), 134.47 (C, C-3), 132.98 (C-Cl, C-4′),
31.46 (CH, C-2″), 128.77 (CH, C-3′, C-5′), 128.58 (CH,
C H -CH CH(OCH CH ) ), 0.98 (t, J = 7.16 Hz, 3H,
6 4 2 2 3 2
1
3
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 162.51
2
3
3
C-6″), 128.07 (CH, C-5″), 127.82 (CH, C-2′, C-6′), 127.76
CH, C-4″), 127.04 (C, C-7a), 125.68 (CH, C-6), 125.46 (C,
C-3″), 124.42 (C, C-3a), 121.86 (CH, C-4), 121.06 (CH, C-
(C, COOCH CH ), 138.21 (C, C-2), 136.82 (C, C-1′),
2 3
(
136.76 (C, C-1″), 134.33 (C, C-3), 132.96 (C-Cl, C-4′),
131.51 (CH, C-2″), 128.77 (CH, C-3′, C-5′), 128.57 (CH, C-
6″), 128.23 (CH, C-5″), 127.80 (CH, C-2′, C-6′), 127.65 (CH,
C-4″), 127.03 (C, C-3″), 125.67 (CH, C-6), 125.52 (C, C-7a),
124.39 (C, C-3a), 121.88 (CH, C-4), 121.04 (CH, C-5),
110.38 (CH, C-7), 103.90 (CH, C H –CH CH(OCH CH ) ),
5
), 110.39 (CH, C-7), 105.39 (CH, C H –CH CH(OCH ) ),
6 4 2 3 2
6
0.61 (CH , COOCH CH ), 53.32 (CH , C H –CH CH
2
2
3
3
6
4
2
(
OCH ) ), 47.62 (CH , N–CH –C H Cl), 39.64 (CH ,
3 2 2 2 6 4 2
C H –CH CH(OCH ) ), 13.58 (CH3, COOCH CH );
6
4
2
3 2
2
3
6
4
2
2
3 2
+
ESI–MS (m/z): [M+Na] Calcd for C H ClNO : 477.17;
61.86 (CH , C H –CH CH(OCH CH ) ), 60.61 (CH ,
2 6 4 2 2 3 2 2
2
8
28
4
Found: 500.27.
COOCH CH ), 47.62 (CH , N–CH –C H Cl), 40.84 (CH ,
2 3 2 2 6 4 2
C H –CH CH(OCH CH ) ), 15.30 (CH , C H –CH CH
6
4
2
2
3 2
3
6
4
2
Ethyl 1-benzyl-3-[3-(2,2-diethoxyethyl)phenyl]-1H-indole-
-carboxylate (5c)
(OCH CH ) ), 13.16 (CH , COOCH CH ); ESI–MS (m/z):
2 3 2 3 2 3
[M+Na] Calcd for C H ClNO : 505.20; Found: 528.31.
30 32 4
+
2
Product was obtained as oil (0.42 g, 44%); FTIR (KBr,
Ethyl 1-benzyl-3-[3-(2,2-diisobutoxyethyl)phenyl]-1H-
indole-2-carboxylate (5e)
−1
cm ) νmax: 3033, 1702, 1606, 1535, 1454, 1246, 1059,
1
7
34, 699; H NMR (400 MHz, CDCl ): δ = 7.60 (d, 1H,
3
−
1
Ar–H), 7.38 (m, 4H, Ar–H), 7.30 (m, 4H, Ar–H), 7.23 (m,
H, Ar–H), 7.15 (m, 1H, Ar–H), 7.12 (m, 2H, Ar–H), 5.81
Product was obtained as oil (0.46 g, 44%); FTIR (KBr, cm )
1
νmax: 3033, 1703, 1606, 1537, 1454, 1245, 1043, 734, 707;

Med Chem Res
1
+
H NMR (400 MHz, CDCl ): δ = 7.58 (d, 1H, Ar–H), 7.35
(m/z): [M+Na] Calcd for C H ClNO : 561.26; Found:
34 40 4
3
(m, 9H, Ar–H), 7.12 (m, 3H, Ar–H), 5.81 (s, 2H,
584.38.
N–CH –C H ), 4.69 (t, J = 5.68 Hz, 1H, C H –CH CH
2
6
5
6
4
2
[
OCH CH(CH ) ] ),
4.11
(q,
J = 7.16 Hz,
2H,
Synthesis of different derivatives of nitrile substituted ethyl
2
3 2 2
COOCH CH ), 3.43 (dd, J = 6.56, 9.08 Hz, 2H, [OCH CH
N-substituted-1H-indole-2-carboxylate
2
3
2
(
CH ) ] ), 3.20 (dd, J = 6.60, 9.04 Hz, 2H, [OCH CH
3 2 2 2
(
CH ) ] ), 2.99 (d, J = 5.64 Hz, 2H, C H –CH CH[OCH CH
To a solution of (5a–f) (2.0 mmol) in dichloromethane (15
mL) were added trimethylsilyl cyanide (6.0 mmol) and
boron trifluoride etherate (0.5 mmol). After 1 h the solution
was diluted with dichloromethane, washed with 5% sodium
bicarbonate, water, and brine, dried over sodium sulfate,
and concentrated. The crude product was purified by col-
umn chromatography (ethyl acetate/hexane, 1:2) and (6a–f)
was isolated as oil.
3
2 2
6
4
2
2
(CH ) ] ), 1.84 (m, 2H, [OCH CH(CH ) ] ), 0.98 (t, J =
3 2 2 2 3 2 2
7
1
.12 Hz, 3H, COOCH CH ), 0.88 (dd, J = 6.68 and 6.68 Hz,
2 3
1
3
2H, [OCH CH(CH ) ] );
C NMR (100 MHz MHz,
2
3 2 2
CDCl ): δ = 162.57 (C, COOCH CH ), 138.33 (C, C-2, C-
3
2
3
1
1
5
1
1
1
′), 136.88 (C, C-1″), 134.45 (C, C-3), 131.56 (CH, C-2″),
28.60 (CH, C-3′, C-5′), 128.53 (CH, C-6″), 128.29 (CH, C-
″), 127.91 (CH, C-4″), 127.16 (CH, C-4′), 127.01 (C, C-7a),
26.36 (CH, C-2′, C-6′), 125.48 (C, C-6), 125.30 (C, C-3″),
24.61 (C, C-3a), 121.77 (CH, C-4), 120.85 (CH, C-5),
10.61 (CH, C-7), 104.29 (CH, C H –CH CH[OCH CH
Ethyl 1-benzyl-3-[3-(2-cyano-2-methoxyethyl)phenyl]-1H-
indole-2-carboxylate (6a)
6
4
2
2
(
CH ) ] ), 73.14 (CH , [OCH CH(CH ) ] ), 60.53 (CH ,
3 2 2 2 2 3 2 2 2
COOCH CH ), 48.17 (CH , N–CH –C H ), 40.86 (CH ,
Product was obtained as oil (0.53 g, 60%); FTIR (KBr,
2
3
2
2
6
5
2
−1
C H –CH CH[OCH CH(CH ) ] ), 28.69 (CH, [OCH CH
cm ) νmax: 3032, 2253, 1702, 1606, 1537, 1454, 1246,
6
4
2
2
3 2 2
2
1
(
CH ) ] ), 19.50 (CH , [OCH CH(CH ) ] ), 13.64 (CH ,
1027, 742, 707; H NMR (400 MHz, CDCl ): δ = 7.59 (d,
3
2 2
3
2
3 2 2
3
3
+
COOCH CH ); ESI–MS (m/z): [M+Na]
Calcd for
1H, Ar–H), 7.41 (m, 4H, Ar–H), 7.35 (m, 1H, Ar–H), 7.30
2
3
C H NO : 527.30; Found: 550.90.
(m, 3H, Ar–H), 7.24 (m, 1H, Ar–H), 7.17 (m, 1H, Ar–H),
34
41
4
7
.13 (m, 2H, Ar–H), 5.82 (s, 2H, N–CH –C H ), 4.62 (t, J
2 6 5
=
6.84 Hz, 1H, C H –CH CH(CN)OCH ), 4.13 (q, J =
6 4 2 3
Ethyl 1-(4-chlorobenzyl)-3-[3-(2,2-diisobutoxyethyl)
7.12 Hz, 2H, COOCH CH ), 3.51 (s, 3H, C H –CH CH
2 3 6 4 2
phenyl]-1H-indole-2-carboxylate (5f)
(CN)OCH3), 2.98 (dd, J = 4.80, 6.64 Hz, 2H,
C H –CH CH(CN)OCH ), 0.98 (t, J = 7.12 Hz, 3H,
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 162.40
6
4
2
3
1
2 3 3
3
Product was obtained as oil (0.60 g, 53%); FTIR (KBr,
−1
cm ) νmax: 3052, 1703, 1608, 1537, 1454, 1246, 1043,
(C, COOCH CH ), 138.31 (C, C-2), 138.22 (C, C-1′),
2 3
1
7
98, 743, 708; H NMR (400 MHz, CDCl ): δ = 7.58 (d,
135.20 (C, C-1″), 133.96 (C, C-3), 131.42 (CH, C-2″),
129.85 (CH, C-6″), 128.62 (CH, C-3′, C-5′), 128.14 (CH,
C-5″), 128.04 (CH, C-4″), 127.21 (CH, C-4′), 126.91 (C, C-
7a), 126.37 (CH, C-2′, C-6′), 125.60 (C, C-6), 124.70 (C, C-
3a, C-3″), 121.62 (CH, C-4), 121.06 (CH, C-5), 117.66 (C,
CN), 110.68 (CH, C-7), 71.86 (CH, C H –CH CH(CN)
3
1
H, Ar–H), 7.36 (m, 4H, Ar–H), 7.29 (m, 4H, Ar–H), 7.16
(
m, 1H, Ar–H), 7.05 (m, 2H, Ar–H), 5.77 (s, 2H,
N–CH –C H Cl), 4.69 (t, J = 5.68 Hz, 1H, C H –CH CH
2
6
4
6
4
2
[
OCH CH(CH ) ] ),
4.11
(q,
J = 7.16 Hz,
2H,
2
3 2 2
COOCH CH ), 3.43 (dd, J = 6.56, 9.08 Hz, 2H, [OCH CH
2
3
2
6
4
2
(
CH ) ] ), 3.20 (dd, J = 6.60, 9.04 Hz, 2H, [OCH CH
OCH3), 60.60 (CH2, COOCH CH ), 58.11 (CH3,
2 3
3
2 2
2
(
CH ) ] ), 2.99 (d, J = 5.68 Hz, 2H, C H –CH CH
C H –CH CH(CN)OCH ), 48.23 (CH , N–CH –C H ),
6 4 2 3 2 2 6 5
3
2 2
6
4
2
[
0
6
OCH CH(CH ) ] ), 1.84 (m, 2H, [OCH CH(CH ) ] ),
39.73 (CH2, C H –CH CH(CN)OCH ), 13.62 (CH3,
6 4 2 3
2
3 2 2
2
3 2 2
+
.98 (t, J = 7.16 Hz, 3H, COOCH CH ), 0.88 (dd, J = 6.72,
COOCH CH ); ESI–MS (m/z): [M+Na] Calcd for
2
3
2 3
1
3
.72 Hz, 12H, [OCH CH(CH ) ] ); C NMR (100 MHz,
C H N O : 438.19; Found: 461.20.
28 26 2 3
2
3 2 2
CDCl ): δ = 162.52 (C, COOCH CH ), 138.21 (C, C-2),
3
2
3
1
(
1
36.90 (C, C-1′), 136.85 (C, C-1″), 134.27 (C, C-3), 132.95
C-Cl, C-4′), 131.54 (CH, C-2″), 128.77 (CH, C-3′, C-5′),
28.50 (CH, C-6″), 128.36 (CH, C-5″), 127.79 (CH, C-2′,
C-6′), 127.58 (CH, C-4″), 127.05 (C, C-3″), 125.67 (CH, C-
Ethyl 1-(4-chlorobenzyl)-3-[3-(2-cyano-2-methoxyethyl)
phenyl]-1H-indole-2-carboxylate (6b)
Product was obtained as oil (0.57 g, 53%); FTIR (KBr,
−1
5
1
), 125.61 (C, C-7a), 124.34 (C, C-3a), 121.92 (CH, C-4),
21.00 (CH, C-5), 110.37 (CH, C-7), 104.24 (CH,
cm ) νmax: 3053, 2253, 1704, 1608, 1537, 1456, 1246,
1
1025, 801, 744, 709; H NMR (400 MHz, CDCl ): δ = 7.59
3
C H –CH CH[OCH CH(CH ) ] ), 73.10 (CH , [OCH CH
(d, 1H, Ar–H), 7.42 (m, 5H, Ar–H), 7.30 (m, 1H, Ar–H),
7.25 (m, 2H, Ar–H), 7.18 (m, 1H, Ar–H), 7.07 (m, 2H,
Ar–H), 5.77 (s, 2H, N–CH –C H Cl), 4.30 (t, J = 6.88 Hz,
6
4
2
2
3 2 2
2
2
(
CH ) ] ), 60.60 (CH , COOCH CH ), 47.61 (CH , N–
3 2 2 2 2 3 2
CH –C H Cl), 40.65 (CH2, C H –CH CH[OCH CH
2
6
4
6
4
2
2
2
6 4
(
CH ) ] ), 28.68 (CH, [OCH CH(CH ) ] ), 19.49 (CH ,
1H, C H –CH CH(CN)OCH ), 4.12 (q, J = 7.08 Hz, 2H,
3
2 2
2
3 2 2
3
6 4 2 3
[
OCH CH(CH ) ] ), 13.62 (CH , COOCH CH ); ESI–MS
COOCH CH ), 3.51 (s, 3H, C H –CH CH(CN)OCH ),
2 3 6 4 2 3
2
3 2 2
3
2
3

Med Chem Res
3
0
.19 (dd, J = 4.24, 6.68 Hz, 2H, C H –CH CH(CN)OCH )
7.25 (m, 2H, Ar–H), 7.17 (m, 1H, Ar–H), 7.06 (m, 2H,
Ar–H), 5.77 (s, 2H, N–CH –C H Cl), 4.36 (t, J = 6.92 Hz,
6
4
2
1
3
3
.98 (t, J = 7.12 Hz, 3H, COOCH CH ); C NMR (100
2
3
2
6 4
MHz, CDCl ): δ = 162.35 (C, COOCH CH ), 138.20 (C,
1H, C H –CH CH(CN)OCH CH ), 4.12 (q, J = 7.12 Hz,
3
2
3
6 4 2 2 3
C-2), 136.74 (C, C-1′), 135.06 (C, C-1″), 133.96 (C, C-3),
2H, COOCH CH ), 3.87 (m, 1H, C H –CH CH(CN)
2 3 6 4 2
1
1
4
33.01 (C–Cl, C-4′), 131.40 (CH, C-2″), 129.83 (CH, C-6″),
28.79 (CH, C-3′,C-5′), 128.14 (CH, C-5″), 128.12 (CH, C-
″), 127.81 (CH, C-2′, C-6′), 126.97 (C, C-7a), 125.79 (CH,
OCH CH ), 3.57 (m, 1H, C H –CH CH(CN)OCH CH ),
2 3 6 4 2 2 3
3.23 (dd, J = 6.92, 10.72 Hz, 2H, C H –CH CH(CN)
6
4
2
OCH CH ), 1.27 (t, J = 7.00 Hz, 3H, C H –CH CH(CN)
2
3
6
4
2
1
3
C-6), 125.00 (C, C-3″), 124.45 (C, C-3a), 121.77 (CH, C-4),
21.21 (CH, C-5), 117.62 (C, CN), 110.43 (CH, C-7), 71.85
CH, C H –CH CH(CN)OCH ), 60.65 (CH2,
COOCH CH ), 58.11 (CH , C H –CH CH(CN)OCH ),
OCH CH ), 0.98 (t, J = 7.12 Hz, 3H, COOCH CH );
C
2
3
2
3
1
(
NMR (100 MHz, CDCl ): δ = 162.36 (C, COOCH CH ),
3 2 3
138.20 (C, C-2), 136.75 (C, C-1′), 134.99 (C, C-1″), 134.12
(C, C-3), 133.01 (C-Cl, C-4′), 131.39 (CH, C-2″), 129.83
(CH, C-6″), 128.78 (CH, C-3′, C-5′), 128.15 (CH, C-5″),
128.11 (CH, C-4″), 127.80 (CH, C-2′, C-6′), 126.97 (C, C-
7a), 125.79 (CH, C-6), 125.04 (C, C-3″), 124.43 (CH, C-
3a), 121.78 (CH, C-4), 121.19 (CH, C-5), 118.11 (C, CN),
6
4
2
3
2
3
3
6
4
2
3
4
7.66 (CH , N–CH –C H Cl), 39.71 (CH , C H –CH CH
2 2 6 4 2 6 4 2
(
CN)OCH ), 13.60 (CH , COOCH CH ); ESI–MS (m/z):
3 3 2 3
+
[
M+Na] Calcd for C H ClN O : 472.15; Found:
28 25 2 3
4
95.04.
1
10.42 (CH, C-7), 70.10 (CH, C H –CH CH(CN)
6 4 2
Ethyl 1-benzyl-3-[3-(2-cyano-2-ethoxyethyl)phenyl]-1H-
OCH CH ), 66.42 (CH , C H –CH CH(CN)OCH CH ),
2 3 2 6 4 2 2 3
indole-2-carboxylate (6c)
60.66 (CH , COOCH CH ), 47.66 (CH , N–CH –C H Cl),
2 2 3 2 2 6 4
3
9.94 (CH , C H –CH CH(CN)OCH CH ), 14.74 (CH ,
2 6 4 2 2 3 3
Product was obtained as oil (0.30 g, 33%); FTIR (KBr,
C H –CH CH(CN)OCH CH ), 13.62 (CH , COOCH CH );
6 4 2 2 3 3 2 3
−1
+
cm ) νmax: 3032, 2253, 1703, 1606, 1537, 1454, 1246,
ESI–MS (m/z): [M+Na] Calcd for C H ClN O : 486.17;
29 27 2 3
1
1
1
3
027, 743, 707; H NMR (400 MHz, CDCl ): δ = 7.59 (d,
Found: 509.05.
3
H, Ar–H), 7.40 (m, 4H, Ar–H), 7.35 (m, 1H, Ar), 7.31 (m,
H, Ar–H), 7.23 (m, 1H, Ar–H), 7.16 (m, 1H, Ar–H), 7.12
(
m, 2H, Ar–H), 5.82 (s, 2H, N–CH –C H ), 4.36 (t, J =
Ethyl 1-benzyl-3-[3-(2-cyano-2-isobutoxyethyl)phenyl]-1H-
2
6 5
6
.96 Hz, 1H, C H –CH CH(CN)OCH CH ), 4.12 (q, J =
indole-2-carboxylate (6e)
6
4
2
2
3
7
.12 Hz, 2H, COOCH CH ), 3.89 (m, 1H, C H –CH CH
2
3
6
4
2
(
CN)OCH CH ), 3.57 (m, 1H, C H –CH CH(CN)
Product was obtained as oil (0.36 g, 38%); FTIR (KBr,
2
3
6
4
2
−1
OCH CH ), 3.23 (dd, J = 6.64, 10.72 Hz, 2H, C H –
CH CH(CN)OCH CH ), 1.19 (t, J = 7.04 Hz, 3H, C H –
cm ) νmax: 3032, 2253, 1703, 1607, 1537, 1454, 1246,
2
3
6 4
1
1027, 734, 707; H NMR (400 MHz, CDCl ): δ = 7.58 (d,
2
2
3
6
4
3
CH CH(CN)OCH CH ), 0.98 (t, J = 7.12 Hz, 3H,
1H, Ar–H), 7.41 (m, 4H, Ar–H), 7.35 (m, 1H, Ar–H), 7.31
(m, 3H, Ar–H), 7.23 (m, 1H, Ar–H), 7.16 (m, 1H, Ar–H),
7.12 (m, 2H, Ar–H), 5.82 (s, 2H, N–CH –C H ), 4.69 (t, J
2
2
3
3
1
COOCH CH ); C NMR (100 MHz, CDCl ): δ = 162.41
2
3
3
(
C, COOCH CH ), 138.31 (C, C-2), 138.22 (C, C-1′),
2 3
2
6 5
1
1
35.14 (C, C-1″), 134.11 (C, C-3), 131.40 (CH, C-2″),
29.84 (CH, C-6″), 128.61 (CH, C-3′, C-5′), 128.10 (CH,
= 6.84 Hz, 1H, C H –CH CH(CN)OCH CH(CH ) ), 4.12
6 4 2 2 3 2
(q, J = 7.08 Hz, 2H, COOCH CH ), 3.56 (m, 1H, OCH CH
2
3
2
C-5″), 128.06 (C, C-4″), 127.20 (CH, C-4′), 126.91 (C, C-
a), 126.36 (CH, C-2′, C-6′), 125.59 (CH, C-6), 124.73 (C,
C-3″), 124.68 (C, C-3a), 121.63 (CH, C-4), 121.03 (CH, C-
), 118.15 (C, CN), 110.66 (CH, C-7), 70.12 (CH,
C H –CH CH(CN)OCH CH ), 66.42 (CH , C H –CH CH
(CH ) ), 3.24 (m, 3H, OCH CH(CH ) , C H –CH CH(CN)
OCH CH(CH ) ), 1.92 (m, 1H, OCH CH(CH ) ), 0.98 (t,
2 3 2 2 3 2
3 2 2 3 2 6 4 2
7
J = 7.08 Hz, 3H, COOCH CH ), 0.88 (dd, J = 2.20, 6.72
2
3
1
2 3 2 3
3
5
Hz, 6H, OCH CH(CH ) ); C NMR (100 MHz, CDCl ): δ
= 162.39 (C, COOCH CH ), 138.30 (C, C-2), 138.23 (C,
6
4
2
2
3
2
6
4
2
2
3
(
CN)OCH CH ), 60.60 (CH , COOCH CH ), 48.22 (CH ,
C-1′), 135.12 (C, C-1″), 134.21 (C, C-3), 131.39 (CH, C-
2″), 129.80 (CH, C-6″), 128.60 (CH, C-3′, C-5′), 128.12
(CH, C-5″), 128.03 (CH, C-4″), 127.19 (CH, C-4′), 126.92
(C, C-7a), 126.35 (CH, C-2′, C-6′), 125.58 (C, C-6), 124.77
(C, C-3″), 124.66 (C, C-3a), 121.63 (CH, C-4), 121.01 (CH,
C-5), 118.19 (C, CN), 110.65 (CH, C-7), 77.50 (CH2,
OCH CH(CH ) ), 70.41 (CH, C H –CH CH(CN)OCH CH
2
3
2
2
3
2
N–CH –C H ), 39.95 (CH , C H –CH CH(CN)OCH CH ),
1
COOCH CH ); ESI–MS (m/z): [M+Na]
C H N O : 452.20; Found: 475.28.
2
6
5
2
6
4
2
2
3
4.75 (CH , C H –CH CH(CN)OCH CH ), 13.63 (CH ,
3
6
4
2
2
3
3
+
Calcd for
2
3
2
9 28 2 3
Ethyl 1-(4-chlorobenzyl)-3-[3-(2-cyano-2-ethoxyethyl)
2
3 2
6
4
2
2
phenyl]-1H-indole-2-carboxylate (6d)
(CH ) ), 60.58 (CH , COOCH CH ), 48.21 (CH , N–
3 2 2 2 3 2
CH –C H ), 39.92 (CH , C H –CH CH(CN)OCH CH
2
6
5
2
6
4
2
2
Product was obtained as oil (0.45 g, 46%); FTIR (KBr,
(CH ) ), 28.30 (CH, OCH CH(CH ) ), 19.16 and 19.13
3 2 2 3 2
−1
cm ) νmax: 3052, 2253, 1703, 1608, 1537, 1456, 1246,
(CH , OCH CH(CH ) ), 13.63 (CH , COOCH CH );
3 2 3 2 3 2 3
1
+
1
098, 801, 744, 708; H NMR (400 MHz, CDCl ): δ = 7.59
ESI–MS (m/z): [M+Na] Calcd for C H N O : 480.24;
3
31 32 2 3
(
d, 1H, Ar–H), 7.42 (m, 5H, Ar–H), 7.31 (m, 1H, Ar–H),
Found: 503.20.

Med Chem Res
Ethyl 1-(4-chlorobenzyl)-3-[3-(2-cyano-2-isobutoxyethyl)
OCH ), 3.29 (s, 3H, C H –CH CH(COOH)OCH ), 3.13
3
6
4
2
3
phenyl]-1H-indole-2-carboxylate (6f)
(m, 1H, C H –CH CH(COOH)OCH ) 3.04 (m, 1H,
6 4 2 3
1
3
C H –CH CH(COOH)OCH );
C
NMR (100 MHz,
6
4
2
3
Product was obtained as oil (0.56 g, 54%); FTIR (KBr,
CDCl ): δ = 176.60 (C, C H –CH CH(COOH)OCH ),
3
6
4
2
3
−1
cm ) νmax: 3053, 2254, 1697, 1609, 1536, 1457, 1246,
166.71 (C, indole-2-COOH), 138.94 (C, C-2), 138.14 (C,
C-1′), 136.10 (C, C-1″), 134.15 (C, C-3), 131.78 (CH, C-
2″), 128.88 (CH, C-6″), 128.63 (CH, C-3′, C-5′), 128.45
(CH, C-5″), 128.03 (CH, C-4″), 127.40 (C, C-7a), 127.24
(CH, C-4′), 127.02 (C, C-3″), 126.38 (CH, C-2′, C-6′),
126.33 (CH, C-6), 123.21 (C, C-3a), 122.02 (CH, C-4),
121.23 (CH, C-5), 110.87 (CH, C-7), 81.33 (CH, C H -
1
1
015, 801, 742, 709; H NMR (400 MHz, CDCl ): δ = 7.58
3
(
7
d, 1H, Ar–H), 7.41 (m, 5H, Ar–H), 7.31 (m, 1H, Ar–H),
.25 (m, 2H, Ar–H), 7.17 (m, 1H, Ar–H), 7.06 (d, 2H,
Ar–H), 5.77 (s, 2H, N–CH –C H Cl), 4.33 (t, J = 6.84 Hz,
2
6 4
1
H, C H –CH CH(CN)OCH CH(CH ) ), 4.12 (q, J = 7.08
6 4 2 2 3 2
Hz, 2H, COOCH CH ), 3.56 (m, 1H, OCH CH(CH ) ),
2
3
2
3 2
6 4
3
.24 (m, 3H, OCH CH(CH ) , C H –CH CH(CN)
CH CH(COOH)OCH ), 58.48 (CH3, C H -CH CH
2 3 6 4 2
2
3 2
6
4
2
OCH CH(CH ) ), 1.92 (m, 1H, OCH CH(CH ) ), 0.98 (t,
(COOH)OCH ), 48.39 (CH , N–CH –C H ), 38.62 (CH ,
3 2 2 6 5 2
C H –CH CH(COOH)OCH ); ESI–MS (m/z): [M] Calcd
6 4 2 3
for C H NO : 429.15; Found: 429.12.
26 23 5
2
3 2
2
3 2
+
J = 7.16 Hz, 3H, COOCH CH ), 0.90 (dd, J = 2.20, 6.72
2
1
3
3
Hz, 6H, OCH CH(CH ) ); C NMR (100 MHz, CDCl ): δ
2
3 2
3
=
162.36 (C, COOCH CH ), 138.20 (C, C-2), 136.77 (C,
2 3
C-1′), 134.98 (C, C-1″), 134.24 (C, C-3), 133.00 (C-Cl, C-
1-(4-chlorobenzyl)-3-[3-(2-carboxy-2-methoxyethyl)
4
′), 131.40 (CH, 2″), 129.80 (CH, C-6″), 128.78 (CH, C-3′,
phenyl]-1H-indole-2-carboxylic acid (7b)
C-5′), 128.23 (CH, C-5″), 128.06 (CH, C-4″), 127.80 (CH,
C-2′, C-6′), 126.99 (C, C-7a), 125.79 (C, C-6), 125.08 (C,
C-3″), 124.42 (C, C-3a), 121.79 (CH, C-4), 121.18 (CH, C-
Product was obtained as white solid (0.53 g, 67%); mp
114–116 °C; FTIR (KBr, cm ) νmax: 3062–2611, 3062,
−1
5
), 118.18 (C, CN), 110.65 (CH, C-7), 77.51 (CH2,
1703, 1680, 1609, 1537, 1457, 1276, 1015, 797, 734, 649;
1
OCH CH(CH ) ), 70.40 (CH, C H –CH CH(CN)OCH CH
H NMR (400 MHz, CDCl ): δ = 10.50 (br, 2H, 2x-
2
3 2
6
4
2
2
3
(
CH ) ), 60.65 (CH , COOCH CH ), 47.65 (CH , N–
COOH), 7.55 (d, 1H, Ar–H), 7.34 (m, 6H, Ar–H), 7.19
(m, 2H, Ar–H), 7.14 (m, 1H, Ar–H), 6.99 (d, 2H, Ar–H),
5.70 (s, 2H, N–CH –C H Cl), 4.02 (t, 1H, C H –CH CH
3
2
2
2
3
2
CH –C H Cl), 39.90 (CH , C H –CH CH(CN)OCH CH
(
2
6
4
2
6
4
2
2
CH ) ), 28.31 (CH, OCH CH(CH ) ), 19.17 and 19.14
3 2 2 3 2
2
6
4
6
4
2
(
CH , OCH CH(CH ) ), 13.63 (CH , COOCH CH );
(COOH)OCH3), 3.31 (s, 3H, C H –CH CH(COOH)
6 4 2
3
2
3 2
3
2
3
+
ESI–MS (m/z): [M+Na] Calcd for C H ClN O :
5
OCH ), 3.15 (m, 1H, C H –CH CH(COOH)OCH ), 3.06
3 6 4 2 3
3
1
31
2
3
1
3
14.20; Found: 537.04.
(m, 1H, C H –CH CH(COOH)OCH ); C NMR (100
6 4 2 3
MHz, CDCl ): δ = 176.99 (C, C H –CH CH(COOH)
3
6
4
2
Synthesis of different derivatives of N-substituted-3-[3-(2-
carboxy-2-alkoxyethyl)phenyl]-1H-indole-2-carboxylic
acids
OCH ), 166.91 (C, indole-2-COOH), 138.89 (C, C-2),
136.64 (C, C-1′), 136.13 (C, C-1″), 133.96 (C, C-3), 133.03
(C-Cl, C-4′), 131.70 (CH, C-2″), 128.93 (CH, C-6″), 128.80
3
(CH, C-3′,C-5′), 128.55 (CH, C-5″), 128.07 (CH, C-4″),
A mixture of (6a–f) (1.7 mmol), ethanol (30 mL), and 6 N
sodium hydroxide (10 mL) was heated to reflux for 3 h.
Water (30 mL) was added, and the solution was acidified
with concentrated hydrochloric acid (6 mL) and then
extracted with ethyl acetate (2 × 20 mL). The combined
organic layers were washed with brine, dried over sodium
sulfate, and concentrated. The product was recrystallized
from ethyl acetate/hexane and obtain (7a–f) as a solid.
127.93 (CH, C-3″), 127.81 (CH, C-2′, C-6′), 127.07 (C, C-
7a), 126.62 (CH, C-6), 122.74 (C, C-3a), 122.20 (CH, C-5),
121.42 (CH, C-4), 110.63 (CH, C-7), 81.28 (CH,
C H –CH CH(COOH)OCH ), 58.56 (CH , C H –CH CH
6
4
2
3
3
6
4
2
(COOH)OCH ), 47.86 (CH , N–CH –C H Cl), 38.66
3
2
2
6 4
(CH , C H –CH CH(COOH)OCH ); ESI–MS (m/z): [M
2
6
4
2
3
+
+Na] Calcd for C H ClNO : 463.11; Found: 486.34.
2
6
22
5
1-Benzyl-3-[3-(2-carboxy-2-ethoxyethyl)phenyl]-1H-indole-
1
-Benzyl-3-[3-(2-carboxy-2-methoxyethyl)phenyl]-1H-
2-carboxylic acid (7c)
indole-2-carboxylic acid (7a)
Product was obtained as white solid (0.48 g, 64%); mp
−
1
Product was obtained as white solid (0.51 g, 70%); mp
109–111 °C; FTIR (KBr, cm ) νmax: 3064–2609, 3034,
02–105 °C; FTIR (KBr, cm− ) νmax: 3062–2611, 3034,
1
1704, 1681, 1608, 1538, 1454, 1271, 1029, 737, 650; H
NMR (400 MHz, CDCl ): δ = 9.25 (br, 2H, 2x-COOH),
1
1
1
1
695, 1680, 1609, 1536, 1453, 1272, 1017, 734, 649; H
3
NMR (400 MHz, CDCl ): δ = 9.02 (br, 2H, 2x-COOH),
7.54 (d, 1H, Ar–H), 7.35 (m, 5H, Ar–H), 7.23 (m, 4H,
Ar–H), 7.13 (m, 1H, Ar–H), 7.06 (d, 2H, Ar–H), 5.78 (s,
2H, N–CH –C H ), 4.12 (t, 1H, C H –CH CH(COOH)
3
7
.54 (d, 1H, Ar-H), 7.33 (m, 5H, Ar–H), 7.22 (m, 4H,
Ar–H), 7.12 (m, 1H, Ar–H), 7.05 (m, 2H, Ar–H), 5.75 (s,
H, N–CH –C H ), 4.62 (t, 1H, C H –CH CH(COOH)
2
6
5
6
4
2
2
OCH CH ), 3.58 (m, 1H, C H –CH CH(COOH)OCH CH ),
2 3 6 4 2 2 3
2
6
5
6
4
2

Med Chem Res
3
.41 (m, 1H, C H –CH CH(COOH)OCH CH ), 3.15 (m,
Ar–H), 7.13 (m, 1H, Ar–H), 7.06 (m, 2H, Ar–H), 5.79 (s,
2H, N–CH –C H ), 4.12 (t, 1H, C H –CH CH(COOH)
6
4
2
2
3
1H, C H –CH CH(COOH)OCH CH ), 3.07 (m, 1H, C H –
6
4
2
2
3
6
4
2
6
5
6
4
2
CH CH(COOH)OCH CH ), 1.13 (t, 3H, C H –CH CH
OCH CH(CH ) ), 3.36 (m, 1H, OCH CH(CH ) ), 3.17 (m,
2 3 2 2 3 2
1H, OCH CH(CH ) ), 3.07 (m, 2H, C H –CH CH(COOH)
2 3 2 6 4 2
2
2
1
3
6
4
2
3
(
COOH)OCH CH ); C NMR (100 MHz, CDCl ): δ =
2
3
3
1
76.56 (C, C H –CH CH(COOH)OCH CH ), 166.73 (C,
OCH CH(CH ) ), 1.82 (m, 1H, OCH CH(CH ) ), 0.80 (d,
2 3 2 2 3 2
6H, OCH CH(CH ) ); C NMR (100 MHz, CDCl ): δ =
6
4
2
2
3
1
3
2 3 2 3
indole-2-COOH), 138.95 (C, C-2), 138.10 (C, C-1′), 136.17
C, C-1″), 134.12 (C, C-3), 131.72 (CH, C-2″), 128.89 (CH,
(
176.87
(C,
C H –CH CH(COOH)OCH CH(CH ) ),
6 4 2 2 3 2
C-6″), 128.61 (CH, C-3′, C-5′), 128.54 (CH, C-5″), 127.98 (C,
C-4″), 127.55 (C, C-7a), 127.23 (CH, C-4′), 127.03 (C, C-3″),
166.83 (C, indole-2-COOH), 138.96 (C, C-2), 138.12 (C,
C-1′), 136.28 (C, C-1″), 134.09 (C, C-3), 131.68 (CH, C-
2″), 128.90 (CH, C-6″), 128.66 (CH, C-5″), 128.61 (CH, C-
3′, C-5′), 127.93 (CH, C-4″), 127.64 (C, C-7a), 127.22 (CH,
C-4′), 127.05 (C, C-3″), 126.37 (CH, C-2′, C-6′, C-6),
122.90 (C, C-3a), 122.04 (C, C-4), 121.18 (C, C-5), 110.84
(CH, C-7), 80.15 (CH, C H –CH CH(COOH)OCH CH
1
1
26.37 (CH, C-2′, C-6′), 123.04 (C, C-3a), 122.02 (CH, C-5),
21.20 (C, C-4), 110.85 (CH, C-7), 79.71 (CH, C H –
6
4
CH CH(COOH)OCH CH ), 66.66 (CH , C H –CH CH
2
2
3
2
6
4
2
(
COOH)OCH CH ), 48.38 (CH , N–CH –C H ), 38.85
2 3 2 2 6 5
(
CH , C H –CH CH(COOH)OCH CH ), 15.02 (CH , C H –
2 6 4 2 2 3 3 6 4
+
6
4
2
2
CH CH(COOH)OCH CH ); ESI–MS (m/z): [M+Na] Calcd
(CH ) ), 77.97 (CH , OCH CH(CH ) ), 48.38 (CH , N–
3 2 2 2 3 2 2
2
2
3
for C H NO : 443.17; Found: 466.17.
CH –C H ), 38.94 (CH , C H –CH CH(COOH)OCH CH
2 6 5 2 6 4 2 2
27
25
5
(
CH ) ), 28.48 (CH,OCH CH(CH ) ), 19.23 and 19.14
3 2 2 3 2
+
1
1
-(4-chlorobenzyl)-3-[3-(2-carboxy-2-ethoxyethyl)phenyl]-
H-indole-2-carboxylic acid (7d)
(CH ,OCH CH(CH ) ); ESI–MS (m/z): [M+Na] Calcd
3 2 3 2
for C H NO : 471.20; Found: 494.23.
29 29 5
Product was obtained as white solid (0.33 g, 41%); mp
1-(4-chlorobenzyl)-3-[3-(2-carboxy-2-isobutoxyethyl)
phenyl]-1H-indole-2-carboxylic acid (7f)
22–124 °C; FTIR (KBr, cm− ) νmax: 3446–2854, 1709,
1
1
1
1
609, 1537, 1458, 1270, 1096, 735, 650; H NMR (400
MHz, CDCl ): δ = 7.55 (d, 2H, Ar–H), 7.35 (m, 5H, Ar–H),
Product was obtained as white solid (0.48 g, 56%); mp
178–180 °C; FTIR (KBr, cm ) νmax: 3053–2606, 3053,
3
−1
7
.25 (m, 2H, Ar–H), 7.16 (m, 1H, Ar–H), 7.02 (d, 2H,
Ar–H), 5.72 (s, 2H, N–CH –C H Cl), 4.52 (br, 2H, 2x-
1700, 1667, 1611, 1533, 1458, 1267, 1016, 801, 738, 699;
2
6 4
1
COOH), 4.14 (t, 1H, C H –CH CH(COOH)OCH CH ),
H NMR (400 MHz, CDCl ): δ = 7.54 (d, 1H, Ar–H), 7.35
6
4
2
2
3
3
3
1
.60 (m, 1H, C H –CH CH(COOH)OCH CH ), 3.50 (m,
(m, 6H, 2x-COOH, Ar–H), 7.25 (s, 2H, Ar–H), 7.21 (d, 2H,
Ar–H), 7.15 (t, 1H, Ar–H), 7.01 (d, 2H, Ar–H), 5.73 (s, 2H,
N–CH –C H Cl), 4.11 (t, 1H, C H –CH CH(COOH)
6
4
2
2
3
H, C H –CH CH(COOH)OCH CH ), 3.12 (br, 2H,
6
4
2
2
3
C H –CH CH(COOH)OCH CH ), 1.15 (br, 3H, C H -
CH CH(COOH)OCH CH ); C NMR (100 MHz, CDCl3):
6
4
2
2
3
6
4
2
6
4
6
4
2
1
3
OCH CH(CH ) ), 3.36 (m, 1H, OCH CH(CH ) ), 3.18 (m,
2 3 2 2 3 2
2
2
3
δ = 176.46 (C, C H –CH CH(COOH)OCH CH ), 165.60
3H, OCH CH(CH ) , C H –CH CH(COOH)OCH CH
2 3 2 6 4 2 2
6
4
2
2
3
(
1
1
C, indole-2-COOH), 138.77 (C, C-2), 136.71 (C, C-1′),
35.96 (C, C-1″), 134.01 (C, C-3), 133.08 (CCl, C-4′),
31.93 (CH, C-2″), 128.91 (CH, C-6″), 128.84 (CH, C-3′,
(CH ) ), 1.84 (m, 1H, OCH CH(CH ) ), 0.82 (d, 6H,
3 2 2 3 2
1
3
OCH CH(CH ) ); C NMR (100 MHz, CDCl ): δ =
2
3 2
3
176.03
(C,
C H –CH CH(COOH)OCH CH(CH ) ),
6
4
2
2
3 2
C-5′), 128.08 (CH, C-5″), 128.02 (C, C-4″), 127.90 (CH, C-
166.19 (C, indole-2-COOH), 138.79 (C, C-2), 136.63 (C,
C-1′), 136.08 (C, C-1″), 133.94 (C, C-3), 133.01 (C-Cl, C-
4′), 131.74 (CH, C-2″), 128.77 (CH, C-3′, C-5′, C-5″, C-6″),
127.95 (CH, C-4″), 127.80 (CH, C-2′, C-6′), 127.62 (C, C-
3″), 127.04 (C, C-3a, 7a), 126.47 (CH, C-6), 122.11 (CH,
C-4), 121.32 (CH, C-5), 110.58 (CH, C-7), 80.06 (CH,
C H -CH CH(COOH)OCH CH(CH ) ), 77.91 (CH2,
2
3
7
′, C-6′), 127.06 (C, C-7a), 125.03 (C, C-3″), 124.09 (C, C-
a), 121.20 (C, C-4), 121.10 (CH, C-5), 110.67 (CH, C-7),
7.31 (CH, C H –CH CH(COOH)OCH CH ), 66.60 (CH ,
6
4
2
2
3
2
C H –CH CH(COOH)OCH CH ), 47.86 (CH , N–CH –
6
4
2
2
3
2
2
C H Cl), 38.76 (CH , C H –CH CH(COOH)OCH CH ),
6
4
2
6
4
2
2
3
1
5.13 (CH , C H –CH CH(COOH)OCH CH ); ESI–MS
3 6 4 2 2 3
6
4
2
2
3 2
+
(
m/z): [M-1] Calcd for C H ClNO : 477.13; Found:
OCH CH(CH ) ), 47.80 (CH , N–CH –C H Cl), 38.77
2 3 2 2 2 6 4
2
7
24
5
4
76.20.
(CH , C H –CH CH(COOH)OCH CH(CH ) ), 28.50 (CH,
2 6 4 2 2 3 2
OCH CH(CH ) ), 19.22 and 19.14 (CH , OCH CH
2
3 2
3
2
+
1
-Benzyl-3-[3-(2-carboxy-2-isobutoxyethyl)phenyl]-1H-
(CH ) ); ESI–MS (m/z): [M+Na]
Calcd for
3
2
indole-2-carboxylic acid (7e)
C H ClNO : 505.16; Found: 528.11.
29 28 5
Product was obtained as white solid (0.40 g, 50%); mp
Molecular docking methods
72–174 °C; FTIR (KBr, cm− ) νmax: 3063–2610, 3034,
1
1
1
1
710, 1681, 1607, 1534, 1454, 1271, 1029, 738, 650; H
The crystal structure of PPARγ (PBD code: 2PRG) com-
plexed with rosiglitazone was selected for the docking
study. The protein was energy optimized, minimized by
NMR (400 MHz, CDCl ): δ = 10.10 (br, 2H, 2x-COOH),
3
7
.54 (d, 1H, Ar–H), 7.37 (m, 5H, Ar–H), 7.26 (m, 4H,

Med Chem Res
Fig. 2 a Crystal structure of rosiglitazone (yellow) interact with H12
of PPARγ ligand binding domain (LBD) through H-bond with Tyr327,
His449, and Tyr473 amino acid residues (orange). The hydrogen
bonding part of compound 7b (cyan) interact with β-sheet (green) of
PPARγ-LBD through H-bond with Ser342 amino acid residue
(magenta) and lie between H3 (red) and β-sheet region (green). b
Crystal structure of rosiglitazone showing H-bond with Tyr327,
His449, and Tyr473 amino acid residue (orange). c–h Crystal structure
of synthesized compounds (7a-f) forming H-bond with Ser342 amino
acid residues (orange), respectively
removing unwanted molecules and other defects reported
by the SYBYL 7.3 software (Verma et al. 2013b). All
newly synthesized molecules were built onto crystal struc-
ture of rosiglitazone extracted from crystal structure of
PPARγ. They were assigned Gasteiger–Huckel charges and
subsequently minimized using the Powel method. The
energy-optimized sketched molecules were subjected to
docking run at the ligand binding site of PPARγ by Surflex
dock in SYBYL7.3 (Sybyl 2006; Verma et al. 2012a, b,
bond distances) of the synthesized molecules at the
respective active sites were also compared to those of
rosiglitazone (Fig. 2).
In vivo analysis
Experimental animals
Male Wistar rats (250–270 g), of 10–12 weeks of age bred
in the Central Animal House, Panjab University, Chandi-
garh, India were used. The animals were housed under
standard laboratory conditions, maintained on a 12 h light
and dark cycle and fed with controlled standard pellet diet
(Ashirwad Industries, Chandigarh, India) and water ad
libitum. The experimental protocols were approved by the
Institutional Animal Ethics Committee, Panjab University,
2
013a, b, 2015). Docking analysis was conducted using the
Surflexdock module to predict and examine the binding
modes of the synthesized derivatives at the active site of
PPARγ. The energy-minimized structure of rosiglitazone
was initially docked into PPARγ to determine binding
conformation of rosiglitazone at the active sites. The
hydrogen bonding interactions (amino acid residues and

Med Chem Res
Chandigarh (PU/IAEC/516 dated 15/4/2014) and conducted
according to Committee for the Purpose of Control and
Supervision on Experiments on Animals guidelines for the
use and care of experimental animals.
(ANOVA). Statistical significance was considered at p <
0.05. The statistical analysis was done using the Jandel
Sigma Stat Statistical Software version 2.0.
Drug
Results and discussion
Chemistry
Streptozotocin was purchased from Sigma (St. Louis, MO,
USA). A glucose oxidase peroxidase diagnostic enzyme kit
was purchased from Span Diagnostic Chemicals, Surat,
India. All other chemicals are of analytical grade.
The synthetic strategy designed for the synthesis of indolyl
linked α-alkoxy carboxylic acids based targeted NCEs
(7a–f) involved the preparation of the indolyl linked
methoxy vinyl derivatives (4a/b) from the corresponding
indolyl linked benzaldehydes (3a/b). These methoxy vinyl
derivatives were then converted to corresponding dialkoxy:
acetal derivatives (5a–f) by simply refluxing with the
alcohol concerned (viz methanol, ethanol and isobutanol) in
the presence of catalytic amount of p-toluenesulphonic acid.
The acetals (5a–f) upon treatment with trimethylsilylcya-
nide in the presence of boron trifluoride gave the required
indolyl linked α-alkoxy propionitriles (6a–f) and which
upon subsequent alkaline hydrolysis while using sodium
hydroxide gave the desired and targeted NCEs (7a–f)
(Schemes 1 and 2). The indolyl linked benzaldehydes (3a/
b) required in this synthetic sequence in turn were prepared
by Suzuki coupling of (2a/b) with commercially available
Induction of diabetes and antidiabetic assay
A single intraperitoneal injection of streptozotocin (55 mg/
kg) prepared in citrate buffer (pH 4.4, 0.1 M) was used to
induce diabetes. The age matched control rats received an
equal volume of citrate buffer. Diabetes was confirmed after
4
8 h of streptozotocin injection, the blood samples were
collected through tail vein and plasma glucose levels were
estimated by enzymatic glucose oxidase peroxidase (GOD-
PAP) diagnostic kit method. The rats having plasma glucose
levels more than 250 mg/dl were selected and used for the
present study (Kuhad and Chopra 2008; Kuhad et al. 2008).
Body weight and plasma glucose levels were measured
before and at the end of the experiment to see the effect of
compounds (7a, 7b, 7c, 7d, 7e, 7f) on these parameters.
3
-formylphenylboronic acid using Pd(PPh ) as catalyst.
3 4
Statistical analysis
The (2a/b) in turn was obtained using commercially avail-
able ethyl 1H-indole-2-carboxylate through its bromination
with NBS and further subsequent benzylation with benzyl
bromide and 4-chlorobenzylbromide (Scheme 1).
Results were expressed as mean ± S.E.M. The intergroup
variation was measured by one way analysis of variance
OH
B
CHO
Br
HO
Br
Br
CHO
X
N
N
COOEt
COOEt
COOEt
b
c
X
N
H
X
1
2a/b
3a/b
d
a
code
X
H
Cl
OCH3
COOEt
2
a/3a/4a
b/3b/4b
N
H
N
2
COOEt
X
4a/b
2 3 3 4
Scheme 1 Reagents and conditions: (a) NBS, dry DMF, rt; (b) K CO , dry DMF, rt; (c) Pd(PPh ) , Dioxane : Water (4:1), reflux, 12 h; (d)
+
−
3 2
Ph P CH OMeCl , LDA, THF, −10 °C-rt, 2 h

Med Chem Res
OR
CN
OR
OCH 3
OR
a
b
N
N
N
COOEt
COOEt
COOEt
X
X
X
4a/b
(5a-f)
(6a-f)
c
Code
X
R
5a/6a/7a
5b/6b/7b
5c/6c/7c
5d/6d/7d
5e/6e/7e
5f/6f/7f
H
Cl
H
CH3
COOH
OR
CH3
CH CH3
2
N
Cl
H
CH CH3
2
COOH
X
CH CH(CH )
3 2
2
Cl
CH CH(CH )
3 2
(7a-f)
2
3 2 2
Scheme 2 Reagents and conditions: (a) ROH, p-TsOH, reflux, 12 h; (b) TMSCN, BF –Et O, DCM, rt, 1 h; (c) NaOH, H O, EtOH, reflux, 3 h
The presence of two weak bands representing the cou-
in the ratios 1:1 and 1:1 respectively for 4a and 4b. The
presence of [M+Na] peak at m/z 434(100), and m/z 468
(100) in the mass spectrum of 4a and 4b, respectively
provide additional support to the structure assigned to the
both molecules.
+
pled doublet characteristic of aldehydic C–H stretch at 2826
−
1
−1
and 2727 cm and at 2826 and 2726 cm along with
−
1
aldehydic C=O stretch at 1702 cm and ester C=O stretch
−
1
at 1701 cm in both aldehydes (3a/b) and respectively in
the infrared (IR) spectrum of both the compounds confirm
the structure assigned. Further support to the structure
assigned is indicated by the presence of 1H singlet at 10.06
and 10.07 ppm for the aldehydic proton and additional
presence of 2H singlet for the benzylic proton at 5.83 and
The presence of C–O–C stretch at around 1245–1043
cm− in all compounds (5a–f) not only confirmed the
structure assigned but also establishes the formation of the
dialkoxy acetal required to be present in these compounds.
The PMR spectrum of all these compounds similarly lacks
the signals corresponding to two isomeric 3H singlets for
the methoxy group present in case of (4a/b) at around
3.73–3.66 and 3.74–3.67 ppm for the trans and cis isomer
respectively and the presence on the other hand of 1H triplet
and 2H doublet at around 4.62, 4.62, 4.72, 4.71, 4.69, 4.69
ppm and 2.98, 2.98, 2.99, 2.99, 2.99, 2.99 ppm for the
methylenic and methynic protons of the ethyl type unit
(–O–C H –CH CH–), thus generated during this reaction
1
5
.79 ppm, respectively in the PMR spectrum of these
aldehydes (3a/b). The structure assigned to both these
compounds was further confirmed from the presence of [M
+
+
Na] peak at m/z 406(100) and at m/z 440(60) in the mass
spectrum of 3a and 3b, respectively.
The appearance of characteristic C=C stretch at
−
1
1
651–1601 cm with the simultaneous disappearance of
the doublet for the coupled C-H stretch of the aldehydic
6
4
2
−1
group at 2826–2727 and 2826–2726 cm and the aldehy-
along with the presence various signals in the ratio and
multiplicities expected for the presence of the required
dialkoxy acetal in all these compounds (5a–f) confirmed the
structure assigned. All these informations coupled with the
−
1
dic C=O stretch at 1702 cm , respectively present in the
IR spectrum of 4a and 4b not only establishes the com-
pletion of the reaction but also confirmed the structure
assigned to the both compounds.
+
presence of [M+Na] peak in the mass spectrum of (5a–f)
Similar information supporting the structure assigned
and indication of the presence of the two geometric isomers
in each of these compounds in the ratios 1:1 were obtained
from the presence of a two isomeric 3H singlet of the
methoxy group at 3.73–3.66 and 3.74–3.67 ppm for the
trans and cis isomer, respectively and two 1H doublets each
at 7.06 -5.87 ppm (J = 13.00–13.00 Hz) and 7.03–5.87 ppm
at m/z 465(100), 500(100), 494(80), 528(100), 550(100)
and 584(100) provide additional support to the structure
assigned.
The presence of a band at around 2253 cm− corre-
sponding to the –CN stretching frequency in the IR spec-
trum of all these compounds (6a–f) along with the presence
of the signals characteristic of the alkoxy group present in
these compounds in the ratio corresponding to monoalkoxy
derivative as two 1H double doublet at 3.56–3.24 ppm and
3.56–3.24 ppm and a 1H multiplet at 1.92–1.92 ppm and a
1
(
J = 13.00–12.97 Hz) for the trans isomer and at 6.13–5.26
ppm (J = 7.00–7.04 Hz) and 6.14–5.26 ppm (J = 7.04–7.04
Hz) for the cis isomer, respectively in their PMR spectrum

Med Chem Res
6
H doublets at 0.88–0.90 ppm, respectively for the methy-
rosiglitazone forms the hydrogen bonding with Tyr327,
His449, and Tyr473. Full agonist rosiglitazone contact
helix12 (H12) in PPARγ, stabilizing the activation function
2 (AF2) through hydrogen bond (H-bond) to Tyr473 (Liu
et al. 2011). The carboxylic groups of all synthesized
compounds (7a–f) lack interaction with Tyr473 in H12, but
interact with β-sheet through H-bond with Ser342 amino
acid residue as found in most of the reported partial agonists
(Fig. 2). Partial agonists did not interact with Tyr473 there
by no stabilization of H12 (Bruning et al. 2007; Einstein
et al. 2008). The binding modes of all novel synthesized
ligands (7a–f) lie between H3 and β-sheet region, which is
very similar to that of other reported partial agonists such as
nTZDpa, SR145, SR147, and MRL-24 (De Groot et al.
2013; Guasch et al. 2011). On the basis of docking studies,
compounds (5a–f) and (6a–f) being intermediates during
synthesis of targeted compounds (7a–f), are not subjected to
biological evaluations as the antidiabetic effect of the tar-
geted compounds is expected because of α-alkoxy car-
boxylic acid moiety being an acyclic analog of
oxazolidinedione which in turn being bioisostere of thia-
zolidinedione moiety (present in standard ligand rosiglita-
zone) for the H-bond interaction rather than the indole unit.
Hence, compounds (5a–f) and (6a–f) being dialkoxy and
alkoxy nitriles lacks α-alkoxy carboxylic acid moiety are
not subjected to antidiabetic studies.
lenic, methynic and terminal dimethyl based protons of the
isobutoxy –CH CH(CN)OCH CH(CH ) group present in
case of 6e and 6f and as two 2H overlapping quartet at
around 3.89 and 3.57 ppm and a 3H triplet at around 1.19
and 1.27 ppm, respectively for the methylinic, methyl based
protons of the ethoxy –CH CH(CN)OCH CH group pre-
sent in 6c and 6d while the methoxy –CH CH(CN)OCH
group in case of 6a and 6b appeared as 3H singlet at 3.51
ppm in its PMR spectrum. The presence of 1H triplet and
2
2
2
2
3 2
2
2
3
2
3
H doublet at 4.62, 4.30, 4.36, 4.36, 4.69, 4.33 ppm and
.98, 3.19, 3.23, 3.23, 3.24, 3.24 ppm for the methylenic
and methynic protons of the ethyl type unit
(
(
–C H –CH CH–) present in case of all these compounds
6 4 2
6a–f) similarly not only confirm the structure assigned but
also support the complete conversion of the dialkoxy acetals
to corresponding alkoxy nitriles as expected. The presence
of [M+Na] peak at m/z 461(100), 495(100), 475(100),
+
5
09(100), 503(100) and 537(100) in the mass spectrum
provide additional support to the structure assigned to these
compounds (6a–f).
The appearance of the a broad band around at
−
1
3
1
400–2600 cm and a strong and sharp band around at
−
1
710–1667 cm in the IR spectrum of all these compounds
(
7a–f) corresponding to the bonded O–H stretch and two
carbonyl C=O stretch of the carboxyl group present in all
these compounds (7a–f) along with simultaneous dis-
−
1
appearance of the band at around 2253 cm corresponding
to the –CN stretching frequency present in the IR spectrum
corresponding alkoxy nitriles (6a–f) confirm the structure
assigned to all these compounds and also established the
completion of the hydrolysis of the nitriles to the required
carboxylic acids. The presence of [M] peak at m/z 429(60)
in case of 7a, [M-1] peak at m/z 476(100) in case of 7d,
and [M+Na] peak at m/z 486(100), 466(100), 494(100)
In vivo studies
Rats were randomly selected and divided into nine groups
of 6 animals each. Group I consisted of control animals
receiving vehicle, group II was the diabetic animals, group
III, IV, V, VI, VII and VIII consisted of diabetic animals
treated with compounds 7a, 7b, 7c, 7d, 7e, and 7f at a dose
of 8 mg/kg/day (orally) and group IX diabetic animals
receiving rosiglitazone (8 mg/kg/day, orally) for 4 weeks
starting from third day after streptozotocin (STZ) injection.
Compounds and standard drug were suspended in 0.25%
CMC before administration in a constant volume of 5 mL/
kg body weight. On last day, blood was collected through
tail vein. Glucose content was determined in blood plasma.
Four weeks after STZ injection, plasma glucose levels were
significantly increased in diabetic rats (456 ± 4.6 mg/dl) as
compared to the control rats (102 ± 3.1 mg/dl). There was a
marked decline in the body weight of STZ-treated rats as
compared to age-matched control rats (Table 1). Chronic
treatment with compounds 7a, 7b, 7c, 7d, 7e, and 7f sig-
nificantly improved the blood glucose levels and body
weight of diabetic rats (p < 0.05). However, compounds 7b,
7c, and 7d showed best glucose lowering effects. Com-
pound 7b has glucose lowering equivalent to rosiglitazone
(Fig. 3).
+
+
+
and 528(100) in case of 7b, 7c, 7e, and 7f respectively in
the mass spectra provide additional support to the structure
assigned to the targeted compounds (7a–f) beyond doubt.
Molecular docking
The α-alkoxy carboxylic acid moiety (present in all targeted
compounds), an acyclic analog of oxazolidinedione, which
in turn being a bioisostere of thiazolidinedione moiety
present in standard drug tends to mimic the thiazolidine-
dione ring of rosiglitazone and hence rosiglitazone (com-
mercial availability) is employed being a full PPARγ
agonist (PDB Code: 2PRG) and to compare the partial
PPARγ agonism expected because of α-alkoxy carboxylic
acid moiety present in the targeted compounds. The com-
pounds (7a–f) were docked into binding site of PPARγ
protein (PDB Code: 2PRG) and taking rosiglitazone as
reference molecules. The thiazolidinedione moiety of

Med Chem Res
Table 1 Effect of compounds on body weight and blood glucose level
Guasch et al. 2011; Kroker and Bruning 2015). The pre-
sence of carboxylic acid group in the structure of all the six
targeted compounds (7a–f) as a hydrogen bonding part
attached to central flat meta-substituted phenyl ring which is
directly linked to the 3-position of indole nucleus, for
imparting constraint into the molecules and the carboxylic
group substituted at 2-position of indole ring was found to
play an important role in H-bond formation with Ser342.
These features could perfectly orient these molecules to fit
the U-shape conformation inside the binding site. The most
active compound 7b is comparable in potency to the rosi-
glitazone (standard drug). Likewise among the alkyl chain a
maximum activity is observed for the methyl group (smaller
group) rather than ethyl or isobutyl. Thus, a series of (7a–f)
α-alkoxy carboxylic acids was synthesized and tested.
The targeted compounds being communicated in this
paper (7a–f) are duly protected (Verma et al. 2016)
under patent application number 201611030034 dated
Groups
Body weight (g)
Blood glucose levels
mg/dl)
(
Onset of
study
End of study Onset of
study
End of study
Control
263 ± 3.0 296 ± 3.3
99 ± 3.2 102 ± 3.1
Diabetic
269 ± 4.4 262 ± 3.0*
101 ± 1.2 456 ± 4.6*
#
#
Rosiglitazone 265 ± 2.8 290 ± 2.9
Compound 7a 264 ± 4.6 277 ± 4.4
Compound 7b 266 ± 3.6 288 ± 3.5
Compound 7c 262 ± 5.7 280 ± 6.4
Compound 7d 268 ± 3.9 284 ± 3.8
Compound 7e 264 ± 2.5 273 ± 2.0
Compound 7f 268 ± 3.7 276 ± 4.9
102 ± 1.9 182 ± 5.6
#
#
#
#
#
#
#
95 ± 0.9 311 ± 7.3
#
102 ± 3.3 189 ± 6.9
#
103 ± 3.5 287 ± 5.9
#
97 ± 1.1 267 ± 4.8
#
101 ± 2.1 322 ± 2.4
#
105 ± 1.6 327 ± 8.8
The result was expressed as mean ± S.E.M.
#
*
p < 0.05 as compared to control animals; p < 0.05 as compared to
diabetic group. The intergroup variation was measured by one way
analysis of variance (ANOVA)
02.09.2016 for permission relating to commercial use of
these compounds please contact principal investigator at
raman_verma58@yahoo.com.
Conclusion
A novel class (7a–f) of potent PPARγ modulators were
developed that display different binding modes in the active
site of PPARγ (PDB: 2PRG) as compared to the marketed
TZD full agonist rosiglitazone but analogs to some standard
partial agonists. All the tested compounds significantly
improved the blood glucose levels leading to anti-diabetic
effect while the adverse effect such as body weight gain was
attenuated as compared to rosiglitazone. However, com-
pounds 7b, 7c, and 7d showed best anti-diabetic effect.
Compound 7b exhibited maximum glucose lowering
equivalent to rosiglitazone.
Acknowledgements Authors are thankful to the Punjabi University,
Patiala authorities for providing the necessary research facilities. We
are also grateful to Manish Kumar and Anoop Patyal of Sophisticated
Analytical Instrumentation Facility (SAIF), Panjab University, Chan-
digarh, respectively, for extending the facilities for spectral analysis of
the compounds reported in this paper. One of the authors (A.S.) is
thankful to UGC, New Delhi for awarding the UGC-BSR Fellowship.
Fig. 3 a Effect of compounds on blood glucose levels in diabetic rats.
*
b Effect of compounds on body weight in diabetic rats. p < 0.05 as
#
compare to control animals; p < 0.05 as compare to diabetic group
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no compet-
ing interest.
Structure–activity relationship (SAR) of the targeted
molecules
The SAR and the crucial pharmacophoric features of the
targeted molecules, which showed high in vivo anti-
hyperglycemic activity, 7b, was matched with that repor-
ted for partial PPARγ agonists (De Groot et al. 2013;
References
Bajare S, Anthony J, Nair A, Marita R, Damre A, Patel D, Rao C,
Sivaramakrishnan H, Deka N (2012) Synthesis of N-(5-chloro-6-

Med Chem Res
(
quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide derivatives
Kuhad A, Chopra K (2008) Effect of sesamol on diabetes-associated
cognitive decline in rats. Exp Brain Res 185:411–420
as non-TZD peroxisome proliferator-activated receptor
γ
(
PPARγ) agonist. Eur J Med Chem 58:355–360
Kuhad A, Sethi R, Chopra K (2008) Lycopene attenuates diabetes-
associated cognitive decline in rats. Life Sci 83:128–134
Liu W, Lau F, Liu K, Wood HB, Zhou G, Chen Y, Li Y, Akiyama TE,
Castriota G, Einstein M, Wang C, McCann ME, Doebber TW,
Wu M, Chang CH, McNamara L, McKeever B, Mosley RT,
Berger JP, Meinke PT (2011) Benzimidazolones: A new class of
selective peroxisome proliferator-activated receptor γ (PPARγ)
Modulators. J Med Chem 53:8541–8554
Berger J, Moller DE (2002) The mechanisms of action of PPARs.
Annu Rev Med 53:409–435
Matin A, Gavande N, Kim MS, Yang NX, Salam NK, Hanrahan JR,
Roubin RH, Hibbs DE (2009) 7-Hydroxy-benzopyran-4-one
derivatives: A novel pharmacophore of peroxisome proliferator-
activated Receptor α and -γ (PPARα and γ) dual agonist. J Med
Chem 52:6835–6850
Bruning JB, Chalmers MJ, Prasad S, Busby SA, Kamenecka TM, He
Y, Nettles KW, Griffin PR (2007) Partial agonists activate PPARγ
Pirat C, Farce A, Lebegue N, Renault N, Furman C, Millet R, Yous S,
Speca S, Berthelot P, Desreumaux P, Chavatte P (2012) Target-
ing peroxisome proliferator-activated receptors (PPARs): Devel-
opment of modulators. J Med Chem 55:4027–4061
Seto S, Okada K, Kiyota K, Isogai S, Iwago M, Shinozaki T, Kitamura
Y, Kohno Y, Murakami K (2010) Design, synthesis, and
structure-activity relationship studies of Novel 2,4,6-trisub-
stituted-5-pyrimidinecarboxylic acids as peroxisome proliferator-
activated receptor γ (PPARγ) partial agonists with comparable
antidiabetic efficacy to rosiglitazone. J Med Chem 53:5012–5024
Sybyl 7.3 (2006) Tripos Inc. 1699 Hanley Road, St. Louis 63144,
USA
Verma RK, Ghosh P, Kumar V, Wadhwa LK (2012a) The application
of comparative molecular field analysis for the design of α-anilino
substituted-3-phenyl propanoic acids as novel PPARα/γ dual
ligands. Med Chem Res 21:2873–2884
Verma RK, Kumar V, Ghosh P, Wadhwa LK (2012b) Heterocyclyl
linked anilines and benzaldehydes as precursors for biologically
significant new chemical entities. J Chem Sci 124:1063–1069
Verma RK, Kumar V, Ghosh P, Wadhwa LK (2013a) 3D-QSAR study
of tyrosine and propanoic acid derivatives as PPARα/γ dual
agonists using CoMSIA. Med Chem Res 22:287–302
Verma RK, Mall R, Ghosh P, Kumar V (2013b) Design and synthesis
of benzimidazole-linked meta-substituted benzylidenes/benzyls
as biologically significant new chemical entities. Synth Commun
43:1882–1895
Verma RK, Mall R, Singh A (2015) Indolyl linked meta-substituted
benzylidene-based novel PPAR ligands: synthetic and docking
studies. Med Chem Res 24:1396–1407
Verma RK, Mall R, Singh A (2016) Novel indole derivatives as anti-
diabetic agents and method thereof. IN Patent 201611030034,
filled 2 September 2016
using
258–1271
De Groot JC, Weidner C, Krausze J, Kawamoto K, Frank C, Schroeder
FC, Sauer S, Bussow K (2013) Structural characterization of
a helix 12 independent mechanism. Structure 15:
1
̈
amorfrutins bound to the peroxisome proliferator-activated
receptor γ. J Med Chem 56:1535–1543
Einstein M, Akiyama TE, Castriota GA, Wang CF, McKeever B,
Mosley RT, Becker JW, Moller DE, Meinke PT, Wood HB,
Berger JP (2008) The differential interactions of peroxisome
proliferator-activated receptor γ ligands with Tyr473 is a physical
basis for their unique biological activities. Mol Pharmacol
7
3:62–74
Epple R, Cow C, Xie Y, Azimioara M, Russo R, Wang X, Wityak J,
Karanewsky DS, Tuntland T, Nguyen-Tran VTB, Ngo CC,
Huang D, Saez E, Spalding T, Gerken A, Iskandar M, Seidel HM,
Tian SS (2010) Novel bisaryl substituted thiazoles and oxazoles
as highly potent and selective peroxisome proliferator-activated
receptor δ agonists. J Med Chem 53:77–105
Guasch L, Sala E, Valls C, Blay M, Mulero M, Arola L, Pujadas G,
Garcia-Vallve S (2011) Structural insights for the design of new
PPARgamma partial agonists with high binding affinity and low
transactivation activity. J Comput Aided Mol Des 25:717–728
Hopkins CR, O’Neil SV, Laufersweiler MC, Wang Y, Pokross M,
Mekel M, Evdokimov A, Walter R, Kontoyianni M, Petrey ME,
Sabatakos G, Roesgen JT, Richardson E, Demuth TP (2006)
Design and synthesis of novel N-sulfonyl-2-indole carboxamides
as potent PPAR-gamma binding agents with potential application
to the treatment of osteoporosis. Bioorg Med Chem Lett
1
6:5659–5663
Kroker AJ, Bruning JB (2015) Review of the structural and dynamic
mechanisms of PPARγ partial agonism. PPAR Res 2015:1–15