The first target specific, highly diastereoselective synthesis, design and characterization of pyranoquinolinyl acrylic acid diastereomers as potential α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bioorg.2018.11.026

In the present investigation we report the first target specific, highly diastereoselective synthesis of new class of pyranoquinolinyl/furoquinolinyl-acrylic acid diastereomers and evaluation of their invitro α-glucosidase inhibitory activity. All the pro

Full text of DOI:10.1016/j.bioorg.2018.11.026

Accepted Manuscript
The first target specific, highly diastereoselective synthesis, design and charac-
terization of pyranoquinolinyl acrylic aciddiasteromers as potential α-glucosi-
dase inhibitors
G. Lavanya, K. Venkatapathy, C.J. Magesh, M. Ramanathan, R. Jayasudha
PII:
S0045-2068(18)30705-3
DOI:
https://doi.org/10.1016/j.bioorg.2018.11.026
YBIOO 2634
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 July 2018
26 October 2018
17 November 2018
Please cite this article as: G. Lavanya, K. Venkatapathy, C.J. Magesh, M. Ramanathan, R. Jayasudha, The first target
specific, highly diastereoselective synthesis, design and characterization of pyranoquinolinyl acrylic
aciddiasteromers as potential α-glucosidase inhibitors, Bioorganic Chemistry (2018), doi: https://doi.org/10.1016/
j.bioorg.2018.11.026
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
The first target specific, highlydiastereoselective
synthesis, design and characterization of
pyranoquinolinylacrylic aciddiasteromers as potential
α-glucosidase inhibitors.
Leave this area blank for abstract info.
G. Lavanyaa, K. Venkatapathya, C. J.Magesha*, M. Ramanathanb, R.Jayasudhaa

The first target specific, highly diastereoselective synthesis, design and characterization
of pyranoquinolinyl acrylic aciddiasteromers as potential α-glucosidase inhibitors.
G. Lavanyaa, K. Venkatapathya, C. J. Magesha*, M. Ramanathanb, R. Jayasudhaa
aPG& Research Department of Chemistry, Arignar Anna Govt Arts College, Cheyyar,
Tamilnadu
bDepartment of Chemistry, National Taiwan University, Roosevelt Road, Taipei, 10617,
Taiwan
Abstract
In the present investigation we report the first target specific, highly diastereoselective
synthesis of new class of pyranoquinolinyl/furoquinolinyl-acrylic acid diastereomers and
evaluation of their invitro α-glucosidase inhibitory activity. All the products were thoroughly
1
13
characterized by H-NMR, C-NMR, FT-IR, Mass spectral and CHN analysis. A highly
diastereoselective target specific route of synthesis for the biologically active diastereomers
were developed by usingchiral catalyst Europium tris[3-heptafluoropropylhydroxyl
methylene]-(-)-camporate (A) or Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-
camporate (B). It was found that among a set of 4 diastereomeric products obtained,
exodiasteromers of pyranoquinolinyl acrylic acid adducts exhibited relatively high α-
glucosidase inhibitory activity. The newly synthesized compounds exhibited IC50 values in
the range of (0.40 ± 0.02 - 30.3 ± 0.84μM) as compared to standard acarbose (IC50=0.65±
0.02μM). It was found that compounds 11a, 11c, 11d and 12d were found to be more active
than standard acarbose. It was also found that unsubstituted compound (11a) or compounds
with chlorine or methoxy substituent (11c, 11d, 12d) showed potential α-glucosidase
inhibitory activity. However a reversal in activity was observed with Nitro substituent (11b,
13b) wherein the endodiastereomers were found to be more active than exodiastereomers.
Molecular docking studies were used for design of the compound and understand the mode of
binding between the compound and target enzyme. A plausible mechanism for the
diastereoselective synthesis was also proposed.
Keywords:Target specific synthesis, α-glucosidase inhibitors, antidiabetic, Diastereoselective
synthesis, pyranoquinolinyl acrylic acid diastereomers.
*Corresponding author.
E-mailaddress:cjmageshchemistry@gmail.com (C. J. MAGESH)

1. Introduction
Diabetes describes a group of metabolic diseases in which the person has high blood
sugar either because of inadequate insulin production (or) because the body’s cells do not
respond properly to insulin (or) both [1-2]. In 2013, it was estimated that over 382 million
people throughout the world had diabetes [3-4]. Different types of drugs such as biguanidus,
sulfonylureas, thiazolidinedones and α-glucosidase inhibitors are used for the control and
mitigation of diabetes [5-6]. α-glucosidase enzyme exists in the brush border surface of the
intestinal cells wherein they slow down the absorption of monosaccharide’s in the intestine
and hence reduce the glucose level in the blood stream [7]. α-glucosidase inhibitors like
acarbose, voglibose, miglitol, nojirimycin are used effectively as a therapeutic drugs for the
last two decenniums [8-9]. During the last two decades, various α-glucosidase inhibitors have
been reported [10-19]. However many of these commercial α-glucosidase inhibitors are
associated with side effects such as flatulence, obesity, hepatic disorders, gastrointestinal
diseases,diarrhea, improper absorption and elimination [20-23]. Christian Bommeret al [24]
reported the economic burden of diabetes, including its diagnosis treatment costs and hence
loss of productivity to be around 1.8% of the global gross domestic product. As a result of its
direct impact on the global economy and on the individual quality of life, the development of
new, potentialantidiabetic compounds with minimal or no side effects is desired. In the
present investigation we report the design, synthesis and characterization of new class of
pyranoquinolinyl/furoquinolinyl acrylic acid diastereomers as potential α-glucosidase
inhibitors. We have also established the diastereoselectivity-α-glucosidase inhibitory activity
relationship. To the best of our knowledge there are no reports in literature on the relationship
between diastereoselectivity and α-glucosidase inhibitory activity of novel
pyranoquinolinyl/furoquinolinyl acrylic acid diastereomers.

2. Chemistry
The target compound was synthesized by a series of steps given in scheme 1. The first
step involves the Perkin condensation reaction between p-nitro benzaldehyde and phenyl
acetic acid in the presence of triethyl amine at 95-100o C to yield a mixture of (2E)-3-(4-
nitrophenyl)-2-phenylprop-2-enoic acid and (2Z)-3-(4-nitrophenyl)-2-phenylprop-2-enoic
acid as reported in literature. The mixture of (2E)-3-(4-nitrophenyl)-2-phenylprop-2-enoic
acid and (2Z)-3-(4-nitrophenyl)-2-phenylprop-2-enoic was separated into their constituent
isomers by using a modified procedure reported by Roger Ketcham [25]. The mixture of cis
and trans 3-(4-nitrophenyl)-2-phenylprop-2-enoic acid (3a) was dissolved in saturated
NaHCO3 and filtered through Whatmann (40) filter paper. The filterate was acidified to pH
4.5 by using glacial acetic acid. The precipitated product (2E)-3-(4-nitrophenyl)-2-
phenylprop-2-enoic acid was filtered and dried (4a). The filtrate was further acidified with
concentrated hydrochloric acid to pH 2.0 - 2.5 and the precipitated (2Z)-3-(4-nitrophenyl)-2-
phenylprop-2-enoic acid was filtered and dried (5a). The purity of the samples was further
established by melting point as reported by Roger Ketcham [25]and high performance liquid
chromatography. The nitro group present in 3-(4-nitrophenyl)-2-phenylprop-2-enoic acid was
further reduced to amine by using NaSH/CH3OH at 95-100oC yielding the corresponding
(2Z)-3-(4-aminophenyl)-2-phenylprop-2-enoic acid (6a) and (2E)-3-(4-aminophenyl)-2-
phenylprop-2-enoic acid (7a) in good yields. The one-pot reaction of 2,3 dihydropyran,
(2Z)-3-(4-aminophenyl)-2-phenylprop-2-enoic acid (6a) and benzaldehyde in the presence of
choline chloride/Zinc chloride ionic liquid as catalyst and medium at 55-60oC via inverse
electron demand Diels Alder reaction (IED) afforded thepyranoquinolinyl acrylic acid
adducts (10a and 11a) in 80% yield in the ratio of 49:51.

H
CHO
COOH
COOH
(CH3CO)2O
O2N
O2N
(C2H5)3N
(1a)
(2b)
(3c)
H
H
H
COOH
COOH
O2N
NaHCO3
COOH
CH3COOH
O2N
O2N
(3c)
(4a)
(5a)
H
H
COOH
COOH
NaSH
O2N
H2N
CH3OH
(4a)
(6a)
H
H
NaSH
CH3OH
COOH
H2N
COOH
O2N
(7a)
(5a)
Scheme 1
COOH
COOH
H
H
H
CHO
COOH
O
Choline chloride.xZnCl2
H
H
H
H
H
55-60oC
O
O
H2N
HN
HN
(9a)
(6a)
(8a)
(10a)
(11a)
Scheme 2
However when a mixture of diastereomers in the ratio of 49:51obtained from the above
reaction (10a and 11a) was evaluated for α-glucosidase inhibitory activity, diminished
activity was found even at higher concentrations as is evident in table 4. Hence the mixture
was separated into their component diastereomers by flash column (200-400 Mesh) and

evaluated for their inhibitory activity. Out of the two diastereomers10a and 11a, the
exodiastereomer (11a) exhibited relatively good α-glucosidase inhibitory activity (IC50=0.62±
0.02μM) whereas the endodiastereomer (10a) exhibited relatively diminished activity
(IC50=4.2 ± 0.52μM) as compared to standard acarbose (IC50=0.65± 0.02μM) which is
evident in table 4.
3. Results and discussion
3.1 Molecular docking
Docking studies were carried out to find which of the diastereomers 10a or 11a
exhibited relatively better α-glucosidase inhibitory activity and also to identify the binding
modes of the compounds. Docking was performed by using GOLD suite program using
genetic algorithm parameters with interactive docking set-up via Hermes. The active site of
the crystal structure of α-glucosidase was obtained from the PDBsum protein data bank and
the c-terminal domain of human intestinal α-glucosidase (PDB ID: IU33) was used as a
molecular target for target-specific binding studies. The docking results revealed that both the
diastereomers are well accommodated in the binding pockets of α-glucosidase. However the
main difference between the binding of two diastereomers was that the carboxylic acid group
of diastereomer 10a formed one hydrogen bond with TYR258 residue (bond length -2.3406
A) whereas the other diastereomer 11a formed three hydrogen bonds (-COOH, -NH, -CH-)
with the aminoacid residues of target enzyme MET328 (bond length -2.3802 A), LEU320
(bond length -2.4001 A), TRP388 (bond length -2.9510 A). Hence better anchorage of the
diastereomer 11a results in improved α-glucosidase inhibitory activity than diastereomer 10a.
Moreover the estimated binding energies were -9.56 kcal/mol for pyranoquinolinyl acrylic
acid adduct 10a whereas -15.43kcal/mol for diasteromer 11a respectively. Invitroα-
glucosidase inhibitory activity studies reported in table.4 revealed an IC50 value

of4.2±0.52μM for diastereomer10a and 0.62± 0.02μM for diastereomer11a which is
consistent with the results of the docking studies.
Binding mode of 11a with α-glucosidase
Binding mode of 10a with α-glucosidase
Hence in order to avoid the formation of less active isomer (10a), avoid the inhibition
of active diastereomer (11a) by (10a) and circumvent the cumbersome separation of
diastereomers by flash chromatography, we have developed a highly diastereoselective, target
specific synthesis of active diastereomer (11a) by reacting 2,3 dihydropyran, (2Z)-3-(4-
aminophenyl)-2-phenylprop-2-enoic acid (6a) and benzaldehyde in the presence of Europium
tris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camporate] (B) as catalyst at 20 mol% at
room temperature affording the pyranoquinolinyl acrylic acid adducts in the ratio of 2:98 and
78% yields (Scheme 3).
CH3
CF3
COOH
COOH
H3C
O
H
H
H
CHO
Eu
CH3 O
COOH
O
3
H
H
H
H
CH3CN
O
H2N
O
R3
R1
n
R2
n=1,2
(8a)
HN
HN
n
n
(9a-e)
(6a)
R3
R1
R3
R1
R2
R2
(10a-e)
Scheme 3
(11a-e)

3.2 Effect of solvent on the IED synthesis of pyranoquinolinyl acrylic acid diastereomers
Inorder to improve the yield and diastereoselectity of the reaction, the reaction of 2,3
dihydropyran, (2Z)-3-(4-aminophenyl)-2-phenylprop-2-enoic acid (6a) and benzaldehyde in
the presence of Europium tris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camporate (B) as
catalyst at 20 mol% was chosen as a model for comparison of solvents. The results of the
reaction are given in Table 1. Among the solvents examined, acetonitrile proved to be the
most effective solvent for Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-
camporate, catalysed IED reaction offering high yields (78%) at room temperature over a
period of 5.0 h with highest diastereoselectivity of 2:98 (%).The reaction also proceeded to
completion within 7.0 h in ethanol medium, however the reaction offered comparatively less
yields in ethanol medium at 80°C whereas in all other solvents the desired reaction proceeded
slowly giving poor yields and less diastereoselectivity.
Table.1 Effect of solvent on the diastereoselective synthesis
COOH
COOH
CH3
CF3
H
H
H3C
H
O
COOH
CHO
Eu
CH3 O
H
H
O
H
H
3
O
H2N
O
Solvent, rt
HN
HN
(9a)
(6a)
(8a)
(10a)
(11a)
Temperature Time
S No
Solvent
Yield (%)
Endo : Exo ratio
(oC)
(h)
8.0
8.0
7.0
8.0
5.0
1
2
3
4
5
CH2Cl2
C6H5CH3
C2H5OH
THF
27
30.0
20.0
65.0
60.0
78.0
22:88
10:90
7:93
110
80
65
9:91
CH3CN
27
2:98

The ratio of diastereomers (endo:exo) were established based on HPLC (Xterra RP-18
reverse phase columns with acetonitrile/methanol/water as solvent, 0.02M ammonium acetate
with UV detector and a flow rate of 1.0mL/min) and column chromatographic yields. The
yields of the products were established after column chromatography.
Fig.1 HPLC chromatogram of pyranoquinolinly acrylic acid adducts(10a:11a)
Name
RT
% Area
0.03
18.719
19.443
21.308
22.424
0.05
Diastereomer (10a) , 411(M+)
Diastereomer (11a) , 411(M+)
2.01
97.91
The stereochemistry of the products was assigned based on the scalar coupling constant
values between the protons C-H (4a) and C-H (5). In the isomer 10a, the coupling constant
value for the doublet obtained around 5.10 δ is J (4a-5) = 5.3Hz which is smaller and typical
for a gauche conformation, wherein the pyran ring and phenyl group are present in cis
orientation. However in the diastereomer 11a the coupling constant value for the doublet
obtained at 4.93 δ is J (4a-5) = 16.0Hz indicating anti-reciprocal orientation of C-H (4a) and

C-H (5). This orientation is possible only when the pyran ring and phenyl group are present
in trans orientation with respect to quinoline ring of 11a.
However when an imino Diels Alder reaction was carried out by reacting the (2E)-3-(4-
aminophenyl)-2-phenylprop-2-enoic acid (7a) with 2,3 dihydropyran and benzaldehyde in
the presence of choline chloride/zinc chloride ionic liquid as catalyst and medium at 55-60oC,
a mixture of diastereomers 12a and 13a was obtained in the ratio of 65:35 in 73 % yield. The
mixture was resolved into their component diastereomers by flash chromatography and
subjected to α-glucosidase inhibitory activity studies it was found that the endo isomer 12a
exhibited relatively good activity (IC50=1.63± 0.37μM) than exo isomer 13a (IC50=3.12±
0.31μM) as is shown in table. 4.
COOH
COOH
H
H
CHO
H
O
Choline chloride.xZnCl2
55-60oC
H
H
H
H
O
O
COOH
HN
HN
H2N
(7a)
(8a)
(9a-e)
(12a)
(13a)
Scheme 4
Hence to synthesize the active diastereomer 12a, we have developed a highly target specific
synthesis of active diastereomer 12a by reacting 2,3dihydropyran, 2E)-3-(4-aminophenyl)-2-
phenylprop-2-enoic acid (7a) and benzaldehyde in the presence of Europium tris[3-
heptafluoropropylhydroxylmethylene]-(-)-camporate (A) as catalyst at 20 mol% by using
acetonitrile as solvent at room temperature affording the pyranoquinolinyl acrylic acid
adducts in the ratio of 98:2 and 80% yields.

F
F
F
F
CF3
CH3
H3C
H
O
H
H
COOH
COOH
CHO
Eu
O
COOH
O
CH3
3
H
O
H
O
H2N
R3
R1
CH3CN
n
R2
n=1,2
(8a)
HN
HN
n
n
H
(9a-e)
H
(7a)
R3
R1
R3
R1
R2
R2
Scheme 5
(12a-e)
(13a-e)
In order to demonstrate the efficiency of this protocol to obtain the target specific active
diastereomer by employing chiral catalyst (A) and (B), we explored the generality of our
methodology by reacting various other aldehydes with 2,3 dihydropyran and (2Z)-3-(4-
aminophenyl)-2-phenylprop-2-enoic acid (6a) or (2E)-3-(4-aminophenyl)-2-phenylprop-2-
enoic acid (7a) in the presence of Europiumtris[3-heptafluoro propylhydroxylmethylene]-(-)
camporate (A) and Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camporate (B)
as catalyst at 20 mol% by using acetonitrile as solvent. The reaction progresses well with
both electron donating and electron withdrawing groups/substituents affording the products in
good yields. The results of the reaction are given in table.2

Table.2 Effect of substituent’s on the Pyranoquinolinyl/furoquinolinyl acrylic acidsynthesis
Sl. Amine
Aldehyde
Dienophile
Chiral
Catalyst
Time Yield
(h)
Endo:Exo
Ratiob
Product
No
No
(%)a
(6a/7a)
(R1/R2/R3)
(n=1,2)
1
2
6a
6a
6a
R1,R2,R3=H
2
B
B
B
B
B
B
A
A
A
A
A
A
5.00
78.0
10a:11a
10b:11b
10c:11c
10d:11d
10e:11e
10f:11f
12a:13a
12b:13b
12c:13c
12d:13d
12e:13e
12f:13f
2:98
2:98
1:99
3:97
1:99
2:98
98:2
96:4
97:3
97:3
98:2
98:2
R1, R3=H, R2=NO2
R1, R3=H, R2=Cl
2
2
2
1
1
2
2
2
2
1
1
7.00
5.50
6.00
6.00
6.00
5.50
7.00
5.30
8.25
5.30
5.45
80.0
81.0
61.8
83.0
63.0
80.0
78.1
79.3
60.0
65.8
69.1
3
4
6a R1, R2, R3= OCH3
5
6a
6a
7a
7a
7a
R1,R2,R3=H
6
R1,R2=Cl, R3=H
R1,R2,R3=H
7
8
R1, R3=H, R2=NO2
R1, R3=H, R2=Cl
9
10
11
12
7a R1, R2, R3= OCH3
7a
7a
R1,R2,R3=H
R1,R2=Cl, R3=H
aThe yield is based on isolation by column chromatography.
bTheendo:exo ratio is based on column chromatographic yield and HPLC.
The oxygen atom on the pyranoquinolinyl acrylic acid diastereomer ring is essential for
potential α-glucosidase inhibitory activity which is evident in the invitro alpha glucosidase
inhibitory studies. On replacing the oxygen atom of the quinoline moiety with carbon atom
by employing cyclopentadiene as dienophile, the α-glucosidase inhibitory activity reduced

considerably (IC50= 10.7 ± 0.31 - 24.4 ± 0.20μM) as shown in table 4. Synthesis of
tetrahydro-3H-cyclopenta[c]quinolin-8-yl)acrylic acid adducts was accomplished by reacting
cyclopenta-1,3-diene, (2Z)-3-(4-aminophenyl)-2-phenylprop-2-enoic acid (6a) and
benzaldehyde in the presence of choline chloride/Zinc chloride ionic liquid as catalyst and
medium at 55-60oC via inverse electron demand Diels Alder reaction (IED) to afford the
cyclopentaquinolinyl acrylic acid adduct (14a) in 68.0% yield. The results of the reaction are
summarized in table.3
COOH
H
H
CHO
COOH
Cholinechoride.xZnCl2
55-600C
H
H
H2N
R1
HN
(7a)
(9a-c)
(13)
R1
Scheme 6
(14a-d)
Table.3 Synthesis of Tetrahydro-3H-cyclopenta[c]quinolin-8-yl) acrylic acid adducts
Sl.
No
Amine
(6a/7a)
6a
Aldehyde
(R1)
H
Time (h) Yield (%)
Product
1
2
3
4
5.0
5.5
4.0
2.0
68.0
52.63
55.5
14a
14b
14c
14d
6a
NO2
NO2
Cl
7a
7a
62.5
3.3. α-glucosidase inhibitory activity
α-glucosidase inhibitory activity studies were carried out to establish the
diastereoselectivity–activity relationship by comparing activities of 31
diastereomericpyranoquinolinyl/furoquinolinylacyrilic acid compounds. When a mixture of
diastereomers (10a and 11a) or (12a and 13a) were subjected to α-glucosidase inhibitory
activity studies, these diastereomeric mixtures exhibited very IC50 values in the range of

(IC50= 28.4 ± 0.21 - 30.3 ± 0.84μM) inhibitions even at high concentrations. However among
pyranoquinolinylacyrilic acid diastereomers (10a, 11a, 12a and 13a), the diastereomer 11a
exhibited relatively good α-glucosidase inhibitory values (IC50=0.62± 0.02μM) when
compared to standard acarabose (IC50=0.65 ± 0.02 μM). All the other diastereomers (10a,
12a, 13a) exhibited IC50 values in the range of 1.63± 0.37 -4.2± 0.52μM. On exploring the
role of substituents on the pyranoquinolinylacyrilic acid diastereomers, it was found that a
trimethoxy substituted pyranoquinolinylacyrilic acids exhibited relatively excellent activity
followed by chloro substituted pyranoquinolinylacyrilic acid diastereomers. Of all the
diastereomers
screened,
(E)-2-phenyl-3-((4aR,5S,10bR)-5-(3,4,5-trimethoxyphenyl)-
3,4,4a,5,6,10b-hexahydro-2H pyrano[3,2-c]quinolin-9yl)acrylic acid (11d) exhibited
excellent IC50 values of 0.40± 0.02μM. Generally, the exo-isomers (11a-e) obtained by
reaction of 2Z)-3-(4-aminophenyl)-2-phenylprop-2-enoic acid (6a) (Cis), with pyran and
aromatic aldehyde exhibited relatively better α-glucosidase inhibitory activity than the endo
isomers. However in the case of pyranoquinolinyl acrylic acid diastereomers obtained by
reacting (2E)-3-(4-aminophenyl)-2-phenylprop-2-enoic acid (7a) (Trans), with pyran and
aromatic aldehyde, it was found that the endo-diastereomers (13a-e) exhibited relatively
better α-glucosidase inhibitory activity than the exo-diastereomers (12a-e). However a
reversal in activity was observed for nitro substituted pyranoquinolinylacyrilic acid
diastereomers wherein the endodiastereomers exhibited relatively better activity than the
exodiastereomers. It is evident from the studies that oxygen atom of the pyranoquinolinyl
ring is essential for α-glucosidase inhibition because upon replacement of the oxygen atom
with carbon as Tetrahydro-3H-cyclopenta[c]quinolin-8-yl) acrylic acid adducts (14a-d) there
was considerable decrease in α-glucosidase inhibitory activity.

Table.4 α-glucosidase inhibitory activity studies
Product
Number
Product
Number
IC50±SEM
(µM )
IC50±SEM
(µM )
Diastereomer
Diastereomer
H
O
H
HOOC
HOOC
H
H
O
H
N
H
HOOC
H
+
10a+11a
(1:1)
OCH3
OCH3
30.3±0.84
11d
0.40±0.02
0.58±0.07
N
H
H
O
H
H
OCH3
N
H
H
O
H
H
H
O
HOOC
H
N
H
H
12a+13a
(1:1)
+
HOOC
OCH3
OCH3
28.4±0.21
4.2±0.52
12d
13d
N
H
H
O
H
OCH3
H
HOOC
HOOC
N
H
H
O
H
H
O
H
H
HOOC
OCH3
OCH3
H
10a
3.18±0.92
4.98±0.25
N
H
N
H
OCH3
H
H
H
H
O
H
H
O
H
H
H
H
H
HOOC
HOOC
H
H
H
11a
12a
0.62±0.02
1.63±0.37
10e
11e
N
H
N
H
O
O
HOOC
H
0.97±0.21
3.80±0.89
HOOC
HOOC
N
H
N
H
O
H
O
H
H
H
H
H
13a
10b
3.1±0.31
6.5±0.39
12e
13e
HOOC
HOOC
N
H
N
H
H
O
O
H
HOOC
H
6.50±0.08
7.84±0.02
N
N
H
H
NO2
H
O
H
O
H
H
HOOC
HOOC
H
H
N
11b
12b
2.8±0.21
8.4±0.38
10f
11f
N
H
O
H
Cl
NO2
H
O
H
H
H
HOOC
H
H
3.04±0.15
HOOC
N
H
N
H
Cl
NO2

H
O
H
H
O
H
H
H
3.8±0.95
H
H
H
13b
10c
11c
12c
3.0±0.27
8.3±0.86
0.58±0.06
3.59±0.67
12f
13f
14a
14b
HOOC
HOOC
HOOC
N
H
N
H
NO2
Cl
Cl
H
O
O
H
HOOC
H
H
7.13±0.01
14.3±0.17
10.7±0.31
N
H
N
H
Cl
H
H
O
H
H
H
HOOC
HOOC
H
N
H
N
H
Cl
H
H
O
H
HOOC
H
H
HOOC
N
N
H
H
NO2
Cl
H
O
H
H
H
H
H
13c
6.98±0.08
14c
14d
12.3±0.91
24.4±0.20
HOOC
HOOC
N
H
N
H
NO2
Cl
H
O
H
H
H
HOOC
H
OCH3
OCH3
H
10d
15
0.69±0.04
N
HOOC
H
N
H
OCH3
Cl
Std. Acarbose
0.65±0.02
3.4 Mechanism
Although the mechanistic details are still under investigation, a plausible mechanism for the
Europium tris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camporate (B) mediated inverse
electron demand Diels Alder reaction is proposed in Scheme 7 wherein a more basic
substrate, such as the 2-azadiene binds to the europium metal centre leading to the formation
of an intermediate hepta-coordinate schiff base – Europium complex. This highly hindered
intermediate might be the plausible reason for the high diastereoselectivity of the IED- Diels
Alder reaction. A plausible mechanism for the diastereoselective synthesis of
pyranoquinolinyl acrylic acid adducts is given in scheme 7.

COOH
H
CH3
CH3
CH3
CH3
CF3
CF3
H3C
H3C
O
O
Eu
Eu
O
O
3
3
N
H
O
O
COOH
COOH
N
N
H
H
H
H
CH3
CH3
H3C
H3C
CF3
CF3
H3C
H3C
O
O
O
CH3
CH3
O
CH3
CH3
Eu
Eu
O
O
O
O
CF3
CF3
O
O
O
O
F3C
F3C
CH3
CH3
H3C
H3C
H3C
H3C
O
O
COOH
COOH
N
N
H
H
H
H
H
O
H
CH3
H3C
CF3
H3C
CH3
H3C
CF3
O
CH3
H3C
O
O
CH3
CH3
Eu
CH3
O
O
Eu
O
CF3
O
O
O
CF3
O
O
F3C
F3C
CH3
H3C
H3C
H3C
CH3
H3C
H3C
H3C
CH3
CH3
CH3
CF3
O
CF3
-
O
-
Eu
Eu
O
O
CH3
3
3
COOH
H
COOH
H
H
H
O
O
HN
HN
H
H
Scheme 7
All the products were evaluated for Lipinski’s rule of five (RO5) and it was found that all the
products were in compliance with Lipinski rule with one or no violations indicating good oral
bioavailability. The results of Lipinski evaluation are given in table.5.

Table.5 Lipinski evaluation for the synthesized products
LIPINSKI’s evaluation
Product
No
MW
MR
No of
cLogP
2.04505
2.04505
2.04505
2.04505
1.78805
1.78805
1.78805
1.78805
2.75805
2.75805
2.75805
2.75805
1.34515
1.34515
1.34515
1.34515
1.61605
1.61605
1.61605
1.61605
2.32905
2.32905
2.32905
2.32905
2.6475
TPSA
58.56
58.56
58.56
58.56
104.38
104.38
104.38
104.38
58.56
58.56
58.56
58.56
86.25
86.25
86.25
86.25
58.56
58.56
58.56
58.56
58.56
58.56
58.56
58.56
49.33
101.14
101.14
49.33
nAON nDOHNH
(cm3/mol) Violations
10a
11a
12a
13a
10b
11b
12b
13b
10c
11c
12c
13c
10d
11d
12d
13d
10e
11e
12e
13e
10f
411
411
411
411
456
456
456
456
445
445
445
445
501
501
501
501
397
397
397
397
431
431
431
431
397
438
438
428
4
4
4
4
7
7
7
7
4
4
4
4
7
7
7
7
4
4
4
4
4
4
4
4
3
6
6
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
122.10
122.10
122.10
122.10
0
0
0
0
128.49
0
128.49
128.49
128.49
126.70
126.70
126.70
126.70
143.58
143.58
143.58
143.58
117.50
117.50
117.50
117.50
122.10
122.10
122.10
122.10
121.82
126.48
126.48
126.43
0
0
0
0
0
0
0
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
11f
12f
13f
14a
14b
14c
14d
2.3905
2.3905
3.3605

4. Conclusion
In conclusion, this work reports the first target specific, design and highly
diastereoselective synthesis of new class of pyranoquinolinyl/furoquinolinyl acrylic acid
diastereomers. This is the first report wherein diastereoselectivity- has been established
among a set of 4 diastereomers for the same molecule. A highly diastereoselective α-
glucosidase inhibitory activity relationship target specific route of synthesis for the active
diastereomer
was
developed
by
using
chiral
(A)
catalyst
Europiumtris[3-
Europium tris[3-
heptafluoropropylhydroxylmethylene]-(-)-camporate
and
(trifluoromethyl)hydroxylmethylene]-(+)-camporate (B). The methodology avoids the
formation of less active isomer, overcomes competitive inhibition of active diastereomer and
circumvents the cumbersome separation of diastereomers by flash chromatography. The
newly synthesized compounds exhibited IC50 values in the range of (0.40± 0.02-30.3 ±
0.84μM) as compared to standard acarbose (IC50=0.65± 0.02μM). Molecular docking studies
were used for design of the compound and understand the mode of binding between the
compound and target enzyme.
5. Experimental
5.1. Typical experimental procedure for the synthesis ofpyranoquinolinyl/furoquinolinyl
adducts.
A mixture of 3-(4-aminophenyl)-2-phenylprop-2-enoic acid (0.0011mol), aromatic aldehyde
(9a) (0.0064mol), 2,3-dihydropyran (8a) (0.0064mol) or 2,3 dihydrofuran (0.0064 mol) and
acetonitrile (10ml) was added into the round bottom flask containingchiral catalyst
Europiumtris[3-heptafluoropropylhydroxylmethylene]-(-)-camporate (A) (20 mol%). The
reaction mixture was stirred at room temperature for an appropriate time (Table 2). After
complete conversion, as indicated by TLC, the solvent was removed by using high vaccum.
Ethylacetate (30ml) and water (20ml) was added to the reaction mixture, sturred for 5
minutes and the reaction mixture was transferred to separating funnel. The organic layer was
separated and concentrated under vacuum. The crude product was purified by column
chromatography on silica gel (Merck, 200 - 400 mesh, ethylacetate/petroleum ether, 1:4) to
give the product (10a) in78%yield.

5.1.1(E)-2-phenyl-3-((4aR,5R,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)acrylic acid (10a)
FT-IR (KBr)max cm-1: 3380, 3325, 2940, 1603, 1484, 1074; 1H NMR (400 MHz, CDCl3) 
: 9.60 (s, 1H), 8.12 (t, 3H), 7.86 (d, 2H), 7.62 (d, 1H), 7.51-7.41 (m, 5H), 7.40-7.23 (m, 3H),
4.92 (s, 1H), 4.60-4.59 (d, 1H, J = 4.00 Hz), 4.46 (brs, 1H, NH), 3.54-3.41 (m, 2H), 2.42 (t,
1H), 2.17 (s, 1H), 1.72 (t, 2H), 1.28 (d, 1H); 13C NMR (125MHz, CDCl3): 175.09, 171.76,
146.54, 143.22, 140.00, 136.53, 131.69, 130.40, 130.3, 129.70, 128.63, 127.94, 127.34,
126.01, 122.99, 118.02, 90.18, 73.44, 63.6, 54.27, 38.72, 24.07, 21.7; MSm/z: 411 (M+);
Anal. Calcd.for C27H25NO3: C, 78.81; H, 6.12; N, 3.40; Found: C, 78.80; H, 6.10; N, 3.38.
5.1.2(E)-2-phenyl-3-((4aR,5S,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)acrylic acid (11a)
FT-IR (KBr)max cm-1: 3323, 2916, 1697, 1589, 1440, 1020; 1H NMR (400 MHz, CDCl3) 
: 9.59 (s, 1H), 8.10 (s, 2H ), 7.84 (d, 2H), 7.59 (s, 1H), 7.51-7.43 (m, 6H), 7.31-7.25 (m, 3H),
4.92 (s, 1H), 4.46 (d, 1H, J = 12.0 Hz), 4.01 (brs, 1H, NH), 3.78-3.63 (m, 2H), 2.17 (s, 2H),
1.54 (t, 2H), 1.28 (m, 1H); 13C NMR (125MHz, CDCl3): 172.9, 159.4, 142.5, 140.3, 138.1,
132.7, 132.9, 131.2, 130.7, 129.3, 129.2, 129.0, 128.1, 119.6, 117.4, 117.3, 99.2, 68.5, 64.9,
38.2, 27.8, 23.8, 22.8; MSm/z: 411 (M+); Anal. Calcd. for C27H25NO3: C, 78.81; H, 6.12;
N, 3.40, Found: C, 78.79; H, 6.09; N, 3.42.
5.1.3(Z)-2-phenyl-3-((4aR,5R,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)acrylic acid (12a)
FT-IR (KBr)max cm-1: 3329, 2926, 1699, 1599, 1460, 1040; 1H NMR (400 MHz, CDCl3) 
: 9.80 (s, 1H), 7.96 (s, 1H), 7.80 (m, 1H), 7.48 (t, 1H), 7.33-7.22 (m, 5H), 7.21 (m, 4H), 6.98
(m, 2H), 5.29 (brs, 1H, NH), 5.01 (s, 1H), 4.63-4.61 (d, 1H, J = 8.00Hz), 4.04-4.01 (m, 2H),
1.97 (t, 2H), 1.36 (d, 1H), 0.81 (m, 2H); 13C NMR (125MHz, CDCl3): 172.9, 159.4, 142.5,
140.3, 138.1, 132.7, 132.9, 131.2, 130.7, 129.3, 129.2, 129.0, 128.1, 119.6, 117.4, 117.3,
99.2, 68.5, 64.9, 38.2, 27.8, 23.8, 22.8; MS m/z : 411 (M+); Anal. Calcd. for C27H25NO3:
C, 78.81; H, 6.12; N, 3.40, Found: C, 78.78; H, 6.13; N, 3.39.
5.1.4(Z)-2-phenyl-3-((4aR,5S,10bR)-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)acrylic acid (13a)
FT-IR (KBr) max cm-1: 3408, 2933. 1693, 1597, 1342, 1078; 1H NMR (400 MHz, CDCl3):
10.08 (s, 1H), 8.14 (d, 1H ), 8.05 (d, 1H), 7.99 (d, 1H), 7.93 (t, 1H), 7.70 (m, 1H), 7.54 (s,

1H), 7.33 (t, 2H), 7.31 (s, 1H), 7.30 (m, 3H), 6.99 (m, 2H), 4.79 (s, 1H), 4.44 (d, 1H,
J=12.0Hz), 4.30 (brs, 1H, NH), 4.06-4.00 (m, 2H), 1.97 (t, 2H), 1.20 (t, 1H), 0.81 (m, 2H);
13C NMR (125MHz, CDCl3): 171.1, 167.8, 147.2, 140.8, 139.2, 135.9, 133.9, 130.9, 129.3,
128.6, 123.9, 123.3, 112.3, 90.1, 71.8, 31.6, 29.7, 27.6, 22.7, 19.10; MS m/z: 411 (M+); Anal.
Calcd.for C27H25NO3: C, 78.81; H, 6.12; N, 3.40; Found: C, 78.83; H, 6.11; N, 3.38.
5.1.5(E)-3-((4aR,5R,10bR)-5-(4-nitrophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)-2-phenylacrylic acid (10b)
FT-IR (KBr) max cm-1: 3381, 3331, 2940, 1603, 1484, 1074; 1H NMR (400 MHz, CDCl3) 
: 12.0 (s, 1H), 7.90 (s, 1H), 7.61-7.20 (m, 10H), 6.37 (d, 1H, J=8.4Hz), 6.01 (d, 1H,
J=8.4Hz), 5.14 (d, 1H, J = 5.44Hz), 5.01 (s, 1H), 3.9 (brs, 1H, -NH), 3.41 (d, 1H), 3.15 (t,
13
1H), 2.17 (m, 1H), 1.51-1.13 (m, 4H); C NMR (125MHz, CDCl3): 172.4, 170.0, 144.2,
143.5, 141.5, 139.5, 136.2, 135.2, 133.6, 131.2, 129.6, 128.2, 127.2, 126.5, 125.5, 124.6,
123.6, 119.9, 113.3, 73.5, 54.5, 38.1, 27.3, 23. 3, 21.4; MS m/z: 456 (M+); Anal. Calcd.
forC27H24N2O5: C, 71.04; H, 5.30; N, 6.14; Found: C, 71.0; H, 5.25; N, 6.10
5.1.6(E)-3-((4aR,5S,10bR)-5-(4-nitrophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)-2-phenylacrylic acid (11b)
FT-IR (KBr) max cm-1: 3385, 3329, 2953, 1613, 1470, 1053; 1H NMR (400 MHz, CDCl3)
:11.4 (s, 1H), 7.81 (s, 1H), 7.35-7.09 (m, 7H), 6.85 (d, 2H, J = 7.76Hz), 6.74 (d, 2H), 6.24 (d,
1H), 4.70 (d, 1H, J = 10.48Hz), 4.2 (s, 1H), 4.03 (brs, 1H, NH), 3.69 (d, 1H), 2.09 (m, 2H),
13
1.80 ( m, 2H), 1.6-1.4 (m, 2H); C NMR (125MHz, CDCl3): 172.0, 159.0, 142.0, 140.8,
138.4, 132.9, 132.4, 131.5, 130.9, 129.6, 129.4, 129.2, 128.2, 119.1, 117.7, 117.1, 99.9, 68.5,
64.2, 38.7, 27.6, 23.9, 22.9; MS m/z: 456 (M+); Anal. Calcd. forC27H24N2O5: C, 71.04; H,
5.30; N, 6.14, Found: C, 70.99; H, 5.29; N, 6.06.
5.1.7(Z)-3-((4aR,5R,10bR)-5-(4-nitrophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)-2-phenylacrylic acid (12b)
1
FT-IR(KBr)max cm-1: 3379, 3325, 2945, 1613, 1489, 1078; H NMR (400 MHz, CDCl3):
11.0 (s, 1H), 8.24 (d, 2H, J = 8.68), 7.89 (s, 1H), 7.55 (d, 2H, J = 8.68), 7.37-7.30 (m, 3H),
7.28 (d, 2H, J = 9.08Hz), 6.85 (d, 2H, J = 8.48Hz), 6.42 (d, 1H, J =8.4Hz), 5.14 (d, 1H, J =
5.24Hz), 4.78 (d, 1H), 4.07 (brs, 1H, NH), 3.40 (d, 1H), 3.16 (t, 1H, J = 11.16 Hz), 2.04 (d,
1H), 1.65-1.27 (m, 3H), 1.03 (s, 1H); 13C NMR (125MHz, CDCl3): 177.3, 166.4, 151.1,
138.3, 132.5, 129.5, 128.8, 127.6, 126.6, 124.5, 123.6, 122.3, 114.9, 112.0, 97.7, 65.5, 60.4,

42.2, 26.6, 24.3, 18.3; MSm/z : 456 (M+); Anal. Calcd. forC27H24N2O5: C, 71.04; H, 5.30;
N, 6.14, Found: C, 71.06; H, 5.28; N, 6.13.
5.1.8(Z)-3-((4aR,5S,10bR)-5-(4-nitrophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)-2-phenylacrylic acid (13b)
FT-IR (KBr) max cm-1: 3368, 3319, 2935, 1600, 1479, 1070; 1H NMR (400 MHz, CDCl3)  :
11.2 (s, 1H), 8.23 (d, 2H, J =8.68), 7.85 (s, 1H), 7.59 (d, 2H, J =14.68Hz), 7.40-7.35 (m, 4H),
7.26 (s, 1H), 6.75 (d, 2H), 6.30 (d, 1H, J = 8.56), 4.81 (d, 1H, J = 12.0 Hz), 4.27 (brs, 1H,
NH ), 4.19 (s, 1H), 3.66 (t, 1H, J = 11.48 Hz), 2.10-1.95 (m, 1H), 1.80-1.68 (m, 3H), 1.42-
1.35 (m, 2H); 13C NMR (125MHz, CDCl3): 173.10, 171.09, 146.50, 143.50, 140.5, 136.94,
135.9, 129.8, 128.3, 127.3, 125.01, 123.35, 111.34, 100.07, 89.9, 75.1, 60.59, 53.05, 29.36,
24.30, 21.06; MSm/z: 456 (M+); Anal. Calcd. forC27H24N2O5: C, 71.04; H, 5.30; N, 6.14,
Found: C, 70.98; H, 5.27; N, 6.07.
5.1.9(E)-3-((4aR,5R,10bR)-5-(4-chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinolin-9-yl)-2-phenylacrylic acid (10c)
FT-IR (KBr) max cm-1: 3375, 3315, 2935, 1609, 1494, 1064; 1H NMR (400 MHz, CDCl3) 
: 9.98 (s, 1H), 8.04 (d, 2H), 7.71 (s, 1H), 7.53-7.33 (m, 4H), 7.29 (d, 3H), 7.05 (t, 2H), 6.72
(t, 1H), 4.67 (d, 1H, J = 8.01 Hz), 4.18 (s, 1H), 4.01 (brs, 1H, NH), 3.66 (t, 2H), 2.38 (s, 1H),
13
2.28 (t, 1H), 2.13 (s, 1H), 1.33 (t, 2H); C NMR (125MHz, CDCl3): 177.19, 172.4, 146.0,
143.5, 141.0, 136.2, 131.2, 130.8, 130.0, 129.9, 128.2, 127.2, 126.9, 122.9, 118.9, 93.5, 74.5,
64.70, 61.12, 38.0, 24.7, 21.4; MS m/z: 445 (M+); Anal. Calcd. for C27H24ClNO3: C, 72.72;
H, 5.42; N, 3.14; Found: C, 72.70; H, 5.39; N, 3.15.
5.1.10(E)-3-((4aR,5S,10bR)-5-(4-chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano
[3,2-c]quinolin-9-yl)-2-phenylacrylic acid (11c)
FT-IR (KBr)max cm-1: 3380, 3325, 2940, 1603, 1484, 1074; 1H NMR (400 MHz, CDCl3) 
: 10.02 (s, 1H), 8.29 (s, 1H), 8.09 (d, 1H), 7.99 (t, 1H), 7.87 (s, 1H), 7.48-7.38 (m, 3H), 7.37
(t, 2H), 7.32 (t, 2H), 7.02 (d, 1H), 6.87 (d, 1H), 4.36 (d, 1H, J = 12.0 Hz), 4.22 (s, 1H), 3.96
13
(brs, 1H, NH), 3.66-3.56 (m, 2H), 2.55 (m, 1H), 2.38 (s, 1H), 2.17 (s, 1H), 1.32 (t, 2H); C
NMR (125MHz, CDCl3): 177.4, 171.7, 165.1, 162.5, 159.1, 158.5, 141.8, 140.8, 133.5,
131.9, 131.2, 131.2, 129.3, 126.9, 119.3, 118.3, 116.7, 100.1, 98.1, 77.5, 65.07, 55.7, 38.0,
30.7, 29.0; MS m/z: 445 (M+); Anal. Calcd. for C27H24ClNO3: C, 72.72; H, 5.42; N, 3.14;
Found: C, 72.71; H, 5.40; N, 3.09.

5.1.11(Z)-3-((4aR,5R,10bR)-5-(4-chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano
[3,2-c] quinolin-9-yl)-2-phenylacrylic acid (12c)
FT-IR (KBr)max cm-1: 3400, 2926, 1681, 1516, 1340, 1085; 1H NMR (400 MHz, CDCl3) 
: 9.96 (s, 1H), 7.90 (m, 1H ), 7.41 (m, 4H), 7.29-7.24 (m, 4H), 7.22-7.15 (m, 4H), 5.12 (d,
1H, J = 4.0Hz), 4.63 (s, 1H), 3.95 (brs, 1H, NH), 3.69 (t, 2H), 2.40 (d, 1H), 1.40 (d, 2H), 1.30
(d, 2H); 13C NMR (125MHz, CDCl3): 178.3, 171.3, 146.4, 141.3, 140.0, 134.5, 132.5,
130.8, 130.1, 129.6, 128.5, 127.2, 127.0, 126.9, 122.4, 118.8, 97.7, 72.7, 60.8, 55.8, 38.7,
24.3, 18.3; MSm/z: 445 (M+); Anal. Calcd. for C27H24ClNO3: C, 72.72; H, 5.42; N, 3.14;
Found: C, 72.68; H, 5.35; N, 3.12.
5.1.12 (Z)-3-((4aR,5S,10bR)-5-(4-chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano
[3,2-c]quinolin-9-yl)-2-phenylacrylic acid (13c)
FT-IR (KBr)max cm-1: 3310, 2935. 1680, 1514, 1340, 1076; 1H NMR (400 MHz, CDCl3):
10.16 (s,1H), 8.44 (d, 2H ), 8.30 (m, 1H), 8.14 (t, 1H), 7.55 (t, 4H), 7.42 (t, 5H), 5.39 (d, 1H,
J = 12.0 Hz), 5.17 (s, 1H), 4.89 (brs, 1H, NH), 4.13 (m, 2H), 2.87 (m, 2H), 2.46 (d, 1H), 1.26
(t, 2H); 13C NMR (125MHz, CDCl3): 172.2, 171.3, 147.0, 143.6, 140.9, 136.8, 131.1,
134.3, 130.5, 130.1, 129.9, 128.3, 127.6, 127.2, 127.0, 126.6, 122.8, 117.8, 90.5, 71.9, 66.05,
58.8, 37.6, 24.7, 21.0; MS m/z: 445 (M+); Anal. Calcd. for C27H24ClNO3: C, 72.72; H, 5.42;
N, 3.14; Found: C, 72.70; H, 5.39; N, 3.05.
5.1.13(E)-2-phenyl-3-((4aR,5R,10bR)-5-( 3,4,5-trimethoxyphenyl)-3,4,4a,5,6,10b-hexa
hydro- 2H-pyrano[3,2-c]quinolin-9-yl)acrylic acid (10d)
FT-IR (KBr)max cm-1: 3377, 3329, 2948, 1605, 1450, 1072; 1H NMR (400 MHz, CDCl3) 
: 9.80 (s, 1H), 7.78 (s, 2H), 7.35 (d, 4H), 7.10 (s, 3H), 6.83 (d, 2H), 5.66 (d, 1H, J= 4.00Hz),
4.99 (s, 1H), 4.48 (brs, 1H, NH), 3.88 (s, 9H, OCH3), 3.51 (m, 2H), 2.10 (s, 1H), 1.91 (s, 2H),
1.18 (s, 2H);13C NMR (125MHz, CDCl3): 178.4, 167.2, 152.1, 139.2, 130.4, 128.3, 127.4,
126.4, 124.1, 123.2, 114.2, 111.7, 98.9, 65.5, 60.4, 60.3, 60.1, 56.6, 42.5, 26.6, 24.2, 20.1;
MSm/z: 501 (M+); Anal. Calcd. for C30H31NO6: C, 71.84; H, 6.23; N, 2.79; Found: C,
71.86; H, 6.21; N, 2.76.
5.1.14(E)-2-phenyl-3-((4aR,5S,10bR)-5-( 3,4,5-trimethoxyphenyl)-3,4,4a,5,6,10b-hexa
hydro-2H-pyrano[3,2-c]quinolin-9-yl)acrylic acid (11d)
FT-IR (KBr)max cm-1: 3384, 3330, 2950, 1607, 1455, 1080; 1H NMR (400 MHz, CDCl3) :
9.46 (s, 1H), 7.77 (s, 1H), 7.29 (d, 3H), 7.17 (d, 3H), 6.83 (d, 2H), 6.48 (d, 2H), 5.25 (s, 1H),

5.19 (d, 1H, J=12.0 Hz), 4.89 (brs, 1H, NH), 4.01 (s, 9H, OCH3), 3.84 (m, 2H), 1.96 (m,
2H), 1.18 (d, 2H), 0.92 (d, 1H);13C NMR (125MHz, CDCl3): 175.3, 164.26, 152.5, 138.2,
130.7, 128.6, 127.9, 123.9, 118.4, 114.5, 97.8, 63.7, 61.4, 60.3, 60.2, 55.8, 41.6, 26.1, 24.7,
20.6; MSm/z: 501 (M+); Anal. Calcd. for C30H31NO6: C, 71.84; H, 6.23; N, 2.79; Found: C,
71.76; H, 6.21; N, 2.76.
5.1.15(Z)-2-phenyl-3-((4aR,5R,10bR)-5-( 3,4,5-trimethoxyphenyl)-3,4,4a,5,6,10b-hexa
hydro-2H-pyrano [3,2-c]quinolin-9-yl)acrylic acid (12d)
FT-IR (KBr)max cm-1: 3421, 2981, 1675, 1559, 1456, 1081; 1H NMR (400 MHz, CDCl3) :
9.83 (s, 1H), 7.33 (d, 3H), 7.18 (s, 3H), 7.07 (s, 2H), 6.81 (m, 2H), 6.53 (d, 1H), 5.63 (d, 1H,
J=4.01Hz), 5.10 (s, 1H), 4.79 (brs, 1H, NH), 3.85 (s, 9H, OCH3), 3.68 (t, 2H), 2.09 (s, 1H),
1.22 (d, 2H), 0.94 (t, 1H), 0.81 (t, 1H); 13C NMR (125MHz, CDCl3): 176.07, 163.80,
150.48, 139.56, 130.24, 128.1, 127.8, 123.61, 115.6, 113.6, 96.73, 65.58, 61.27, 60.91, 60.2,
55.2, 45.63, 29.06, 25.0, 21.2; MSm/z: 501 (M+); Anal. Calcd. for C30H31NO6: C, 71.84; H,
6.23; N, 2.79; Found: C, 71.81; H, 6.19; N, 2.70.
5.1.16(Z)-2-phenyl-3-((4aR,5S,10bR)-5-( 3,4,5-trimethoxyphenyl)-3,4,4a,5,6,10b-hexa
hydro-2H-pyrano [3,2-c]quinolin-9-yl)acrylic acid (13d)
FT-IR (KBr)max cm-1: 3417, 2933, 1683, 1452, 1350, 1082; 1H NMR (400 MHz, CDCl3) 
:9.81 (s, 1H), 7.76 (d, 1H), 7.30 (t, 3H), 7.26 (t, 3H), 7.15 (t, 3H), 6.80 (d, 1H), 5.25 (s, 1H),
5.19 (d, 1H, J= 12.0Hz), 4.89 (brs, 1H, NH), 4.03 (s, 9H, OCH3), 3.33-3.24 (m, 2H), 2.01 (s,
1H), 1.27 (d, 3H), 1.00 (d, 1H); 13C NMR (125MHz, CDCl3): 176.80, 163.65, 150.59,
139.92, 128.25, 127.70, 123.69, 115.54, 113.68, 96.80, 65.51, 61.20, 60.86, 60.15, 55.13,
45.71, 30.21, 25.6, 21.3 ; MS m/z: 501 (M+); Anal. Calcd. for C30H31NO6: C, 71.84; H, 6.23;
N, 2.79; Found: C, 71.79; H, 6.23; N, 2.76.
5.1.17(E)-2-phenyl-3-((3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]
quinolin-8-yl)acrylic acid (10e)
FT-IR (KBr)max cm-1:3420, 2925, 1680, 1579, 1450, 1078; 1H NMR (400 MHz, CDCl3)  :
10.00 (s, 1H), 8.13 (m, 3H), 7.96 (m, 1H), 7.61 (d, 2H), 7.49 (m, 3H), 7.45 (m, 3H), 7.29 (t,
2H), 5.00 (s, 1H), 4.83 (brs 1H, NH), 4.42 (d, 1H, J=4.0 Hz), 4.04 (m, 1H), 3.84 (m, 1H),
13
1.80 (m, 2H), 1.23 (s, 1H); C NMR (125MHz, CDCl3): 176.45, 170.79, 165.84, 162.81,
156.90, 152.89, 147.54, 146.85, 133.61, 130.29, 128.98, 128.64, 128.25, 126.60, 123.98,
123.29, 141.31, 106.06, 97.78, 64.89, 57.29, 42.67, 32.36, 19.70; MSm/z: 397 (M+); Anal.
Calcd. for C26H23NO3: C, 78.57; H, 5.83; N, 3.52; Found: C, 78.54; H, 5.79; N, 3.50.

5.1.18(E)-2-phenyl-3-((3aR,4S,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]
quinolin-8-yl)acrylic acid (11e)
FT-IR (KBr)max cm-1: 3417, 2900, 1673, 1569, 1468, 1080;1H NMR (400 MHz, CDCl3)  :
9.97 (s, 1H), 7.88-7.77 (m, 2H), 7.60 (d, 2H), 7.48 (d, 2H), 7.37-7.32 (m, 5H), 7.27 (m, 3H),
5.56 (s, 1H), 5.02 (d, 1H, J = 20.0 Hz), 4.85 (brs, 1H, NH), 3.78-3.65 (m, 2H), 2.44 (d, 1H),
1.29 (d, 2H); 13C NMR (125MHz, CDCl3): 174.35, 171.68, 163.84, 160.79, 155.90, 153.31,
147.59, 145.03, 133.61, 131.09, 128.94, 128.51, 125.59, 124.28, 123.23, 106.06, 98.32,
63.06, 55.31, 41.04, 32.30, 20.19; MS m/z: 397 (M+); Anal. Calcd. for C26H23NO3: C, 78.57;
H, 5.83; N, 3.52; Found: C, 78.56; H, 5.85; N, 3.51.
5.1.19(Z)-2-phenyl-3-((3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-
c]quinolin-8-yl)acrylic acid (12e)
FT-IR (KBr)max cm-1: 3427, 2935, 1683, 1589, 1458, 1082; 1H NMR (400 MHz, CDCl3) 
: 9.98 (s, 1H), 7.83 (t, 2H), 7.34-7.28 (m, 5H), 7.19 (d, 3H), 6.87 (d, 2H), 6.58 (d, 1H), 6.37
(d, 1H), 5.23 (s, 1H), 5.18 (d, 1H, J = 4.0 Hz), 5.03 (brs, 1H, NH), 3.81-3.73 (m, 2H), 1.97
(d, 1H), 1.19 (t, 2H); 13C NMR (125MHz, CDCl3): 172.06, 163.11, 159.81, 157.16, 154.52,
152.51, 147.53, 142.56, 135.94, 132.94, 130.30, 128.65, 127.29, 124.26, 113.65, 106.74,
99.43, 89.79, 65.54, 45.61, 34.68, 27.69, 21.07; MSm/z: 397 (M+); Anal. Calcd. for
C26H23NO3: C, 78.57; H, 5.83; N, 3.52; Found: C, 78.50; H, 5.82; N, 3.49.
5.1.20(Z)-2-phenyl-3-((3aR,4S,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]
quinolin-8-yl) acrylic acid (13e)
FT-IR (KBr)max cm-1: 3406, 2872, 1691, 1450, 1219, 1016; 1H NMR (400 MHz, CDCl3) 
: 9.90 (s, 1H), 8.29 (s, 2H), 7.87 (s, 1H), 7.81 (t, 2H), 7.29 (s, 2H), 7.19 (t, 2H), 7.02 (d, 1H),
6.93 (m, 2H), 6.88 (m, 2H), 5.69 (s, 1H), 5.37 (d, 1H, J=12.0 Hz), 5.03 (brs, 1H, NH), 3.92-
3.78 (m, 2H), 1.87-1.69 (m, 2H), 1.18 (d, 1H); 13C NMR (125MHz, CDCl3): 173.34,
172.83, 152.56, 148.06, 147.12, 142.79, 141.66, 140.78, 136.39, 136.34, 135.94, 135.63,
134.51, 132.98,132.71, 129.85, 125.84, 99.0, 67.05, 65.59, 30.88, 29.72, 23.42; MS m/z: 397
(M+); Anal. Calcd. for C26H23NO3: C, 78.57; H, 5.83; N, 3.52; Found: C, 78.56; H, 5.80; N,
3.49.
5.1.21 (E)-3-((3aR,4R,9bR)-4-(4-chlorophenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-
c]quinolin-8-yl)-2-phenyl acrylic acid (10f)
FT-IR (KBr)max cm-1: 3378, 3320, 2950, 1600, 1490, 1070; 1H NMR (400 MHz, CDCl3) 
: 10.00 (s, 1H), 8.09 (s, 1H), 8.07 (t, 3H), 7.84 (d, 1H), 7.61 (d, 1H), 7.46-7.34 (m, 5H), 7.28

(d, 2H), 5.51 (d, 1H, J=8.00 Hz), 5.39 (s, 1H), 5.07 (brs, 1H, NH), 3.92-3.72 (m, 2H), 2.63
13
(m, 1H), 1.59 (m, 1H), 1.26 (s, 1H); C NMR (125MHz, CDCl3): 171.76, 168.45, 163.45,
159.82, 157.46, 153.86, 147.54, 144.22, 139.53, 131.59, 128.63, 127.94, 119.34, 116.01,
111.02, 108.02, 97.78, 67.89, 66.51, 51.27, 30.72, 25.77; MSm/z: 431 (M+); Anal. Calcd. for
C26H22ClNO3: C, 72.30; H, 5.13; N, 3.24; Found: C, 72.27; H, 5.10; N, 3.20.
5.1.22(E)-3-((3aR,4S,9bR)-4-(4-chlorophenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]
quinolin-8-yl)-2-phenyl acrylic acid (11f)
FT-IR (KBr)max cm-1: 3350, 3315, 2945, 1610, 1480, 1064; 1H NMR (400 MHz, CDCl3) 
: 9.72 (s, 1H), 8.14 (d, 1H), 8.02-7.93 (m, 1H), 7.60 (d, 1H), 7.51 (s, 1H), 7.44 -7.40 (m, 5H),
7.38 (s, 1H), 7.37 (t, 2H), 7.20 (s, 1H), 5.51 (d, 1H, J=12.0Hz), 5.38 (s, 1H), 5.07 (brs, 1H,
13
NH), 3.87-3.72 (m, 2H), 2.07-1.92 (m, 2H), 1.29 (t, 1H); C NMR (125MHz, CDCl3)  :
175.47, 167.49, 162.52, 158.82, 154.17, 146.85, 142.27, 131.29, 128.94, 126.62, 123.67,
123.30, 115.02, 110.05, 107.43, 104.40, 97.77, 56.89, 49.29, 45.01, 35.97, 27.39; MSm/z:
431 (M+); Anal. Calcd. for C26H22ClNO3: C, 72.30; H, 5.13; N, 3.24; Found : C, 72.28; H,
5.12; N, 3.19.
5.1.23(Z)-3-((3aR,4R,9bR)-4-(4-chlorophenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]
quinolin-8-yl)-2-phenyl acrylic acid (12f)
FT-IR (KBr)max cm-1: 3370, 3310, 2840, 1625, 1454, 1090; 1H NMR (400 MHz, CDCl3) 
: 10.00 (s, 1H), 8.02 (d, 2H), 7.92-7.53 (m, 1H), 7.51 (d, 1H), 7.42-7.38 (m, 4H), 7.36-7.19
(m, 5H), 5.39 (d, 1H, J = 4.0 Hz), 5.17 (brs, 1H, NH), 4.58 (s, 1H), 3.74-3.67 (m, 2H), 2.57-
2.46 (m, 1H), 1.57-1.50 (m, 1H), 1.25 (s, 1H); 13C NMR (125MHz, CDCl3): 170.68,
147.89, 147.22, 141.58, 140.91, 137.91, 134.54, 131.98, 131.29, 130.96, 130.59, 129.61,
129.33, 127.95, 127.69, 126.60, 125.32, 122.92, 122.33, 106.06, 105.69, 67.53, 57.21, 40.76,
35.78, 25.06; MSm/z: 431 (M+); Anal. Calcd. for C26H22ClNO3: C, 72.30; H, 5.13; N, 3.24;
Found: C, 72.29; H, 5.09; N, 3.21.
5.1.24(Z)-3-((3aR,4S,9bR)-4-(4-chlorophenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]
quinolin-8-yl)-2-phenyl acrylic acid (13f)
FT-IR (KBr)max cm-1: 3345, 3305, 2900, 1660, 1474, 1070; 1H NMR (400 MHz, CDCl3) 
: 9.99 (s, 1H), 8.20 (d, 2H), 8.10 (d, 1H), 7.92 (s, 1H), 7.62 (d, 1H), 7.48 (d, 2H), 7.40-7.36
(m, 4H), 7.31 (d, 1H), 7.19 (s, 1H), 5.50 (d, 1H, J = 12.0 Hz), 5.38 (s, 1H), 5.03 (brs, 1H,
13
NH), 3.82-3.74 (m, 2H), 2.21 (s, 1H), 1.64-1.54 (m, 1H), 1.26 (s, 1H); C NMR (125MHz,

CDCl3): 175.76, 170.40, 165.46, 159.80, 154.84, 149.56, 142.57, 134.58, 128.63, 127.66,
123.63, 115.01, 112.68, 107.04, 104.40, 99.43, 67.89, 55.93, 46.66, 30.05, 25.74; MSm/z:
431 (M+); Anal. Calcd. for C26H22ClNO3: C, 72.30; H, 5.13; N, 3.24; Found: C, 72.26; H,
5.12; N, 3.22.
5.1.25(E)-2-phenyl-3-((3aS,4R,9bR)-4-phenyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]
quinolin-8-yl)acrylic acid (14a)
FT-IR (KBr) max cm-1: 3350, 2902, 1654, 1479, 1265, 1080; 1H NMR (400 MHz, CDCl3) 
: 9.97 (s, 1H), 8.04-7.97 (m, 5H), 7.41 (s, 5H), 7.23 (d, 3H), 6.82 (s, 1H), 6.65 (s, 1H), 6.49
(s, 1H), 5.08 (s, 1H), 4.46 (d, 1H, J=8.0Hz), 3.85 (brs, 1H, NH), 1.25 (s, 1H), 1.00 (d, 1H),
0.86 (d, 1H); 13C NMR (125MHz, CDCl3): 171.77, 171.10, 146.85, 141.22, 140.61, 139.25,
137.89, 135.57, 133.91, 132.93, 131.14, 130.21, 130.97, 129.92, 129.58, 129.53, 128.64,
127.65, 126.61, 124.65, 123.68, 123.30, 29.72, 26.41, 19.40, 19.11; MSm/z: 393 (M+); Anal.
Calcd. for C27H23NO2: C, 82.42; H, 5.89; N, 3.56; Found: C, 81.36; H, 5.78; N, 3.53.
5.1.26(E)-3-((3aS,4R,9bR)-4-(4-nitrophenyl)-3a,4,5,9b-tetrahydro -3H-cyclopenta[c]
quinolin-8-yl)-2-phenylacrylic acid (14b)
FT-IR (KBr)max cm-1: 3354, 2909, 1664, 1489, 1275, 1089; 1H NMR (400 MHz, CDCl3) 
: 1H NMR (400 MHz, CDCl3): 10.16 (s, 1H), 8.41 (t, 2H), 8.09-7.96 (m, 6H), 7.41 (d, 3H),
7.40-7.20 (m, 4H), 5.97 (s, 1H), 5.47 (d, 1H, J=8.0Hz), 4.76 (brs, 1H, NH), 1.29 (t, 2H), 0.82
(t, 1H); 13C NMR (125MHz, CDCl3): 171.77, 171.10, 146.85, 141.22, 140.61, 139.25,
137.89, 135.57, 133.91, 132.93, 131.14, 130.21, 130.97, 129.92, 129.58, 129.53, 128.64,
127.65, 126.61, 124.65, 123.68, 123.30, 29.72, 26.41, 19.40, 19.11; MSm/z: 438 (M+); Anal.
Calcd. for C27H22N2O4: C, 73.96; H, 5.06; N, 6.39; Found: C,73.90; H, 5.01; N, 6.36.
5.1.27(Z)-3-((3aS,4S,9bR)-4-(4-nitrophenyl)-3a,4,5,9b-tetrahydro -3H-cyclopenta[c]
quinolin-8-yl)-2-phenylacrylic acid (14c)
FT-IR (KBr)max cm-1: 3365, 2925, 1674, 1499, 1260, 1077; 1H NMR (400 MHz, CDCl3) 
: 10.01 (s, 1H), 8.26 (d, 3H) ), 7.84 (s, 4H), 7.63 (d, 2H), 7.52 (t, 2H), 7.41 (m, 2H), 6.81 (d,
1H), 6.73 (s, 1H), 4.70 (s, 1H), 4.15 (d, 1H, J=8.0Hz), 3.84 (brs, 1H, NH), 2.48-2.42 (m, 1H),
2.05 (s, 1H), 1.26 (d, 1H); 13C NMR (125MHz, CDCl3): 172.5, 149.6, 147.3, 146.1, 142.6,
136.4, 133.5, 132.4, 130.2, 129.9, 128.8, 127.8, 127.6, 127.2, 125.7, 125.0, 123.9, 115.6,
57.0, 45.3, 31.2, 21.0; MSm/z: 438 (M+); Anal. Calcd. for C27H22N2O4: C, 73.96; H, 5.06; N,
6.39; Found: C, 73.95; H, 4.99; N, 6.35.

5.1.28(Z)-3-((3aS,4S,9bR)-4-chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]
quinolin-8-yl)-2-phenylacrylic acid (14d)
FT-IR (KBr)max cm-1: 3379, 2922, 1674, 1489, 1276, 1087; 1H NMR (400 MHz, CDCl3) 
: 10.02 (s, 1H), 8.04 (t, 2H) ), 7.67 (s, 1H), 7.43 (d, 1H), 7.41-7.37 (m, 3H), 7.22-7.29 (m,
4H), 7.29 (s, 1H), 6.91 (d, 1H), 6.77 (t, 1H), 6.42 (d, 1H), 4.62 (d, 1H, J = 12.0Hz), 4.28 (s,
13
1H), 3.64 (brs, 1H, NH), 1.28 (d, 2H), 0.88 (t, 1H); C NMR (125MHz, CDCl3): 170.3,
148.8, 146.4, 143.0, 140.2, 135.7, 131.5, 130.0, 129.4, 128.4, 128.7, 128.5, 127.2, 125.1,
122.8, 115.4, 56.9, 45.5, 29.2, 19.0; MSm/z: 428 (M+); Anal. Calcd. for C27H22ClNO2: C,
75.78; H, 5.18; N, 3.27; Found: C, 75.69; H, 5.17; N, 3.26.
5.2 α-glucosidaseinhibiton assay
Alpha-glucosidase inhibition was analysed by using kinetic end-point assay described
by Pistia-Brueggeman. Alpha-glucosidase inhibitory activity was performed by following the
modified method of PistiaBrueggeman and Hollingsworth [26]. In a 96-well plate reader, a
reaction mixture containing 50 µl of phosphate buffer (50 mM; pH 6.8), 10 µl of alpha-
glucosidase (1 U/ml) and 20 µl of the given compound of varying concentrations was pre-
incubated for 5 min at 37°C, and then 20 µl of 1 mM PNPG was added to the mixture as a
substrate. After further incubation at 37°C for 30 min, the reaction was stopped by adding 50
µl of sodium carbonate (0.1M). All the enzyme, inhibitor and substrate solutions were made
using the same buffer. Acarbose was used as a positive control and water as negative control.
The yellow colour produced (due to pnitrophenol formation) was quantitated by colorimetric
analysis and reading the absorbance at 405 nm. Each experiment was performed in triplicates,
along with appropriate blanks. The % inhibition has been obtained using the formula given
below. Percentage inhibition = {Absorbance (control) –Absorbance (sample)}/ Absorbance
(control) x100. IC50 values were calculated from non-linear regression curve of percentage
inhibition versus log compound concentration.
Acknowledgement
One of the authors Mr. K. Venkatapthy is grateful to the authorities of Department of
Collegiate Education, Directorate of collegiate education, Chennai, for financial support
(Rc.No. 49200/K2/2016).

Referrence
[1]
H. Fernemark, C. Jaredsson, B. Bunjaku, U. Rosenqvist, F H. Nystrom, H.
Guldbrand, A randomized cross-over trial of the postprandial effects of three different
diets in patients with type 2 diabetes, Public library of Science. 8 (2013) 79324.
S. Kumar, S. Narwal, V. Kumar, O. Prakash, α-glucosidase inhibitors from plants: A
natural approach to treat diabetes, Pharmacogn. Rev. 9 (2011) 19‒29.
Centers for disease control and prevention of diabetes. Working to Reverse the US
epidemic.http://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.html
(October 28, 2016).
[2]
[3]
[4]
World Health Organization. Diabetes Fact Sheet. June 2016.
http://www.who.int/mediacentre/factsheets/fs312/en/ (October 28, 2016).
[5]
[6]
[7]
C. Mizuno, S. Chittiboyina, A.G. Kurtz, T.W. Pershadsingh, H.A. Avery, Type 2
diabetes and oral antihyperglycemic drugs, M.A. Curr. Med. Chem. 15 (2008) 61.
A.B. Olokoba, O.A. Obateru, L.B. Olokoba, Type 2 Diabetes Mellitus: A Review of
Current Trends, Oman Med. J. 27 (2012) 269.
J. Zhang Albert, M. Rimando Agnes, S. Mizuno Cassia, T. Mathews Suresh, α-
Glucosidase inhibitory effect of resveratrol and piceatannol, The Journal of
Nutritional Biochemistry. 47 (2017) 86-93.
[8]
Bell DS. Type 2 diabetes mellitus: what is the optimal treatment regimen?
Am J Med., 116 (2004) 23S-29S.
[9]
H. Bischoff, Pharmacology of alpha-glucosidase inhibition, Eur. J. Clin. Invest. 24
(1994) 3-10.
[10]
M. Toeller,alpha-Glucosidase inhibitors in diabetes: efficacy in NIDDM subjects,
Eur. J. Clin. Invest. 24 (1994) 31-5.
[11] A.L. Aguilar, J. Escribano, P.Wentworth, T.D. Butters, Synthetic 1-deoxynojirimycin
N-substituted peptides offer prolonged disruption to N-linked glycan processing,
Chem Med Chem. 9 (2014) 2809-2813.