Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines

Article abstract of DOI:10.1016/j.bmcl.2017.04.078

A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar –NH₂ group, 10f/11f having polar –OH group on phenyl ring displayed 3–4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.

Full text of DOI:10.1016/j.bmcl.2017.04.078

Accepted Manuscript
Synthesis and α-Glucosidase Inhibition Activity of Dihydroxy Pyrrolidines
Sivaprasad Kasturi, Sujatha Surarapu, Srinivas Uppalanchi, Jaya Shree
Anireddy, Shubham Dwivedi, Hasitha Shilpa Anantaraju, Yogeeswari Perumal,
Dilep Kumar Sigalapalli, Bathini Nagendra Babu, Krishna S. Ethiraj
PII:
S0960-894X(17)30451-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.04.078
BMCL 24931
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 December 2016
22 April 2017
25 April 2017
Please cite this article as: Kasturi, S., Surarapu, S., Uppalanchi, S., Anireddy, J.S., Dwivedi, S., Anantaraju, H.S.,
Perumal, Y., Sigalapalli, D.K., Babu, B.N., Ethiraj, K.S., Synthesis and α-Glucosidase Inhibition Activity of
Dihydroxy Pyrrolidines, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/10.1016/j.bmcl.
2017.04.078
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Synthesis and α-Glucosidase Inhibition Activity of Dihydroxy Pyrrolidines
Sivaprasad Kasturia,b, Sujatha Surarapua, Srinivas Uppalanchia, Jaya Shree Anireddyb,*, Shubham Dwivedic,
Hasitha Shilpa Anantarajuc, Yogeeswari Perumalc, Dilep Kumar Sigalapallid, Bathini Nagendra Babud, Krishna
S. Ethiraja

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Synthesis and α-Glucosidase Inhibition Activity of Dihydroxy Pyrrolidines
Sivaprasad Kasturia,b, Sujatha Surarapua, Srinivas Uppalanchia, Jaya Shree Anireddyb,* , Shubham
Dwivedic, Hasitha Shilpa Anantarajuc, Yogeeswari Perumalc, Dilep Kumar Sigalapallid, Bathini Nagendra
Babud, Krishna S. Ethiraja
a Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, Plot.No.28 A, IDA, Nacharam, Hyderabad 500076, Telangana State, India
b Centre for Chemical Sciences & Technology, Institute of Science and Technology, JNTUH, Kukatpally, Hyderabad 500085, Telangana State, India
c Pharmacology Division, Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus,
Hyderabad 500078, Telangana State, India
dDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, Telangana State, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-
dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological
screening test against α-glucosidase showed that some of these compounds have the positive
inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the
olefinic amides. Among all the compounds, 5o/6o having polar –NH2 group, 10f/11f having
polar –OH group on phenyl ring displayed 3-4 fold more potent than the standard drugs.
Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds
6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were
done for compounds to identify
Revised
Accepted
Available online
Keywords:
Acarbose
Alpha glucosidase inhibitor (GI)
3,4-Dihydroxypyrrolidine
Tartaric acid
important binding modes responsible for inhibition activity of α-glucosidase.
2009 Elsevier Ltd. All rights reserved
.
Diabetes mellitus is a well-known metabolic disorder that has
become a serious problem of modern society due to severe long-
term health complications associated with it. In particular, type 2
diabetes (T2DM) is the most encountered form of diabetes.
Glucose metabolism disturbances are major factors leading to
diabetes. T2DM is characterized by an abnormal postprandial
increase of blood glucose level.1, 2 Acute hyperglycemia induces
vascular damage through direct action on vascular endothelium
and finally causes myocardial infarction, coronary heart disease,
cerebral stroke, retinopathy and severely affects the patient’s
quality of life.3, 4 Current oral anti-diabetic drugs approved by the
U.S. FDA are mainly classified into five categories: biguanides,
thiazolidinediones, sulfonylureas, meglitinides and α-glucosidase
inhibitors. However, some of these drugs have unacceptable side
effects in some patients or lose their effectiveness over a period
of time. Therefore, the search for new anti-diabetic drugs has
continued to attract considerable interest. Among these drugs, α-
glucosidase inhibitors are oral anti-diabetic agents which
suppress postprandial hyperglycemia by blocking the activity of
α-glucosidase which is responsible for the degradation of
carbohydrates. α-Glucosidase inhibitors can offer several
advantages and have been recommended by the Third Asia-
Pacific Region Diabetes Treatment Guidelines as the first-line of
treatment for lowering postprandial hyperglycemia.5
Several α-glucosidase inhibitors (AGIs), such as Acarbose
(Glucobay®), Voglibose (Volix®, Basen®) and Miglitol (Glyset®)
(Fig 1) can reversibly inhibit α-glucosidase consequently
delaying the absorption of sugars from the gut and have been
used clinically in the treatment of diabetes mellitus6. Only a few
α-glucosidase inhibitors are commercially available. All of them
contain sugar moieties and their synthesis involves tedious
multistep procedures like Voglibose (13 steps from (-) shikimic
acid)6 and Miglitol (13 steps from (R)-methyl 2-benzamido-3-
((tert-butyldimethylsilyl)oxy)propanoate).6 Moreover, clinically
they have been associated with serious gastrointestinal side
effects such as flatulence and diarrhea. Thus the discovery of
small molecules with potent α-glucosidase inhibitory activities
have attracted great attention in recent years.7-10
Natural Products traditionally have played an important role in
drug discovery and were the basis of most early medicines.11-13 In
this context, we have chosen two natural products, Deacetyl
Sarmentamide B and Chaplupyrrolidone A, B to make
semisynthetic / close analogues to evaluate for their glucosidase

inhibitory activity. The deacetyl Sarmentamide B and
Chaplupyrrolidone A, B (Fig 2) were isolated from dried leaves
of Piper sarmentosum Roxb14 (Piperales: Piperaceae), commonly
known in Thai as Chaplu, is a climbing or erect herb with a
characteristic pungent odour within the family Piperaceae, which
is comprised of over 700 known species worldwide (Parmar et
al., 1997). The two compounds, chaplupyrrolidone A & B were
shown negligible α-glucosidase inhibitory activity and the
deacetyl Sarmentamide B has no potency. The effect of
electronics on phenyl ring and double bond of amide derivatives
and sulfonamides on the glucosidase inhibitory activity has been
studied.
We adopted the literature protocol15 for the quick access of
enantiopure pyrrolidines 4a and 4b in which optically pure
tartaric acids were converted to N-benzyl dihydroxy succinimides
2a and 2b (Scheme 1). Reduction of amide was cleanly achieved
by using BH3-THF. Debenzylation under catalytic
hydrogenolysis finally afforded the desired 3,4-dihydroxy
pyrrolidines 4a and 4b. Diverse chemoselective N-acylations (5/6
(a-f), 5/6 (m-s)) were successfully achieved by using HATU /
DIPEA. Catalytic hydrogenation was utilized to prepare saturated
amides (5/6 g-l) from their corresponding α, β-unsaturated
amides. Same set of reaction sequence is used to synthesize the
meso analogues (7a-7d). During the synthesis of 3-(4-
aminophenyl)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)propan-
1-one and 3-(4-aminophenyl)-1-((3S,4S)-3,4-
Figure 1. Structures of some of the available the α-
glucosidase inhibitors
dihydroxypyrrolidin-1-yl)propan-1-one because of the free NH2
group, the di-amidatinated by-products (5m and 6m) were
formed and were characterized. The α-glucosidase inhibitory
activities of 5m and 6m analogues were found very encouraging
and hence more number of compounds in this series were made
by treating 3,4-dihydroxy pyrrolidines 4a, 4b with tert-butyl 4-
(3-amino-3-oxopropyl)phenylcarbamate in presence of
HATU/DIPEA, further de-protection of boc group was done by
using HCl to afford 5o and 6o. Corresponding sulfonamides (8/9
a-c) were obtained by controlled sulfonation with diverse
sulfonyl chlorides and products are tabulated in table 1. Amides
(10/11a-g) and sulfonamides (12/13 a-c) of 3-(4-aminophenyl)-1-
(3,4-dihydroxypyrrolidin-1-yl)propan-1-one were accessed
following the earlier reaction sequence (Scheme 2) and products
are tabulated in table 2.
Sixty-seven compounds were made with 3,4-dihydroxy
pyrrolidine to evaluate their α-glucosidase inhibitory activity in
comparison to acarbose, miglitol and voglibose as reference
standards and Baker’s yeast α-glucosidase inhibitory activity was
assayed using the reported method.14 The IC50 (best fit) were
calculated using graph pad prism v 6.0 where n=3 and results are
tabulated in table 3.
Figure 2. Structures of isolated natural products from Piper
sarmentosum Roxb14
HO
OH
N
R2
O
5m-s
3R, 4R; trans
6m-s 3S, 4S; trans
7b
3S, 4R; meso
(iv)
HO
OH
O
HO
OH
HO
O
HO
OH
OH
HO
OH
OH
(i)
(ii)
(iii)
(iv)
(vi)
COOH
O
HOOC
N
N
N
N
N
OH
Bn
H
R1
R1
Bn
O
1a 2S, 3S; trans
1b
2a 3S, 4S; trans
2b
3a 3R, 4R; trans
3b
4a 3R, 4R; trans
5a-f
3R, 4R; trans
5g-l
3R, 4R; trans
4b
3S, 4S; trans
2R, 3R; trans
1c 2R, 3S; meso
3R, 4R; trans
2c 3R, 4S; meso
3S, 4S; trans
3c 3S, 4R; meso
6a-f 3S, 4S; trans
6g-l 3S, 4S; trans
7c 3S, 4R; meso
4c 3S, 4R; meso
7a
3S, 4R; meso
(v)
5n/6n/7b
5o/6o/7d
HO
OH
(vii)
N
S
R3
O
O
8a-c
3R, 4R; trans
9a-c 3S, 4S; trans
Scheme 1. Reagents and conditions: (i) BnNH2, xylene, 190 °C, 6 h, 76-83 %; (ii) BH3 in THF (1.0 M), THF then MeOH, 70 °C, 3 h, 73-88 %; (iii) Pd-C, H2,
100 psi, EtOH, RT, 24 h, 78-83%; (iv) R1COOH or R2COOH, HATU, DIPEA, DMF, RT, 16 h, 38-87%; (v) R3SO2Cl, Pyridine, THF, RT, 16 h, 58-86 %; (vi)
Pd-C, H2, 50 psi, EtOH, RT, 4 h, 72-90 %; (vii) 4M HCl in dioxane, DCM, 0 °C to RT, 4 h, 71-80%.

Some of the screened compounds displayed potent α-
glucosidase inhibitory activity, with IC50 values in the range of
98.47-272.3 µM as compared to standard references acarbose
(IC50 = 363.3 µM), miglitol (IC50 = 465.1 µM) and voglibose
(IC50 = 320.2 µM). Compound 11f, bearing –OH group on para
position of the phenyl ring, represented the most potent α-
glucosidase inhibitory activity with IC50 values of 98.47 µM
which is more active than the standard drugs.
The activity was further slightly improved in the case of p-
hydroxy cinnamide 5e/6e. SAR suggests polar group on the
phenyl ring of 3,4-dyhdroxypyrrolidine cinnamide has significant
influence on the α-glucosidase inhibitory activity. No
encouragement results observed in thiophene analogues, 5f/6f.
Saturated amides 5/6 g-l were synthesized by the reduction of
trans-3,4-dyhdroxypyrrolidine cinnamides 5/6 a-f and 5/6 m-s
were made by the amidation reaction with saturated carboxylic
acids. Dramatic change in potency of α-glucosidase inhibitory
activity was observed from unsaturated cinnamides 5c/6c to
saturated amides 5i/6i. The saturated version of
deacetylsarmentamides 5g/6g and the monofluoro analogues
5h/6h has shown no detectible activity. The trifluoromethyl
analogues 5i/6i has exhibited excellent activity compared to their
unsaturated compounds and more potent than the standard drugs.
A 2-fold activity was observed for 6i when compared to 5i. Not
much improvement in the activity was observed in the case of
5j/6j, 5k/6k and 5l/6l compounds.
The parent compounds, deacetylsarmentamide 5a (L) and 6a
(D) were shown very poor or no inhibition against α-glucosidase.
Various trans-3,4-dyhdroxypyrrolidine cinnamides 5/6 a-f were
made with corresponding cinnamic acids. Thiophene acrylic acid
was used to make 5f/6f to screen the effect of heteroaryl group on
α-glucosidase inhibition. It was observed that there is a visible α-
glucosidase inhibitory activity by changing the groups on the
phenyl ring of cinnamides. Negligible or no improvement in the
activity in case of mono-fluorinated compounds 5b/6b. Minor
improvement in the potency was observed by replacing the mono
fluoro group with trifluoromethyl group at ortho position in 5c/6c
and para in 5d/6d.
Table 1. Synthesized 3,4-dihydroxypyrrolidin derivatives
HO
OH
N
HO
OH
N
O S O
R1 or R2
R3
O
Sulfonamides (8 & 9 series)
Amides (5, 6 & 7 series)
CF3
F
S
HO
F3C
F3C
5a/6a
5g/6g
H2N
5b/6b
5c/6c
5d/6d
5e/6e
5f/6f
F
CF3
S
HO
5h/6h
5i/6i
5j/6j
5k/6k
5l/6l
O
N
O2N
BocHN
H2N
H
5m/6m
5n/6n
5o/6o
5p/6p
N
N
N
5q/6q
5r/6r
5s/6s
H2N
F3C
BocHN
F3C
7d
7b
7a
7c
8c
F
F
F
F
F
HO
F
O
F
8a/9a
8b/9b
9c

HO
O
OH
N
NH
10g 3R, 4R; trans
11g
R5
O
3S, 4S; trans
(iii)
HO
O
HO
OH
OH
HO
OH
HO
O
OH
N
N
HO
N
OH
N
(i)
(ii)
(iii)
(iv)
O
O
N
H
NH
NH
Boc
N
NH2.HCl
H
R4
R4
O
O
3R, 4R; trans
3S, 4S; trans
4a
4b
3R, 4R; trans
3S, 4S; trans
5n
6n
3R, 4R; trans
3S, 4S; trans
5o
6o
10a-c 3R, 4R; trans
11a-c 3S, 4S; trans
10d-f 3R, 4R; trans
11d-f 3S, 4S; trans
(v)
HO
O
OH
N
(iv)
NH
O
S
R6
O
3R, 4R; trans
12a and b
13a, b and c 3S, 4S; trans
Scheme 2 Reagents and conditions: (i) 3-(4-(tert-butoxycarbonylamino)phenyl)propanoic acid, HATU, DIPEA, DMF, 78%; (ii) HCl in 1,4-Dioxane, DCM, 0 °C to
RT, 6 h, 91 %; (iii) RCOOH, HATU, DIPEA, DMF, 55-71%; (iv) H2, Pd/C, EtOH, 72-77 %; (v) RSO2Cl, Pyridine, THF, 59-68 %;
Table 2. Synthesized 3-(4-aminophenyl)-1-(3,4-dihydroxypyrrolidin-1-yl)propan-1-one derivatives
HO
OH
HO
O
HO
OH
OH
N
N
N
O
O
O
O
S
O
R6
S
R4 or R5
R6
N
N
N
O
O
H
H
O S O
R6
Amides (10 & 11 series)
Sulfonamides (12 & 13 series)
F
HO
F3C
10a/11a
10b/11b
10c/11c
S
HO
F3C
F
10d/11d
10e/11e
10f/11f
10g/11g
F
F3C
F3C
13c
12a/13a
12b/13b

Table 3. α-glucosidase enzyme inhibitory effect of derivatives.
Figure 3. Promising active compounds identified
Significant α-glucosidase inhibition was observed in a case of by-
products 5m/6m with IC50 = 258.6 µM for 5m & 262.2 µM for
6m. A substantial α-glucosidase inhibitory activity was displayed
To compare the α-glucosidase inhibition activity of enantiopure
pyrrolidine analogues with meso pyrrolidine analogues, we have
made four meso pyrrolidine analogues (7a-d). There is no much
difference in the activity of α-glucosidase inhibition of meso
analogues 7a, 7b, 7c compared to corresponding enantiopure
pyrrolidine analogues 5d/6d, 5n/6n and 5j/6j, whereas meso
analogue 7d showed lower potency compared to corresponding
enantiopure pyrrolidine analogues 5o/6o.
by 5o, 3-4 fold potent than the standard drugs with an IC50
=
107.6 µM, corresponding enantiomer 6o also exhibited excellent
potency with an IC50 value of 184.7 µM whereas corresponding
NH-boc-group protected amides 5n/6n has shown zero potency.
Polar -NH2 group on the phenyl ring derivatives 5o/6o showed
significant α-glucosidase inhibitory activity. Compounds 5p/6p
has no influence on α-glucosidase.
To check the α-glucosidase inhibition activity of amides with
sulfonamides, we have synthesized six sulfonamide analogues
(8/9 a-c) in first series. Sulfonamide with -OCF3 group on phenyl
ring 7b/8b has displayed excellent activity.
We have prepared the few hetero aryl analogues (5f/6f, 5l/6l, 5/6
q-s) to screen the effect of heteroaryl group on α-glucosidase
inhibition. It is clearly showed that heteroaryl analogues were
showed lower potency compared to aromatic systems.

Figure 4. a) Binding model of the most active compound 11f (magenta colour stick) and b) its ligand-protein
interactions in the binding site of modeled α-glucosidase. The red dashed lines represent hydrogen bonds. The black
lines indicates arene-arene interaction with His 237 and Phe155
Tyr69, Val106, Phe155, Phe156, Phe175, Pro238, Phe300,
Phe310, Phe311 and Tyr313 are the other residues that stabilized
the binding of the compound 11f in the active site of α-
glucosidase. Similar interactions were found in compound 10f
with residues Asp66, Lys153, Phe155, Asp212, Arg439 and
His237, these interactions made this compound second active
compound in the series. From this docking simulation, we
observed that the importance of hydroxyl group at para position
of phenyl ring. In general, the hydroxyl group is strong activating
group which polarize the molecule and enable it to make several
interactions with other residues. The most active compounds 11f
and 10f have this p-hydroxyl group and this hydroxyl group is
responsible for some of the key interactions with active site
residues. In case of compound 10f, the p-hydroxyl group
establishing hydrogen bond interaction with Lys153.
As we discussed earlier, by-products 5m/6m showed significant
activity hence we have extended our work and synthesized di-
amides (10/11 a-g), sulfonamides (12a/13a and 12b/13b) and di-
sulfonamide 13c using 5o/6o.
In the di-amide series, mono fluoro compound 10a has exhibited
3-4 fold activity and a 2-fold activity was shown by 11a.
Compounds 10/11b-e were shown no potency in the activity.
Surprisingly, excellent activity was observed in saturated
hydroxyl compounds 10f and 11f. These two compounds were
3-4 fold active than reference standards (IC50 = 104.4 µM for 10f
and 98.47 µM for 11f. This suggests that the polar groups are
necessary for the compounds to be active. Moderate activity was
observed in the ase of sulfonamides 12a/13a and 12b/13b.
Corresponding di-sulfonamide 13c has shown encouraging
results with IC50 = 113.8 µM.
In case of compound 5o, 6i, 6o, 10a and 13c, the p-hydroxyl
group was not exist as in compound 10f and 11f, but several
interactions was observed with active site residues which made
them promising active compounds in this series of synthesized
molecules. Similarly, Compound 5i, 5m, 6m, 9b and 11a also
showing the good docking score and more protein-ligand
interactions with the active site residues of α-glucosidase
enzyme. On the basis of our molecular docking study, it was
found that the biological activity of synthesized dihydroxy
pyrrolidines via occupying the active site of α-glucosidase and
making favorable interactions with its key residues.
Three dimensional (3D) model of yeast α-glucosidase (Fig 5 in
supplementary material) was built by comparative modeling
using Prime 3.5 in Schrödinger Suite (Schrödinger, LLC, New
York, NY)16 and crystallographic structure of related protein as a
template (PDB ID: 3A4A)17. Modeled structure was validated by
Ramchandran plot analysis. Binding pocket of enzyme and
docking simulation were predicted using Schrödinger Suite.
From the docking simulation study, it was observed that the top
ranked conformation of all the compounds were nicely
accommodated inside the active site of the homology model of α-
glucosidase (table 4 in supplementary material). Computationally
most of the synthesized compounds showed interaction with the
hydroxyl groups attached to pyrrolidine ring of the compounds
with the important active site residues. In case of the most active
compound 11f has six hydrogen bond interactions and two π-
interactions through arene-arene bond were found with the
catalytically active residues Asp66, Phe155, Asp212, Glu274,
Arg312, Arg439, Phe155 and His237 as shown in Fig 4.
Additionally, several hydrophobic interactions were observed
between the compound 11f and the active site residues, e.g.,
In conclusion, we have synthesized a series of novel 3,4-
dihydroxypyrrolidine compounds and studied for their α-
glucosidase inhibitory activity. Compounds 5i, 6i, 5m, 6m, 5o,
6o, 9b, 10a, 11a, 10f, 11f and 13c were exhibited excellent α-
glucosidase inhibitory activity (Fig. 3). Among all these
compounds 5o, 10a, 10f, 11f and 13c are considered to be more
potent. Polar –OH or -NH2 groups on phenyl ring has a high
impact on the potency of the compounds. SAR studies reveal that
the further structural modification of these active derivatives may
lead to a prospective anti-diabetic candidate molecule and 3,4-
dihydroxy piperidine derivatives in this area is in progress.

9. Shen, Q.; Shao, J.; Peng, Q.; Zhang, W.; Ma, L.; Chan, A.S.; Gu,
L. J. Med. Chem. 2010, 53, 8252.
Acknowledgments
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Authors wish to sincerely thank GVK Biosciences Pvt. Ltd.,
for the Higher Education Program, financial support and
encouragement. Help from the analytical department for all
spectral analysis is highly appreciated. We are thankful to Dr.
Sudhir Kumar Singh for his immense support and motivation.
We are also thankful to JNTUH, Hyderabad and BITS-Pilani,
Hyderabad.
11. Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat. Prod. Rep.
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Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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Natori, Y.; Yoshimura, Y.; Nash, R. J.; Shimaoka, H.; Nakagome,
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