Ionic liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a]pyrimidines as α-glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2016.06.086

A simple and facile synthesis of fused tetrazolo[1,5-a]pyrimidine derivatives based on the multicomponent reaction of acetophenone, dimethylformamidedimethylacetal and 5-aminotetrazole is described. A green chemical synthesis has been achieved by using1-b

Full text of DOI:10.1016/j.bmcl.2016.06.086

Accepted Manuscript
Ionic liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a] pyr-
imidines as α-glucosidase inhibitors
Lingala Suresh, P. Onkara, P. Sagar Vijay Kumar, Y. Pydisetty, G.V.P.
Chandramouli
PII:
S0960-894X(16)30696-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.06.086
BMCL 24039
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 April 2016
27 June 2016
29 June 2016
Please cite this article as: Suresh, L., Onkara, P., Sagar Vijay Kumar, P., Pydisetty, Y., Chandramouli, G.V.P., Ionic
liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a] pyrimidines as α-glucosidase inhibitors,
Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.06.086
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Ionic liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a]
pyrimidines as α-glucosidase inhibitors
Lingala Suresha, Onkara. Pb, P. Sagar Vijay Kumara, Y. Pydisettyc and G. V. P.
Chandramouli*a
aDepartment of Chemistry, National Institute of Technology, Warangal, 506 004, Telangana,
India
bDepartment of Biotechnology, National Institute of Technology, Warangal, 506 004,
Telangana, India
cDepartment of Chemical Engineering, National Institute of Technology, Warangal, 506 004,
Telangana, India
Telephone: +91-870-246-2660, Fax: +91-870-245-9547, *E-mail: gvpc2000@gmail.com
Abstract
A simple and facile synthesis of fused tetrazolo[1,5-a]pyrimidine derivatives based on
the multicomponent reaction of acetophenone, dimethylformamidedimethylacetal and 5-
aminotetrazole is described. A green chemical synthesis has been achieved by using1-butyl-
3-methylimidazolium hydrogen sulphate [Bmim]HSO4 ionic liquid as a reusable medium.
Short synthetic route, operational simplicity, good yields, eco-friendliness and recyclability
of the ionic liquid are the advantages of this method. The synthesized compounds were
screened for α-glucosidase inhibitory activity using yeast maltase (MAL12) as a model
enzyme. Inhibition and kinetic studies have shown that compounds 4d and 4g are found to be
active showing comparable inhibitory potency with acarbose. Further docking studies of the
derivatives with MAL12 homology model identified a similar binding mode consistent with
the binding of acarbose. These studies along with in-silico predicted ADMET properties
suggest that these molecules could represent a new scaffold that may be useful for the
development of new anti-diabetic drugs.
1

Keywords: Ionic liquid, tetrazolo[1,5-a]pyrimidine, antidiabetic, α-glucosidase inhibition,
docking studies, ADMET properties
Type 2 diabetes mellitus is the most common form of diabetes mellitus in which the
body does not use insulin properly and the condition is called as insulin resistance. Improper
use of insulin triggered by insulin resistance leads to abnormally high blood glucose levels
called as hyper glycaemia. In human system, four enzymes namely salivary α-amylase,
pancreatic α-amylase, α-glucosidase (also called as maltase–glucoamylase) and sucrase-
isomaltase are known for the thorough breakdown of complex carbohydrates like starch into
glucose, which is then absorbed into the blood stream by a specific transport system.1 α-
glucosidase inhibitors are a class of hypo glycemic oral anti-diabetic drugs used in the
treatment of type 2 diabetes mellitus. These drugs prevent the digestion of carbohydrates in
general and disaccharides in particular. Indirectly α-glucosidase inhibitors decrease the
influence of carbohydrates on the glycemic level of blood. Several natural products with α-
glucosidase inhibitor action have been well documented. Though several enzyme-inhibitor
models have been employed for in-vitro screening of inhibitor action, the yeast α-glucosidase
(MAL12) enzyme a member of the GH13 family has been widely used in enzymatic assays to
screen new α-glucosidase inhibitors owing to its ready availability and ease of handling.2
Multi-component processes have been gaining considerable cost-effective and
environmental interests as they address the fundamental principles of synthetic efficiency and
reaction design. These reactions were proven to be very elegant and quick to access complex
structures in a synthetic operation by starting from simple construction blocks and with high
selectivity. A one-pot, multi-component reaction (MCR) can allow good yields which are
primarily different from the two-component reactions in several aspects. MCRs allow rapid
2

access to combinatorial libraries of organic molecules for efficient lead structure
identification and optimization in drug discovery.3
Pyrimidine derivatives have been reported as potent inhibitors of the enzymes
responsible for diabetes,4 and particularly, pyrimidine fused heterocycles are identified as
specific α-glucosidase inhibitors (Fig.1).5 Heterocyclic compounds containing the
tetrazolopyrimidine moieties are significant targets in medicinal chemistry as they exhibit
various biological activities, such as antimicrobial,6 antioxidant,7 anticonvulsant,8
antidepressant9 and anticancer.10 Some of these compounds act as sodium channel blockers11
and transforming growth factor-β type I receptor (ALK5) inhibitors.12 They are also used as
human neutrophil lactase inhibitors in the treatment of pulmonary and cardiovascular
diseases13 and antidiabetes.14 Prior studies have also emphasized various uses of
tetrazolopyrimidines in the treatment of obesity, diabetes, hypertension, coronary heart
disease, hypercholesterolemia, hyperlipidemia and congestive heart failure.15
Fig. 1. The molecular structure of a pyrimidine based α-glucosidase inhibitor
In the past decade, ionic liquids gained considerable attention in several branches of
the chemical industry as potential “green” substitutes for conventional organic solvents.16
Recently, ionic liquids (ILs) especially of acidic types have attracted increasing interest in
heterocyclic syntheses, as they can provide green and efficient media for multicomponent
reactions (MCRs).17 As a part of our continued research in the development of highly
expedient multicomponent reactions for the synthesis of pyrimidine containing heterocyclic
3

compounds of biological importance,18 we herein report the synthesis of a novel class of
structurally diverse tetrazolo[1,5-a]pyrimidine derivatives possessing potent α-glucosidase
inhibitor activity using a three-component one-pot protocol under mild reaction conditions.
The present work is a part of our ongoing research program on the development of novel
multicomponent reactions for the construction of important heterocyclic ring systems by
green chemical methods.19
Initially, 4-chloroacetophenones 1b, dimethylformamidedimethylacetal 2 and 5-
aminotetrazole 3 were chosen as the coupling partners to determine the optimal reaction
conditions for the preparation of the compound 4b, using different solvents at various
temperatures. The results of the optimized conditions are summarized in Table 1. The
optimization studies show that when the reaction was carried out in neat condition the
reaction did not go to completion even after 24h and nearly no product was obtained (Table
1, entry 1). When different solvents such as water, ethanol, propanol, acetic acid, acetonitrile
and dimethylformamide were used, the obtained yields were poor (Table 1, entry 2-7). By
using typical ionic liquids like [Bmim]Br, [Bmim]Cl, [Bmim]PF6, [Bmim]BF4 and
[Bmim]HSO4, the yields were observed to be in the range of 74-92% (Table 1, entry 8-12). In
comparison with other ionic liquids, [Bmim]HSO4 gave better yield and shortened the time
by effectively promoting the reaction. Decreasing the reaction temperature to 60 °C, 50 °C
and room temperature, decreased the yield percentage. Even increase of temperature above
70 oC did not affect the yield of the reaction (Table 1, entry 13-16). It is also inferred that the
ionic liquid [Bmim]HSO4 was found to be the best optimal solvent for the above synthesis,
producing maximum yields at 70 oC and at 1h reaction time.
4

Table 1. Optimization of reaction conditions for the synthesis of 4b
Entrya
Solvent
Temp (oC)
Time (h)
bYield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
neat
water
EtOH
n-Propanol
AcOH
70
70
70
70
70
70
70
70
70
70
70
70
r.t
24
21
16
15
12
12
10
9
9
8
6
2
----
14
26
30
36
22
46
76
74
68
84
92
48
54
67
92
Acetonitrile
DMF
[Bmim]Br
[Bmim]Cl
[Bmim]PF6
[Bmim]BF4
[Bmim]HSO4
[Bmim]HSO4
[Bmim]HSO4
[Bmim]HSO4
[Bmim]HSO4
2
2
2
2
50
60
80
aReaction conditions: 4-chloroacetophenone (1 mmol), dimethylformamidedimethylacetal
(1 mmol), 5-aminotetrazole (1 mmol) and solvent (1 mL), bIsolated yields.
The reaction was conducted by using different substituted-acetophenones (1 mmol),
dimethylformamidedimethylacetal (1 mmol) and 5-aminotetrazole (1 mmol), under similar
conditions, the reaction proceeded smoothly producing tetrazolo[1,5-a]pyrimidine derivatives
(4a-l) in good yields. Substituted-acetophenones with electron-withdrawing as well as
electron-donating groups underwent the one-pot transformation with same ease, to produce
the corresponding tetrazolo[1,5-a]pyrimidine derivatives in good yields (Table 2). It was
observed that acetophenones possessing groups like 4-fluro, 2-hydroxy required more
reaction times and there was a little decrease in yield. Similarly, when 2-acetyl pyridine and
5

2-acetyl thiophene were employed in the place of acetophenone, there was an increase of
reaction time, without decrease in yield. Lowering of yields and increase of reaction times
were observed when 3-acetylcoumarin and 2-acetylbenzofuran were adopted instead of
acetophenone. The reaction dynamics depends upon the type of aryl/hetro-aryl moiety present
on the aromatic side of acetophenones.
Table 2. Synthesis of fused tetrazolo[1,5-a]pyrimidine derivatives (4a-l) a
aReaction conditions: aromatic acetophenone (1 mmol),dimethylformamidedimethylacetal (1
mmol) and 5-aminotetrazole (1 mmol), in the presence of ionic liquid [Bmim]HSO4 (1 mL)
bYields of the isolated products
6

A plausible mechanism for the formation of the tetrazolo[1,5-a]pyrimidine derivatives
is shown in Scheme 1. Firstly, aromatic acetophenone 1, condensation with N,N-
dimethylformamide dimethylacetal 2 by the formation of α,β-unsaturated ketone intermediate
A. These intermediate A attack with 5-aminotetrazole 3 to producing intermediate B,
subsequently loses dimethyl amine to form intermediate C. Finally, the keto-enol
tautomerisation of intermediate C, followed by cyclization via elimination of water to the
form the corresponding product 4.
Scheme 1. Plausible mechanism for the synthesis of tetrazolo[1,5-a]pyrimidines (4a-l)
The newly synthesized novel class of non-glycosidic tetrazolopyrimidines (4a-l) was
tested for their α-glucosidase inhibitory activity by in-vitro enzyme assay. Homology
modeling of the receptor (α-glucosidase) followed by the molecular docking we examined.
The ligand enzyme connections are in accordance with in-vitro results obtained in the wet
7

lab. The results of inhibitory activity of the fused tetrazolo[1,5-a]pyrimidine derivatives (4a-
l) at 5mM concentration against α-glucosidase are shown in Fig.2. The tested molecules (4a-
l) have shown more selective inhibition towards α-glucosidase. The selective inhibition of α-
glucosidase over α-amylase is greatly required, because, non-specific inhibition of α-amylase
may lead to accumulation of non-digested carbohydrates, which in turn may result in
abdominal cramping, diarrhoea and flatulence.20 The tested compounds (4a-l) have shown
varying degree of α-glucosidase inhibition with IC50 values ranging from 49.8±0.29 µM to
1739.0±2.51 µM (Table 3). In vitro antidiabetic activity results indicated that compound 4d
(49.8±0.29µM) and 4g (85.7±1.2µM) exhibited similar activity comparable with standard
drug acarbose (33.9±3.2 µM). The inhibitors 4d and 4g which showed top two minimal IC50
values against antidiabetic (α-glucosidase) activity were taken for further investigation.
Enzyme kinetic studies showed that the tested compounds were inhibiting the α-glucosidase
by mixed uncompetitive mode of inhibition. Different types of inhibition modes by different
types of inhibitors were reported for α-glucosidase (antidiabetic) activity.21 The mode of
inhibition of these two (4d and 4g) inhibitors was determined from their Michaelis-Menten
Kinetic values. The KM values were found to be decreasing with increasing concentration of
inhibitors and Vmax values of the enzyme were found to be increasing with the increasing
concentration of inhibitors (4d and 4g) as shown in Fig.3 and 4. From this we conclude that
the enzyme kinetic studies indicate that mode of inhibition of 4d and 4g may be mixed
uncompetitive inhibition (Table 4).
8

Fig. 2. Inhibition profile of α-amylase and α-glucosidase by fused tetrazolo[1,5-a]pyrimidine
derivatives (4a-l) at 5 mM concentration.
Table 3. The IC50 value of fused tetrazolo[1,5-a]pyrimidine derivatives (4a-l) for α -
glucosidase inhibition
Compound
IC50 Value µM
422.3±1.47
421.2±0.986
177.6±0.27
49.8±0.29
307.5±2.14
1739.0±2.51
85.7±1.2
4a
4b
4c
4d
4e
4f
4g
4h
ND
4i
591.2±1.39
446.1±0.97
ND
4j
4k
4l
1011.9±2.09
33.9±3.2
Acarbose
*ND – Not Determined
9

Table 4: IC50, Kim and inhibition mode of selected fused tetrazolo[1,5-a]pyrimidine
derivatives 4d and 4g at 25 µM concentration
Compound
IC50 (µM)
49.8±0.29
85.7±1.2
KM (µM)
0.478
KiM (µM) (i=25 µM)
Mode of inhibition
Mixed-Uncompetitive
Mixed-Uncompetitive
4d
4g
3.756
1.15
0.478
Fig. 3. Lineweaver-Burk plot displaying the mode of Inhibition of α-glucosidase by
fused tetrazolo[1,5-a]pyrimidine derivative 4d.
Fig. 4. Lineweaver-Burk plot displaying the mode of Inhibition of α-glucosidase by
fused tetrazolo[1,5-a]pyrimidine derivative 4g
10

Backing the in-vitro screening results a complete homology model of α-glucosidase
(MAL12) was built by taking the crystal structure of Saccharomyces cerevisiaeisomaltase
(PDB ID 3AJ7) as the template. The high degree of sequence identity of 72.4% with the
target sequence was considered while choosing the best template structure for constructing
the homology model. The in-silico screening studies were carried out using various modules
of VLifeMDS software version 4.6.22 The homology model was built using Biopredicta
module. The final model consisting of a single polypeptide chain with 584 residues was built
for further docking studies (Fig.5). The same module was used to perform docking studies
with the newly built model and the fused tetrazolo[1,5-a]pyrimidine derivatives (4a-l). The
mode of binding and interactions between the active site of the α-glucosidase and the
synthesized compounds were assessed.
Fig. 5. Graphical representation of the homology modelled structure of MAL12 with active
site residues (ASP214, GLU276 and ASP349) highlighted.
11

All the tested compounds occupied the same region of the binding pocket as that of
the cyclohexenyl ring of acarbose forming similar contacts with the enzyme active site.
Further analysis of the compounds with the interaction viewer module revealed that the
important residues PHE157A, HIS279A, PHE300A, THR301A, GLU304A, PRO309A,
ARG312A, in addition to the active site residues ASP214, GLU276A and ASP349 were
involved in the α-glucosidase inhibition. The residues mentioned above were found to
interact with one or more atoms of the tested compounds. The interactions between MAL12
model residues and compounds acarbose, 4d and 4g are summarized in Table 5.
Table 5: Key interactions between MAL12 model residues and compounds acarbose, 4d and
4g
Residue (Name, atom)
Ligand (Name, Atom)
Distance (Å)
4.095
2.527
2.544
2.469
2.539
2.586
2.337
2.444
2.065
1.571
2.481
1.814
5.019
4.974
4.549
1.926
2.244
1.654
2.163
2.319
5.157
Interaction Type*
GLU304A
THR215A
HIS279A
HIS279A
GLY306A
GLY306A
THR307A
THR307A
SER308A
SER308A
HIS279A
HIS279A
PHE157A
HIS279A
HIS279A
HIS279A
HIS279A
HIS279A
HIS279A
HIS279A
PHE300A
4829O
3435O
4463H
4463H
4851N
4855H
4863O
4865H
4872N
4882H
4463H
4463H
2516C
4452C
4452C
4463H
4463H
4463H
4463H
4463H
4760C
Acarbose
19N
81H
1O
CHARGE_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
AROMATIC_INTERACTION
3O
82H
13O
80H
11O
80H
11O
14N
15N
8N
4d
4g
1C
AROMATIC_INTERACTION
8N
AROMATIC_INTERACTION
8N
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
HYDROGENBOND_INTERACTION
AROMATIC_INTERACTION
10N
13N
14N
15N
8N
12

Among the several compounds that exhibited multiple interactions, again compounds
4d and 4g, were found to be potent and promising compounds in the series. Compounds 4d
and 4g formed Aromatic Interaction, Hydrophobic interaction and Hydrogen bond with
THR301, PRO309, GLU304, PHE157, and HIS279, in the binding pocket. Aromatic
interactions were observed between 1C and HIS279 (4.9Å), 8N and HIS279 (4.5Å) and 8N
and PHE157 (5.0Å). Hydrophobic interactions were observed between 16C and THR301 and
PRO309 with (between 4.0 Å – 4.8Å) respectively. H-bond was observed between 14N and
HIS279 (2.481 Å) and 15N and HIS279 (1.814 Å) both in close vicinity and adjacent to the
active site residue GLU276. 3D docking interactions for acarbose, interaction of 4d and 4g
inside the active site cavity of MAL12 homology Model are shown in Fig.6. bond
interactions, blue dashed line; Hydrophobic interactions, sky blue dashed
line;Aromaticinteractions, magenta dashed line; Charge interactions, yellow dashed line.
In-silico prediction of ADMET properties for the fused tetrazolo[1,5-a]pyrimidine
derivatives (4a-l) was performed by accessing the free ADMET prediction server
FAFDrugs3server.23 We analysed various pharmaceutically related properties and physical
descriptors for ADME (Adsorption, Distribution, Metabolism, and Excretion) properties.
Significant pharmacokinetic descriptors contain hydrogen-bond acceptor count (HBA),
octanol-water partition coefficient (log P), hydrogen-bond donor count (HBD). Drug-likeness
of dataset compounds was evaluated by Lipinski’s rule-of-five. As per Lipinski’s rule-of-five,
an orally administrated drug should have HBA ≤10, log P ≤5, HBD ≤5, and molecular weight
(MW) <500 Daltons. However, compounds which meet only two criteria, i.e. topological
polar surface area (tPSA) ≤ 140 Å2 and rotatable bonds ≤ 15 are expected to have proper oral
bioavailability. tPSA is a parameter used to calculate transport properties of drugs and used
for passive molecular transport of drug molecules.
13

a
b
c
Fig. 6. 3D docking interactions for (a) acarbose, (b) 4d and (c) 4g inside the active
site cavity of MAL12 homology Model.2D interaction of acarbose, 4d, and 4g.Legand: H-
14

The dataset compound showed tPSA value ranging between 55.97 and 101.79 which
showed good cell permeability. All synthesized tetrazolo[1,5-a]pyrimidine showed ADMET
parameters within reference range (Table 6).
Table 6: In-silico prediction of ADMET properties of fused tetrazolo[1,5-a]pyrimidine
derivatives(4a-l)
Lipinski
violation
Compounds
MW
LogP
HBA
HBD
tPSA
4a
4b
4c
4d
4e
4f
4g
4h
197.19
231.64
215.18
211.22
242.19
213.19
227.22
275.10
198.18
265.22
237.21
203.22
645.60
1.32
1.95
1.42
1.68
1.15
0.96
1.29
2.13
0.29
1.32
1.76
1.04
-8.53
5
5
5
5
8
6
6
4
6
7
6
5
19
0
0
0
0
0
1
0
0
0
0
0
0
14
55.97
55.97
55.97
55.97
101.79
76.2
0
0
0
0
0
0
0
0
0
0
0
0
3
65.2
43.08
68.86
86.18
69.11
84.21
321.17
4i
4j
4k
4l
Acarbose
In conclusion, we have successfully established a new, flexible and practical three-
component reaction for the synthesis of fused tetrazolo[1,5-a]pyrimidine derivatives with
good yields using ionic liquid as a green solvent. The compounds were screened for in-vitro
and in-silico yeast α-glucosidase and pancreatic α-amylase inhibition by taking acarbose as
the reference. The compound 4d showed best inhibition (IC50 = 49.8±0.29 µM). Docking
studies of the tested compounds were performed upon a model of yeast α-glucosidase
(MAL12) enzyme. The interactions and binding modes of the compounds elucidate that
better inhibitory activity was exhibited by compounds 4d and 4g.
15

Acknowledgement
The authors are thankful to the Director, National Institute of Technology, Warangal, for
providing facilities. LS is grateful to the Ministry of Human Resource Development and
PSVK is grateful to CSIR, New Delhi, India [File 09/922 (0005) 2012 /EMR-I] for financial
support.
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Ionic liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a]
pyrimidines as α-glucosidase inhibitors
Lingala Suresha, Onkara. Pb, P. Sagar Vijay Kumara, Y. Pydisettyc and G. V. P.
Chandramouli*a
aDepartment of Chemistry, National Institute of Technology, Warangal, 506 004, Telangana,
India
bDepartment of Biotechnology, National Institute of Technology, Warangal, 506 004,
Telangana, India
cDepartment of Chemical Engineering, National Institute of Technology, Warangal, 506 004,
Telangana, India
Telephone: +91-870-246-2660, Fax: +91-870-245-9547, *E-mail: gvpc2000@gmail.com
Graphical abstract
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