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

Accepted Manuscript Ionic liquid-promoted multicomponent synthesis of fused tetrazolo[1,5-a] pyrimidines as α-glucosidase inhibitors Lingala Suresh, P. Onkara, P. Sagar Vijay Kumar, Y. Pydisetty, G.V.P. Chandramouli PII: DOI: Reference:

S0960-894X(16)30696-5 http://dx.doi.org/10.1016/j.bmcl.2016.06.086 BMCL 24039

To appear in:

Bioorganic & Medicinal Chemistry Letters

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 a

Department of Chemistry, National Institute of Technology, Warangal, 506 004, Telangana,

India b

Department of Biotechnology, National Institute of Technology, Warangal, 506 004,

Telangana, India c

Department of Chemical Engineering, National Institute of Technology, Warangal, 506 004,

Telangana, India Telephone: +91-870-246-2660, Fax: +91-870-245-9547, *E-mail: [email protected] Abstract A simple and facile synthesis of fused tetrazolo[1,5-a]pyrimidine derivatives based on the multicomponent reaction of acetophenone, dimethylformamidedimethylacetal and 5aminotetrazole is described. A green chemical synthesis has been achieved by using1-butyl3-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.

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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 sucraseisomaltase 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 αglucosidase 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 αglucosidase 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

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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

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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 5aminotetrazole 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]HSO 4 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.

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Table 1. Optimization of reaction conditions for the synthesis of 4b

Entrya

Solvent

Temp (oC)

Time (h)

b

Yield (%)

1 neat 70 24 ---2 water 70 21 14 3 EtOH 70 16 26 4 n-Propanol 70 15 30 5 AcOH 70 12 36 6 Acetonitrile 70 12 22 7 DMF 70 10 46 8 [Bmim]Br 70 9 76 9 [Bmim]Cl 70 9 74 10 [Bmim]PF6 70 8 68 11 [Bmim]BF4 70 6 84 12 [Bmim]HSO4 70 2 92 13 [Bmim]HSO4 r.t 2 48 14 [Bmim]HSO4 50 2 54 15 [Bmim]HSO4 60 2 67 16 [Bmim]HSO4 80 2 92 a Reaction 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

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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

a

Reaction conditions: aromatic acetophenone (1 mmol),dimethylformamidedimethylacetal (1

mmol) and 5-aminotetrazole (1 mmol), in the presence of ionic liquid [Bmim]HSO4 (1 mL) b

Yields of the isolated products

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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,Ndimethylformamide 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

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lab. The results of inhibitory activity of the fused tetrazolo[1,5-a]pyrimidine derivatives (4al) at 5mM concentration against α-glucosidase are shown in Fig.2. The tested molecules (4al) have shown more selective inhibition towards α-glucosidase. The selective inhibition of αglucosidase 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).

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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

4a

422.3±1.47

4b

421.2±0.986

4c

177.6±0.27

4d

49.8±0.29

4e

307.5±2.14

4f

1739.0±2.51

4g

85.7±1.2

4h

ND

4i

591.2±1.39

4j

446.1±0.97

4k

ND

4l

1011.9±2.09

Acarbose

33.9±3.2

*ND – Not Determined

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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)

KM (µM)

KiM (µM) (i=25 µM)

Mode of inhibition

4d

49.8±0.29

0.478

3.756

Mixed-Uncompetitive

4g

85.7±1.2

0.478

1.15

Mixed-Uncompetitive

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

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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.

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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) Acarbose

Distance (Å)

Interaction Type*

19N

4.095

CHARGE_INTERACTION

GLU304A

4829O

THR215A

3435O

81H

2.527

HYDROGENBOND_INTERACTION

HIS279A

4463H

1O

2.544

HYDROGENBOND_INTERACTION

HIS279A

4463H

3O

2.469

HYDROGENBOND_INTERACTION

GLY306A

4851N

82H

2.539

HYDROGENBOND_INTERACTION

GLY306A

4855H

13O

2.586

HYDROGENBOND_INTERACTION

THR307A

4863O

80H

2.337

HYDROGENBOND_INTERACTION

THR307A

4865H

11O

2.444

HYDROGENBOND_INTERACTION

SER308A

4872N

80H

2.065

HYDROGENBOND_INTERACTION

SER308A

4882H

11O

1.571

HYDROGENBOND_INTERACTION

HIS279A

4463H

14N

2.481

HYDROGENBOND_INTERACTION

HIS279A

4463H

15N

1.814

HYDROGENBOND_INTERACTION

PHE157A

2516C

8N

5.019

AROMATIC_INTERACTION

HIS279A

4452C

1C

4.974

AROMATIC_INTERACTION

HIS279A

4452C

8N

4.549

AROMATIC_INTERACTION

HIS279A

4463H

8N

1.926

HYDROGENBOND_INTERACTION

HIS279A

4463H

10N

2.244

HYDROGENBOND_INTERACTION

HIS279A

4463H

13N

1.654

HYDROGENBOND_INTERACTION

HIS279A

4463H

14N

2.163

HYDROGENBOND_INTERACTION

HIS279A

4463H

15N

2.319

HYDROGENBOND_INTERACTION

PHE300A

4760C

8N

5.157

AROMATIC_INTERACTION

4d

4g

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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.

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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-

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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) Compounds

MW

LogP

HBA

HBD

tPSA

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l Acarbose

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 65.2 43.08 68.86 86.18 69.11 84.21 321.17

Lipinski violation 0 0 0 0 0 0 0 0 0 0 0 0 3

In conclusion, we have successfully established a new, flexible and practical threecomponent 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.

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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. References 1. 2.

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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 a

Department of Chemistry, National Institute of Technology, Warangal, 506 004, Telangana,

India b

Department of Biotechnology, National Institute of Technology, Warangal, 506 004,

Telangana, India c

Department of Chemical Engineering, National Institute of Technology, Warangal, 506 004,

Telangana, India Telephone: +91-870-246-2660, Fax: +91-870-245-9547, *E-mail: [email protected]

Graphical abstract

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