Synthesis of Novel molecular hybrid 3-(4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives and In Vitro α-glucosidase and α-amylase inhibitory activity

 

Vikas N. Telvekar¹, Krishna N. Mundlod²*, Ghanshyam B. Jadhav², Navnath T. Hatvate¹, Shrikant M. Ghodse¹

¹Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,

Mumbai-400019. (Maharashtra) India.

²Department of Pharmaceutical Chemistry, MVP Samaj’s College of Pharmacy, Nashik - 422002.

Dist - Nashik (Maharashtra) India.

 

ABSTRACT:

A novel series of 3-(4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives was designed based on molecular hybridization technique. A series of 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives (6a–6p) that incorporate a variety of substituents at the 2 and 4 position of the benzyl moiety have been synthesized. These compounds were evaluated for their antidiabetic activity against α-glucosidase and α-amylase. The biological screening indicates that these hybrid derivatives exhibited promising IC₅₀ values in the range of 91.24μM -261.82μM and 85.03μM -237.78μM respectively. Two analogs, 6j and 6m have shown most potential activity against both α-glucosidase and α-amylase were identified as potent antidiabetic agents.

 

 

 

INTRODUCTION:

There are two types of diabetes; type 1 diabetes is due to lack of insulin Type 2 diabetes mellitus (T2DM) which is due to body’s ineffective use of insulin. T2DM is a metabolic disease characterized by high blood sugar level¹. Diabetes can be managed by regular healthy diet and physical activity. It can be treated through various pathways by controlling blood glucose level². For the treatment of diabetes U.S. FDA approved the drugs can be categorized into five classes: sulfonylureas, meglitinides, Biguanides, thiazolidinediones and α-glucosidase inhibitors (AGIs)³. Several AIGs, such as voglibose, acarbose and miglitol can reversibly inhibit α-glucosidase, and extending the absorption of sugars from the gut. These are used in the treatment of DM⁴.

 

Multistep syntheses and tedious reaction was the drawback of these commercially available AGIs⁵. AGIs reduce the workload of pancreatic cells to control the Postprandial hyperglycaemia (PPHG)⁶. Acarbose was the first AGI and was made commercially available in 1990⁷. Acarbose has effects on various intestinal enzymes; it mainly inhibits α-amylases, including glucoamylase, sucrose, maltase and isomaltase^8,9. Alpha-Glucosidase found in intestinal cells which cleave α-glycosidic bonds from carbohydrate source and produce the glucose¹⁰. Glucosidase inhibitors can be used for the treatment of DM, because they can decrease the rate of sugar absorption and suppress PPHG^11,12.

 

Over the last two decades, coumarins have been established as one of the key naturally occurring oxygen containing heterocyclic compounds found in various plants. These coumarins have wide range of application and reported to possess many pharmacological activities like anti-inflammatory, antioxidant¹³, bronchodilator, Anti-amoebic, antibacterial¹⁴, anti-HIV¹⁵ and antifungal activities¹⁶. Synthetic coumarin derivatives has been reported for the diabetes treatment by various mechanism like activation of phosphatidylinositol-3-kinase¹⁷. Coumarins pharmacological activity were depends on type and position of substitution on coumarin rings. There were very few reports on synthetic coumarin compounds as α-glucosidase and α-amylase inhibitors to treat T2DM¹⁸.

 

Pyrazole and substituted pyrazolines is having Considerable attention because their wide biological activities. Pyrazoline have possess antifungal¹⁹, antidepressant, anticonvulsant, anti-inflammatory, antibacterial²⁰, anti- tumor, and antidiabetic properties. Different substituted pyrazoles were known for their antidiabetic activity, because they are acting on β-cell pancreatic membrane and potentiate the production of insulin²¹.

 

We decided to explore new hybrid molecule containing coumarin ring through molecular hybridization technique. Based on this approach, various studies have been reported to hybridize 4-hydroxycoumarins with different bioactive molecules like resveratrol, maleimide and alpha-lipoic acid which resulted in novel hybrids showing antiplatelet, antioxidant, antiinflammatory and Antidiabetic activities^22,23.

 

We aimed to synthesize novel hybrid molecule containing 4-hydroxycoumarins and pyrazole through chalcone formation. As chalcones are key intermediates for the synthesis of various heterocyclic compounds, they play a significant role in medicinal chemistry. The hybridized molecule is shown in figure 1

 

Figure 1: Designed hybrid molecule

 

MATERIAL AND METHODS:

Synthesis of substrate molecule given in the scheme:

General synthesis procedure of 3-acetyl-4-hydroxy coumarin (2).:

To a solution of 4-hydroxy-2H-chromen-2-one (3g, 1mmole) in acetic acid (16ml) was added phosphorus oxychloride (5.6mL). The mixture was heated at reflux for 30min. After cooling of precipitate was collected and recrystallized from ethanol to give 3acetyl-4-hydroxy 2H-chromen-2-one as white crystals²⁴. (Yield = 90%); MP 134-136^oc was obtained.

 

General procedure of 3-cinnamoyl-4-hydroxy-2H-chromen-2-one synthesis (3):

A solution of 3-acetyl-4-hydroxycoumarin (2g, 6 mmol) in ethanol (20ml) and the selected aromatic aldehyde (6 mmol) in the presence of piperidine (1ml) was refluxed for 3–4h. The solution was cooled and ice cold water was added then added 2N HCl to get precipitate the desired chalcone compounds. Recrystallization in hot ethanol to get needle shape crystals. The reaction has been monitored by on TLC²⁵.

 

Synthesis of 4-hydroxy-3-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (4a-d):

A mixture of the appropriate chalcones 3a-3d (1 mmol) and 99% hydrazine hydrate (2 mmol) in ethanol (30 ml) was refluxed for 1 h. The reaction mixture was cooled and the formed precipitate was filtered it, washed and recrystallized from methyl alcohol to give 4a-4d compounds.

 

Synthesis of 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one (6a-d):

To compound 4(a-d) (1 mmol) in pyridine (10ml), different Aroyl chloride 5(a-d) (2 mmol) was added. Attached the reflux condenser to reaction mixture containing RBF for 3hours and then poured the reaction mixture over crushed ice mixed with dilute HCl. The solid separated out was filtered on pump, washed with water, dried in the oven and recrystallized from ethyl alcohol to give Compound 6(a-p). The reaction has been monitored by on TLC²⁶.

 

Scheme: (a) POCl₃, in Glacial acetic acid reflux for 1-2h (b) Piperidine in ethanol, diff. aldehydes, reflux for 3-4h (c) 99% NH₂-NH₂ in ethanol, reflux for 3-4h (d) Diff. aroyl chlorides in Hot pyridine, 3-4h

 

Table 1: Synthesis of 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives 6a-p.

Compound code	R1	R2	Compound code	R1	R2
6a	-H	-H	6i	-NO2	-H
6b	-H	-F	6j	-NO2	-F
6c	-H	-NO2	6k	-NO2	-NO2
6d	-H	-CF3	6l	-NO2	-CF3
6e	-OCH3	-H	6m	-Cl	-H
6f	-OCH3	-F	6n	-Cl	-F
6g	-OCH3	-NO2	6o	-Cl	-NO2
6h	-OCH3	-CF3	6p	-Cl	-CF3

 

Analytical Characterization:

All chemicals and solvents of commercial grade used without further purification and were supplied by spectrochemicals and Aldrich chemicals. Melting points (M.P.) were identified in capillaries and are uncorrected. Reactions were monitored and compounds are purified by Thin Layer Chromatography (TLC) with pre coated plate of silica gel and column chromatography was performed. Petroleum ether/ethyl acetate and chloroform/methanol were the adopted solvent system. ¹H spectra were run on Bruker 400 MHz NMR spectrometer respectively, using CDCl₃ and DMSO-d₆ as solvents. The chemical shifts were expressed in parts per million with TMS as internal reference. J Values are given in hertz.

 

Table 2: Analytical characterization of synthesized compounds.

Compound code	% yield	Melting Point (°C)	TLC (Rf value)	IR Spectral study (Ѵmax cm-1)	1H NMR Spectral study (400Hz CDCl3 DMSO-d6)
6a	83	238	0.42	3393 (O–H), 3059 (C–H), 1710 (C=O), 1643, 1613 (C=N), 1491, 1457, 1329, 1276, 1177, 1032, 823	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.82 (s, 1H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 4H, Ar-H)
6b	75	235	0.41	3689 (O–H), 2996(C–H), 1719 (C=O), 1680, 1614 (C=N), 1509, 1461, 1367, 1276, 1157, 1031, 823	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.82 (s, 1H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)
6c	86	237	0.42	3396 (O–H), 3064 (C–H), 1710 (C=O), 1663, 1616 (C=N), 1527and1347 (NO2), 1421, 1331, 1232, 1196, 1032, 823	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.82 (s, 1H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)
6d	76	227	0.40	3669 (O–H), 3070 (C–H),1723 (C=O), 1675, 1614 (C=N), 1558, 1432, 1314, 1267, 1130, 1029, 755	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.82 (s, 1H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)
6e	83	225	0.41	3691 (O–H), 2952 (C–H), 1723 (C=O), 1644, 1611 (C=N), 1510, 1457, 1334, 1250, 1177, 830	δ 13.02 (s, 1H, O-H), δ 7.78 (d, J= 7.8, 2H, Ar-H), δ 7.57 (d, J= 6.3, 2H, Ar-H), δ 7.48 (t, 3H, Ar-H), δ 7.39 (t, 3H, Ar-H), δ 7.33-7.16 (m, 4H, Ar-H), δ 7.13 (d, J= 8.4, 2H, Ar-H), δ 3.95 (t, 3H, O-CH3)
6f	85	231	0.42	3675 (O–H), 2925 (C–H), 1724 (C=O), 1687, 1604 (C=N), 1514, 1466, 1337, 1249, 1033, 904, 758	δ 13.02 (s, 1H, O-H), δ 7.78 (d, J= 7.8, 2H, Ar-H), δ 7.57 (d, J= 6.3, 2H, Ar-H), δ 7.48 (t, 3H, Ar-H), δ 7.39 (t, 3H, Ar-H), δ 7.33-7.16 (m, 3H, Ar-H), δ 7.13 (d, J= 8.4, 2H, Ar-H), δ 3.95 (t, 3H, O-CH3)
6g	89	235	0.42	3463 (O–H), 2961 (C–H), 1724 (C=O), 1663, 1609 (C=N), 1564, 1515and1349 (NO2) 1447, 1260, 1099, 864, 778	δ 13.02 (s, 1H, O-H), δ 7.78 (d, J= 7.8, 2H, Ar-H), δ 7.57 (d, J= 6.3, 2H, Ar-H), δ 7.48 (t, 3H, Ar-H), δ 7.39 (t, 3H, Ar-H), δ 7.33-7.16 (m, 3H, Ar-H), δ 7.13 (d, J= 8.4, 2H, Ar-H), δ 3.95 (t, 3H, O-CH3)
6h	80	220	0.41	3703 (O–H), 2922 (C–H), 1716 (C=O), 1672, 1608 (C=N), 1567, 1463, 1316, 1253, 1134, 832	δ 13.02 (s, 1H, O-H), δ 7.78 (d, J= 7.8, 2H, Ar-H), δ 7.57 (d, J= 6.3, 2H, Ar-H), δ 7.48 (t, 3H, Ar-H), δ 7.39 (t, 3H, Ar-H), δ 7.33-7.16 (m, 3H, Ar-H), δ 7.13 (d, J= 8.4, 2H, Ar-H), δ 3.95 (t, 3H, O-CH3)
6i	75	220	0.42	3647 (O–H), 3053 (C–H), 1711 (C=O), 1655, 1613 (C=N), 1499, 1549 and1342 (NO2), 1269, 1191, 1004, 855	δ 13.0 (s, 1H, O-H), δ 8.21 (d, J= 8, 2H, Ar-H), δ 7.97 (d, J= 7.6, 2H, Ar-H), δ 7.91 (d, J= 8.8, 2H, Ar-H), δ 7.65-7.54 (m, 4H, Ar-H), δ 7.41 (t, 3H, Ar-H), δ 7.33 (s, 1H, Ar-H), δ 2.09 (d, J= 7, 2H, Ar-H).
6j	82	210	0.41	3445 (O–H), 2924 (C–H), 1739 (C=O), 1639, 1602 (C=N), 1415, 1513 and1350 (NO2), 1239, 1152, 1007, 746	δ 13.1 (s, 1H, O-H), δ 8.22 (d, J= 8.4, 2H, Ar-H), δ 7.91 (t, 3H, Ar-H), δ 7.69-7.56 (m, 7H, Ar-H), δ 7.41 ((t, 3H, Ar-H).
6k	87	224	0.40	3658 (O–H), 2929 (C–H), 1724 (C=O), 1603 (C=N), 1436, 1513 and 1351 (NO2), 1211, 1107, 1032, 763	δ 13.00 (s, 1H, O-H), δ 8.41 (d, J= 8.52, 2H, Ar-H), δ 8.29 (d, J= 8, 2H, Ar-H), δ 7.97 (t, 3H, Ar-H),δ 7.76 (t, 3H, Ar-H),δ 7.55 (d, J= 8.4, 2H, Ar-H), δ 7.36 (t, 3H, Ar-H).
6l	85	268	0.42	13692 (O–H), 2927 (C–H), 1715 (C=O), 1608 (C=N), 1435, 1513 and1350 (NO2), 1211, 1174, 1035, 962, 779	δ 13.00 (s, 1H, O-H), δ 8.29 (d, J= 8.4, 2H, Ar-H), δ 7.87 (d, J=8, 2H, Ar-H), δ 7.82 (d, J= 7.6, 2H, Ar-H), , δ 7.72 (t, 3H, Ar-H),δ 7.66 (t, 3H, Ar-H), δ 7.56 (d, J= 8.8, 2H, Ar-H), δ 7.51 (d, J= 7.2, 2H, Ar-H).
6m	81	221	0.43	3703 (O–H), 2929 (C–H),1720 (C=O), 1650, 1608 (C=N), 1569,1488, 1365, 1272, 1163, 993, 822. 758	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.82 (s, 1H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)
6n	80	258	0.43	13691 (O–H), 2918 (C–H),1720 (C=O), 1664, 1608 (C=N), 1566, 1432, 1334, 1230, 1160, 1031, 823	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)
6o	80	268	0.43	3686 (O–H), 2929 (C–H), 1720 (C=O), 1664, 1606 (C=N), 1524and1345 (NO2), 1457, 1278, 1202, 1088, 823	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)
6p	75	225	0.40	3669 (O–H), 3070 (C–H),1723 (C=O), 1675, 1614 (C=N), 1558, 1432, 1314, 1267, 1130, 1029, 755	δ 13.18 (s, 1H, O-H), δ 7.97 (d, J= 7.5, 2H, Ar-H), δ 7.65 (t, 3H, Ar-H), δ 7.6-7.34(m, 4H, Ar-H), δ 7.3(t, 3H, Ar-H)δ 7.27-7.16 (m, 3H, Ar-H)

 

Biological Activity Methods:

In vitro Inhibition Assay for α-Glucosidase Activity^27,28:

The inhibition of α-glucosidase activity was determined using the published method. The sample solution was replaced by DMSO as a control. Acarbose was used as a positive control. All experiments were carried out in triplicate.

 

The enzyme inhibition rate expressed as percentage of inhibition was calculated using the following formula:

Inhibition of α- glucosidase activity (%) = ((Abs C - Abs S)/Abs C)*100

 

Where Abs C is the absorbance of the control (100 % enzyme activity) and Abs S is the absorbance of the tested sample (Synthesized compounds or acarbose).

 

The enzyme activity was calculated and the IC50 value of inhibition shown in the (Table 3).

 

In vitro Inhibition assay for α-amylase activity^29,30:

The inhibition of α-glucosidase activity was determined using the published method. A control experiment was conducted in the same manner by replacing the drug sample with 1mL DMSO. Acarbose was used as a positive control. All experiments were carried out in triplicate.

 

The inhibition percentage of α-amylase was calculated using a formula. The enzyme activity was calculated and the IC₅₀ value of inhibition shown in the (Table 3).

 

Table 3: Result of α-Glucosidase and α-amylase inhibitory activity of novel derivatives (6a–p).

Compound code	IC50 (µM)
	α-glucosidase	α-amylase
6a	261.82	237.78
6b	152.64	212.17
6c	179.97	173.36
6d	149.58	257.32
6e	288.04	206.06
6f	188.47	163.51
6g	209.64	155.58
6h	227.71	220.39
6i	158.26	150.61
6j	93.55	89.21
6k	107.76	103.84
6l	225.86	218.04
6m	91.24	85.03
6n	141.25	166.46
6o	193.85	163.96
6p	126.32	119.46
Acrabose	133.50	127.84

 

RESULT AND DISCUSSION:

Chemistry:

A series of novel 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives (6a–6p) were synthesized as shown in Scheme. 4-hydrpxy-2H-chromen-2-one 1 was reacted with phosphorus oxychloride in acetic acid to form 3-acetyl-4-hydroxy coumarin 2, which reacted with different aromatic aldehyde to provide 3-cinnamoyl-4-hydroxy-2H-chromen-2-one 3a-3d. Treatment of 3a-3d with hydrazine hydrate to give 4-hydroxy-3-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one 4a-4d. Condensation of 4a-4d with different commercially available Aroyl chloride 5a–5d in the pyridine afforded the target molecule 6a-6p 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives. All the synthesized compounds are new and have not been reported in the literature upto date. The structures of all the synthesized compounds (6a–6p) were elucidated from spectral data.

 

α-Glucosidase and α-Amylase inhibition assay:

All synthetized compounds were evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. The results showed that the majority of compounds exhibited potent α-glucosidase and α-amylase inhibitory activity in the range 91.24 to 261.82μM, and 85.03μM to 237.78μM, respectively when compared to the standard drug acarbose (IC₅₀=133.50μM). Among the compounds in the series, compounds 6j and 6m exhibits potent inhibitory potential against both the enzyme α-glucosidase and α-amylase. Compounds 6j and 6m showed α-glucosidase inhibitory IC₅₀ values of 93.55 and 91.24μM respectively. Also Compounds 6j and 6m showed α-amylase inhibitory IC₅₀ values of 89.21μM and 85.03μM respectively. Compound 6m (IC₅₀= 91.24μM), containing chloro and hydrogen atom at the 4- position of Phenyl ring and 4-positions of the benzoyl ring respectively, it was lead to be the highest active compound that inhibits α-glucosidase and α-amylase activity. Compounds 6k and 6p also showed good inhibition with IC₅₀ values of 107.76μM and 126.32μM respectively. The other compounds showed low.

 

CONCLUSION:

The present study describes the synthesis of sixteen novel 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one (6a–6p) compounds by condensation of 4-hydroxy-3-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-2H-chromen-2-one (4a–d) with different Aroyl chloride 5(a-d) and evaluates these compounds for their α-amylase and α-glucosidase inhibition. The structures of all the novel synthesized compounds were confirmed by elemental and spectroscopic analysis (IR, 1H-NMR). The biological potential of the synthesized compounds was investigated through in vitro α-glucosidase and α-amylase inhibition activity. The results showed that some of them having significant inhibitory activities. Compound 6j and 6m showed a remarkable potent inhibitory potential with IC₅₀ values of 89.21μM and 85.03μM, respectively. 6j containing chloro and hydrogen atom at the 4- Phenyl and 4-positions of the benzoyl rings. 6m containing nitro group at 4- position of phenyl ring and fluorine at the 4- position of the benzoyl ring was found to be the most potent compound that inhibits α-glucosidase and α-amylase activity, when compared to the standard drug acarbose IC₅₀ = 133.50μM and 127.84μM respectively.

 

ACKNOWLEDGEMENT:

Authors thanks the Savitribai Phule Pune University Board of Dean (BOD) for the award of the research Grant.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 04.01.2020           Modified on 12.02.2020

Accepted on 06.03.2020         © RJPT All right reserved