Synthesis and Antidiabetic Evaluation of Some New Coumarin Coupled            4-Thiazolidinone Derivatives

 

K. Ishwar Bhat, Apoorva A, Abhishek Kumar*, Pankaj Kumar

 

ABSTRACT:

A series of new 4-thiazolidinone derivatives were synthesized by reacting various coumarinyl schiff bases with thioglycollic acid. The intermediate coumarinyl schiff bases were synthesized by reacting 4-hydroxyl coumarin with various substituted anilines in alcohol medium. All the newly synthesized compounds were characterized on the basis of IR, ¹H NMR and mass spectral data. All the newly synthesized compounds were evaluated for in-vitro antidiabetic activity by alpha-glucosidase inhibition assay. Most of the synthesised compounds showed good antidiabetic activity.

 

 

 

INTRODUCTION:

Coumarin compounds are a class of lactones structurally constructed by a benzene ring fused to α-pyrone ring, and essentially possesses conjugated system with rich electron and good charge transport properties. Coumarins are best known aromatic lactones¹. The IUPAC nomenclature of coumarin ring system is 2H-1-benzopyran-2-one.

 

The coumarin ring system has an easy acceptability in the biological system when compared to its isomeric chromones and flavones nucleus and is widely distributed in nature². Coumarin display a broad range of pharmacologically useful profile and are considered as a promising group of bioactive compound that exhibit wide range of biological activities like antioxidant³, anti-inflammatory, anti-bacterial, anti-diabetic⁴, anticancer⁵ and anthelmintic activities. These biological activities make coumarin compounds more attractive and testing as novel therapeutic compounds. 4-Hydroxycoumarin derivatives constitute an important class of compounds with a wide range of biological activities. In particular, they are important as photochemotherapeutic agents that are used to treat a variety of skin diseases⁶.

 

 

The literature survey reveals that there are many synthetic routes for the synthesis of thiazolidinone. The main synthetic route involves an aldehyde or amine is treated with mercaptoacetic acid either in one step or two step process. The process involves formation of Schiff bases which undergoes attack by sulphur nucleophile followed by intermolecular cyclisation with the elimination of water molecule to form 4-thiazolidinone.

 

The oxo derivative of thiazolidine is known as thiazolidinone. Thiazolidinones are five membered heterocyclic compounds with one nitrogen atom and one sulphur atom. The diversity in the biological response of 4-thiazolidinone has attracted the attention of many researchers to explore the framework for its potential. The derivative of 4-thiazolidinone have occupied a unique role in the field of medicinal chemistry due to its wide range of biological activities such as anticonvulsant, antidiabetic⁷, anticancer⁸, antimicrobial⁹, anti-tubercular, analgesic and antioxidant¹⁰. The chemistry of thiazolidine-4-one ring system is of considerable interest as it acts as pharmacophore in various synthetic pharmaceuticals displaying broad spectrum of activity. By considering the above facts and their increasing importance in pharmaceutical and biological field, it was contempletated to synthesize some new heterocyclic moieties incorporating the two active pharmacophores in a single molecular frame work and to evaluate their biological activities. Hence an attempt was made towards the incorporation of 4-thiazolidinone with coumarin moiety and to probe how this combination could influence the antidiabetic activity.

 

MATERIALS AND METHODS:

All the chemicals were of analytical grade: 4-hydroxy coumarin, pyridine, piperidine, substituted aromatic amine, acetyl chloride, ethanol, thioglycollic acid and dioxane.

 

Melting points were determined by open capillary method and are uncorrected. Purity of the intermediates and final compounds were monitored by thin layer chromatography (TLC) using silica gel G plates. The spots were visualized under UV light. n-Hexane: Ethylacetate (7:3) was used as solvent for running the TLC of these compounds. All IR spectra were recorded in Alpha Bruker using ATR method. ¹H NMR spectra were recorded on Bruker spectrophotometer (400 MHz) in DMSO-d₆ solvent using tetra methyl silane (TMS) as an internal standard. Mass spectra was recorded by ESI method.

 

General Procedure:

Synthesis of 3-acetyl-4-hydroxy coumarin¹¹

4-hydroxy coumarin (2.4g) was dissolved in pyridine (30ml) and few drops of piperidine were added and the contents were cooled to 0-4°C. Acetyl chloride (2.4g) was added to the reaction mixture and shaken for 48 hours. The reaction mixture was cooled and poured into crushed ice (100ml) and acidified with conc. HCl (pH 1-2). The precipitated compound was filtered, washed with water and recrystallized from ethanol.

 

Synthesis of 4-hydroxyl-3-(1-(arylimino) ethyl) chromen-2-one¹²

Equimolar solutions of 3-acetyl-4-hydroxy coumarin and substituted aromatic amine were mixed in ethanol (50ml) and the reaction mixture was refluxed for 4 hours. After cooling, the reaction mixture was poured into crushed ice (100ml). The product was filtered, washed with water and recrystallized from ethanol.

 

Synthesis of 4-thiazolidinone derivatives¹³

Mixture of Schiff bases (0.001moles) and thioglycollic acid (0.002moles) were mixed in dioxane (10ml) and refluxed for 9-10 hours. The reaction mixture was cooled and poured into crushed ice (100ml). The precipitated compound was filtered and recrystallized from ethanol.

 

 

Figure 1: Reaction scheme for 4-thiazolidinone derivatives

 

Spectral data

3-(2-chlorophenyl)-2-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-methyl thiazolidin-4-one (TKA2)

IR (cm^-1): 3380 (OH str), 1102 (C-O-C str), 1323 (C-N str), 681 (C-S-C str), 1650 (C=O str), 1472 (aliphatic C-H bend), 2332 (Ar C-H bend).

¹H NMR (400 MHz, DMSO-d₆): δ 7.21-7.60 (8H, m, Ar-H), 4.72 (1H, s, Ar-OH), 1.25 (2H, d, CH₂ of thiazolidinone),1.87 (3H, s, CH₃)

Mass (m/z): 322 (M⁺)

3-(2,4-dinitrophenyl)-2-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-methyl thiazolidin-4-one (TKA10)

IR (cm^-1): 3332 (OH str), 1124 (C-O-C str), 1026 (C-N str), 694 (C-S-C str), 1390 (aliphatic C-H bend).

 

¹H NMR (400 MHz, DMSO-d₆): δ 7.06-7.32 (7H, m, Ar-H), 4.72 (1H, s, Ar-OH), 1.25 (2H, d, CH₂ of thiazolidinone), 1.85 (3H, s, CH₃)

 

Mass (m/z): 443 (M⁺)

3-(3-chloro-4-fluorophenyl)-2-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-methyl thiazolidin-4-one (TKA12)

IR (cm^-1): 3363 (OH str), 1103 (C-O-C str), 1028 (C-N str), 682 (C-S-C str), 1657 (C=O str), 3027 (aliphatic C-H str), 3068 (Ar C-H str). 

 

¹H NMR (400 MHz, DMSO-d₆): δ 7.31-7.92 (7H, m, Ar-H), 4.74 (1H, s, Ar-OH), 1.25 (2H, d, CH₂ of thiazolidinone), 1.87 (3H, s, CH₃)

Mass (m/z): 405 (M⁺)  

 

Antidiabetic activity:

Invitro antidiabetic activity was performed for the synthesised compounds by alpha glucosidase inhibition assay.

 

 

Alpha glucosidase inhibition assay¹⁴

Alpha-glucosidase is an enzyme that catalyses the breakdown of polysaccharides in to monosaccharaides which are able to absorb in small intestine and leads to type II diabetes mellitus. Alpha-glucosidase inhibitors competitively and reversibly inhibit the enzyme in the intestine. This inhibition lowers the rate of glucose absorption through delayed carbohydrate digestion and extended digestion time. Alpha-glucosidase inhibitory activity of the synthesised compounds was carried according to standard method. Phosphate buffer (50μl, 0.1M, pH 6), alpha glucosidase (10μl, 1unit/ml), varying concentration of the sample (20μl, 10-50μg/ml) was incubated at 37°C for 15min. Then, p-nitrophenanglucopyranoside (20μl, 5mM) was added as substrate and further incubated at 37°C for 20 min. The reaction was stopped by adding sodium carbonate (50μl, 0.1M). The absorbance of the released p-nitro phenol was measured at 405nm using multiplate reader. Acarbose was used as standard. The result was expressed in percentage inhibition, which was calculated using formula,

 

Percentage inhibition = [(A₀-A₁)/A₀]*100

 

Where A₀ is absorbance of control and A₁ is absorbance of sample.

 

RESULTS AND DISCUSSION:

Table 1: Physicochemical data of 4-thiazolidinone derivatives (TKA1-TKA13)

Compound Code	R	Mol. Formula	Mol. wt	Physical state	Melting point °C	% Yield
TKA1	H	C19H15NO4S	353.39	White crystals	80-82	69
TKA2	2-Cl	C19H14ClNO4S	387.84	White crystals	104-106	71
TKA3	4-Cl	C19H14ClNO4S	387.84	Yellow crystals	118-120	70
TKA4	2-NO2	C19H14N2O6S	398.39	White crystals	152-154	65
TKA5	4-NO2	C19H14N2O6S	398.39	Yellow crystals	108-110	80
TKA6	4-Br	C19H14BrNO4S	432.29	White crystals	198-200	66
TKA7	4-F	C19H14FNO4S	311.38	Yellow crystals	148-150	60
TKA8	2-CH3	C20H17NO4S	367.42	Yellow crystals	184-186	62
TKA9	3-OCH3	C20H17NO5S	383.42	White crystals	208-210	68
TKA10	2,4-NO2	C19H13N3O8S	443.39	Orange crystals	158-160	78
TKA11	2-CH3 4-NO2	C20H16N2O6S	412.42	Brown crystals	174-176	81
TKA12	3-Cl 4-F	C19H13ClFNO4S	405.83	White crystals	180-182	79
TKA13	3,4-Cl	C19H13Cl2NO4S	422.28	Yellow crystals	184-186	82

 

Table 2: Data of invitro antidiabetic activity by alpha-glucosidase inhibition assay of 4-thiazolidinone derivatives

Concentration (μg/ml)
% inhibition	Sample Code	10	20	30	40	50	IC50
	Std (Acarbose)	19.32	45.21	58.23	61.2	62.69	20.52
	TKA1	34.06	47.25	67.03	92.30	93.406	9.73
	TKA2	67.39	71.73	73.91	76.06	80.43	-58.57
	TKA3	13.18	36.26	37.36	47.25	64.83	28.94
	TKA4	18.68	35.16	36.26	38.46	40.65	54.1
	TKA5	8.63	68.63	70.45	82.72	90.90	12.01
	TKA6	35.16	41.75	47.25	50.54	60.43	25.00
	TKA7	9.09	69.54	77.27	84.54	90.00	10.89
	TKA8	29.67	37.36	40.65	46.15	67.03	26.97
	TKA9	40.65	45.05	58.24	82.41	87.91	10.25
	TKA10	47.82	50.00	71.73	76.08	89.13	4.40
	TKA11	53.63	69.54	74.54	76.81	85.45	-7.81
	TKA12	38.46	56.04	57.14	64.83	75.82	9.86
	TKA13	0.58	1.76	28.52	63.82	68.52	28.7

 

Figure No 2: Alpha-glucosidase inhibition assay of compounds (TKA1-TKA13)

 

Antidiabetic activity:

Invitro antidiabetic activity was conducted for the synthesised compound by alpha glucosidase inhibition assay. Most of the compound showed good to moderate activity when compared with the standard acarbose. Compounds TKA1, TKA5, TKA7, TKA9, TKA10 and TKA12 have shown good antidiabetic activity when compared to the standard drug. The presence of electron releasing group like methoxy and electron withdrawing groups like nitro, chloro, and fluoro resulted in increased antidiabetic activity when compared to standard drug acarbose.

 

CONCLUSION:

The study reports the successful synthesis of coumarin incorporated 4-thiazolidinone derivatives with moderate yields and most of the synthesized compounds showed good antidiabetic activity.

 

ACKNOWLEDGEMENTS:

The authors are thankful to NITTE (Deemed to be University) for providing the necessary facilities to carry out this research. The authors are grateful to SIF VIT University Vellore for providing NMR spectra and DST- PURSE Laboratory, Mangalore University, Mangalagangotri for proving Mass Spectra.

 

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Received on 07.05.2019           Modified on 10.06.2019

Accepted on 01.07.2019         © RJPT All right reserved