INTRODUCTION:

Diabetes mellitus is a chronic metabolic disorder marked by Excessive blood glucose levels brought on by insufficient insulin production or function. It impacts almost 500 million people globally, with around 2 million deaths each year attributed to complications related to diabetes¹. Various antidiabetic drugs, such as sulfonylureas², DPP4 inhibitors³, and GLP-1 analogs⁴, help manage β-cell dysfunction but fail to prevent long-term vascular complications or ensure stable glycaemic control fully. Common clinical manifestations include polydipsia, polyuria, weight loss, and visual disturbances, with persistent hyperglycaemia that can lead to damage in organs such as the heart, kidneys, and eyes⁵.

Coumarins, a class of flavonoids, have shown diverse biological activities, including antidiabetic⁶, analgesic⁷, anticancer⁸, antioxidant⁹, antifungal¹⁰, anti-inflammatory¹¹and anticoagulant¹²offering the potential for new therapeutic approaches. Thiazole, a five-membered heterocyclic compound with the formula C₃H₃NS, is widely employed in pharmaceutical applications due to its capacity to interact with enzymes or receptors through non-covalent binding mechanisms. Its derivatives exhibit diverse pharmacological activities, including antibacterial, anticancer, anti-inflammatory and antidiabetic¹³ properties. To enhance biological activity and address current treatment limitations, synthesized coumarin-thiazole derivatives for potential use in novel antidiabetic drugs.

Computational software allows for predicting a molecule's pharmacokinetic profile before synthesis, aiding in the early assessment of potential toxicity. These simulations can model physiological systems or target specific receptors, reducing the need for animal testing and the labour-intensive process of culturing tissue samples^14-15.

The current study includes the synthesis and characterization of thiazolyl coumarin derivatives. In-silico analysis, Antioxidant and antidiabetic activities against α-glucosidase and α-amylase revealed compounds.

MATERIALS AND METHODS:

Chemistry:

Analytical-grade solvents and laboratory-grade chemicals from Sigma were employed in the synthesis. All compound Melting points were obtained using the open capillary tube technique with an Equitronics EQ 730 digital melting point instrument, providing uncorrected values¹⁶. The chemical purity of each molecule was assessed through thin-layer chromatography on a silica plate by utilising n-hexane and ethyl acetate in varying ratios as a solvent. Infrared spectral data were recorded on an Alpha Bruker device using the ATR method¹⁷. The 1H-Nuclear magnetic resonance spectra were obtained with a 400 MHz Bruker Advance II NMR Spectrometer in chloroform-d and dimethyl sulfoxide (DMSO), using tetramethyl silane as a standard¹⁸. Finally, mass spectra were acquired through electron impact ionization using a GC-MS Perkin Elmer Clarus 680 Spectrometer.

Figure 1: Scheme for Thiazolyl-fused Coumarin derivatives

Procedure for the Synthesis of Thiazolyl-fused Chromen-2-one Derivatives:

Synthesis of 3-acetyl-2H-chromen-2-one derivatives¹⁹

In the round-bottom flask, add a dropwise mixture of salicylaldehyde (18mmol), ethyl acetoacetate (24 mmol), ethanol (1.0mL), and piperidine (0.1mL) The reaction mixture should be heated on a hot plate at 50°C for 5minutes. Let the solid result settle to room temperature before filtering and recrystallizing it with ethanol. Fine yellow needles will form as a result.

Synthesis of 3-(2-amino-thiaziol-4-yi)-chromen-2-one 1²⁰

The molecular combination of 3-acetyl-2H-chromen-2-one (1.55g, 8mmol) with thiourea 0.6g, 8mmol) was prepared in 10ml of the toluene solution, catalyzed by ammonium acetate (0.61g, 8mmol). The mixture was heated for around 5hours with reflux and cooled. The resultant precipitate was filtered, dried out, and recrystallized using methanol.

Synthesis of Thiazolyl-fused Coumarin Derivatives:²⁰

Procedure 1: In 15mL of DMC, 8mmol of 3-acetyl coumarin, 8mmol of ammonium acetate, and an aromatic aldehyde were dissolved in a round bottom flask. Then, 8mmol of thiourea was added to the mixture. Transfer the reaction flask to a hot oil bath for reflux. To monitor the course of the reaction thin layer chromatography method was used. Remove the round bottom flask from the oil bath when the reaction is done and let it cool to room temperature to aid precipitation.

Procedure 2: A solution of 3-acetyl coumarin(8mmol) and thiourea (8mmol) was refluxed in 10 ml of toluene solution with 8mmol of ammonium acetate as a catalyst for 5 hours. The resulting solid was filtered out and recrystallised with methanol when it reached room temperature to get intermediate 3-(2-amino-thiazol-4-yl)-chromen-2-one. Subsequently, equimolar concentrations of 3-(2-amino-thiazol-4-yl)-chromen-2-one and aromatic aldehyde were refluxed in 15 ml of DMC for 4 hours. The products were then recrystallized from hexane and dichloromethane.

Spectral analysis:

3-(2-((4-chlorobenzylidene)amino)thiazol-4-yl)-6-methoxy-2H-chromen-2-one(C1) Molecular formula C₂₀H₁₃ClN₂O₃S; m.p. 210-214°C; Yield 68%; IR (cm-1 ): 1224 (C-O-C str of coumarin), 1682 (C=N str), 845 (C-Cl str), 1723(C=O str) 1H NMR (400 MHz, CDCl3): δ 6.98-7.85 (m, 3H Coumarin), 6.85-7.66 (m, 4H, benzylidenimin), 8.45 (s, CH, thiazole) Mass (m/z): (M+) 396.84

3-(2-((4-hydroxybenzylidene) amino) thiazol-4-yl)-2H-chromen-2-one (C2):

Molecular formula C₁₉H₁₂N₂O₃S; m.p.210-214°C; Yield 68%; IR (cm-1): 1623 (O-C=O str), 1714 (C=O str), 1210 (C-N str), 626 (C-S str); Mass (m/z): (M+) 348.37

3-(2-((4-fluorobenzylidene) amino) thiazol-4-yl)-2H-chromen-2-one (C3):

Molecular formula C₁₉H₁₁N₂O₂S; m.p.210-214°C; Yield 68%; IR (cm-1): 1720 (C=O str), 1175 (C-O-C str), 614 (C-F str), 3386 (N-H str) 1H NMR (400 MHz, CDCl3): δ 6.98-7.85 (m, 3H Coumarin), 67.47- 7.76 (m, 4H, benzylidenimin), 8.27 (s, CH, thiazole), 3.16 (s, 3H, CH3): Mass (m/z): (M+) 350.36

3-(2-((2-methoxybenzylidene) amino) thiazol-4-yl)-2H-chromen-2-one (C4):

Molecular formula C₂₀H₁₄N₂O₃S; m.p. 206-210°C; Yield 36%; IR (cm-1): 1725 (C=N str), 1580 (O-C=O str), 1849 (C=O str), 680 (C-S str); Mass (m/z): (M+) 362.40

3-(2-((2-hydroxybenzylidene) amino) thiazol-4-yl)-2H-chromen-2-one (C7):

Molecular formula C₁₉H₁₂N₂O₃S; m.p. 185-189°C; Yield 75%; IR (cm-1): 1174 (C-O-C str), 1722 (C=O str), 753 (C-S str), 1578 (C=N str), 3380 (O-H str); Mass (m/z): (M+) 348.37

In silico platform:

In this study, we designed a series of thiazolyl-fused chromen-2-one derivatives (C1-C12) with various substituents. These compounds underwent molecular docking, ADME analysis, and evaluation of their antidiabetic properties. Disease targets were identified using DisGeNET and the Swiss Target prediction tool was utilised to predict targets related to the ligand. Venny 2.0 tool analysis revealed human lysosomal alpha-glucosidase²¹ (PDB ID: 5NN8) and human pancreatic alpha-amylase²² (PDB ID: 1B2Y) as the most relevant targets. From the RCSB protein databank protein structures were retrieved.

Molecular docking:

The Schrödinger 2020-1 suite's Maestro version 11.7.012 was used for the computational studies. A DELL 27" workstation with an Intel Core i7-7700 CPU @ 3.60 GHz x8 cores, 8 GB of RAM, a 1000 GB hard drive, and an operating system running Linux X86_64 was used to accomplish the task^.

Designing and generation of canonical smiles were generated by using the ChemDraw 20.0 tool. which were then docked against human lysosomal alpha-glucosidase (PDB ID: 5NN8) and human pancreatic alpha-amylase (PDB ID: 1B2Y). During the docking process, the ligand preparation was done by the LigPrep module of Schrödinger, which involved neutralizing all ligands and generating all possible combinations as one—protein preparation involved adding missing side chains and loops, followed by optimization. Finally, a receptor grid was generated, allowing the docking of the designed compounds (C1-C12) to obtain their docking scores. Compounds with the highest docking scores were further analyzed, and binding free energy (ΔG_bind, kcal/mol) was calculated using the MMGBSA method in the Prime module of Schrödinger 2020-4.

ADME properties:

Determining the ADME properties of molecules provides essential insights into their druggable potential. This analysis predicts the physicochemical characteristics of the compounds. It evaluates their compliance with Lipinski's Rule of Five, including parameters like H-bond acceptors and donors, as well as the log P value, which is crucial for biological activity. In this study, the ADME properties of the selected docked ligand were assessed using the Qikprop module from the Schrodinger suite 2020-1.

Biological evaluation:

Antioxidant study:

DPPH (1, 1-diphenyl-2-picrryl-hydrazyl) free radical scavenging assay:²³

The assay was performed in a 96-well plate with 100μL of the test sample and standard drug (10-50μg) in DMSO, with an equal amount of DMSO serving as the control. After adding 100μL of 0.5mM DPPH solution, the mixture was left at room temperature for 30 minutes. The absorbance was measured at 517nm, and the DPPH scavenging effect (%) was calculated using:

DPPH scavenging effect (%) or Percent inhibition

= A₀ - A ₁ / A₀ × 100.

Where, A₀ is the absorbance of the control reaction, A₁ is the absorbance in the presence of the test or standard sample

Nitric oxide inhibition method:²⁴

The assay was conducted in a 96-well microtiter plate. The mixture containing of 100μL of each test sample (10-50μg) in DMSO, and 50μL of sodium nitroprusside (1mM) in phosphate-buffered saline was prepared. A control was made with DMSO only. After incubating at 25°C for 150 minutes, 50μL of Griess reagent (composed of 1% sulfanilamide, 2% H₃PO₄, and 0.1% N-(1-naphthyl) ethylenediamine dihydrochloride) was added. The absorbance of the solutions was measured at 540nm. The percentage of nitrite radical scavenging activity was calculated using the following formula:

Nitric oxide scavenged (%)

= A_control − A_test/ A_control × 100

where, A_control = absorbance of control sample, A_test = absorbance in the presence of the test samples or standard.

Antidiabetic activity:

The current study primarily investigated the α-glucosidase and α-amylase inhibitory activities of the synthesized compounds (C1-C12). In-vitro α-glucosidase inhibitory method and the α-amylase inhibitory activity were employed for the anti-diabetic study.

Alpha-Amylase inhibition assay:²⁵

To evaluate the anti-diabetic activity of a compound α-Amylase inhibition assay was conducted. The assay mixture consists of 200μL sodium phosphate buffer of pH 6.9, 20μL of α-Amylase solution(1mg/ml), and 500 μL of the test compound at varying concentrations (10-50μg/ml). This mixture was incubated at 25°C for 10 minutes. 5 ml of distilled water was added to all the test tubes when it attained room temperature. The absorbance was measured at 540nm, and the percentage inhibition of α-Amylase activity was calculated.

% Inhibition = A_control − A_test / A_control × 100

Where, A_control= absorbance of control sample, A_test= absorbance in the presence of the test samples.

Alpha-glucosidase inhibition assay:

50μl of phosphate buffer (100mM, pH=6.8), 10μL α-glucosidase solution (1U/ml), 20μl of test compounds (10-50μg/ml) were incubated at 37°C for 15min in 96 well plates. Further, 50μl p-nitrophenyl αglucopyranoside solution (5mM) was added and incubated for another 20min. The reaction was stopped with 0.1M Sodium carbonate, and absorbance was measured at 405nm. The percentage inhibition was calculated.

% Inhibition = A_control− A_test / A_control × 100

Where, A_control= absorbance of control sample, A_test= absorbance in the presence of the test samples.

RESULT AND DISCUSSION:

Twelve Thiazolyl-fused chrome-2-one derivatives were synthesized by reacting salicylaldehyde, and ethyl acetoacetate with substituted aldehydes in the presence of Thiourea, DMS, and ammonium acetyl as catalysts. These derivatives were confirmed by spectral characterization such as IR, ¹H NMR, ¹³C NMR, and Mass.

Molecular docking:

The twelve Thiazolyl-fused chromen-2-one derivatives were docked with 5NNE, and 1B2Y (Tables 1and2 and Figures 2 a, and b). compound C1 showed the highest binding affinity with 5NNE receptor with PRO125, TRP126, CYS127, ALA93, TYR110, ILE98, ALA97 hydrophobic interaction, GLN124 polar interaction and ILE98 hydrogen bond interati0on with amino acids. Were as compound C2 showed the highest binding affinity with 1B2Y receptor with LEU162, LEU165, ALA198, TRP59, TRP58, TYR62 hydrophobic interaction, THR163, GLN63, HIE101, ASN298, HIS299, HIE305 polar interaction and ARG195, ASP300, GLN63 hydrogen bond interati0on with amino acids.

These results indicate that both compounds have distinct binding profiles, suggesting potential specificity towards their respective receptors. Further exploration of these interactions could lead to insights into their mechanisms of action and therapeutic potential.

Table 1: Docking scores of Thiazolyl coumarin derivatives (C1-12) with 5NN8 and1B2Y

Compound	5NN8		1B2Y
Compound	Glide score	ΔG Bind	Glide score	ΔG Bind
C1	-4.358	-57.91	-4.325	-46.79
C2	-2.779	-56.21	-5.830	-44.30
C3	-3.867	-57.48	-5.819	-50.87
C4	-4.123	-54.47	-4.005	-59.10
C5	-3.955	-51.25	-3.529	-39.37
C6	-3.211	-44.01	-4.549	-41.68
C7	-3.719	-59.85	-3.544	-29.59
C8	-3.701	-64.46	-4.119	-48.68
C9	-2.482	-48.07	-4.170	-46.33
C10	-3.172	-46.77	-3.816	-35.02
C11	-2.894	-57.63	-3.431	-45.82
C12	-2.656	-57.90	-3.478	-42.99
Acarbose	-10.331	-82.55	-12.066	-66.45

Table 2: Docking interactions of Thiazolyl coumarin derivatives (C1-12) with 5NN8 and1B2Y

Compound	Protein ID	Hydrophobic Interactions	Polar Interactions	Hydrogen Bonding	Pi-Pi stacking
C1	5NN8	PRO125, TRP126, CYS127, ALA93, TYR110, ILE98,	GLN124	ILE98	-
	1B2Y	TYR62, TRP59, LEU165, LEU162, ALA198, ILE235	GLN63, THR163, HIE101, HIS299, HIS201, HIE305	GLN63
C2	5NN8	ALA93, TYR110, ILE98, PRO125, TRP126, CYS124	GLN124	-	TRP 126
	1B2Y	LEU162, LEU165, ALA198, TRP59, TRP58, TYR62	THR163,GLN63,HIE101,ASN298, HIS299, HIE305	ARG195, ASP300,
C3	5NN8	TYR110, ALA93 PRO125, TRP126, CYS127, ILE98,	GLN124	ILE98	-
	1B2Y	ILE235, ALA198, LEU162, LEU165, ALA106, VAL107,	GLN63, HIE305, HIE101, THR163, ASN105	GLN63, ALA106	TRP 59
C4	5NN8	ALA93, TYR110,PRO125, TRP126, CYS127, ALA97,	GLN124	ILE98	-
	1B2Y	ALA198, LEU162, LEU165, TRP59, TYR62, ILEE51,	THR163, GLN63, HIE101	GLN63	TRP 59
C5	5NN8	ALA93, PRO94, PRO125, TRP126, CYS127, ALA97,	-	ILE98	-
	1B2Y	ILE235, ALA198, LEUY162, LEU165, TRP59, TRP58,	HIS201, HIE101, HIS299, HIE305, GLN63	GLN63	TRP 59
C6	5NN8	VAL321, TYR543, ILE98, ALA97, PRO94, ALA93,	-	ASP91, CYS127	-
	1B2Y	ILE235, ALA198, LEU162, LEU165, TYR62, TRP59,	HIS299, HIS305, HIE101, HIE201, GLN63,	GLN63	TRP 59
C7	5NN8	ALA93, PRO125, TRP126, CYS127, TYR110, ILE98	GLN124, THR99	GLN124	TRP 126
	1B2Y	ALA198.LEU162, LEU165, TYR62, TRP59, TRP58	GLN63, HIE101, ASN298, HIS299,		TRP 59
C8	5NN8	ALA93, PRO125, TRP126, CYS127, TYR110, ILE98	GLN124, THR99	GLN124	TRP 126
	1B2Y	LEU162, LEU165, TYR62, TRP59, ALA198, ILE235	THR163, GLN63, HIE101, HIS299, HIS201	ASP300 , GLN63
C9	5NN8	ALA93, PRO125, TRP126, CYS127, ALA113, TYR110,	GLN124, GLN115	-	-
	1B2Y	LEU162, LEU165, ALA198, TYR62, TRP59, TRP58,	HIE305, HIS201, THR163, GLN63	GLN63	TRP 59
C10	5NN8	ALA93, PRO94, ALA97, ILE98, CYS127, TRP126,	THR99	CYS127, TRP126, ILE98	TRP 126
	1B2Y	LEU165, LEU162, VAL98, ALA198, TYR62, ILE235,	HIE101, GLN63, HIS201, HIS299, HIE305	GLN63	TRP 59
C11	5NN8	ALA113, TYR110, ALA93, ILE98, PRO125, TRP126,	GLN115, GLN124, THR99	-	TRP 126
	1B2Y	LEU162, LEU165, TYR62, TRP59, ALA198, ILE235	HIE305, HIS201, HIE101, HIS299, GKLN63	GLN63	TRP 59
C12	5NN8	ALA93, ILE98, PRO125, TRP126,CYS127,	GLN124	-	TRP 126
	1B2Y	LEU165, LEU162, AL198, ILE235, TYR62, TRP59	GLN63, THR163, HIS201, HIS305	GLN63
Acarbose	5NN8	TYR543, PRO125, TRP126, CYS127, ALA93, PRO94,	GLN100, THR99, GLN124	GLN124, ARG331, ASP91,	-
	1B2Y	LEU165, LEU162, ALA106, TRP58, TRP59, TYR62,	THR163, ASN105, HIE305, HIE101, GLN63, HIS299	THR163, HIE305, ASP300, ASP197,	-

Table 3. ADMET properties of Compounds (C1-12) derivatives

Compound	Qppcaco	% Human oral absorption	QPLog S	#meta b	QPPM DCK
Acceptable range	<25 poor>500great	>80%ishigh<25%ispoor	-6.5 to 0.5	1-8	<25poor>500great
C1	1945.82	100.00	-5.28	2	4668.71
C2	586.48	95.09	-4.60	2	519.25
C3	1921.06	100.00	-4.75	1	3376.59
C4	2215.75	100.00	-4.50	2	2207.10
C5	1936.10	100.00	-4.49	2	1880.09
C6	587.59	100.00	-5.34	2	1284.17
C7	732.36	100.00	-4.56	2	660.55
C8	896.44	100.00	-5.17	2	2075.01
C9	2670.03	100.00	-4.79	3	2672.09
C10	332.10	89.51	-4.06	2	281.55
C11	1906.27	100.00	-4.96	1	4116.01
C12	1928.69	100.00	-5.13	1	4629.41
Acarbose	0.14	0.00	0.71	13	0.03

Table 4: Physicochemical properties of Compounds (C1-12) derivatives

Compound	Molecular weight	Molecular volume	tPSA	Log P	H- acceptor	H- donor	RO5
Acceptable range	<500	500-2000	7-200	–2.0 - 6.5	<10	<5	<5
C1	396.84	1138.57	67.30	4.25	5.75	0.00	0
C2	348.37	1042.50	81.59	3.17	5.75	1.00	0
C3	350.36	1035.88	59.09	3.93	5.00	0.00	0
C4	362.40	1096.73	65.43	3.87	5.75	0.00	0
C5	362.40	1097.77	67.31	3.77	5.75	0.00	0
C6	382.82	1087.04	81.58	3.67	5.75	1.00	0
C7	348.37	1039.92	80.16	3.24	5.75	1.00	0
C8	382.82	1078.17	78.92	3.77	5.75	1.00	0
C9	375.44	1149.03	62.50	4.06	6.00	0.00	0
C10	377.37	1081.23	103.74	2.98	6.00	0.00	0
C11	366.82	1060.32	59.09	4.14	5.00	0.00	0
C12	366.82	1063.89	59.07	4.19	5.00	0.00	0
ACARBOSE	645.61	1706.57	313.04	-6.91	32.100	14.000	3

Antioxidant study:

Antioxidant activity was evaluated using DPPH radical scavenging and Nitric oxide inhibition assay. Out of all the compounds, C1 was found to have an IC50 value of 16.61, outperforming ascorbic acid (IC₅₀ 24.42), while C3 had an IC50 value of 0.934 in nitric oxide assay compared to that of ascorbic acid at an IC50 value of 16. C1 and C3 exhibited the highest percentage inhibition, showing significant antioxidant activity at 50μg/ml, comparable to ascorbic acid. The antioxidant activity was concentration-dependent, likely influenced by chloro (electron-withdrawing) and methoxy (electron-donating) groups on the coumarin and phenyl rings.

In-vitro antidiabetic acivity:

The antidiabetic activity was performed using an Alpha-amylase assay. Of all compounds, C4 had an IC₅₀ value of 32.49, outperforming acarbose with an IC₅₀ value of 40.97. The antidiabetic activity was performed using an Alpha-glucosidase inhibition assay. C7 had an IC₅₀ of 13.57 in the Alpha-glucosidase inhibition assay compared to that of acarbose at an IC₅₀ value of 24.08. Both C4 and C7 exhibited the highest percentage inhibition at 50μg/ml, comparable to the standard acarbose. This suggests that the antidiabetic action of the investigated drugs is concentration dependent. Therefore, from in vitro antidiabetic study, it was revealed that compounds C4 and C7 have significant antidiabetic activity. The presence of electron-withdrawing and methoxy (electron donating) groups on the coumarin and phenyl rings likely contributed to their significant activity.

Table 5: Antioxidant and Antidiabetic activity of Thiazolyl coumarin derivatives assay.

Compound	Antioxidant activity (IC₅₀)		Antidiabetic activity (IC₅₀)
Compound	DPPH	Nitric oxide	Alpha-amylase	Alpha-glucosidase
C1	16.61	26.35	62.61	30.31
C2	35.36	42.70	74.59	35.93
C3	26.85	0.934	92.39	35.53
C4	147.52	22.14	32.49	54.03
C5	61.65	14.69	94.98	78.54
C6	34.76	25.18	42	38.49
C7	59.39	20.85	55.67	13.57
C8	180.15	10.5	74.31	37.09
C9	158.92	28.79	269.45	51.13
C10	54.82	17.66	35.62	131.13
C11	61.09	7.59	60.35	28.72
C12	215.31	19.16	161.10	46.94
Acarbose	24.42	16.19	40.97	24.08

CONCLUSION:

Novel thiazolyl fused chromen-2-one derivatives were synthesized with yields of 36% to 75%. In-silico studies showed favorable physicochemical and ADMET properties, with compounds C1, and C2 displaying the highest docking scores. In-vitro assays revealed that C1 and C3 exhibited the strongest antioxidant activity, while C4 and C7 demonstrated significant antidiabetic activity in alpha-amylase and alpha-glucosidase inhibition assays. Overall, the synthesized compounds showed promising antioxidant and antidiabetic potential.

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Received on 05.10.2024 Revised on 25.02.2025

Accepted on 30.04.2025 Published on 08.11.2025

Available online from November 13, 2025

Research J. Pharmacy and Technology. 2025;18(11):5431-5437.

DOI: 10.52711/0974-360X.2025.00783

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