INTRODUCTION:

Diabetes mellitus has become one of the primary chronic non-communicable diseasesthat are commonly characterized by chronic hyperglycemia resulting in defects in insulin secretion, insulin action, and damage to pancreatic β cells. Some of the symptoms marked by hyperglycemia include polydipsia, polyurea, weight loss, blurred vision, and polyphagia. Acute uncontrolled diabetes occurs due to hyperglycemia with ketoacidosis or nonketotic hyperosmolar syndrome¹.The international diabetes federation (IDF) reported that around 75-80% of people suffering from diabetes died due to complications of cardiovascular diseases². The eyes, nerves, blood arteries, heart, and kidneys are just a list of the organs that have been linked to long-term damage, dysfunction, or failure in diabetes³.

This disorder progresses quickly, which leads to chronic macrovascular and microvascular complications composed of retinopathy, neuropathy, and nephropathy⁴.

Received on 23.05.2023 Modified on 20.08.2023

Research J. Pharm. and Tech 2023; 16(12):6077-6080.

DOI: 10.52711/0974-360X.2023.00986

Hypertension is also one of the major complications for the patient with diabetes, which causes stroke, peripheral artery disease (PAD), and coronary heart disease (CHD) which depends on age, sex, duration of diabetes, and the presence of kidney disease. Diabetic individuals are more common with hypertension and heart failure than nondiabetic individuals⁵.

Thiazole is a five-membered heterocyclic nucleus which is widely used in pharmaceutical chemistry as a heterocyclic moiety⁶. Thiazole named as 1,3-thiazole which consists of two atoms, Nitrogen and Sulphur, with molecular formula C₃H₃NS⁷. Notable natural compounds that include the thiazole ring include penicillin and vitamin B1 (thiamine). Thiazole, commonly referred to as the "wonder nucleus," is used in a variety of biological areas. The flexibility of the Thiazole molecule is wide, and it has shown many diverse potent activities from different derivatives such as antibacterial^8,9, anti-inflammatory^10,11, anticonvulsant¹², analgesic¹³, antifungal¹⁴, antiprotozoal and anti-tumor¹⁵, antimicrobial¹⁶, antimalarial, antiparkinsons, antidiabetic¹⁷. For the development of new drug molecules to improve antidiabetic activity, a thiazole nucleus is used to develop increased compliance and reduced side effects.

LITERATURE:

Suri Babu Patchipala et al. conducted a study on the synthesis and evaluation of 30novel thiazole fused pyridine derivatives. They have achieved this by reacting 4,4,7,7–tetramethyl-4,5,6,7-tetrahydrobenzo [d]thiazol–2-amine with 6– chloronicotinate and then condensed with benzaldehyde to give two distinct series of hydrazides. The study compared the compounds with the reference drug, glibenclamide, and found that they reduced glucose levels. The researchers conducted in-vivo anti-diabetic activity on Swiss albino mice and found that two compounds, ethyl6-((4,4,7,7-tetramethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl) amino) nicotine, were particularly effective in reducing fasting blood glucose levels. Additionally, in Insilico studies, compound no. 11-f and 11-g showed the highest binding affinities with the human PPAR-gamma protein complexed with RXR alpha nuclear receptor when equated to the marketed drug Rosiglitazone¹⁸.

Figure 1a: (Z)-N’-benzylidine-6 - ((4, 4, 7, 7 - tetra-methyl - 4, 5, 6, 7-tetrahydrobenzo[d]thiazol-2-amino)nicotinohydrazide derivatives)

Figure 1b:(Z)-N’-benzylidine -6- ((cyclopropylmethyl)(4, 4, 7, 7 – tetra – methyl - 4, 5, 6, 7 - tetrahydrobenzo[d]thiazol -2- amino) nicotinohydrazide derivatives)

R= a:H, b:2-F, c:3,4-F, d: 4-F, e: 2,5-F, f: 3-OCH₃, 4-F, g: 3-F, 6-NO₂, h: CF₃, 4-F, i: 4-CF₃, j: 2-NO₂, k: 2-OCH₃, l: 4-OCH₃, m: Pyridine aldehyde, n: 2-F, 6-OCH₃, o: 2,3-OCH₃

Sucheta et al. using Knovengeal condensation A novel sequence of 5-(substituted benzaldehyde) thiazolidine – 2,4-dione derivatives were synthesized. The reaction steps were monitored by thin-layer chromatography, and the compounds were evaluated for their structural activity relationship. Compounds 10, 12, and 15, which had an electron releasing group on the benzylidene portion of thiazolidinedione, demonstrated improved anti-diabetic activity. The final synthesized compounds showed good antihyperglycemic, antimicrobial, and antioxidant action compared to standard drugs, as determined by specific methods. The antihyperglycemic potency of the final synthesized compounds wereexamined by using α-amylase inhibitory activity, which was performed by calorimetric method using diastase. The activity of different compounds was compared to that of the standard Acarbose solution, and the ratio of inhibition of α-amylase were calculated. Compounds 3, 4, 9, 10, 12, and 15 showed the potentaction¹⁹.

Figure 2: 5-(substituted benzaldehyde) thiazolidine-2,4-dione derivatives

Where, R2 = H, Cl, NO₂, OCH₃, OH; R3 = H, NO₂, OCH₃, OC₂H₅, Cl; R4 = NO₃, Cl, OH, N(CH₃), N(C₂H₅)₂, Br, OCH₃; R5 = H, OCH₃; R6 = H

T. V. Sravanthi et al. conducted a study to synthesize novel substituted pyrazole derivatives with indole and thiazole moieties and evaluate their antihyperglycemic potency against α- amylase and α- glucosidase enzymes. They also performed molecular docking studies of seven synthesized compounds using PDB 1NHZ as a target for glucocorticoid receptors. The in-vitro antidiabetic activity of the compounds was assessed and compared with standard drug acarbose. Compounds 6e, 6f, and 6g exhibited better inhibition of α-amylase and α-glucosidase enzymes with an increase in concentration than acarbose. Among the compounds synthesized, 2-(5-(1H– indol– 3-yl) – 3 – phenyl-1H – pyrazol–1-yl)-4-(4-bromo phenyl) thiazole showed the most potent antihyperglycemic potency with an IC₅₀value of 171.8 g/mL compared to acarbose. Insilico studies were also performed to explore the binding pattern of designed ligands with the specific receptor²⁰.

Figure 3: 2-(5-(1H indol – 3-yl) - 3 – phenyl – 1H – pyrazol – 1-yl)-4-substituted phenylthiazole

Where Ar is as follows:

Oya Bozdag-Dundar et al. reported Knoevenagel reaction between substituted benzyl-2,4-thiazolidinediones (4a-f) and chlorothiazolecarbaldehydes, thiazolyl-2,4-thiazolidinediones (2,3a-b) were produced. The effects of the synthesized substances on INS-1 cells grown in microplates with fetal calf serum were examined for their insulinotropic effects. Rat insulin radioimmunoassay was used to measure the released insulin. If and IIa compounds exhibited insulinotropic actions. Compound IIa's behavior was comparable with that of previously researched insulinotropic medicines, having a more pronounced action at lower doses²¹.

Figure 4a: Ia-b

Compd.	R
Ia	H
Ib	OCH₃

Figure 4b : II a-f

Compd.	Y	Y₁	Compd.	Y	Y₁
IIa	H	H	IId	H	Br
IIb	H	F	IIe	Cl	Cl
IIc	H	Cl	IIf	H	NO₂

Figure 4c:IIIa-f

Compd.	Y	Y₁	Compd.	Y	Y₁
IIIa	H	H	IId	H	Br
IIIb	H	F	IIe	Cl	Cl
IIIc	H	Cl	IIf	H	NO₂

Figure 4d: IVa-f

Compd.	Y	Y₁	Compd.	Y	Y₁
IVa	H	H	IVd	H	Br
IVb	H	F	IVe	Cl	Cl
IVc	H	Cl	IVf	H	NO₂

Hai-De Gao et al. have reported the synthesis and characterization of a number of Sulfonamide - 1, 3, 5 - trazine-thiazole hybrid compounds 8(a-j). When the substances were tested for their capacity to inhibit DPP-4, 8c was discovered to be the most effective (2.32 nM) in comparison to the common medication alogliptin. When substance 8c was docked onto the DPP-4 enzyme's active site (PDB- 2FJP), it inhibited the enzyme in vivo and reduced blood glucose levels in test subjects. By raising insulin levels and improving antioxidant enzyme systems, the chemical also demonstrated a favorable pharmacokinetic profile and a dose-dependent decrease in blood glucose levels in diabetic rats caused by STZ. A new family of strong DPP-4 inhibitors with potential therapeutic usefulness is introduced in this work²².

Figure 5: Sulphonamide 1,3,5-triazine thiazole derivatives

Where R= H, 4-Cl, 4-F, 4-CF₃, 4-NO₂, 4-OH, 4-CH₃, 4-SCH₃, C₄H₆N₂, C₆H₇N

Melis E. et al. synthesized novel derivatives of Morpholinothiazolyl-2,4-thiazolidindione and evaluated their antidiabetic activity. Thiazolidine derivatives have been used as insulin resistance agents targeting Peroxisome Proliferator-Activated Receptor, but they have side effects such as fluid retention and heart failure. Therefore, the researchers synthesized safe and effective derivatives that do not have side effects. They synthesized four thiazolidinedione N-derivatives including benzyl, acetic acid, phenacyl, and acetic acid ethyl ester that contain morpholino thiazole. INS-1 rat insulinoma cell line were used to assess glucose absorption and insulin release activities. The study revealed that R-COOH, carboxylic acid group, benzyl, and phen-acyl groups showed the best biological activity in increasing insulin activity as imidic hydrogen and thiazolidinedioneimidic hydrogen on the TZD at the N-3 position. Six of the fifteen compounds examined showed increased glucose uptake activity and their effects on insulin release. Furthermore, some of these compounds showed additional pancreatic effects²³.

Figure 6a: Morpholino thiazolyl – 2, 4 – thiazolidinediones

Figure 6b: 2, 4 - Thiazolidinedione acetic acid ethyl ester

CONCLUSION:

Based on the review study various thiazole derivatives have been synthesized and evaluated for hypoglycemic properties using variousmethods. The reviewed studies have proven the effect of thiazole derivatives as a potential hypoglycemic agent. Apart from this, the effect of substituent-like electron withdrawing group or electron-donating on thiazole ring along with different heterocyclic rings such as pyridine, hydrazine, and imidazole had been synthesized and evaluated for hypoglycemic properties and developed the structure-activity relationship relating the effect of these differentsubstituent and heterocyclic rings Based upon the review it can be concluded that thiazole derivatives can be a potential candidate for designing and synthesizing as a hypoglycemic agentwith help of defined SAR it would help in designing and synthesizing the various different thiazole substituted compound which further evaluated of its hypoglycemic properties and eventually bring a new molecule which can be used clinically.

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Received on 28.04.2022 Modified on 05.12.2022

Research J. Pharm. and Tech 2023; 16(12):6071-6076.

DOI: 10.52711/0974-360X.2023.00985