INTRODUCTION:

Diabetes mellitus, a chronic, progressive condition associated with multiple metabolic disorders is caused either by the body’s inability to produce adequate amounts of insulin or lack of response to the produced insulin or both. Genetically defective pancreatic cells act as one of the causes for the inefficiency of insulin. Age, obesity and lack of physical activity also contribute to the cause. This leads to a significant increase in the blood glucose level for a prolonged period of time. Insufficient metabolism of carbohydrates, lipids and proteins as well as hypertension and hyperlipidemia are some of the major symptoms associated with diabetes. The disease not only causes prolonged damage, dysfunction and failing of different body organs, but also ketoacidosis or non-keto hyperosmolar state in severe conditions, leading to stupor, coma and death if not treated effectively.^1-4

Insulin, an endocrine peptide hormone, produced in the beta cells of pancreas, is responsible for the glucose uptake and its utilization by the body tissue rendering hypoglycemic effects and the autoimmune destruction of these cells leads to insulin deficiency causing type I diabetes or insulin abnormalities which results in resistance to insulin action, leading to type II diabetes.^5,6 Type I accounts for about 10% while Type II, also called adult-onset diabetes, makes up to 90% of the global diabetic cases.^7-9 By 2030, 50% of the adult population of economically advanced countries are predicted to be diagnosed with type II diabetes, mainly due to the contributions of increasing urbanization, aging populations, obesity and sedentary lifestyles.^10,11

We know that oxadiazoles and its derivatives are considered to be one of the major classes of heterocyclics. It is derived from furan, where the two nitrogen atoms replace the two methylene groups. This replacement causes the decrease in the aromaticity of the ring, and makes it similar to a conjugated diene system.^12-14 The isomerism in the nucleus provides it structural diversity, offering a number of biological activities like antioxidant,¹⁵ antimicrobial,^16-18 antifungal,^19,20 anti-inflammatory,^21,22 analgesic,^23,24 antiviral,^25,26 anticancer,^27,28 anthelmintic, anti-protozoal,²⁹ anti-tubercular,^30,31 anti-parkinsonian³² and anti-diabetic properties.Among the four regioisomers, 1,2,4-oxadiazoles and 1,3,4-oxadiazoles are widely studied for its broad spectrum of biological and chemical properties, hence are considered as one of the vital molecules employed in research and development of newer drug candidates. Extensive literature has been documented on different applications of this versatile scaffold.^33,35

Figure i: Regioisomers of oxadiazole

Numerous researches have been conducted on the isomers of oxadiazoles, especially 1,2,4 and 1,3,4-oxadiazoles and their hypoglycemic potential has been studied and evaluated. These studies have roughly given the idea of the mechanism of the antihyperglycemic action of the scaffold. The oxadiazole derivatives have been found to elicit glucose lowering effect mainly by targeting the digestive enzymes like α-glucosidase and α-amylase and inhibiting them, which leads to the decrease in post prandial hyperglycemia. Along with the two, oxadiazole derivatives are found to act on other potential targets of antidiabetic therapy like Glycogen Synthase Kinase-3Peroxisome Proliferator Activating Receptor gamma, Protein tyrosine phosphatase 1B (PTP1B), Aldose reductase (ALR1 and ALR2), Fructose-1,6-bisphosphatase (FBPase), etc. and have shown prominent hypoglycemic activity.³⁶ Recent studies have shown that some oxadiazole derivatives act as non-steroidal agonist of G-protein bile acid receptor 1 (GRBAR1). GPBAR1 has also been considered as an important target to treat the metabolic and inflammatory diseases like Type II diabetes.³⁷ The current review attempts to throw light upon some of the studies conducted to assess the antidiabetic potential of various substituted oxadiazole derivatives, by carrying out various in vitro, in vivo and in silico analysis on different targets involved in antidiabetic therapy.

Various oxadiazole derivatives as anti-diabetic agents:

Ramesh et al.,³⁸ synthesized noveloxadiazole-2-thiolsand carried out their in vitro as well as in vivoantidiabetic evaluation. The synthesized compounds were characterized using LC-MS and¹HNMR. In vitrohypoglycemic potential was determined using α-amylase enzyme and α-glucosidase enzyme inhibitory assays, while the genetic model of Drosophila melanogaster was used for the in vivo assessment. Insilico studies were done, where the docking of the compounds in the active site of the maltase-glucoamylase enzyme (PDB ID: 2QMJ), which not only helped in prediction of ligand protein interactions, but also in calculating the predicted bond energies. The IC₅₀ value of the compounds for α-amylase inhibition in the range of 40.00-80.00µg/ml while for inhibition of α-glucosidase, the range was determined to be within 46.01-81.65 µg/ml. The results of in vitro and in vivo studies concluded that1 has good glucose lowering potential in comparison to the standard Acarbose.

Figure ii:2-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-5-(4-nitrobenzylthio)- 1,3,4-oxadiazole

Radia et al.,³⁹ designed and synthesizeddifferent1,3,4-oxadiazole based azaspirocyclesin order to assess theirin vitro antidiabetic activity. The compounds were synthesized at room temperature by an efficient and mild synthetic procedure, which was catalyzed by NaI. In vitro α-amylase inhibitory assay for the antidiabetic screening was carried out by following the 3,5-dinitrosalicylic acid (DNSA) method, with Acarbose as the reference standard and the % inhibition was analyzed at different concentrations of the test compounds. The IC₅₀value of these compounds were also determined and it was seen that compound 2significant enzyme inhibition while the others showed moderate inhibitory potential.

Figure iii: Azaspirocycle substituted 1,3,4-oxadiazole

Paranjeet et al.,⁴⁰ designed nineteen trans acrylic acid derivativesof 1,2,4-oxadiazole by the addition of an aryl or methylene linker group. In silico studies of their potential as dual agonists of PPAR alpha/gamma receptors, was carried out by employing a software named AutoDock Vina.The results were compared with that of the standard Pioglitazone, and six were found to be comparable with the standard based on the affinity scores, in silico ADME and toxicity studies. These compounds also showed higher lipophilicity (iLogP) in the range of 0.9 to 3.19. In vitro studywas done for these six compounds by PPAR and transcriptional assay method. Cayman transcription factor assay kit was used and it was observed that they were more selective towards PPAR-. Compound 4 was found to have EC₅₀ values of 0.07±0.0006μM and 0.06±0.0005μM respectively, and hence was found to be the most potent agonists of bothα and receptors. Furtherin vivo evaluationwas done using female Sprague Dawley (SD) rats. Different parameters like body weight, plasma glucose level, total cholesterol, oxidative biomarkers were evaluated along with histopathological evaluation and statistical analysis were also carried out to deduce the effects of thesenovel compounds in type II diabetic rat model.

Figure iiv: 1,2,4-oxadiazole based trans- acrylic acid derivative

Arefeh et al.,⁴¹ aiming to study the oxidative stress induced pancreatic β-cell destruction due to the impaired endogenous antioxidant defense caused by chronic postprandial hyperglycemia, designed and synthesizedsome 1,2,4-oxadiazole derivatives. The structural characterization of these eleven triaryl-1,2,4-oxadiazole derivatives was performed by Mass spectroscopy,¹H and ¹³C-NMR. These compounds were screened for their enzyme inhibitory activity against α-glucosidase obtained from Saccharomyces cerevisiae, using p-Nitrophenyl-α-D-glucopyranoside (pNPG) as substrate. The molecular docking studies against the PDB 3A4A (isomaltase from Saccharomyces cerevisiae) were also performed to study the mode of binding to the target site. AutoDock (4.2.6), AutoDock Tools (1.5.6) and Discovery studio (16.1.0.15350) were employed in the docking studies. Thestudies conducted in vitroshowed that compound 5possesses potent inhibitory activity, which also proved the predictions of the in-silico studies. Enzyme kinetic studies concluded that compound5 showed competitive mode of enzyme inhibition, with the estimated inhibition constant K_i value of 213μM.

Figure v: 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole

Taha et al.,⁴² synthesized a series of twenty-one tris-indole - oxadiazole hybrids for type II Diabetes management. The in-silico studies as well as the in vitro-glucosidase inhibitory assay were carried out. Docking studies were performed using Glide tool in the Schrodinger Maestro software against the protein structure of -glucosidase (PDB ID: 3TOP). The QikProp tool was used to study the ADME properties of the compounds. IC₅₀values of the compounds were determined to be in the range of 2.00±0.01 – 292.40± 3.16µM and they showed superior enzyme inhibitory activity in comparison to Acarbose. The structural activity relationship of these hybrid analogs was rationalized based on the pattern of substituted groups on the indole moiety. Compound6wasfound to possess higher enzyme inhibitory potency with their IC₅₀ values 2.00±0.01, 2.40±0.01 and 3.50±0.01µM respectively

Figure vi: Tris-indole 1,3,4-oxadiazole hybrid

Taha et al.,⁴³ synthesized and evaluated the antiglycation potential of a series of twenty-fivenovel 2-(2-methoxyphenyl)-1,3,4-oxadiazole derivatives. The synthesis protocol involved two steps and the compounds were characterized using various spectroscopic techniques like FT-IR, UV, EI-MS, NMR and CHN analysis. The in vitro antiglycation assay was carried out using Bovine serum albumin (BSA) and it was observed that fourteen analogs out of the twenty-five showed variable degrees of antiglycation activities in comparison to the standard Rutin (IC₅₀= 295.09± 1.04µM). The IC₅₀ values were determined to be between 160.2±0.50 and 668.25±3.74µM. Compound 7, with a trihydroxylated phenyl ring showed the highest potency, followed by dehydroxylated analogs. Lesser antiglycation capacity was found in compounds with monohydroxy group, hence confirming the role of -OH groups in antiglycation activity.

Figure vi: 2-(5-(2-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)benzene-1,3,5-triol

Kashtoh et al.,⁴⁴ synthesized some oxadiazole derivatives, and evaluated the α-glucosidase inhibitory capacities of these compounds. Kinetic studies of the fifteen most active derivatives were also carried out, in order to determine the mode of inhibition and the dissociation constant (K_i). Compound 8,the most potent derivative having IC₅₀ = 11.8 ± 0.07μM and K_i= 4.36± 0.017μM showed non-competitive enzyme inhibition. Evaluation of the potential of the most potent compounds against enzymes like carbonic anhydrase-II and phosphodiesterase-I was also done to study their selectivity but the results showed that they exhibited selectivity towards α-glucosidase enzyme and were inactive towards the other enzymes.

Figure viii: 2-({5-[4-(Benzyloxy)phenyl]-1,3,4-oxadiazol-2-yl} sulfanyl)-1-(2-methoxyphenyl)-1-ethanone

Shriram et al.,⁴⁵ designed and synthesized a series of ten 1, 3, 4-oxadiazole derivatives and carried out theirin-silico studies to predict the possible Glycogen Synthase Kinase-3β (GSK-3β) inhibitory potential. The structural analysis of the derivatives was done using FTIR, NMR and Mass Spectroscopy. Integrated software, Docking Server, was employed in the docking analysis of the compounds. The designed ligands were docked in the Inhibitor Binding Site of the X-Ray crystal structure of the GSK-3β (PDB ID: 3F7Z) and the protein-ligand complex models were constructed and observed. Molinspiration tool was employed in predicting the different properties of these compounds. All the synthesized compounds showed GSK-3β inhibitory potential out of which compound 14 containing activating group (-NH₂) substituted at the oand p position of the aromatic rings at the 2nd and 5th position of the 1,3,4-oxadiazole ring.

Figure ivii: 2-[5-(4-aminophenyl)-1, 3, 4-oxadiazol-2-yl] aniline

Conclusion:

As diabetes mellitus is emerging into a lifestyle disease in today’s world, there is a need for the development of newer drugs with higher potency and efficacy and lower side effects. Oxadiazoles are considered to be an important class of heterocycles, known to show a wide spectrum of therapeutic activity and this review concludes that oxadiazole derivatives possess potent hypoglycemic activity, found to be mainly due to their α-glucosidase and α-amylase inhibitory activity. Not only the two enzymes, but PPAR- receptor, GSK-3β and Aldose reductase enzymes are also found to be some of the potential targets for the substituted oxadiazoles to elicit their hypoglycemic action. The SAR derived from the various group of oxadiazole derivatives is helpful in designing and synthesizing novel potential antihyperglycemic agents.

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Received on 25.03.2022 Modified on 29.06.2022

Research J. Pharm. and Tech 2023; 16(6):2771-2775.

DOI: 10.52711/0974-360X.2023.00455