Potential Antidiabetic Agents Research Articles

Overview of oxadiazole-containing compounds as potential antidiabetic agents

1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives are amongst the family of heterocycles which showed many promising pharmaceutical applications.Extensive literature survey of 1,3,4-oxadiazole scaffold revealed the activities such as antimicrobial, anti-inflammatory, anti-tubercular, anti-oxidant, anti-cancer, anti-convulsant, anti-diabetic and analgesic properties. 1,2,4-oxadiazole, have shown activity against a variety of diseases like Alzheimer's, parasitic worms (helminths) and other internal parasites, edema, infectious diseases, diabetes, pain and cramp, cardiovascular disease, HIV, tuberculosis, antioxidant, cancer, seizure disorders, and arthritis.As oxadiazoles exhibited many different types of pharmacological activities, we reviewed its pharmacological activities reported by different researchers in the field.In present article we reviewed different articles which has been published in English literature. The search engine used to search for the articles were Scopus, Google scholar, Bentham science, Science direct, Tayler and Francis, Springer nature, Frontiers, and Hindawi. Oxadiazole patent applications have grown by 100% in the previous 9 years, reaching a total of 646, making this a highly sought-after compound in the scientific community. From present review we concluded that Oxadiazoles are potent enough to be developed as potential antidiabetic agents more precisely as DPP-IV inhibitors. We believe that present review can provide insight to the researchers working to develop some novel Oxadiazole derivatives as potential antidiabetic agents.

Nano TiO2.SiO2 catalyzed, microwave assisted synthesis of new α-aminophosphonates as potential anti-diabetic agents: In silico ADMET and molecular docking study

Nano TiO2.SiO2 catalyzed, microwave assisted synthesis of new α-aminophosphonates as potential anti-diabetic agents: In silico ADMET and molecular docking study

Anti-diabetic, anti-inflammatory and anti-oxidant properties of four underutilized ethnomedicinal plants of West Bengal, India: an in vitro approach

The present study was undertaken to evaluate the in vitro anti-oxidant, anti-diabetic and anti-inflammatory properties of four underutilized ethno-medicinal plants viz. Apluda mutica, Mikania micrantha, Kyllinga nemoralis and Cleome rutidosperma, growing in different parts of West Bengal, India. The anti-oxidant properties were evaluated using four different solvent extracts. The 70% aq. ethanol extract of investigated plant samples were found to have adequate quantities of total phenolic (141.94±0.67-230.45±0.12 mg GAE/g dry extract), total flavonoid (23.27±0.04-71.05 ±0.06 mg RE/ g dry extract) and anti-oxidant capacities documented by DPPH, ABTS, FRAP, reducing power, anti-lipid peroxidation and metal chelating activities. The 70% aq. ethanol extracts of the plants showed most promising antioxidant activity and were investigated for phenolics quantification by HPLC, anti-diabetic properties by assessing α-amylase, α-glucosidase inhibitory activities and anti-inflammatory capabilities by protein denaturation inhibition. HPLC studies revealed the presence of several phenolic acids and flavonoids in variable levels. M. micrantha exhibited α- amylase inhibition (IC50=58.44 ± 0.01 µg/mL), which was comparable to that of standard acarbose (IC50 = 53.80 ± 0.01 µg/mL). The maximum inhibition of protein denaturation was observed in M. micrantha (IC50=89.27 ± 0.01 µg/mL) followed by K. nemoralis (IC50 = 98.78 ± 0.01 µg/mL). The principal component analysis (PCA) revealed clear separation among the wild plants under investigation. The outcomes demonstrate that these plants were shown to contain a remarkable amount of different bioactive compounds, hence affirming their contribution in several biological activities and to serve as a potential anti-oxidant, anti-inflammatory and anti-diabetic agent in food and pharmaceutical industries.

Verification of the folkloric and anecdotal antidiabetic effects of Hypoxis hemerocallidea (Fisch., C.A. Mey. & Avé-Lall) and isolated, β-sitosterol using early-stage type II spontaneous diabetic mutant BKS-Leprdb mice

BackgroundPrevious studies in our laboratory in ex vivo assays have demonstrated H. hemerocallidea extract as potential antidiabetic agent through increased insulin release from pancreatic beta cells. Thus, for this study the early stage type II spontaneous diabetic mutant mice model was used to evaluate and determine the degree of the antidiabetic efficacy of H. hemerocallidea.MethodsEight-weeks-old type II spontaneous pre-diabetic mutant BKS-Leprdb mice were fed with feed supplemented with either H. hemerocallidea extract, isolated compound (β-sitosterol) or chlorpropamide (positive control) for 4 weeks. The haematological parameters, clinical chemistry, glucose tolerance, feed intake, faecal output and body weights were measured.ResultsThe blood glucose concentrations of all the animals treated with plant extract, β-sitosterol compound and non-treated pre-diabetic animals did not return to baseline levels. Only the β-sitosterol treatment and positive control groups resulted in a respective small decrease of 5.8 and 5.2% in the mouse weights over the study period, with no significant changes (p > 0.05) in food intake. However, there was a general trend for decrease in faecal output for all the groups. Albumin, triglycerides, and total cholesterol levels in β-sitosterol and chlorpropamide-treated animals were lower, relative to untreated-animals. Animals fed with plant extract showed large amounts of internal fat. There were no significant changes (p > 0.05) in total serum protein, globulin, alanine aminotransferase, alkaline phosphatase, urea nitrogen and creatinine attributed to administration of treatments. In all groups, some animals showed lesions associated with cardiac puncture. Few animals except animals treated with plant extract, showed presence of a left-ventricular hypertrophic cardiomyopathy. The liver and kidneys for all groups appeared macroscopically normal and the thymuses were small (±2 mg). There were pathological signs in some of the animals particularly in myocardial fibres, renal tubular, glomerular, hepatocyte granularity and pancreas islets. However, there was no significance trend between the groups.ConclusionBased on the results, none of the treatments could be considered highly effective for the management of type II pre-diabetes as sole therapeutic intervention.

Syzygium samarangense leaf extract exhibits distinct antidiabetic activities: Evidences from in silico and in vivo studies

The wax apple, Syzygium samarangense , is widely used in traditional medicine. We have previously described a plethora of biological activities from its leaf extract. These include antioxidant, anti-inflammatory, antiulcer, antitrypanosomal and hepatoprotective effects. Here, we explored the antidiabetic activities from the bioactive leaf extract in silico on two crucial receptors involved in the management of diabetes disease namely peroxisome proliferator activated receptor gamma (PPARɣ) and glucagon like peptide-1 (GLP-1) and in vivo against streptozotocin-induced diabetic rats. Altogether, 457 secondary metabolites belonging to 10 classes (phenolic acids (86 compounds), flavonoids (139 compounds), anthocyanins (61 compounds), alkylphenols (17 compounds), chalcone (15 compounds), stilbenes (9 compounds), lignans (29 compounds), tannins (29 compounds), tyrosols (13 compounds), and terpenes and others (59 compounds), were docked into the active site of PPARɣ and GLP-1 receptors. From the PDB codes used for each receptor, the co-crystallized ligand was extracted and docked together with a known reference ligand. This was done simultaneously with docking the extract’s compounds to serve as references for comparative purposes. Out of the docked candidates, the top 30 compounds affording the best docking scores were compiled for further inspection and they appeared to exhibit better scores than the respective co-crystallized and reference ligands, highlighting the antidiabetic potential of the tested extract. Nine compounds exhibited highly negative scores on both receptors, demonstrating their high probability of being potent antidiabetic agents through forming stable ligand-receptor complexes. These activities were also confirmed in STZ diabetic rats where the extract reduced the elevated levels of serum glucose and lipid peroxides and increased the declined serum insulin hormone level. Taking all together, S. samarangense can be a potential candidate for further investigations for the treatment of numerous health disorders including diabetes.

Antidiabetic Properties of Dietary Chrysin: A Cellular Mechanism Review.

Diabetes mellitus is the most common chronic metabolic disorder and is considered one of the leading causes of morbidity and mortality. The improperly-treated chronic hyperglycemia of diabetes has been related to several long-term complications and multiple organ failures, including nephropathy, which can lead to kidney failure, retinopathy with the potential loss of vision, and cardiovascular symptoms. Current commercially available synthetic glucose-lowering agents have been reported to have several adverse effects. Therefore, the search for alternative remedies such as medicinal plants and their active compounds have attracted attention. Chrysin is an active flavonoid that exists widely in various plants and diets and has been reported to possess pharmacological properties, including antidiabetic activity. Many studies have been conducted to characterize the antidiabetic of chrysin, as well as its potential pathways, in in vitro and in vivo experiments. Chrysin has shown promise as an antidiabetic agent in animal studies, thus, demonstrating its potential to be developed as an antidiabetic drug. This review discussed the antidiabetic action of chrysin and its mechanisms, including targeting different mechanisms such as stimulation of insulin signaling, blockage of endoplasmic reticulum stress and oxidative damage, promotion of skeletal glucose uptake, as well as modulation of apoptosis and autophagy signaling. Additionally, this review would be useful for further studies regarding the mechanism of work of plant derived-compound as a potential antidiabetic agent.

Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKα activation

We found compound 12 N - p -trifluoromethylbenzenesulfonyl matrinane ( 1 ) was a potent anti-diabetic agent. Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes, taking 1 as the lead. In high-fat diet (HFD) and STZ induced diabetic mice, 9a significantly lowers blood glucose, improves glucose tolerance, and especially alleviates diabetic nephropathy and islet damage. Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio, as well as liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase (CaMKK), which synergistically activates AMPK α and then stimulates glucose transporter 4 (GLUT4) membrane translocation and 2-deoxyglucose (2-DG) uptake to exert anti-diabetic efficacy. Therefore, compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism, worthy of further investigation. Tricyclic matrinic derivative 9a exerts good anti-diabetic effects, and alleviates diabetic nephropathy and islet damage in vivo by activating AMPK α and stimulating GLUT4 membrane translocation and 2-DG uptake.

3-(((1S,3S)-3-((R)-Hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione: Design and Synthesis of New Stereopure Multi-Target Antidiabetic Agent.

The chiral drug candidates have more effective binding affinities for their specific protein or receptor site for the onset of pharmacological action. Achieving all carbon stereopure compounds is not trivial in chemical synthesis. However, with the development of asymmetric organocatalysis, the synthesis of certain vital chiral drug candidates is now possible. In this research, we have synthesized 3-(((1S,3S)-3-((R)-hydroxy(4-(trifluoromethyl)phenyl)methyl)-4-oxocyclohexyl)methyl)pentane-2,4-dione (S,S,R-5) and have evaluated it potential as multi-target antidiabetic agent. The stereopure compound S,S,R-5 was synthesized with a 99:1 enantiomeric ratio. The synthesized compound gave encouraging results against all in vitro antidiabetic targets, exhibiting IC50 values of 6.28, 4.58, 0.91, and 2.36 in α-glucosidase, α-amylase, PTP1B, and DPPH targets, respectively. The molecular docking shows the binding of the compound in homology models of the respective enzymes. In conclusion, we have synthesized a new chiral molecule (S,S,R-5). The compound proved to be a potential inhibitor of the tested antidiabetic targets. With the observed results and molecular docking, it is evident that S,S,R-5 is a potential multitarget antidiabetic agent. Our study laid the baseline for the animal-based studies of this compound in antidiabetic confirmation.

Synthesis and Inhibitory Activity of Curculigoside A Derivatives as Potential Anti-Diabetic Agents with β-Cell Apoptosis

• It is the aim to synthesize aglycone of curculigoside A derivatives using acyl chloride in a mild condition by using imidazole and operating at room temperature. • Compounds 1, 2 , and 6 inhibit α-glucosidase are more effectively than acarbose. • Compounds 3, 4 , and 6 are inhibited TNF-α receptors better than or comparable to acarbose • Compound 6 has the potential to be an anti-diabetic by improving insulin resistance as well as inducing β-cell death. Diabetes mellitus (T1D, T2D, and DD) is a chronic metabolic condition that affected 4.2 million people in 2019 and is expected to reach 700 million by 2045. Hybrid or double diabetes (DD), which presents symptoms of both T1D and T2D, is caused by β-cell failure and apoptosis. The aglycone of curculigoside A derivatives was assessed in silico to optimize the pharmacokinetics and safety profile, as well as the binding mechanism and stability of anti-diabetic medicines with α-glucosidase. The objectives of this study are to synthesize, evaluate the biological activity of α-glucosidase, and simulate the inhibitory activity of the aglycone of curculigoside A derivatives on the tumor necrosis factor alpha (TNF-α) receptor as prospective anti-diabetic agents with β-cell apoptosis. Synthesis was carried out by using the esterification technique with halogenated carboxylic acids under moderate reaction conditions. Synthesized compounds 1 - 6 were assessed for their insulin resistance using α-glucosidase and investigated in silico by using the TNF-α receptor for its action in β-cell destruction. Compounds 3 - 6 have pharmacochemical properties that can be absorbed in the gastrointestinal tract, whereas compounds 1 and 2 are more water-soluble. The proposed methodology for the synthesis of the aglycone of curculigoside A derivatives by the esterification technique using halogenated carboxylic acids under moderate reaction conditions gives good yields. The biological evaluation study indicates that compounds 1, 2 , and 6 inhibit α-glucosidase more effectively than acarbose. By in silico study, compounds 3, 4 , and 6 inhibited TNF-α receptors are better than or comparable to acarbose, indicating that they have the ability to reduce β-cell apoptosis. In conclusion, 4-hydroxybenzyl-4-fluorobenzoat (compound 6 ) has the potential to be an anti-diabetic by inducing β-cell death.

In vitro antioxidant and anti-diabetic analysis of Andrographis echioides and Andrographis paniculata ethanol extract.

It is of interest to analyse and compare the antioxidant and anti-diabetic activity of ethanolic extracts of Andrographis echioides and Andrographis paniculata. Andrographis echioides and Andrographis paniculata were collected from a local farm. In vitro antioxidant activity was assessed by the potential of Piperine, Lupeol, beta sitosterol; DPPH free radical scavenging assay was performed by Liyana Pathirana and Shahidi method. In vitro anti-diabetic activity was assessed by alpha amylase inhibitory activity and alpha glucosidase inhibitory activity. The data were analysed by one-way-ANOVA to check the statistical significance among the groups and considered at the levels of p<0.05. Both the ethanolic extracts of Andrographis echioides and Andrographis paniculata showed significant antioxidant and anti-diabetic potential in a dose-dependent manner (100-500µg) and can be used as potential antidiabetic agents. Similar to antioxidant potential, Andrographis paniculata exhibited an increased anti-diabetic potential compared to Andrographis echioides. Data shows that the ethanolic extracts of Andrographis echioides and Andrographis paniculata possessed antioxidant and anti-diabetic activity and hence our present findings conclude that both plants can be considered for the development of natural drugs for the management of diabetes.

Co-Crystal of Rosiglitazone With Berberine Ameliorates Hyperglycemia and Insulin Resistance Through the PI3K/AKT/TXNIP Pathway In Vivo and In Vitro.

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by insulin resistance and hyperglycemia. This study examined the effect and elucidated the mechanism of improvement of hyperglycemia and insulin resistance by a co-crystal of rosiglitazone with berberine (RB) in high-sugar high-fat diet (HSHFD)-induced diabetic KKAy mice. Methods: Diabetic KKAy mice were randomly divided into seven groups: KKAy model control group (DM control) treated with 3% sodium carboxymethyl cellulose; RB groups, administered daily with RB 0.7 mg/kg (RB-L), 2.11 mg/kg (RB-M), or 6.33 mg/kg (RB-H); positive control groups, administered daily with rosiglitazone 1.04 mg/kg (RSG), berberine 195 mg/kg (BBR), or combination of 1.04 mg/kg RSG and 1.08 mg/kg BBR (MIX). Test compounds were administered orally for 8 weeks. Non-diabetic C57BL/6J mice were used as normal control (NC). Blood glucose, food intake, body weight, glucose-lipid metabolism, and pathological changes in the pancreas and liver were examined. We further evaluated the mechanism of action of RB in C2C12 and HepG2 cells stimulated with high glucose and palmitate. Results: RB treatment improved glucolipid metabolism and insulin resistance in diabetic KKAy mice. RB reduced blood glucose levels, white fat index, plasma triglyceride (TG), low-density lipoprotein (LDL), gastric inhibitory peptide (GIP), and insulin levels, increased the levels of plasma glucagon-like peptide-1 (GLP-1), high-density lipoprotein (HDL), and glycogen content in the liver and muscle; and improved oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and pathological changes in the pancreas and liver of KKAy mice. Moreover, RB upregulated p-PI3K and p-AKT levels and reduced TXNIP expression in KKAy mice and in HepG2 and C2C12 cells. Conclusion: These data indicate that RB ameliorates insulin resistance and metabolic disorders, and the mechanism might be through regulating the PI3K/AKT/TXNIP signaling pathway . Thus, the co-crystal drug RB may be considered as a potential antidiabetic agent for future clinical therapy.

A comprehensive review of recent advances in the biological activities of 1,2,4-oxadiazoles.

Nitrogen heterocycles play an essential role in medication development. The 1,2,4-oxadiazole heterocycle has been extensively studied, yielding a large variety of molecules with varied biological functions. The 1,2,4-oxadiazole shows bioisosteric equivalency with ester and amide moieties. In recent years, the 1,2,4-oxadiazole nucleus has received a lot of attention in medicinal chemistry. It was thought to be a pharmacophore component in the production of biologically intriguing drugs. This review presents a comprehensive overview of the recent achievements in the biological activities of 1,2,4-oxadiazoles as potential antimicrobial, anticancer, anti-inflammatory, neuroprotective, and antidiabetic agents. The structure-activity relationship and mechanisms of action are also reviewed.

Isatin thiazoles as antidiabetic: Synthesis, in vitro enzyme inhibitory activities, kinetics, and in silico studies.

Diabetes mellitus is one of the most prevalentdiseases nowadays. Several marketed drugs are available for the cure and treatment of diabetes, but there is still a dire need of introducing compatible drug molecules with lesser side effects. The current study is based on the synthesis of isatin thiazole derivatives 4-30 via the Hantzsch reaction. The synthetic compounds were characterized using different spectroscopic techniques and evaluated for their α-amylase and α-glucosidase inhibition potential. Of 27 isatin thiazoles, five (4, 5, 10, 12, and 16) displayed good activities against the α-amylase enzyme with IC50 values in the range of 22.22 ± 0.02-27.01 ± 0.06 µM, and for α-glucosidase, the IC50 values of these compounds were in the range of 20.76 ± 0.17-27.76 ± 0.17 µM, respectively. The binding interactions of the active molecules within the active site of enzymes were studied with the help of molecular docking studies. In addition, kinetic studies were carried out to examine the mechanism of action of the synthetic molecules as well. Compounds 3a, 4, 5, 10, 12, and 16 were also examined for their cytotoxic effect and were found to be noncytotoxic. Thus, several molecules were identified as good antihyperglycemic agents, which can be further modified to enhanceinhibition ability and to find the lead molecule that can act as a potential antidiabetic agent.

Hypericum Perforatum L. Hairy Root Extracts – Regulation of Glycemic, Metabolic, Serum Enzyme and Lipid Profile in STZ - Induced Diabetic Rats

Abstract Apart from currently available therapeutics for the treatment of diabetes mellitus, much attention has been paid to discover phytochemicals from natural resources, mainly due to their low side-effects. Hypericum perforatum hairy root (HR) transformed with Agrobacterium rhizogenes A4 represent prospective experimental system enriched in xanthones, known as potent antidiabetic agents. Thus, the aim of this study was to evaluate HR extracts for their potential antihyperglycemic activity in streptozotocin (STZ)-induced diabetic rats, also compared to the effects of wild-growing Hyperici herba (HH). We conducted an acute-toxicity study, multiple dose study, and 24h blood glucose measurements after a single dose administration of HH and HR (200 mg/kg) in diabetic rats. Furthermore, we examined the effects of 14-days administration of HH and HR extracts on blood glucose levels, metabolic parameters, enzyme, and lipid status in healthy and diabetic rats. Both extracts produced a fall of about 70% in blood glucose level after 24h of administration. Two-week treatment with HH and HR induced a significant decrease (70-72%) in blood glucose levels. Moreover, we found an improvement of the dysregulated metabolic parameters (body weight, food, and water consumption and urine output). Serum enzyme (AST, ALT, and γ-GT) and lipid profile parameters (CHOL, TAG, and HDL) were also improved by both extracts. These findings might provide a new insight for managing diabetic hyperglycemia and dysregulated serum enzyme and lipid profile, using extracts from transgenic roots cultures from H. perforatum.

Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, ameliorates type 2 diabetes via reduced gluconeogenesis

AimsPyruvate dehydrogenase (PDH) catalyzes the decarboxylation of pyruvate to acetyl-CoA, which plays a key role in linking cytosolic glycolysis to mitochondria metabolism. PDH is physiologically inactivated by pyruvate dehydrogenase kinases (PDKs). Thus, activation of PDH via inhibiting PDK may lead to metabolic benefits. In the present study, we investigated the antidiabetic effect of PDK inhibition using dichloroacetate (DCA), a PDK inhibitor. Main methodsWe evaluated the effect of single dose of DCA on plasma metabolic parameters in normal rats. Next, we investigated the antidiabetic effect of DCA in diabetic ob/ob mice. In addition, we performed in vitro assays to understand the effect and mechanism of action of DCA on gluconeogenesis in mouse myoblast cell line C2C12 and rat hepatoma cell line FaO. Key findingsIn normal rats, a single dose of DCA decreased the plasma level of pyruvate, the product of glycolysis, and the plasma glucose level only in the fasting state. Meanwhile, a single dose of DCA lowered the plasma glucose level, and a three-week treatment decreased the fructosamine level in diabetic ob/ob mice. In vitro experiments demonstrated concentration-dependent suppression of lactate production in C2C12 myotubes. In addition, DCA suppressed glucose production from pyruvate and lactate in FaO hepatoma cells. Thus, DCA-mediated restricted supply of gluconeogenic substrates from the muscle to liver, and direct suppression of hepatic gluconeogenesis might have contributed to its glucose-lowering effect in the current models. SignificancePDK inhibitor may be considered as a potential antidiabetic agent harboring inhibitory effect on gluconeogenesis.

In vivo biological evaluation of some benzamide derivatives as potential antidiabetic agents in streptozotocin induced diabetic model

Diabetes Mellitus (DM) is a chronic health illness that is caused by a number of geanetic and/or environmental factors. Type 2 diabetes mellitus (T2DM) accounts for more than 95 percent of all instances of diabetes in adults. According to the World Health Organization, India is one of the epicenters of the global diabetes epidemic, and it has the second highest number of diabetics in the world, with a population of over 900 million people (about 69 million people as of 2015).In present study, in vivo antidiabetic activity of some benzamide derivatives have been performed in STZ-nicotinamide-induced diabetic model in rats. The antidiabetic potential has been determined by estimating different serum biochemical and antioxidant parameters. Amongst all the tested molecules, compound 5h demonstrated significant antidiabetic and antioxidant potential when compared to the metformin-treated group. Compound 5h possesses cloprothiazole substitution with benzamide nucleus. It was concluded that compound 5h can be treated as a lead molecule for the design and development of novel antidiabetic agents. Keywords: T2DM, Streptozotocin, Benzamide, Diabetes, Rats.

Effect of Lycium barbarum Polysaccharide on Decreasing Serum Amyloid A3 Expression through Inhibiting NF-κB Activation in a Mouse Model of Diabetic Nephropathy.

Lycium barbarum polysaccharide (LBP) as one of the main bioactive constituents of the fruit of Lycium barbarum L. (LBL.) has many pharmacological activities, but its antihyperglycemic activity is not fully understood yet. This study investigated the hypoglycemic and renal protective effects of LBP on high-fat diet/streptozotocin- (HFD/STZ-) induced diabetic nephropathy (DN) in mice. Blood glucose was assessed before and after 8-week administration of LBP, and the homeostasis model assessment-insulin resistance (HOMA-IR) index was calculated for evaluating the antidiabetic effect of LBP. Additionally, serum creatinine (sCr), blood urea nitrogen (BUN), and urine microalbumin were tested to evaluate the renal function. HE and PAS stainings were performed to evaluate the morphology and injury of the kidney. The results showed that LBP significantly reduces the glucose level and ameliorates the insulin resistance of diabetic mice. Importantly, LBP improves renal function by lowering the levels of sCr, BUN, and microalbumin in diabetic mice and relieves the injury in the renal glomeruli and tubules of the DN mice. Furthermore, LBP attenuates renal inflammation as evidenced by downregulating the mRNA levels of TNFα, IL1 β, IL6, and SAA3 in the renal cortex, as well as reducing the elevated circulating level and protein depositions of SAA3 in the kidney. In addition, our western blot results showed that NF-κB p65 nuclear translocation and the degradation of inhibitory κB-α (IκBα) occurred during the progress of inflammation, and such activated signaling was restrained by LBP. In conclusion, our findings suggest that LBP is a potential antidiabetic agent, which ameliorates the inflammation in DN through inhibiting NF-κB activation.

In Vivo Analgesic, Anti-Inflammatory, and Anti-Diabetic Screening of Bacopa monnieri-Synthesized Copper Oxide Nanoparticles.

In this work, an ecofriendly approach for biogenic production of copper oxide nanoparticles (CuO-NPs) was proposed by utilizing the Bacopa monnieri leaf extract as a reducing and stabilizing agent. The synthesis of CuO-NPs was instantly confirmed by a shift in the color of the copper solution from blue to dark gray. The use of UV–visible spectroscopy revealed a strong narrow peak at 535 nm, confirming the existence of monoclinic-shaped nanoparticles. The average size of CuO-NPs was 34.4 nm, according to scanning electron microscopy and transmission electron microscopy studies. The pristine crystalline nature of CuO-NPs was confirmed by X-ray diffraction. The monoclinic form of CuO-NPs with a crystallite size of 22 nm was determined by the sharp narrow peaks corresponding to 273, 541, 698, 684, and 366 Bragg’s planes at different 2θ values. The presence of different reducing metabolites on the surface of CuO was shown by Fourier transform infrared analysis. The biological efficacy of CuO-NPs was tested against Helicobacter felis, Helicobacter suis, Helicobacter salomonis. and Helicobacter bizzozeronii. H. suis was the most susceptible strain with an inhibition zone of 15.84 ± 0.89 mm at 5 mg/mL of NPs, while the most tolerant strain was H. bizzozeronii with a 13.11 ± 0.83 mm of inhibition zone. In in vivo analgesic activity, CuO-NPs showed superior efficiency compared to controls. The maximum latency time observed was 7.14 ± 0.12 s at a dose level of 400 mg/kg after 90 min, followed by 5.21 ± 0.29 s at 400 mg/kg after 60 min, demonstrating 65 and 61% of analgesia, respectively. Diclofenac sodium was used as a standard with a latency time of 8.6 ± 0.23 s. The results observed in the rat paw edema assays showed a significant inhibitory activity of the plant-mediated CuO-NPs. The percentage inhibition of edema was 74% after 48 h for the group treated with CuO-NPs compared to the control group treated with diclofenac (100 mg/kg) with 24% edema inhibition. The solution of CuO-NPs produced 82% inhibition of edema after 21 days when compared with that of the standard drug diclofenac (73%). CuO-NPs vividly lowered glucose levels in STZ-induced diabetic mice, according to our findings. Blood glucose levels were reduced by about 33.66 and 32.19% in CuO-NP and (CuO-NP + insulin) groups of mice, respectively. From the abovementioned calculations, we can easily conclude that B. monnieri-synthesized CuO-NPs will be a potential antibacterial, anti-diabetic, and anti-inflammatory agent on in vivo and in vitro basis.

An in silico ADMET, molecular docking study and microwave-assisted synthesis of new phosphorylated derivatives of thiazolidinedione as potential anti-diabetic agents

A series of new phosphorylated derivatives of thiazolidinedione was synthesized for the first time with high yields (92–96%) in short reaction time (7–15min) by the reaction of 4-{[(5E)-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}phenyl ethyl phosphorochloridate with various heterocyclic amines by microwave irradiation technique under solvent-free condition. A study on in silico ADMET and molecular docking was performed for all the molecules to acquire an insight on drug likeliness behavior and also their ability to inhibit the enzyme, α-amylase. The molecules with momentous pharmacokinetic properties with substantial binding affinity were synthesized. The synthesized compounds were characterized spectroscopically to confirm their structure and then in vitro α-amylase inhibitory activity was also carried out for all the newly prepared compounds. The compounds 9b, 9e, 9f, and 9j reported the highest inhibition amongst the synthesized compounds. All the leftover compounds displayed modest to excellent inhibition in comparison with reference drug, Acarbose.

New spiropyrrolothiazole derivatives bearing an oxazolone moiety as potential antidiabetic agent: Design, synthesis, crystal structure, Hirshfeld surface analysis, ADME and molecular docking studies

In a sustained search for novel and effective antihyperglycemics, a new series of fifteen isomeric oxazolone-fused dispiropyrrolothiazoles resulting from one-pot three component reaction between L-4-thiazolidine carboxylic acid, arylidene-oxazolones and isatin (or acenaphthenequinone) has been synthesized. Four crystal structure determinations further corroborate the proposed stereochemistry and composition of these spirocompounds. The Hirshfeld surface analysis was carried out to quantify the intermolecular interactions involved in the crystalline environment. Results showed the main contribution of H···H and C···H/ H···C contacts for the crystal structures 4b, 5c, 6a and 6e as well as those of O···H/ H···O contacts followed by the S···H/ H···S contacts. Furthermore, the hypoglycemic potency of these heterocycles has been evaluated against both α-amylase from human saliva (HAA) and α-glucosidase from Saccharomyces cerevisiae (SCAG). Among the spiropyrrolothiazole derivatives, the high significantly were 4b (IC50 (HAA) = 1.76 ± 0.14 μM; IC50 (SCAG) = 4.81 ± 0.24 μM) and 5d (IC50 (HAA) = 2.88 ± 0.19 μM; IC50 (SCAG) = 7.78 ± 0.37 μM), while in dispiropyrrolothiazole analogues, those of 6f (IC50 (HAA) = 2.18 ± 0.17 μM), 6e (IC50 (HAA) = 2.28 ± 0.18 μM) and 6c (IC50 (HAA) = 2.49 ± 0.20 μM) and 6e (IC50 (SCAG) = 6.41 ± 0.25 μM), 6f (IC50 (SCAG) = 6.93 ± 0.34 μM) and 6c (IC50 (SCAG) = 7.11 ± 0.31 μM) were found to be the most active, respectively as compared to the standard drug, acarbose (IC50 (HAA) = 1.28 ± 0.13 μM; IC50 (SCAG) = 2.80 ± 0.20 μM). Structural activity relationships (SARs) and molecular dockings of the most active inhibitors into the binding sites of HAA (1B2Y) and SCAG (3W37) were also established. Furthermore, pharmacokinetic studies indicate that the heterocycles exhibit acceptable predictive ADME properties and good drug ability. Overall, our results indicate that these derivatives could be a promising template to design potent dual HAA and SCAG inhibitors.