Potential Antidiabetic Agents Research Articles

Synthesis and evaluation of novel peptidomimetics bearing p-aminobenzoic acid moiety as potential antidiabetic agents.

Aim: Search for a new class of potential antidiabetic agents. Methodology: A series of novel peptidomimetics bearing the p-aminobenzoic acid moiety (TM3-TM6) were designed and synthesized. For all synthetic target molecules, the peroxisome proliferator response element (PPRE) activated activities have been evaluated and the toxicity were computed. Results & discussion: 46 new p-aminobenzoic acid derivatives have been characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The results of in vitro PPRE-activated activity, molecular docking study and toxicity prediction revealed that these compounds had potential antidiabetic activities and low toxicity. In particular compound 3b had up to 87% PPRE-activated activity compared with pioglitazone. This discovery may provide new insights for finding novel PPRE lead compound.

Coumarin-based Scaffold as α-glucosidase Inhibitory Activity: Implication for the Development of Potent Antidiabetic Agents.

Delaying the absorption of glucose through α-glucosidase enzyme inhibition is one of the therapeutic approaches in the management of Type 2 diabetes, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense by inducing oxidative stress-induced pancreatic β-cell destruction through uncontrolled generation of free radicals such as ROS, which in turn, leads to various macrovascular and microvascular complications. The currently available α -glucosidase inhibitors, for instance, acarbose, have some side effects such as hypoglycemia at higher doses, liver problems, meteorism, diarrhea, and lactic acidosis. Therefore, there is an urgent need to discover and develop potential α-glucosidase inhibitors. Based on suchmotifs, researchers are intrigued to search for the best scaffold that displays various biological activities. Among them, coumarin scaffold has attracted great attention. The compound and its derivatives can be isolated from various natural products and/or synthesized for the development of novel α-glucosidase inhibitors. This study focused on coumarin and its derivatives as well as on their application as potent antidiabetic agents and has also concentrated on the structure-activity relationship. This review describes the applications of coumarin-containing derivatives as α - glucosidase inhibitors based on published reports which will be useful for innovative approaches in the search for novel coumarin-based antidiabetic drugs with less toxicity and more potency.

Green Synthesis of Gold Nanoparticles Capped with Procyanidins from Leucosidea sericea as Potential Antidiabetic and Antioxidant Agents

In this study, procyanidins fractions of dimers and trimers (F1–F2) from the Leucosidea sericea total extract (LSTE) were investigated for their chemical constituents. The total extract and the procyanidins were employed in the synthesis of gold nanoparticles (Au NPs) and fully characterized. Au NPs of 6, 24 and 21 nm were obtained using LSTE, F1 and F2 respectively. Zeta potential and in vitro stability studies confirmed the stability of the particles. The enzymatic activity of LSTE, F1, F2 and their corresponding Au NPs showed strong inhibitory alpha-amylase activity where F1 Au NPs demonstrated the highest with IC50 of 1.88 µg/mL. On the other hand, F2 Au NPs displayed the strongest alpha-glucosidase activity at 4.5 µg/mL. F2 and F2 Au NPs also demonstrated the highest antioxidant activity, 1834.0 ± 4.7 μM AAE/g and 1521.9 ± 3.0 μM TE/g respectively. The study revealed not only the ability of procyanidins dimers (F1 and F2) in forming biostable and bioactive Au NPs but also, a significant enhancement of the natural products activities, which could improve the smart delivery in future biomedical applications.

An Insight of Alpha-amylase Inhibitors as a Valuable Tool in the Management of Type 2 Diabetes Mellitus.

Among the millions of people around the world, the most prevalent metabolic disorder is diabetes mellitus. Due to the drawbacks which are associated with commercially available antidiabetic agents, new therapeutic approaches are needed to be considered. Alpha-amylase is a membrane- bound enzyme which is responsible for the breakdown of polysaccharides such as starch to monosaccharides which can be absorbed. We searched the scientific database using alpha-amylase, diabetes, antidiabetic agents as the keywords. Here in, only peer-reviewed research articles were collected which were useful to our current work. To overcome the research gap, the alpha-amylase enzyme is regarded as a good target for antidiabetic agents to design the drug and provide an alternate approach for the treatment of type 2 diabetes mellitus. Basically, alpha-amylase inhibitors are classified into two groups: proteinaceous inhibitors, and non-proteinaceous inhibitors. Recently, non-proteinaceous inhibitors are being explored which includes chalcones, flavones, benzothiazoles, etc. as the potential antidiabetic agents. Herein, we discuss various potential antidiabetic agents which are strategically targeted alpha-amylase enzyme. These are having lesser side effects as compared to other antidiabetic agents, and are proposed to prevent the digestion and absorption of glucose leading to a decrease in the blood glucose level.

Inhibition of Digestive Enzymes and Antioxidant Activity of Extracts from Fruits of Cornus alba, Cornus sanguinea subsp. hungarica and Cornus florida–A Comparative Study

The fruits of some Cornus species (dogwoods) are used in traditional medicine and considered potential anti-diabetic and hypolipemic agents. The aim of the study was to determine the ability of extracts from Cornus alba (CA), Cornus florida (CF), and Cornus sanguinea (CS) to inhibit digestive enzymes namely α-amylase, pancreatic lipase, and α-glucosidase, as well as isolation of compounds from plant material with the strongest effect. In addition, the phytochemical profile and antioxidant activity of extracts from three dogwoods were compared with HPLC-DAD-MS/MS and DPPH scavenging assay, respectively. Among the aqueous-ethanolic extracts, the activity of α-amylase was the most strongly inhibited by the fruit extract of CA (IC50 = 115.20 ± 14.31 μg/mL) and the activity of α-glucosidase by the fruit of CF (IC50 = 38.87 ± 2.65 μg/mL). Some constituents of CA fruit extract, such as coumaroylquinic acid, kaempferol, and hydroxytyrosol derivatives, were isolated. Among the three species of dogwood studied, the greatest biological potential was demonstrated by CA extracts, which are sources of phenolic acids and flavonoid compounds. In contrast, iridoid compounds or flavonoid glycosides found in fruits of CF or CS extracts do not play a significant role in inhibiting digestive enzymes but exert antioxidant activity.

Anti-diabetic activity of crude polysaccharide and rhamnose-enriched polysaccharide from G. lithophila on Streptozotocin (STZ)-induced in Wistar rats

The aim of the present study was to elucidate the anti-diabetic effects of the crude polysaccharide and rhamnose-enriched polysaccharide derived from G. lithophila on streptozotocin (STZ)-induced diabetic Wistar rats. Treatment with crude polysaccharide and rhamnose-enriched polysaccharide showed increases in body weight and pancreatic insulin levels and a decrease in blood glucose levels compared with control diabetic rats. The blood concentrations of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) decreased, and high-density lipoprotein (HDL) increased both in the crude polysaccharide- and rhamnose-enriched polysaccharide-treated rats. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels increased, and malondialdehyde (MDA) levels decreased in the livers, kidneys and pancreases of crude polysaccharide- and rhamnose-enriched polysaccharide-treated rats. Immunohistological examination further confirmed that restoration of the normal cellular size of the islets of Langerhans and the rebirth of β-cells were found to be greater in the body region than in the head and tail regions of the pancreas. The crude polysaccharide- and rhamnose-enriched polysaccharide-treated diabetic rats showed normal blood glucose levels and insulin production, and reversed cholesterol levels and enzymatic actions. Therefore, rhamnose-enriched polysaccharide from G. lithophila acts as a potent anti-diabetic agent to treat diabetes and can lead to the development of an alternative medicine for diabetes in the future.

S-Equol ameliorates insulin secretion failure through Chrebp/Txnip signaling via modulating PKA/PP2A activities

BackgroundS-Equol, produced from daidzein by gut microbiota, has been suggested as an potential anti-diabetic agent, but the underlying mechanisms remain unclear. Recent evidences demonstrated that carbohydrate response element-binding protein (Chrebp)/Thioredoxin-interacting protein (Txnip) signaling played central roles on diabetes progression, particularly in relation to the function maintenance and apoptosis of pancreatic β-cell. Here, we investigated the effects of S-Equol on β-cell function and Chrebp/Txnip signaling.MethodsZucker diabetic fatty rats were treated with racemic Equol (120 mg/kg.BW.d) for 6 weeks. The glucose and lipid metabolism were monitored during the supplementation, and the Chrebp and Txnip expression were measured by using Western blotting. INS-1 cells were incubated with high glucose (26.2 mM) with or without S-Equol (0.1 μM, 1 μM, 10 μM) for 48 h. Glucose-stimulated insulin secretion (GSIS) was evaluated by radioimmunoassay, and the apoptosis of INS-1 cells was analyzed using Annexin V-FITC/PI and TUNEL assay. The dual luciferase reporter assay, chromatin immunoprecipitation assay and Western-blotting followed by Chrebp small interfering RNAs were utilized to clarify the mechanism of transcriptional regulation of S-Equol on Chrebp/Txnip signaling and the activities of protein kinase A (PKA) and protein phophatase (PP2A) were also detected.ResultsIn vivo, Equol supplementation delayed the onset of the hyperglycemia and hyperlipemia, ameliorated insulin secretion failure, enhanced GSIS in isolated islets, and significantly reduced Chrebp and Txnip expression in islets. In vitro, S-Equol treatment enhanced GSIS of high glucose cultured INS-1 cell, and reduced apoptosis of INS-1 cells were also observed. Moreover, S-Equol dramatically suppressed Txnip transcription, as evident by the reduction of Txnip protein and mRNA levels and decrease in the Txnip promoter-driven luciferase activity. Meanwhile, S-Equol significantly inhibited Chrebp/Mlx expression and decreased occupancy of Chrebp on the Txnip promoter, and combined with siChrebp, we confirmed that S-Equol improvement of insulin secretion was partially through the Chrebp/Txnip pathway. Furthermore, S-Equol significantly decrease nuclear translocation of Chrebp, which was related with the decrease activity of protein kinase A (PKA) and the increase activity of protein phophatase (PP2A).ConclusionsS-Equol could ameliorate insulin secretion failure, which was dependent on the suppression of Chrebp/Txnip signaling via modulating PKA/PP2A activities.

Synthesis of Novel molecular hybrid 3-(4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives and In Vitro α-glucosidase and α-amylase inhibitory activity

A novel series of 3-(4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives was designed based on molecular hybridization technique. A series of 3-(1-benzoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-4-hydroxy-2H-chromen-2-one derivatives (6a-6p) that incorporate a variety of substituents at the 2 and 4 position of the benzyl moiety have been synthesized. These compounds were evaluated for their antidiabetic activity against α-glucosidase and α-amylase. The biological screening indicates that these hybrid derivatives exhibited promising IC50 values in the range of 91.24μM -261.82μM and 85.03μM -237.78μM respectively. Two analogs, 6j and 6m have shown most potential activity against both α-glucosidase and α-amylase were identified as potent antidiabetic agents.

5-Methoxyindole-2-Carboylic Acid (MICA) Fails to Retard Development and Progression of Type II Diabetes in ZSF1 Diabetic Rats

5-Methoxyindole-2-carboxylic acid (MICA) is a well-established reversible inhibitor of mitochondrial dihydrolipoamide dehydrogenase (DLDH). This chemical, as an indole derivative, has been shown to be neuroprotective against ischemic stroke injury when administered either before or after ischemic stroke in animal models. MICA has also been studied as a potential antidiabetic agent by numerous investigators, though the underlying mechanisms remain sketchy. To attempt to elucidate the mechanisms of its antidiabetic action, we tested the effect of MICA on ZSF1 rat, a widely used rodent model of type 2 diabetes. ZSF1 rats as well as its healthy controls were fed with control diet or MICA-containing diet (200 mg/kg/day) for 9 weeks. Unexpectedly, comparison of body weight changes and blood glucose levels at the end of the 9-week's feeding period indicated that MICA failed to show any anti-diabetic effect in the ZSF1 diabetic rats. The reasons for this failure were discussed.

Identification of glucagon-like peptide-1 (glp-1) receptor agonists as a potential antidiabetic agent through molecular docking

Intake of the high level of sugar may cause diabetes which is a metabolic disorder. It is characterized by hyperglycemia, glycosuria, hyperlipidemia, negative nitrogen balance, and ketonemia. Types of diabetes are type 1, is dependent on insulin. The pancreatic islets beta cells are destroyed where most of the cases are autoimmune (Type IA) antibodies that destroy beta cells are detectable in blood, but some are idiopathic also (Type IB). Type 2, is the type of diabetes that is independent of insulin. There is a reduction in the insulin level. GLP-1 is an important incretin that will induce insulin from the pancreatic beta-cell. It will inhibit the release of glucagon. The GLP-1 receptors will get activated where the appetite will get suppressed. In this research, we have designed different novel GLP-1 agonists by changing the amino group of ligand pyrazole carboxamide. The designed ligands were docked on protein 5vex. Among these UDI29 is chosen for further studies like interaction, with a bindinghigh affinity of -8.4 kcal/mol.

Cu/TEMPO catalyzed dehydrogenative 1,3-dipolar cycloaddition in the synthesis of spirooxindoles as potential antidiabetic agents.

A series of spiro-[indoline-3,3′-pyrrolizin/pyrrolidin]-2-ones, 4, 5 and 6 were synthesized in a sequential manner from Cu–TEMPO catalyzed dehydrogenation of alkylated ketones, 1 followed by 1,3-dipolar cycloaddition of azomethine ylides via decarboxylative condensation of isatin, 2 and l-proline/sarcosine, 3 in high regioselectivities and yields. The detailed mechanistic studies were performed to identify the reaction intermediates, which revealed that the reaction proceeds via dehydrogenative cycloaddition. Additionally, the regio and stereochemistry of the synthesized derivatives were affirmed by 2D NMR spectroscopic studies. The synthesized derivatives were explored further with molecular docking, in vitro antioxidant, and anti-diabetic activities.

Inhibition of Digestive Enzyme and Stimulation of Human Liver Cells (HepG2) Glucose Uptake by Date Seeds Extract.

Type 2 diabetes mellitus is increasing worldwide, and the United Arab Emirates is presenting one of the world's highest prevalence rates. Dietary polyphenols exert an antidiabetic effect by modulating carbohydrates digestion and cellular glucose uptake. Due to their particularly high content in polyphenols, date seeds represent a potential antidiabetic agent. This study aims to determine if date seed polyphenols inhibit the activity of the enzymes (α-amylase and α-glucosidase), responsible for the digestion of carbohydrates and modulating the glucose uptake by human liver cells. In vitro activity of the intestinal α-glucosidase, pancreatic α-amylase, the glucose uptake by HepG2 cells, and the expression of GLUT4 and AMPK analyzed by western blotting (with and without date seeds extract). Our result showed that the maximum enzymes inhibition was obtained with 400 μg/mL and 900 μg/mL DSE for α-amylase and α-glucosidase, respectively. The HepG2 cell viability significantly decreased up to 80% at 4000 μg/mL DSE. The expression of GLUT4 was higher at 100 μg/mL DSE (with insulin and without insulin). However, the expressions of P-AMPK and AMPK were increased by DSE, mainly in a non-insulin-dependent manner. Therefore, DSE, by inhibiting carbohydrate digestion and stimulating glucose uptake by HepG2, can potentially demonstrate the therapeutic potential for diabetes management.

Investigations on the structural, vibrational, computational, and molecular docking studies on potential antidiabetic chemical agent Diosmetin.

In the present study, the harmonic vibrational frequencies of Diosmetin(5, 7 dihydroxy-2(3-hydroxy-4 methoxyphenyl) chromen-4-one) have been investigated by both experimental (FTIR and FT-Raman) and theoretical (HF and DFT/B3LYP) method. The calculated harmonic vibrational frequencies were compared with experimental data. A detailed interpretation of the vibrational spectra of the compound has been made on the basis of the calculated potential energy distribution (PED). The 1 H, 13 C NMR chemical shifts and TD-DFT calculations of the molecule were calculated and compared with the available experimental observations. A study on the molecular electrostatic potential surface (MEP) of the compound was performed, and the electrophilic and nucleophilic reactive sites were identified. Furthermore, the inhibition effect of compound against aldose reductase enzyme has been analyzed by molecular docking method, and the results were compared with the standard drug. The docking study indicates that the investigated compound shows better inhibitory activity toward aldose reductase enzyme than the standard drug, and hence this study may be supportive in the field of drug discovery to design more potential antidiabetic agents.

Benzoylquinazolinone derivatives as new potential antidiabetic agents: α‐Glucosidase inhibition, kinetic, and docking studies

AbstractBenzoylquinazolinone derivatives 3a–n were synthesized via a simple one‐step reaction, and evaluated for in vitro α‐glucosidase inhibitory activity. Compounds 3d, 3f–g, 3i, and 3m–n showed more inhibitory activity than standard drug acarbose (IC50 = 750.0 ± 1.5 μM), and among them, compound 3d displayed the highest α‐glucosidase inhibitory activity (IC50 = 261.6 ± 0.1 μM). The kinetic analysis of the compound 3d revealed that this compound inhibited α‐glucosidase in a competitive manner (Ki = 255 μM). The docking studies were applied to predict binding modes of the synthesized compounds in active site of α‐glucosidase.

In vitro Callus Induction of Coccinia indica (W. and A) and Analysis of Its Phytochemical, Antimicrobial, Antioxidant and α-Amylase Inhibitory Activity - A Comparative Study

In the present study an attempt has been made to evaluate the phytochemical, antimicrobial, antioxidant and α-amylase inhibitory activity of Coccinia indica (W. and A) leaf extracts using four solvents and compare it with the callus extracts. Callus was initiated from the leaf explants of C. indica with 90% efficiency using MS medium supplemented with BAP (1 mg/l) + NAA (0.2 mg/l). Successive extraction method of C.indica was found to be an efficient method of extraction and methanol was observed to be the best suited solvent for the extraction of phytochemicals and macromolecules that were responsible for antimicrobial, antioxidant and α-amylase inhibition. GC-MS analysis of C. indica has confirmed the presence of bioactive compounds (Example: 9-Octadecanoic acid, 2-octadecycloxy ethyl ester (100%) in successive methanolic callus extract) in all the extracts where the FTIR analysis has confirmed the presence of various important functional groups of the identified bioactive compounds. Successive methanol extract of callus of C. indica was found to be the potent antimicrobial agent with drug efflux pump inhibitor property against 5 bacterial strains, Klebsiella pneumoniae (ATCC700603), Escherichia coli (ATCC25922), Staphylococcus aureus (ATCC 25923), Proteus mirabilis (ATCC 25933) and Pseudomonas aeruginosa (clinical isolate) and 3 fungal strains, Candida albicans (IFM 40009), Candida tropicalis (IFM 55058) and Candida krusei (IFM 46521). Successive methanol extract of callus of C. indica was found to be an efficient antioxidant agent and an efficient α-amylase inhibitor, which proves it to be a potent anti-diabetic agent with IC50 concentration to be 82.5µg/ml. This study is one of the strong evidence for this plant to be used by the traditional practitioners as a phytopharmaceutical agent.

Evaluation of the effects of metformin administration on morphine tolerance in mice

Opioids are used in clinical practice to relieve moderate to severe pain. Prolonged use of opioids can lead to a situation of analgesic tolerance and dependence. Several mechanisms are involved in the tolerance to analgesic opioids, including desensitization or internalization of the opioid receptor, elevation of cAMP levels, microglial activation and neuroinflammation, elevation of spinal mTOR activity and change in the expression of some proteins involved in tolerance, such as nNOS. Activation of the AMPK pathway inhibits mTOR and p38 MAPK ameliorating neuroinflammation and tolerance induced by morphine. Metformin, a potent antidiabetic agent, can also activate AMPK.Morphine tolerance was induced in mice by intraperitoneal administration three times daily at 08:00, 11.00 and 16.00 h of 50, 50 and 75 mg/kg morphine, respectively during four days. On the fifth day mice received a single injection of morphine 50 mg/kg. To evaluate the effects of metformin in development of morphine-induced analgesic tolerance a group of mice received metformin (10 mg/kg) 45 min before each morphine administration. Tail flick and hot plate tests were performed to estimate analgesic latency on days 1, 3 and 5. At five days, the animals were sacrificed, the brain dissected and nitrite levels determined.Chronic metformin administration significantly increased the analgesic latency on days 3 and 5 compared to the morphine group in hot plate test and in tail flick test. Chronic and acute metformin administration significantly decreased nitric oxide level compare to morphine group. The present results revealed that metformin attenuated analgesic tolerance induced by repeated intraperitoneal injections of morphine in mice.

SGLT1 inhibition boon or bane for diabetes-associated cardiomyopathy.

Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes-related cardiac perturbations.

Evaluation of vegetables and fish oils for the attenuation of diabetes complications

The present study was accomplished to examine and compare the effect of specific antioxidant-rich oils on hyperglycemia, dyslipidemia, renal function markers and oxidative renal damage in diabetic rats for four weeks. Papaya (P), olive (O), fenugreek (Fe), bitter gourd (B) and fish (Fi) oils were used for this purpose. Streptozotocin (STZ) was injected intraperitoneally in a single dose to induce diabetes. All oils were given orally at a dose of 3g/kg for four weeks in respective group after induction of diabetes. After treatment with oils, blood was collected, and their kidneys were stored. The level of fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C) and very low-density lipoprotein-cholesterol (VLDL-C) increased while amylase and high-density lipoprotein cholesterol (HDL-C) level decreased in the diabetic rats. These changes were augmented by fenugreek, bitter gourd and olive oils treatment. Diabetic rats showed elevated renal function markers in serum, including, serum creatinine (Scr), blood urea nitrogen (BUN) and alkaline phosphatase (ALP), which were restrained significantly by fenugreek and bitter gourd oil treatment. Moreover, fenugreek and bitter gourd oils treatment significantly modulated the level of thiobarbituric reactive substances (TBARS), malonaldehyde (MDA) and catalase (CAT) in the kidney of diabetic rats. The histopathological examination also showed the protective effect of these oils. The study suggests that vegetable oils are effective in reducing hyperglycemia, dyslipidemia and renal damage related to the side effects of diabetes. Thus they may have therapeutic value for preventing diabetes side effects and may be included in oil diet treatment synergically. Thus, our data suggest that oils as potent antidiabetic agent and beneficial in the control of diabetes-related abnormalities such as hyperglycemia, dyslipidemia and renal damage of STZ induced rat model of type 2 diabetes. Our study also supports the suggestion that synergistic possibilities exist concerning the use of these oils in the treatment of diabetes mellitus.

Iso-Mukaadial Acetate from Warburgia salutaris Enhances Glucose Uptake in the L6 Rat Myoblast Cell Line.

Diabetes mellitus (DM) is a chronic metabolic disorder which has become a major risk to the health of humankind, as its global prevalence is increasing rapidly. Currently available treatment options in modern medicine have several adverse effects. Thus, there is an urgent need to develop alternative cost-effective, safe, and active treatments for diabetes. In this regard, medicinal plants provide the best option for new therapeutic remedies desired to be effective and safe. Recently, we focused our attention on drimane sesquiterpenes as potential sources of antimalarial and antidiabetic agents. In this study, iso-mukaadial acetate (Iso) (1), a drimane-type sesquiterpenoid from the ground stem bark of Warburgia salutaris, was investigated for glucose uptake enhancement in the L6 rat myoblast cell line. In vitro assays with L6 skeletal muscle cells were used to test for cytotoxicity, glucose utilisation, and western blot analysis. Additionally, the inhibition of carbohydrate digestive enzymes and 1,1-diphenyl-2- picrylhydrazyl (DPPH) scavenging activity were analysed in vitro. The cell viability effect of iso-mukaadial acetate was the highest at 3 µg/mL with a percentage of 98.4. Iso-mukaadial acetate also significantly and dose-dependently increased glucose utilisation up to 215.18% (12.5 µg/mL). The increase in glucose utilisation was accompanied by enhanced 5’ adenosine monophosphate-activated protein kinase (AMPK)and protein kinase B (AKT) in dose-dependent manner. Furthermore, iso-mukaadial acetate dose-dependently inhibited the enzymes α-amylase and α-glucosidase. Scavenging activity against DPPH was displayed by iso-mukaadial acetate in a concentration-dependent manner. The findings indicate the apparent therapeutic efficacy of iso-mukaadial acetate isolated from W. salutaris as a potential new antidiabetic agent.

Design, synthesis, and biological evaluation of novel dual FFA1 (GPR40)/PPARδ agonists as potential anti-diabetic agents

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptor δ (PPARδ) were considered as potential anti-diabetic targets, and the dual FFA1/PPARδ agonists might provide synergistic effect in insulin secretion and sensibility. Herein, we further develop dual agonists by screening 7 series of heterocycles, resulting in the discovery of compound 19 with considerable oral pharmacokinetic profile. Compound 19 exhibited a balanced potency between FFA1 and PPARδ, and high selectivity over PPARα and PPARγ. Moreover, compound 19 exerted improved glucose-lowering effects and insulin sensitivity in a dose-dependent manner, which might be attributed to its dual effects to simultaneously regulate insulin secretion and resistance. Our results extended the existing chemical space, and provided a potent tool compound 19.