Exploration of alpha-glucosidase inhibitors: A comprehensive in silico approach targeting a large set of triazole derivatives.

BACKGROUND: The increasing prevalence of diabetes and the side effects associated with current medications necessitate the development of novel candidate drugs targeting alpha-glucosidase as a potential treatment option. METHODS: This study employed computer-aided drug design techniques to identify potential alpha-glucosidase inhibitors from the PubChem database. Molecular docking was used to evaluate 81,197 compounds, narrowing the set for further analysis and providing insights into ligand-target interactions. An ADMET study assessed the pharmacokinetic properties of these compounds, including absorption, distribution, metabolism, excretion, and toxicity. Molecular dynamics simulations validated the docking results. RESULTS: 9 compounds were identified as potential candidate drugs based on their ability to form stable complexes with alpha-glucosidase and their favorable pharmacokinetic profiles, three of these compounds were subjected to the molecular dynamics, which showed stability throughout the entire 100 ns simulation. CONCLUSION: These findings suggest promising new alpha-glucosidase inhibitors for diabetes treatment. Further validation through in vitro and in vivo studies is recommended to confirm their efficacy and safety.

2ß-Acetoxyferruginol derivatives as α-glucosidase inhibitors: Synthesis and biological evaluation.

To find potential α-glucosidase inhibitors, a series of 2ß-acetoxyferuginol derivatives containing cinnamic acid (WXC-1 âˆ¼ 25) were synthesized and investigated their biological activity. All derivatives (WXC-1 âˆ¼ 25) displayed better inhibitory activity (IC50 values: 7.56 ± 1.35 âˆ¼ 25.63 ± 1.72 µM) compared to acarbose (IC50 vaule: 564.28 ± 48.68 µM). In particularly, WXC-25 with 4-hydroxycinnamic acid section showed the best inhibitory activity (IC50 vaule: 2.02 ± 0.14 µM), ∼75-fold stronger than acarbose. Kinetics results suggested WXC-25 being one reversible non-competition inhibitors. Fluorescence quenching results indicated that WXC-25 quenched the fluorescence of α-glucosidase in a static manner. 3D fluorescence spectra results indicated that WXC-25 treatment could cause the conformation changes of α-glucosidase. Moreover, molecular docking simulated the detailed interaction of WXC25 with α-glucosidase.

Identification and molecular mechanism of novel hypoglycemic peptide in ripened pu-erh tea: Molecular docking, dynamic simulation, and cell experiments.

Ripened pu-erh tea is known to have beneficial hypoglycemic properties. However, it remains unclear whether the bioactive peptides produced during fermentation are also related to hypoglycemic potential. This study aimed to identify hypoglycemic peptides in ripened pu-erh tea and to elucidate their bioactive mechanisms using physicochemical property prediction, molecular docking, molecular dynamics simulations, and cell experiments. Thirteen peptides were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Among them, AADTDYRFS (AS-9) and AGDGTPYVR (AR-9) exhibited high α-glucosidase inhibitory activity, with half-maximal inhibitory concentration (IC50) values of 0.820 and 3.942 mg/mL, respectively. Molecular docking and dynamics simulations revealed that hydrogen bonding, hydrophobic interactions, and van der Waals forces assist peptides AS-9 and AR-9 in forming stable and tight complexes with α-glucosidase. An insulin-resistance (IR)-HepG2 cell model was established. AS-9 was non-toxic to IR-HepG2 cells and significantly increased the glucose consumption capacity, hexokinase, and pyruvate kinase activities of IR-HepG2 cells (p < 0.05). AS-9 alleviated glucose metabolism disorders and ameliorated IR by activating the IRS-1/PI3K/Akt signaling pathway and increasing the expression levels of MDM2, IRS-1, Akt, PI3K, GLUT4, and GSK3ß genes. In addition, no hemolysis of mice red blood cells red blood cells occurred at concentrations below 1 mg/mL. This work first explored hypoglycemic peptides in ripened pu-erh tea, providing novel insights for enhancing its functional value.

Metabolites profiling of Sapota fruit pulp via a multiplex approach of gas and ultra performance liquid chromatography/mass spectroscopy in relation to its lipase inhibition effect.

Background: Sapota, Manilkara zapota L., are tasty, juicy, and nutrient-rich fruits, and likewise used for several medicinal uses. Methods: The current study represents an integrated metabolites profiling of sapota fruits pulp via GC/MS and UPLC/MS, alongside assessment of antioxidant capacity, pancreatic lipase (PL), and α-glucosidase enzymes inhibitory effects. Results: GC/MS analysis of silylated primary polar metabolites led to the identification of 68 compounds belonging to sugars (74%), sugar acids (18.27%), and sugar alcohols (7%) mediating the fruit sweetness. Headspace SPME-GC/MS analysis led to the detection of 17 volatile compounds belonging to nitrogenous compounds (72%), ethers (7.8%), terpenes (7.6%), and aldehydes (5.8%). Non-polar metabolites profiling by HR-UPLC/MS/MS-based Global Natural Products Social (GNPS) molecular networking led to the assignment of 31 peaks, with several novel sphingolipids and fatty acyl amides reported for the first time. Total phenolic content was estimated at 6.79 ± 0.12 mg gallic acid equivalent/gram extract (GAE/g extract), but no flavonoids were detected. The antioxidant capacities of fruit were at 1.62 ± 0.2, 1.49 ± 0.11, and 3.58 ± 0.14 mg Trolox equivalent/gram extract (TE/g extract) via DPPH, ABTS, and FRAP assays, respectively. In vitro enzyme inhibition assays revealed a considerable pancreatic lipase inhibition effect (IC50 = 2.2 ± 0.25 mg/mL), whereas no inhibitory effect towards α-glucosidase enzyme was detected. This study provides better insight into sapota fruit's flavor, nutritional, and secondary metabolites composition mediating for its sensory and health attributes.

Structurally Diverse Stilbenoids as Potent α-Glucosidase Inhibitors with Antidiabetic Effect from Morus alba.

Fifteen stilbenoid derivatives, including five previously undescribed ones (albaphenols A-E, 1-5) with diverse scaffolds, were obtained from the well-known agricultural economic tree Morus alba. Their structures, including absolute stereochemistries, were fully characterized by detailed interpretation of spectroscopic data and quantum chemical computational analyses of nuclear magnetic resonance (NMR) and electric circular dichroism (ECD). Albaphenol A (1) features an unprecedented rearranged carbon skeleton incorporating a novel 2-oxaspiro[bicyclo[3.2.1]octane-6,3'-furan] motif; albaphenol C (3) is likely derived from a cometabolite through an interesting intramolecular transesterification reaction; and albaphenol E (5) bears a cleavage-reconnection scaffold via a dioxane ring. All of the compounds exhibited significant inhibition against the diabetic target α-glucosidase, with low to submicromole IC50 values (0.70-8.27 µM), and the binding modes of selected molecules with the enzyme were further investigated by fluorescence quenching, kinetics, and molecular docking experiments. The antidiabetic effect of the most active and abundant mulberrofuran G (6) was further assessed in vivo in diabetic mice, revealing potent antihyperglycemic activity and comparable antidiabetic efficacy to the clinical drug acarbose.

Design, synthesis and inhibition evaluation of novel chalcone amide α-glucosidase inhibitors.

Aim: The purpose of this study is to design and synthesize a series of novel chalcone amide α-glucosidase (AG) inhibitors (L1-L10) based on virtual screening and molecular dynamics (MD) simulation. Materials & methods: Target compounds (L1-L10) were synthesized from 2-hydroxyacetophenone and methyl 4-formylbenzoate. Results: In vitro activity test shows that most compounds have good AG inhibition. Specially, compound L4 (IC50 = 8.28 ± 0.04 µM) had the best inhibitory activity, superior to positive control acarbose (IC50 = 8.36 ± 0.02 µM). Molecular docking results show that the good potency of L4 maybe attributed to strong interactions between chalcone skeleton and active site, and the torsion of carbon nitrogen bond in amide group. Conclusion: Compound L4 maybe regard as a good anti-Type II diabetes candidate to preform further study.

[Box: see text].

Bioactive Naphthoquinone and Phenazine Analogs from the Endophytic Streptomyces sp. PH9030 as α-Glucosidase Inhibitors.

A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G (5) and seven previously identified compounds, 6-12, were obtained from Streptomyces sp. PH9030. The structure of 5 was identified by comprehensive examination of its HRESIMS, 1D NMR, 2D NMR and ECD data. The inhibitory activities of all the compounds toward α-glucosidase and their antibacterial properties were investigated. The α-glucosidase inhibitory activities of 5, 6, 7 and 9 were reported for the first time, with IC50 values ranging from 66.4 ± 6.7 to 185.9 ± 0.2 µM, as compared with acarbose (IC50 = 671.5 ± 0.2 µM). The molecular docking and molecular dynamics analysis of 5 with α-glucosidase further indicated that it may have a good binding ability with α-glucosidase. Both 9 and 12 exhibited moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, with minimum inhibitory concentration (MIC) values of 16 µg/mL. These results indicate that 5, together with the naphthoquinone scaffold, has the potential to be further developed as a possible inhibitor of α-glucosidase.

Agrocybe cylindracea Dietary Fiber Modification: Sodium Hydroxide Treatment Outperforms High-Temperature, Cellulase, and Lactobacillus Fermentation.

Agrocybe cylindracea dietary fiber (ADF) contains 95% water-insoluble dietary fiber, resulting in poor application performance. To address this issue, ADF was modified by four methods (cellulase, sodium hydroxide, high-temperature, and Lactobacillus fermentation) in this paper. By comparing the physicochemical properties, microstructures, monosaccharide compositions, and functional characteristics (antioxidant and α-glucosidase inhibitory activities in vitro) of all modified ADF samples, the optimal modification method was selected. Results showed that sodium hydroxide treatment was deemed the most effective modification method for ADF, as alkali-treated ADF (ADF-A) revealed a higher oil-holding capacity (2.02 g/g), swelling capacity (8.38 mL/g), cholesterol adsorption (6.79 mg/g), and α-glucosidase inhibitory activity (more than 70% at 0.4-0.6 mg/mL) than the other modified samples. The looser microstructure in ADF-A might be attributed to molecular rearrangement and spatial structure disruption, which resulted in smaller molecular sizes and decreased viscosity, hence improving ADF's physicochemical and functional qualities. All these findings indicate the greater application potential of modified ADF products in food and weight-loss industries, providing a comprehensive reference for the industrial application of ADF.

Antioxidant and Antidiabetic Activity of Cornus mas L. and Crataegus monogyna Fruit Extracts.

The present study evaluated three green extraction methods, accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), and laser irradiation extraction (LE), for the polyphenolic compounds and vitamin C extraction of Cornus mas L. and Crataegus monogyna fruit extracts. The polyphenols and vitamin C of extracts were quantified using HPLC-DAD, and the total phenolic content, flavonoid content, antioxidant activity (DPPH and reducing power), and antidiabetic activity were also studied. The antidiabetic activity was examined by the inhibition of α-amylase and α-glucosidase, and in vitro on a beta TC cell line (ß-TC-6). The results showed significant differentiation in the extraction yield between the methods used, with the ASE and LE presenting the highest values. The C. mas fruit extract obtained by ASE exhibited the best antioxidant activity, reaching an IC50 value of 31.82 ± 0.10 µg/mL in the DPPH assay and 33.95 ± 0.20 µg/mL in the reducing power assay. The C. mas fruit extracts obtained by ASE and LE also have the highest inhibitory activity on enzymes associated with metabolic disorders: α-amylase (IC50 = 0.44 ± 0.02 µg/mL for the extract obtained by ASE, and 0.11 ± 0.01 µg/mL for the extract obtained by LE at combined wavelengths of 1270 + 1550 nm) and α-glucosidase (IC50 of 77.1 ± 3.1 µg/mL for the extract obtained by ASE, and 98.2 ± 4.7 µg/mL for the extract obtained by LE at combined wavelengths of 1270 + 1550 nm). The evaluation of in vitro antidiabetic activity demonstrated that the treatment with C. mas and C. monogyna fruit extracts obtained using ASE stimulated the insulin secretion of ß-TC-6 cells, both under normal conditions and hyperglycemic conditions, as well. All results suggest that C. mas and C. monogyna fruit extracts are good sources of bioactive molecules with antioxidant and antidiabetic activity.

Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of Thiourea Derivatives Based on 3-Aminopyridin-2(1H)-Ones.

Reactions with allyl-, acetyl-, and phenylisothiocyanate have been studied on the basis of 3-amino-4,6-dimethylpyridine-2(1H)-one, 3-amino-4-phenylpyridine-2-one, and 3-amino-4-(thiophene-2-yl)pyridine-2(1H)-one (benzoyl-)isothiocyanates, and the corresponding thioureide derivatives 8-11a-c were obtained. Twelve thiourea derivatives were obtained and studied for their anti-diabetic activity against the enzyme α-glucosidase in comparison with the standard drug acarbose. The comparison drug acarbose inhibits the activity of α-glucosidase at a concentration of 15 mM by 46.1% (IC50 for acarbose is 11.96 mM). According to the results of the conducted studies, it was shown that alkyl and phenyl thiourea derivatives 8,9a-c, in contrast to their acetyl-(benzoyl) derivatives and 10,11a-c, show high antidiabetic activity. Thus, 1-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9a has the highest inhibitory activity against the enzyme α-glucosidase, exceeding the activity of the comparison drug acarbose, which inhibits the activity of α-glucosidase by 56.6% at a concentration of 15 mm (IC50 = 9,77 mM). 1-(6-methyl-2-oxo 4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9c has inhibitory activity against the enzyme α-glucosidase, comparable to the comparison drug acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mm per 41.2% (IC50 = 12,94 mM). Compounds 8a, 8b, and 9b showed inhibitory activity against the enzyme α-glucosidase, with a lower activity compared to acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mM by 23.3%, 26.9%, and 35.2%, respectively. The IC50 against α-glucosidase for compounds 8a, 8b, and 9b was found to be 16.64 mM, 19.79 mM, and 21.79 mM, respectively. The other compounds 8c, 10a, 10b, 10c, 11a, 11b, and 11c did not show inhibitory activity against α-glucosidase. Thus, the newly synthesized derivatives of thiourea based on 3-aminopyridine-2(1H)-ones are promising candidates for the further modification and study of their potential anti-diabetic activity. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.

Identification of Antioxidant Methyl Derivatives of Ortho-Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity.

α-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since α-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds' effect on enzymatic activity, their molecular modeling on α-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as α-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, α-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.

The Anti-Diabetic Effects of Medicinal Plants Belonging to the Liliaceae Family: Potential Alpha Glucosidase Inhibitors.

Background: Diabetes mellitus is a complex metabolic disorder that has an enormous impact on people's quality of life and health. Although there is no doubt about the effectiveness of oral hypoglycemic agents combined with lifestyle management in controlling diabetes, no individual has ever been reported to have been completely cured of the disease. Globally, many medicinal plants have been used for the management of diabetes in various traditional systems of medicine. A deep look in the literature has revealed that the Liliaceae family have been poorly investigated for their antidiabetic activity and phytochemical studies. In this review, we summarize medicinal plants of Liliaceae utilized in the management of type II diabetes mellitus (T2DM) by inhibition of α-glucosidase enzyme and phytochemical content. Methods: The literature search was conducted using databases including PubMed, ScienceDirect, and Google Scholar to find the significant published articles about Liliaceae plants utilized in the prevention and treatment of antidiabetics. Data were filtered to the publication period from 2013 to 2023, free full text and only English articles were included. The keywords were Liliaceae OR Alliaceae OR Amaryllidaceae AND Antidiabetic OR α-glucosidase. Results: Six medicinal plants such as Allium ascalonicum, Allium cepa, Allium sativum, Aloe ferox, Anemarrhena asphodeloides, and Eremurus himalaicus are summarized. Phytochemical and α-glucosidase enzymes inhibition by in vitro, in vivo, and human studies are reported. Conclusion: Plants of Liliaceae are potential as medicine herbs to regulating PPHG and prevent the progression of T2DM and its complication. In silico study, clinical application, and toxicity evaluation are needed to be investigated in the future.

[Anti-diabetic active constituents of pomegranate peel-derived extracellular nanovesicles].

Pomegranate peel-derived extracellular nanovesicles(PPENs) were isolated and purified by ultra-high speed centrifugation and sucrose density gradient centrifugation. Their morphology and structure were characterized. In vitro α-glucosidase inhibition assay and model test of insulin resistance(IR) in HepG2 cells showed that PPENs had good anti-diabetic activity. The IC_(50) value of α-glucosidase inhibition was(35.3±1.1) µg·mL~(-1), significantly better than the positive drug acarbose. At a concentration of 100 µg·mL~(-1), PPENs could increase the glucose absorption of IR cells significantly. Lipidome, proteome, and metabolite analysis of PPENs were performed using chromatography-mass spectrometry. MicroRNA(miRNA) sequences were identified, and target genes of miRNA were predicted. The analysis results indicated that PPENs contained abundant lipids and transport proteins, providing a material basis for the transportation and distribution of PPENs in tissue. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis suggested that lipids and miRNAs may be the key components of PPENs to exert anti-diabetic activity.

Subcritical Water Extraction of Undaria pinnatifida: Comparative Study of the Chemical Properties and Biological Activities across Different Parts.

The subcritical water extraction of Undaria pinnatifida (blade, sporophyll, and root) was evaluated to determine its chemical properties and biological activities. The extraction was conducted at 180 °C and 3 MPa. Root extracts exhibited the highest phenolic content (43.32 ± 0.19 mg phloroglucinol/g) and flavonoid content (31.54 ± 1.63 mg quercetin/g). Sporophyll extracts had the highest total sugar, reducing sugar, and protein content, with 97.35 ± 4.23 mg glucose/g, 56.44 ± 3.10 mg glucose/g, and 84.93 ± 2.82 mg bovine serum albumin (BSA)/g, respectively. The sporophyll contained the highest fucose (41.99%) and mannose (10.37%), whereas the blade had the highest galactose (48.57%) and glucose (17.27%) content. Sporophyll had the highest sulfate content (7.76%). Key compounds included sorbitol, glycerol, L-fucose, and palmitic acid. Root extracts contained the highest antioxidant activity, with IC50 values of 1.51 mg/mL (DPPH), 3.31 mg/mL (ABTS+), and 2.23 mg/mL (FRAP). The root extract exhibited significant α-glucosidase inhibitory activity with an IC50 of 5.07 mg/mL, indicating strong antidiabetic potential. The blade extract showed notable antihypertensive activity with an IC50 of 0.62 mg/mL. Hence, subcritical water extraction to obtain bioactive compounds from U. pinnatifida, supporting their use in functional foods, cosmetics, and pharmaceuticals is highlighted. This study uniquely demonstrates the variation in bioactive compound composition and bioactivities across different parts of U. pinnatifida, providing deeper insights. Significant correlations between chemical properties and biological activities emphasize the use of U. pinnatifida extracts for chronic conditions.

Changes in Phenolic Composition and Bioactivities of Ayocote Beans under Boiling (Phaseolus coccineus L.).

Ayocote beans (Phaseolus coccineus L.) are a rich source of some bioactive molecules, such as phenolic compounds that exhibit antioxidant capacity that promote health benefits. Ayocote is mainly consumed after cooking, which can impact the antioxidant characteristics of the phenolic compounds responsible for some of its health benefits. Therefore, this study investigated the effects of boiling on the phenolic composition and bioactivities of ayocote beans before and after boiling. Boiling decreased the total phenolic content (70.2, 60.3, and 58.2%), total anthocyanin (74.3, 80.6, and 85.7%), and antioxidant activity (DPPH: 41.2, 46.9, and 59.1%; ORAC: 48.23, 53.6 and 65.7%) of brown, black, and purple ayocote beans, respectively. All the extracts also inhibited the activity of α-glucosidase with efficacy values from 29.7 to 87.6% and α-amylase from 25.31 to 56.2%, with moderate antiglycation potential (15.2 to 73.2%). Phenolic acids, anthocyanins, and flavonoid decreases were detected in boiled samples by HPLC-MS analysis. Although boiling reduced the phenolic compounds, bioactive compounds remained in a considerable content in boiled ayocote.

Comprehensive metabolomics and chemometrics unravel potential anti-diabetic metabolites of pumpkin (Cucurbita pepo L.) fruits through UPLC-QqQ-MS and GC-MS analyses.

This comprehensive study explores the phytoconstituents of different parts of pumpkin (Cucurbita pepo) including flesh, peel, seeds, pumpkin juice, and pumpkin seed oil. Utilizing advanced analytical techniques including UPLC-QqQ-MS and GC-TSQ-MS combined with multivariate statistical analysis, 94 distinct chromatographic peaks from various chemical classes were annotated. Predominant classes included phenolic acids, flavonoids, cucurbitacins, amino acids, triterpenoids, fatty acids, sterols, carotenoids, and other compounds. For more comprehensive chemical profiling of the tested samples, fractionation of the different parts of the fruit was attempted through successive solvent extraction. The unsaponifiable part of the oils, analyzed by GC, showed that the phytosterols, namely ß-sitosterol, and stigmasterol are in the majority. All pumpkin extracts showed significant inhibition of carbohydrase enzymes and glucose uptake promotion by cells. Pumpkin flesh butanol fraction exhibited potent α-glucosidase inhibition, while pumpkin defatted seed methylene chloride fraction showed strong α-amylase inhibition. Additionally, pumpkin seed oil and defatted seed petroleum ether fraction demonstrated high glucose uptake activity. Bioactive metabolites including vaccenic acid, sinapic acid, kuguacin G, luteolin hexoside, delta-7-avenasterol, cucurbitosides and others were unveiled through OPLS multivariate models elucidating the anti-diabetic potential of pumpkin. These findings support the use of pumpkin as a functional food, offering insights into its mechanisms of action in diabetes management.

Identification of procyanidins as α-glucosidase inhibitors, pancreatic lipase inhibitors, and antioxidants from the bark of Cinnamomum cassia by multi-bioactivity-labeled molecular networking.

This study examined the suppressive effects of 16 selected plant-based foods on α-glucosidase and pancreatic lipase and their antioxidant properties. Among these, the bark of Cinnamomum cassia (Cinnamon, WLN-FM 15) showed the highest inhibitory activity against α-glucosidase and the highest antioxidant activity. Additionally, WLN-FM 15 showed promising results in the other tests. To further identify the bioactive constituents of WLN-FM 15, a multi-bioactivity-labeled molecular networking approach was used through a combination of GNPS-based molecular networking, DPPH-HPLC, and affinity-based ultrafiltration-HPLC. A total of nine procyanidins were identified as antioxidants and inhibitors of α-glucosidase and pancreatic lipase in WLN-FM 15. Subsequently, procyanidins A1, A2, B1, and C1 were isolated, and their efficacy was confirmed through functional assays. In summary, WLN-FM 15 has the potential to serve as a functional food ingredient with the procyanidins as its bioactive constituents. These results also suggest that the multi-bioactivity-labeled molecular networking approach is reliable for identifying bioactive constituents in plant-based foods.

Design of new α-glucosidase inhibitors based on the bis-4-hydroxycoumarin skeleton: Synthesis, evaluation, and in silico studies.

In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure-activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.

Evaluation of the Antidiabetic Potential of Xanthone-Rich Extracts from Gentiana dinarica and Gentiana utriculosa.

Despite the existence of various therapeutic approaches, diabetes mellitus and its complications have been an increasing burden of mortality and disability globally. Hence, it is necessary to evaluate the efficacy and safety of medicinal plants to support existing drugs in treating diabetes. Xanthones, the main secondary metabolites found in Gentiana dinarica and Gentiana utriculosa, display various biological activities. In in vitro cultured and particularly in genetically transformed G. dinarica and G. utriculosa roots, there is a higher content of xanthones. The aim of this study was to investigate and compare antidiabetic properties of secondary metabolites (extracts) prepared from these two Gentiana species, cultured in vitro and genetically transformed with those collected from nature. We compare HPLC secondary metabolite profiles and the content of the main extract compounds of G. dinarica and G. utriculosa methanol extracts with their ability to scavenge DPPH free radicals and inhibit intestinal α-glucosidase in vitro. Anti-hyperglycemic activity of selected extracts was tested further in vivo on glucose-loaded Wistar rats. Our findings reveal that the most prominent radical scavenging potential and potential to control the rise in glucose level, detected in xanthone-rich extracts, were in direct correlation with an accumulation of xanthones norswertianin and norswertianin-1-O-primeveroside in G. dinarica and decussatin and decussatin-1-O-primeveroside in G. utriculosa.

Discovery of novel thiazole derivatives containing pyrazole scaffold as PPAR-γ Agonists, α-Glucosidase, α-Amylase and COX-2 inhibitors; Design, synthesis and in silico study.

A novel series of thiazole derivatives with pyrazole scaffold 16a-l as hybrid rosiglitazone/celecoxib analogs was designed, synthesized and tested for its PPAR-γ activation, α-glucosidase, α-amylase and COX-2 inhibitory activities. Regarding the anti-diabetic activity, all compounds were assessed in vitro against PPAR-γ activation, α-glucosidase and α-amylase inhibition in addition to in vivo hypoglycemic activity (one day and 15 days studies). Compounds 16b, 16c, 16e and 16 k showed good PPAR-γ activation (activation % ≈ 72-79 %) compared to that of the reference drug rosiglitazone (74 %). In addition, the same derivatives 16b, 16c, 16e and 16 k showed the highest inhibitory activities against α-glucosidase (IC50 = 0.158, 0.314, 0.305, 0.128 µM, respectively) and against α-amylase (IC50 = 32.46, 23.21, 7.74, 35.85 µM, respectively) compared to the reference drug acarbose (IC50 = 0.161 and 31.46 µM for α-glucosidase and α-amylase, respectively). The most active derivatives 16b, 16c, 16e and 16 k also revealed good in vivo hypoglycemic effect comparable to that of rosiglitazone. In addition, compounds 16b and 16c had the best COX-2 selectivity index (S.I. = 18.7, 31.7, respectively) compared to celecoxib (S.I. = 10.3). In vivo anti-inflammatory activity of the target derivatives 16b, 16c, 16e and 16 k supported the results of in vitro screening as the derivatives 16b and 16c (ED50 = 8.2 and 24 mg/kg, respectively) were more potent than celecoxib (ED50 = 30 mg/kg). In silico docking, ADME, toxicity, and molecular dynamic studies were carried out to explain the interactions of the most active anti-diabetic and anti-inflammatory compounds 16b, 16c, 16e and 16 k with the target enzymes in addition to their physiochemical parameters.