Potent Α-glucosidase Inhibitors Research Articles

Synthesis, biological evaluation, and molecular docking study of chromen-linked hydrazine carbothioamides as potent α-glucosidase inhibitors.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen-linked hydrazine carbothioamide (3a-r) were designed and synthesized by condensation of chromone-3-carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques (1 H NMR, 13 C NMR, and ESI-MS). The resulted compounds were screened for α-glucosidase inhibitory potential and all the compounds (3a-r) exhibited potent inhibition of α-glucosidase with IC50 values ranging 0.29-53.70 µM. Among them compounds 3c, 3f, 3h, and 3r displayed the highest α-glucosidase inhibitor capability with IC50 values of 1.50, 1.28, 1.08, and 0.29 µM, respectively. Structure-activity relationship showed that different substituted groups are responsible for the variation in the α-glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 ± 0.31 µM. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H-bonding, or π-π stacking, with the key residues of α-glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of α-glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a-r reflects that these molecules have acceptable range of these properties.

Mechanisms of sesamol and sesamin inhibiting α-glucosidase activity by spectroscopy and molecular docking

Sesamol and sesamin inhibit α-glucosidase activity and may therefore be effective in treating type 2 diabetes, but their mechanisms remain unknown. Therefore, the inhibitory effects of sesamol and sesamin on α-glucosidase activity were analyzed by multispectral technique and molecular docking. Our findings indicated that the sesamol and sesamin had a significant influence on α-glucosidase activity, with IC50 values of 0.96 mM and 0.33 mM, respectively, and their inhibition types were non-competitive. Both sesamol and sesamin quenched the fluorescence by a static quenching mechanism. The results of three-dimensional (3D) fluorescence, circular dichroism (CD) spectroscopy and Fourier transform infrared spectrometer (FT-IR) showed that both sesamol and sesamin had certain effects on the conformation of α-glucosidase. Molecular docking results revealed that both sesamol and sesamin could spontaneously bind to α-glucosidase and form hydrogen bonds with some of the amino acid residues of the enzyme. As a result, this study sheds new light on sesamol/sesamin as a potential α-glucosidase inhibitor.

Thiadiazole based triazole/hydrazone derivatives: Synthesis, in vitro α-glucosidase inhibitory activity and in silico molecular docking study

Thiadiazole-based hydrazide was treated with different substituted phenyl isothiocyanates and benzaldehyde to synthesize thiadiazole-based triazole/hydrazone derivatives (4a–h & 5a–n). The synthesized compounds were fully characterized via different spectroscopic techniques i.e., 1H NMR, 13C NMR and HR-ESI-MS and evaluated for in vitro α-glucosidase activity. All analogues showed moderate to good α-glucosidase inhibitory potentials having IC50 values ranged from 0.40 ± 0.10 to 13.40 ± 0.30 μM (thiadiazole-based triazole) and 0.10 ± 0.05 to 15.40 ± 0.30 μM (thiadiazole-based hydrazone) as compared to the standard drug acarbose (IC50 = 12.30 ± 1.10 μM). Derivatives 4f (IC50 = 0.40 ± 0.10 µM) and 5j (IC50 = 0.30 ± 0.05 µM) was found the most potent among the series which is many fold better than the standard drug on the basis of IC50 values. Structure activity relationship was carried out which mainly depend upon the nature, number, position, electron donating/withdrawing effect of the substituent/s on phenyl rings. In addition, molecular docking study was carried out for most active analogues in order to explore the binding interactions of synthesized scaffolds with active site of enzyme and results obtained supported the experimental data. All Compounds were verified for cytotoxicity against 3T3 mouse fibroblast cell line and detected nontoxic.

Sericin mediated gold/silver bimetallic nanoparticles and exploration of its multi-therapeutic efficiency and photocatalytic degradation potential

The current investigation aimed at bimetallic gold-silver nanoparticles (Au/Ag NPs), here called BM-GS NPs, synthesis using sericin protein as the reducing agent in an easy, cost-effective, and sustainable way. The obtained BM-GS NPs were characterized by UV–Visible spectroscopy, Transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDS), atomic force microscopy (AFM), Dynamic light scattering (DLS) and Zeta potential, X-ray Powder Diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), and Thermogravimetric analysis followed by evaluation of its multitherapeutic and photocatalytic degradation potentials. The TEM analysis revealed its spherical nature and the EDS result displayed the presence of both Ag and Au elements, confirming the synthesis of BM-GS NPs. The XRD pattern verified the crystalline nature of the nanoparticles (NPs). The DLS analysis showed an average size of 86.08 d nm and the zeta potential showed a highly negative value (−26.3 mV) which specifies that the generated bimetallic NPs are stable. The BM-GS NPs exhibited positive wound healing potential (with 63.38% of wound closure rate at 25 μg/ml, as compared to 54.42% by the untreated control) with very negligible toxicity effect on the cell viability of the normal keratinocyte cells. It also demonstrated promising antioxidant properties with 65.00%, 69.23%, and 63.03% activity at 100 μg/ml concentration for ABTS (2, 2-azinobis) (3-ethylbenzothiazoline-6-sulfonic acid)), DPPH (1, 1 diphenyl-2-picrylhydrazyl) and SOD (superoxide dismutase enzyme) assays respectively, antidiabetic potential (with a significantly high α-glucosidase inhibition potential of 99.69% at 10μg/ml concentration and 62.11% of α-amylase enzyme inhibition at 100 μg/ml concentration) and moderate tyrosinase inhibitory potential (with 17.09% at 100 μg/ml concentration). Besides, it displayed reasonable antibacterial potential with the diameter of zone of inhibition ranging between 10.89 and 12.39 mm. Further, its antibacterial mode of action reveals that its effects could be due to being very smaller, the NPs could have penetrated inside the cellular membrane thereby causing rupture and damage to the interior materials leading to cellular lysis. The photocatalytic evaluation showed that synthesized BM-GS NPs have the efficiency of degrading methylene blue dye by 34.70% within 3 h of treatment. The above findings revealed the multi-therapeutic efficacy of the sericin globular protein-mediated BM-GS NPs and its potential future applications in the cosmetics and food sector and environmental contamination management industries.

In Vitro and In Vivo Antidiabetic, α-Glucosidase Inhibition and Antibacterial Activities of Three Brown Algae, Polycladia myrica, Padina antillarum, and Sargassum boveanum, and a Red Alga, Palisada perforata from the Persian Gulf.

In recent decades, algae have attracted worldwide attention for their great biological activities, such as antidiabetic and antibacterial properties. We measured antibacterial and α-glucosidase inhibition potential of methanol and 80% methanol extracts of three brown algae species, Polycladia myrica, Padina antillarum, and Sargassum boveanum, and a red alga, Palisada perforata, from the Persian Gulf coasts. Antibacterial activity of the algal extracts was assessed by broth dilution method against three gram-negative and -positive bacteria, including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa; Staphylococcus epidermidis, Staphylococcus aureus, and Bacillus subtilis, respectively. Furthermore, the yeast's α-glucosidase inhibition of the algal extracts was measured via colorimetric assay. In addition, we investigated the beneficial effect of 80% MeOH extract of S. boveanum on the blood glucose levels in streptozotocin-induced diabetic rats. The MeOH extract of S. boveanum was the best antibacterial extract with MIC = 2.5 mg/mL against all bacterial strains except for E. coli. The MeOH and 80% MeOH extracts of P. myrica and P. antillarum inhibited α-glucosidase at most with IC50 values of 12.70 ± 1.88 µg/mL and 13.06 ± 4.44 µg/mL, respectively. The oral gavage of S. boveanum extract in streptozotocin- (STZ-) induced diabetic rats resulted in decreasing their postprandial blood glucose levels. The algae and acarbose decreased blood glucose levels after sucrose administration in 60 minutes, compared to the non-drug-treated animals, with p values of 0.03 and 0.007, respectively. Overall, due to the in vitro and in vivo antidiabetic potential of S. boveanum, we suggest the alga as a new source for the isolation and identification of potential antidiabetic and antibacterial compounds.

Optimization of Ultrasonic-Assisted Extraction of α-Glucosidase Inhibitors from Dryopteris crassirhizoma Using Artificial Neural Network and Response Surface Methodology.

Dryopteris crassirhizoma Nakai is a plant with significant medicinal properties, such as anticancer, antioxidant, and anti-inflammatory activities, making it an attractive research target. Our study describes the isolation of major metabolites from D. crassirhizoma, and their inhibitory activities on α-glucosidase were evaluated for the first time. The results revealed that nortrisflavaspidic acid ABB (2) is the most potent α-glucosidase inhibitor, with an IC50 of 34.0 ± 0.14 μM. In addition, artificial neural network (ANN) and response surface methodology (RSM) were used in this study to optimize the extraction conditions and evaluate the independent and interactive effects of ultrasonic-assisted extraction parameters. The optimal extraction conditions are extraction time of 103.03 min, sonication power of 342.69 W, and solvent-to-material ratio of 94.00 mL/g. The agreement between the predicted models of ANN and RSM and the experimental values was notably high, with a percentage of 97.51% and 97.15%, respectively, indicating that both models have the potential to be utilized for optimizing the industrial extraction process of active metabolites from D. crassirhizoma. Our results could provide relevant information for producing high-quality extracts from D. crassirhizoma for functional foods, nutraceuticals, and pharmaceutical industries.

Screening, characterization of trace α-glucosidase inhibitors from the root of Pueraria lobata and evaluation of their hypoglycemic activity

Pueraria lobata (Willd.) Ohwi (Gegen) is a nutritious medicine food homology plant that has been recorded in many ancient remedies for diabetes. However, its hypoglycemic active components and related mechanisms have not been fully elucidated. In this study, potential α-glucosidase inhibitors in Pueraria lobata were investigated by liquid-liquid refined extraction, high-resolution profiling and their hypoglycemic activity were evaluated. Ten compounds showing α-glucosidase inhibitory bioactivity were separated and identified, including two new compounds, 8-geranyl-7, 3′, 4′-trihydroxy-isoflavone (4) and 8-geranyl-7, 2′, 4′-trihydroxy-isoflavone (6), and eight known compounds. All screened compounds showed potential hypoglycemic activity, in which compounds 4, 6, 7, 8, 9 and 10 showed strong inhibitory activity (IC50 < 8 μM). Furthermore, molecular docking simulation revealed binding energy and interacting amino acid residues of the screened compounds with α-glucosidase, strongly supporting their potential as α-glucosidase inhibitors.

Design and synthesis of 2-amino-4,6-diarylpyrimidine derivatives as potent α-glucosidase and α-amylase inhibitors: structure–activity relationship, in vitro, QSAR, molecular docking, MD simulations and drug-likeness studies

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their in vitro α-glucosidase and α-amylase enzyme inhibition assays. The outcomes proved that this class of compounds exhibit considerable inhibitory activity against both enzymes. Among the target compounds, compounds 4p and 6p demonstrated the most potent dual inhibition with IC50 = 0.087 ± 0.01 μM for α-glucosidase; 0.189 ± 0.02 μM for α-amylase and IC50 = 0.095 ± 0.03 μM for α-glucosidase; 0.214 ± 0.03 μM for α-amylase, respectively as compared to the standard rutin (IC50 = 0.192 ± 0.02 μM for α-glucosidase and 0.224 ± 0.02 μM for α-amylase). Remarkably, the enzyme inhibition results indicate that test compounds have stronger inhibitory effect on the target enzymes than the positive control, with a significantly lower IC50 value. Moreover, these series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 0.087 ± 0.01 μM to 1.952 ± 0.26 μM. Furthermore, molecular docking studies were performed to affirm the binding interactions of this scaffold to the active sites of α-glucosidase and α-amylase enzymes. The quantitative structure–activity relationship (QSAR) investigations showed a strong association between 1p–15p structures and their inhibitory actions (IC50) with a correlation value (R 2) of 0.999916. Finally, molecular dynamic (MD) simulations were carried out to assess the dynamic behavior, stability of the protein–ligand complex, and binding affinity of the most active inhibitor 4p. The experimental and theoretical results therefore exposed a very good compatibility. Additionally, the drug-likeness assay revealed that some compounds exhibit a linear association with Lipinski’s rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets. Communicated by Ramaswamy H. Sarma

Inhibition mechanism of α-glucosidase inhibitors screened from Tartary buckwheat and synergistic effect with acarbose

Tartary buckwheat has been shown to provide a good antihyperglycemic effect. However, it is unclear which active compounds play a key role in attenuating postprandial hyperglycemia. Presently, acetone extract from the hull of Tartary buckwheat had the best effect for α-glucosidase inhibition (IC50 = 0.02 mg/mL). Twelve potential α-glucosidase inhibitors from Tartary buckwheat were screened and identified by the combination of ultrafiltration and high-performance liquid chromatography coupled with mass spectrometry. Myricetin and quercetin exhibited the highest anti-α-glucosidase activity with IC50 values of 0.02 and 0.06 mg/mL, respectively. These inhibitors manifested different types of inhibition manners against α-glucosidase via direct interaction with the amino acid residues. The results of structure–activity relationships indicated that an increase in the number of –OH on the B-ring greatly strengthened α-glucosidase inhibitory activity, but glucoside and rutinoside replacement on the C-ring obviously weakened this influence. Furthermore, a synergistic effect was observed between inhibitors with different inhibition manners.

Antioxidant and Antidiabetic Activities, and UHPLC-ESI-QTOF-MS-Based Metabolite Profiling of an Endophytic Fungus Nigrospora sphaerica BRN 01 Isolated from Bauhinia purpurea L.

Diabetes-associated postprandial hyperglycemia is a major risk factor in cardiovascular disease. Since enzyme α-glucosidase is primarily responsible for glucose release during digestion, inhibiting it mitigates post-meal spike in blood glucose level. Metabolites from endophytic fungi could be potential natural inhibitors of this enzyme. Endophytic fungi isolated from Bauhinia purpurea L. were screened for their potential antioxidant and antidiabetic activities. Ethyl acetate extract of Nigrospora sphaerica BRN 01 (NEE) displayed high antioxidant activity with an IC50 value of 9.72 ± 0.91µg/ml for DPPH assay and ferric reducing antioxidant power (FRAP) of 1595 ± 0.23µmol AAE g-1 DW. NEE also showed high degree of inhibition of α-glucosidase activity with an IC50 value of 0.020 ± 0.001mg/ml, significantly greater than the standard drug acarbose (0.494 ± 0.009mg/ml). Metabolite profiling of NEE was carried using ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) and 21 metabolites identified based on the MS/MS fragmentation patterns. Docking analysis of all 21 identified metabolites was carried out. Of these, 6 showed binding energies higher than acarbose (- 6.6kcal/mol). Based on the analysis of interactions of feruloyl glucose with active site residues of the enzyme, it could be a potential α-glucosidase inhibitor. Metabolites of Nigrospora sphaerica BRN 01, therefore, could be potential lead molecules for design and development of antidiabetic drugs.

Bioassay-guided isolation of α-glucosidase inhibitors from Byrsonima garcibarrigae Cuatrec.

Introduction:Byrsonima garcibarrigae is an endemic tree of Amazonas state, Brazil, with pharmacological and chemical knowledge poorly understood. Aim: To investigate the antidiabetic potential of the B. garcibarrigae stem bark. Methods: The stem bark was sequentially extracted by maceration with hexane (EHBG), ethyl acetate (EABG), and methanol (EMBG). The antioxidant capacity, α-glucosidase inhibitory potentials and anti-glycation capacities were evaluated. A bio-guided fractionation gave compounds that were characterized by MS and NMR. Results: 8 compounds were identified by HPLC-MS. EMBG showed the highest α-glucosidase inhibitory activity (1.09±0.32 μg/mL), antioxidant activity (9.2±0.23 μg/mL) and phenolic compounds content (61.43±0.50%), thus was fractionated producing hexane (FHX), chloroform (FCL) and hydromethanolic (FHM) fractions. After additional anti-α-glucosidase assays, FHM (1.02±0.49 μg/mL) was fractionated giving quercitrin and epicatechin. The anti-glycation assay showed that EMBG, FHM and quercitrin presented higher activities in comparison to the positive control, aminoguanidine. Conclusions:B. garcibarrigae displayed antidiabetic potential since inhibited α-glucosidase, as well as presented expressive antioxidant and anti-glycation activities were recorded.

Cellulose filter paper immobilized α-glucosidase as a target enzyme-oriented fishing tool for screening inhibitors from Cyclocarya paliurus leaves

Cyclocarya paliurus leaves have exhibited a good hypoglycemic activity, however, the active compounds and inhibitory mechanisms against α-glucosidase remained unclear. In this study, a target enzyme-oriented fishing strategy based on cellulose filter paper (CFP) immobilized α-glucosidase combined with ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) and molecular docking was developed to screen and identify potential α-glucosidase inhibitors from C. paliurus leaves. Cellulose filter paper (CFP) as the carrier was modified by polydopamine/polyethyleneimine (PDA/PEI) co-deposition to form a uniform positive charge coating on the surface, and then α-glucosidase was immobilized on the modified CFP by electrostatic adsorption. By virtue of its instantaneous separation characteristic, the CPF-immobilized α-glucosidase was used as a target enzyme-oriented fishing tool to rapidly capture active compounds bound to α-glucosidase from the complex plant system. 36 active compounds were fished out from 70% ethanol fraction of C. paliurus leaves (IC50, 17.81 µg/mL), and further characterized by UPLC-QTOF-MS/MS. Furthermore, molecular docking was employed to predict inhibitory mechanisms, and the result showed that cyclocarioside A, cypaliuruside K, cypaliuruside J, cyclocarioside C, cyclocarioside I and pterocaryoside A could effectively interact with α-glucosidase by forming hydrogen bonds, hydrophobic bindings and Van der Waals force, and affinity energies ranged from −9.4 to −8.0 kJ/mol. Such a target enzyme-oriented fishing strategy would open a pathway for discovering targeted active compounds from medicinal plants.

Synthesis and structure–activity relationship studies of benzimidazole-thioquinoline derivatives as α-glucosidase inhibitors

In this article, different s-substituted benzimidazole-thioquinoline derivatives were designed, synthesized, and evaluated for their possible α-glucosidase inhibitory activities. The most active compound in this series, 6j (X = 4-bromobenzyl) exhibited significant potency with an IC50 value of 28.0 ± 0.6 µM compared to acarbose as the positive control with an IC50 value of 750.0 µM. The kinetic study showed a competitive inhibition pattern against α-glucosidase for the 6j derivative. Also, the molecular dynamic simulations were performed to determine key interactions between compounds and the targeted enzyme. The in silico pharmacodynamics and ADMET properties were executed to illustrate the druggability of the novel derivatives. In general, it can be concluded that these derivatives can serve as promising leads to the design of potential α-glucosidase inhibitors.

Studies on 1-deoxynojirimycin biosynthesis in mulberry (Morus alba L.) seeds through comparative transcriptomics

Mulberry (Morus alba L.) plants are rich in 1-deoxynojirimycin (DNJ), which is a potential α-glucosidase inhibitor exhibiting various physiological activities. Compared to other tissues, Morus alba L. seeds contain the highest DNJ content, however, the DNJ biosynthesis mechanisms are unclear. In this study, we examined fruits of 27 mulberry varieties and found that variety MS02 had the highest DNJ levels (22.28 mg/g), whereas variety MS15 contained the lowest DNJ levels (0.37 mg/g). Through comparative transcriptomics, 1,719 differentially expressed genes (DEGs) were identified, 1,170 of which were upregulated, and 549 were downregulated in MS02 compared to MS15. DEGs were associated with cellular processes, metabolic processes, and catalytic activity. Specifically, nine DEGs were identified to be involved in alkaloid biosynthesis pathways, according to Kyoto Encyclopaedia of Genes and Genomes enrichment analysis, and four enzymes, i.e. polyphenol oxidase, tyrosine aminotransferase, aromatic-L-amino-acid decarboxylase, and tropinone reductase, are proposed to play important roles in DNJ biosynthesis. In conclusion, DNJ biosynthesis in mulberry seeds appears to be mediated by upregulation of polyphenol oxidase, tyrosine aminotransferase, aromatic-L-amino-acid decarboxylase, and tropinone reductase.

Survey of Edible Amanita in Northern Thailand and Their Nutritional Value, Total Phenolic Content, Antioxidant and α-Glucosidase Inhibitory Activities.

Edible wild mushrooms are extremely popular among consumers and are highly valued for their potential economic benefits in northern Thailand. In this present study, a total of 19 specimens of edible Amanita were collected during investigations of wild edible mushrooms in northern Thailand during the period from 2019 to 2022. Their morphological characteristics and the phylogenetic analyses of the internal transcribed spacer (ITS) and partial large subunit (nrLSU) of ribosomal RNA, RNA polymerase II second-largest subunit (rpb2) and partial translation elongation factor 1-alpha (tef-1) indicated that the collected specimens belonged to A. hemibapha, A. pseudoprinceps, A. rubromarginata, A. subhemibapha, and Amanita section Caesareae. This is the first report of A. pseudoprinceps and A. subhemibapha from Thailand. Full descriptions, illustrations and a phylogenetic placement of all specimens collected in this study are provided. Subsequently, the nutritional composition and total phenolic content, as well as the antioxidant and α-glucosidase inhibitory activities, of each species were investigated. The results indicate that the protein contents in both A. pseudoprinceps and A. subhemibapha were significantly higher than in A. hemibapha and A. rubromarginata. The highest total phenolic content was found in the extract of A. pseudoprinceps. In terms of antioxidant properties, the extract of A. pseudoprinceps also exhibited significantly high antioxidant activity by 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. However, the extract of A. rubromarginata had the lowest total phenolic content and level of antioxidant activity. Additionally, α-glucosidase inhibitory activity varied for different Amanita species and the highest level of α-glucosidase inhibitory activity was found in the extract of A. pseudoprinceps. This study provides valuable information on the nutrient content, phenolic content and the antioxidant and α-glucosidase inhibitory potential of edible Amanita species found in northern Thailand.

Synthesis of Diarylpentadienones and Pyrazoline Derivatives as Potential α-Glucosidase Inhibitor and Their Antioxidant Activities

Synthesis of Diarylpentadienones and Pyrazoline Derivatives as Potential α-Glucosidase Inhibitor and Their Antioxidant Activities

Geranylation of Chalcones by a Fungal Aromatic Prenyltransferase

Geranylated chalcones mainly exist in plants, and many of them have attracted attention because of their diverse pharmacological and biological activities. Herein, we report geranylation of eight chalcones by the Aspergillus terreus aromatic prenyltransferase AtaPT. Ten new mono-geranylated enzyme products (1G-5G, 6G1, 6G2, 7G, 8G1, and 8G2) were obtained. Most of the products are C-geranylated products with prenyl moieties at ring B. In comparison, plant aromatic prenyltransferases usually catalyze the geranylation at ring A. Therefore, AtaPT can be used complementarily for chalcone geranylation to increase the structural diversity of small molecules. In addition, seven compounds (1G, 3G, 4G, 6G1, 7G, 8G1, and 8G2) exhibited a potential inhibitory effect on α-glucosidase with the IC50 values ranging from 45.59 ± 3.48 to 82.85 ± 2.15 μg/mL. Among them, compound 7G (45.59 ± 3.48 μg/mL) was the most potential α-glucosidase inhibitor, which is about seven times stronger than the positive control acarbose (IC50 = 346.63 ± 15.65 μg/mL).

New β-carboline derivatives as potential α-glucosidase inhibitor: Synthesis and biological activity evaluation

α-Glucosidase is an important therapeutic target of diabetes mellitus. To find potent α-glucosidase inhibitors, thirty-one β-carboline derivatives containing piperazine moieties (6a∼6u, 7a∼7j) were synthesized and evaluated their α-glucosidase inhibitory activity. Most β-carboline derivatives showed potential α-glucosidase inhibitory activity, especially, compound 7c presented obvious α-glucosidase inhibitory activity (IC50: 8.9 ± 0.2 μM), ∼ 69 folds stronger than acarbose (IC50: 610.7 ± 0.1 μM). Inhibition mechanism and kinetics explained compound 7c to be a reversible and mixed-type inhibitor. CD spectra, 3D fluorescence, and molecular docking were employed to reveal the mechanisms of 7c against α-glucosidase. Cell cytotoxicity assay ascertained low cytotoxicity of 7c.

Screening of Potential α-Glucosidase Inhibitors from the Roots and Rhizomes of Panax Ginseng by Affinity Ultrafiltration Screening Coupled with UPLC-ESI-Orbitrap-MS Method.

Panax ginseng was a traditional Chinese medicine with various pharmacological activities and one of its important activities was hypoglycemic activity; therefore, panax ginseng has been used in China as an adjuvant in the treatment of diabetes mellitus. In vivo and in vitro tests have revealed that ginsenosides, which are derived from the roots and rhizomes of panax ginseng have anti-diabetic effects and produce different hypoglycemic mechanisms by acting on some specific molecular targets, such as SGLT1, GLP-1, GLUTs, AMPK, and FOXO1. α-Glucosidase is another important hypoglycemic molecular target, and its inhibitors can inhibit the activity of α-Glucosidase so as to delay the absorption of dietary carbohydrates and finally reduce postprandial blood sugar. However, whether ginsenosides have the hypoglycemic mechanism of inhibiting α-Glucosidase activity, and which ginsenosides exactly attribute to the inhibitory effect as well as the inhibition degree are not clear, which needs to be addressed and systematically studied. To solve this problem, affinity ultrafiltration screening coupled with UPLC-ESI-Orbitrap-MS technology was used to systematically select α-Glucosidase inhibitors from panax ginseng. The ligands were selected through our established effective data process workflow based on systematically analyzing all compounds in the sample and control specimens. As a result, a total of 24 α-Glucosidase inhibitors were selected from panax ginseng, and it was the first time that ginsenosides were systematically studied for the inhibition of α-Glucosidase. Meanwhile, our study revealed that inhibiting α-Glucosidase activity probably was another important mechanism for ginsenosides treating diabetes mellitus. In addition, our established data process workflow can be used to select the active ligands from other natural products using affinity ultrafiltration screening.

Development of coumarin tagged 1,2,3-triazole derivatives targeting α-glucosidase inhibition: Synthetic modification, biological evaluation, kinetic and in silico studies

Coumarin derivatives have been demonstrated as promising anti-diabetic compounds through α-glucosidase inhibition. This is a ubiquitous brush border membrane-bound enzyme and an effective curative target for the treatment of diabetes. A novel series of compounds namely N-aryl-2-(4-(((2-oxo-2H-chromen-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)acetamide 8a-p were synthesized conveniently. Furthermore, the α-glucosidase inhibition potential of synthesized compounds was investigated, and based on the obtained data, all derivatives showed excellent inhibitory effect against α-glucosidase compared to standard antidiabetic drug acarbose. Among them, compounds 8d and 8j were represented to be the most potent ones with IC50s = 6.4 ± 0.1 and 3.5 ± 0.1, respectively. Kinetic enzymatic assays investigated that compound 8j was a competitive inhibitor of the enzyme, and further studies represented a Ki value of 2.2 µM for compound 8j. Moreover, the binding energy for compound 8j was obtained -8.30 kcal/mol in the molecular docking study. The structural dynamics incurred by the most potent compound have been investigated through the RMSD and RMSF studies. Underlining their physicochemical parameters, they have promising drug-like properties.