Search Results (464)

1-Deoxynojirimycin (DNJ), a well-characterized α-glucosidase inhibitor, remains an important target for dose-reduction and formulation strategies. In the present study, we evaluated the individual and combined α-glucosidase inhibitory activities of nine dietary flavonoids with DNJ, quantified synergistic effects using the combination index (CI) method, and elucidated the molecular mechanism through integrated enzyme kinetics, multi-spectroscopic techniques and molecular docking. (+)-Catechin exhibited the strongest inhibitory activity (IC₅₀ = 33.7 ± 2.7 μM), and its combination with DNJ produced synergistic inhibition across all doses (CI < 0.7). Kinetic analysis confirmed that DNJ acted as a competitive inhibitor, while (+)-catechin functioned as a non-competitive inhibitor. Fluorescence quenching assays revealed that (+)-catechin pre-incubation increased the binding affinity of DNJ to α-glucosidase by 393%. Circular dichroism spectroscopy showed that (+)-catechin induced a marked β-sheet-to-α-helix conformational conversion, and co-incubation of both inhibitors produced more secondary structural changes than either inhibitor alone. Molecular docking further confirmed their distinct binding sites. These findings demonstrate that (+)-catechin synergistically potentiates DNJ activity through allosteric conformational modulation, providing an experimental basis for optimizing DNJ-containing formulations. Full article

Background: Polygodial (9), a drimane sesquiterpene dialdehyde from Drimys winteri, has not previously been examined against carbohydrate-hydrolyzing enzymes. Methods: Regioselective Wittig olefination at C12 gave the enoate 10; reduction of the remaining C11 aldehyde with NaBH₄ was followed by spontaneous intramolecular conjugate addition, affording the annellated tetrahydrofuran 12a and the bridged ether 12b. Results: All three derivatives inhibited α-glucosidase and α-amylase more strongly than the parent compound. Compound 12a was the most active α-glucosidase inhibitor (IC₅₀ = 53.98 ± 3.0 µM, against 90.36 ± 4.0 µM for acarbose) and, in docking, the only derivative to occupy the acarbose-binding site of the enzyme (−8.1 kcal/mol). However, this 12a–α-glucosidase pose was not maintained during the 200 ns simulations. The enoate 10 was the most active α-amylase inhibitor (IC₅₀ = 42.32 ± 2.1 µM, against 78.24 ± 3.9 µM for acarbose; −8.5 kcal/mol). Over 200 ns of molecular dynamics, the 10–α-amylase complex remained associated, with binding attributed by MM-GBSA mainly to van der Waals and lipophilic terms. Conclusions: Converting the dialdehyde into an enoate or a cyclic ether increases carbohydrase inhibition and determines which of the two enzymes is preferentially inhibited. Full article

Background: Combining natural products with conventional antidiabetic agents to inhibit α-glucosidase activity is an effective strategy for preventing postprandial hyperglycemia. Baicalein, a natural flavonoid with well-documented low toxicity, showed potential synergistic effect with acarbose in diabetic models; however, the synergistic performance and mechanisms of the two agents targeting human maltase–glucoamylase (MGAM) remain unclear. Methods: Recombinant human MGAM-C and MGAM-N were expressed in Pichia pastoris for in vitro inhibition assays. Maltose-loaded mice were used to assess the in vivo hypoglycemic activity and intestinal maltase inhibition. Inhibitor–enzyme interactions were investigated by fluorescence spectroscopy, circular dichroism (CD), multiple molecular docking, and molecular dynamics (MD) simulations. Results: Baicalein potently inhibited MGAM-C and MGAM-N with IC₅₀ values of 20.41 ± 4.80 μM and 14.04 ± 0.94 μM, respectively, and demonstrated a synergistic effect when combined with acarbose. In vivo, co-administration significantly reduced blood glucose levels and suppressed small intestinal maltase activity in maltose-loaded mice. Mechanistic studies revealed that baicalein functions as a non-competitive inhibitor by binding to the allosteric site of MGAM-C via stable hydrogen bonds with residues Ile1716 and Trp1749. This interaction induces conformational changes in the enzyme’s secondary structure and optimizes the hydrophobic microenvironment of the active site, thereby enhancing the binding affinity and hydrogen bond stability of acarbose. These molecular events collectively contribute to the synergistic inhibition of MGAM-C hydrolytic activity. Conclusions: This research revealed the synergistic inhibitory effect of baicalein and acarbose on MGAM and the underlying mechanisms, thereby providing a theoretical basis for developing pharmaceutical formulations to enhance acarbose efficacy. Full article

The skipjack tuna (Katsuwonus pelamis) is one of the least commercially exploited tuna globally. The possible medicinal benefits of K. pelamis extract have not been explored. We investigated the 70% ethanol (EtOH) soluble fractions of skipjack tuna heart for the inhibition of protein-tyrosine phosphatase 1B (PTP1B) and α-glucosidase. The dichloromethane (CH₂Cl₂) fraction significantly inhibited the activities of PTP1B and α-glucosidase. Repeated column chromatography of the active CH₂Cl₂ fraction based on bioactivity-guided fractionation yielded cholesterol, cholesteryl myristate, and sn-1,3-dipalmitoyl-2-oleoylglycerol; the latter significantly inhibited PTP1B and α-glucosidase. Kinetic study revealed that sn-1,3-dipalmitoyl-2-oleoylglycerol showed mixed-type inhibition against PTP1B. Docking simulations showed that sn-1,3-dipalmitoyl-2-oleoylglycerol selectively inhibited PTP1B and α-glucosidase by targeting its active site and exhibited good binding affinity, with a docking score of −7.4 and −7.1 kcal/mol, respectively. Moreover, 70% EtOH, CH₂Cl₂ and EtOAc fractions, and sn-1,3-dipalmitoyl-2-oleoyl glycerol significantly inhibited ONOO−mediated albumin nitration. These results implicate tuna heart extract as a potential functional food ingredient for the prevention and treatment of diabetes and its associated complications. Full article

Persicaria odorata (Lour.) contains considerable amounts of phytochemicals, including phenolics and essential oils, which have been reported to inhibit α-glucosidase activity. However, which bioactive compounds play a key role in inhibiting the α-glucosidase activity is unclear. To address this issue, the methanolic extract of P. odorata was assayed via in vitro studies, and forty-four compounds in P. odorata extracts were elucidated using in silico studies. The extract strongly inhibited yeast α-glucosidase with an IC₅₀ value of 0.31 µg/mL, which was 450-fold more potent than acarbose (IC₅₀ = 139.47 µg/mL), under experimental conditions. The Lineweaver–Burk plots indicated that the inhibition type of the extract on α-glucosidase is a noncompetitive inhibitor. Molecular docking demonstrated that procyanidin B (P9) and rutin (P19), which belong to the flavonoids, were predicted by computational approaches to be bioactive compounds that have more favorable binding interactions to yeast α-glucosidase residues compared to forty-four other compounds and acarbose. Molecular dynamics simulations revealed that P9 and P19 complexes with yeast α-glucosidase remained stable during the 500 ns simulations. Moreover, both P9 and P19 were predicted to qualify as α-glucosidase inhibitors with low toxicity. These findings suggest that P. odorata could be used as an alternative edible plant to manage postprandial hyperglycemia in T2DM, and could serve as basic scientific data. Further experimental studies of the pure bioactive compounds are necessary to support these findings. Full article

α-Glucosidase inhibitors (AGIs) significantly regulate blood glucose by delaying carbohydrate digestion and slowing glucose absorption, thus playing a critical role in glycemic control. Structurally, dihydromyricetin (Unless otherwise stated, the term dihydromyricetin used throughout this manuscript refers to trans-(2R,3R)-(+)-dihydromyricetin.) differs from myricetin in that the C2=C3 double bond in the C-ring is saturated, resulting in a dihydroflavonol instead of a flavonol. This study investigated the inhibition mechanism of α-glucosidase by the C2=C3 double bond structure using a set of integrated and multi-perspective approaches combining enzyme kinetics, multi-spectroscopic methods, molecular docking, isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR). Myricetin (IC₅₀ = 13.648 ± 0.157 μM) was found to be a more potent α-glucosidase inhibitor than dihydromyricetin (IC₅₀ = 453.922 ± 1.643 μM). Enzyme kinetics indicated that myricetin acted as a competitive inhibitor, whereas dihydromyricetin functioned as a non-competitive inhibitor. To further examine these interactions, multi-spectroscopic analysis demonstrated that binding of myricetin caused significant changes in the microenvironment around fluorescent amino acids (such as tyrosine and tryptophan) in α-glucosidase, resulting in slight unfolding of the enzyme structure. Additionally, molecular docking provided a detailed molecular perspective, identifying hydrogen bonding and hydrophobic interactions as the primary forces driving the binding of two flavonoids to α-glucosidase. Delving deeper into the binding mechanism, ITC analysis provided thermodynamic evidence that myricetin (K_D = 6.215 ± 0.022 μM) exhibited a stronger binding affinity to α-glucosidase than dihydromyricetin (K_D = 232.648 ± 1.236 μM), with both interactions being enthalpy-driven and primarily mediated by hydrogen bonds. Building on this, SPR analysis offered additional insights into the binding process, showing that myricetin not only had a higher binding affinity (K_D = 3.416 ± 0.015 μM) but also a faster association rate (k_a = 1668 ± 23 M⁻¹ s⁻¹) compared to dihydromyricetin (K_D = 11.539 ± 0.056 μM, k_a = 339.7 ± 17.1 M⁻¹ s⁻¹). In conclusion, this study demonstrated that the C2=C3 double bond plays a key role in enhancing α-glucosidase/inhibitor interactions, providing a theoretical basis for the design of novel AGIs and proposing a new set of multi-perspective methods for elucidating these inhibition mechanisms. Full article

Background/Objectives: Morinda lucida Benth is widely distributed throughout Central and West Africa. It has traditionally been used to treat and manage various diseases. However, scientific research on its phytochemical and pharmacological properties remains scarce. This study investigated the phytochemical profiles, antioxidant activities, α-glucosidase inhibitors, and cytotoxic effects of compounds derived from various parts of M. lucida. Methods: Seventy-seven natural compounds were putatively annotated using ¹H-NMR, UHPLC–Q Exactive Orbitrap MS, and molecular networking techniques. The antioxidant activities of the crude extracts were assessed in vitro using DPPH free radical scavenging and reducing power assays, whereas the in vitro α-glucosidase inhibition activity and toxicity of the crude extracts were evaluated using the α-glucosidase inhibition and MTT assays. Molecular docking was used to assess the interactions between the identified glycosides and the α-glucosidase protein. Results: The root extract exhibited the highest DPPH free radical scavenging (IC₅₀ = 7.7550 ± 6.9142 μg/mL) and reducing power capacity (IC_0.5 = 0.0052 ± 0.0025 μg/mL). In contrast, the stem bark extract demonstrated significant inhibition of alpha-glucosidase (IC₅₀ = 79.9 ± 16.1 µg/mL). Sophoricoside, formononetin 7-O-glucoside, and epicatechin identified in the stem bark extract showed notable in silico interactions with the α-glucosidase protein. The stem bark and leaf extracts were more toxic than the root extract at different concentrations. Conclusions: The results of this study demonstrate the therapeutic potential of M. lucida and provide information on its phytochemical composition and pharmacological properties. Full article

Backgroud: The growing prevalence of diabetes mellitus necessitates the development of safe and effective inhibitors of carbohydrate-metabolizing enzymes, particularly α-amylase and α-glucosidase. Methods: In this study, a series of pyrimidine–oxadiazole derivatives (1–10) was synthesized and structurally characterized using elemental analysis, HREI-MS, and ¹H/¹³C NMR spectroscopy. The compounds were evaluated for in vitro inhibitory activity against both enzymes, with acarbose as the reference drug. Results: IC₅₀ values ranged from 6.70 ± 0.20 to 21.10 ± 0.10 μM for α-amylase and 7.10 ± 0.20 to 21.80 ± 0.40 μM for α-glucosidase. Compounds 2, 3, and 6 displayed superior dual inhibitory activity compared to acarbose (IC₅₀ = 10.10 ± 0.20 and 10.50 ± 0.10 μM, respectively). Structure–activity relationship analysis revealed that electronic effects of aromatic substitutions significantly influenced enzyme inhibition. Molecular docking supported the experimental findings by demonstrating stable binding interactions within the enzyme active sites. Preliminary safety profiling in male Wistar rats showed no observable behavioral changes, hematological abnormalities, or hepatic and renal dysfunction following repeated administration of the lead compound. Conclusions: These results highlight pyrimidine–oxadiazole derivatives as promising and well-tolerated dual enzyme inhibitors for further antidiabetic drug development. Full article

This study highlights the therapeutic innovation potential of bioactive plant extracts derived from the selected Thai Rejuvenation Remedy 2 (TRJ 2) for antidiabetic applications. By integrating phytochemical profiling with in vitro α-glucosidase inhibition assays and in silico analyses, including molecular docking and density functional theory (DFT), a comprehensive evaluation of the extract’s bioactivity and mechanistic basis was achieved. The findings demonstrate that both the relative abundance and chemical reactivity of constituent compounds contribute to the overall inhibitory effect through synergistic and competitive interactions. Piperine was identified as a potential bioactive metabolite, with a theoretically strong binding affinity and high reactivity toward the target enzyme. Among the tested extracts, the 80% ethanol extract exhibited the highest inhibitory activity (IC₅₀ = 34.32 µg/mL), underscoring the importance of extraction optimization for maximizing therapeutic efficacy. Furthermore, formulation of the extract with cyclodextrin significantly enhanced solubility and improved pharmaceutical characteristics, meeting the quality requirements of the Thai Herbal Pharmacopoeia (THP). However, the detection of cadmium slightly above permissible levels indicates the need for stricter raw material quality control. Overall, TRJ 2 represents a promising source of bioactive plant-derived compounds and a viable candidate for development into innovative, ready-to-use herbal therapeutics for diabetes management. Full article

Diabetes mellitus remains a major metabolic disorder requiring the development of new and effective α-glucosidase inhibitors. The present study aimed to identify, design, and optimize novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-α]pyrimidine derivatives with promising inhibitory activity against the α-glucosidase enzyme using a comprehensive in silico strategy. Approximately 300 molecular descriptors were calculated to characterize a dataset of 32 compounds (Peytam et al.) and to investigate the structural factors governing their biological activity. Based on these descriptors, a multiple linear regression model was developed to predict the inhibitory activities of the compounds against alpha-glucosidase. The developed model demonstrated satisfactory predictive performance and was internally and externally validated to ensure its accuracy, robustness, and reproducibility. In addition, the applicability domain analysis confirmed the reliability of the predictions. Using the validated QSAR model, seven new derivatives were designed with predicted pIC₅₀ values exceeding the maximum activity of the parent compounds. The leverage analysis demonstrated that all newly designed compounds were located within the applicability domain of the model, supporting the reliability of the predictions. To further evaluate their inhibitory potential, molecular docking studies were performed to investigate the interactions between the designed compounds and the α-glucosidase active site. The docking results revealed favorable binding interactions comparable to those reported for known α-glucosidase inhibitors. Furthermore, ADMET analysis indicated generally favorable pharmacokinetic properties, although potential CYP3A4 inhibition-related pharmacokinetic risks were identified and discussed. Molecular dynamics simulations, including replicated runs and MM/GBSA binding free energy calculations, confirmed the stability of the most promising protein–ligand complexes throughout the simulation period. In conclusion, this study proposes a robust and integrated computational workflow combining descriptor generation, QSAR modeling, applicability domain analysis, molecular docking, ADMET prediction, and molecular dynamics simulations for the rational design of potential α-glucosidase inhibitors. The findings highlight the therapeutic potential of the designed derivatives and provide a valuable in silico framework for the future development of antidiabetic agents. Full article

The iminosugar N-butyldeoxynojirimycin (Miglustat) is clinically used for the inhibition of ceramide glucosyltransferase for treating Type 1 Gaucher and Niemann–Pick type C diseases. This drug also inhibits glycogen debranching enzyme (GDE), the enzyme responsible for terminal glycogen catabolism via coordinated glucotransferase and amylo-α-1,6-glucosidase (GC) activities, although the structural basis for inhibition has been undefined. Here, we report the crystal structure of Candida glabrata GDE in complex with Miglustat, revealing inhibitor engagement at the conserved GC domain in an area that was previously hypothesized to accommodate the α-1,6-linked glucose moiety of glycogen. Structure-guided mutagenesis demonstrates that alanine substitution of residues at the GC site abolishes Miglustat binding, functionally validating the pocket and defining the interaction hot spots. To assess the possible relevance of these observations to the human enzyme, in silico docking predicts that Miglustat binds to the human enzyme in a pose close, albeit not identical, to our structure. These findings provide an opportunity to determine the molecular basis of GDE–inhibitor recognition, rationalize reported off-target effects of Miglustat, and provide a template for designing iminosugar therapies with reduced off-target binding. Full article

In this study, a new range of carbazole linked mono- and bis-ester derivatives were successfully synthesized and evaluated for their in vitro anti-diabetic activity through α-amylase and α-glucosidase inhibition. The synthetic approach for the preparation of mono-esters 5a–j and bis-esters 7a–j was achieved by the reaction of carbazole-3-methanol 4 and carbazole-3,6-dimethanol 6 with a variety of acyl chlorides. The targeted compounds displayed generally weak α-amylase inhibition but significant and selective inhibition against α-glucosidase. Among them, 7a, 7g, and 7j exhibited dual inhibitory activity, while 7f was selective for α-glucosidase, and 7d and 5g for α-amylase. Notably, 7g was the most potent compound (IC₅₀ = 22.79 µM), surpassing Acarbose. In addition, molecular docking studies of the synthesized compounds were carried out to investigate their interactions with the α-glucosidase enzyme. Overall, targeted carbazole-based ester derivatives show promising results as selective anti-diabetic agents. Full article

Background/Objectives: Diabetes mellitus (DM) is a critical metabolic condition with escalated blood glucose levels caused by insulin resistance, restricted insulin production, and the activity of alpha-amylase and alpha-glucosidase enzymes. Methods: This current work focuses on the synthesis and evaluation of novel Pyrimidine-derived pyrazole-based thiadiazole derivatives to target DM by inhibiting α-amylase and α-glucosidase. Results: The findings exhibited that, except for three compounds, all other synthesized derivatives inhibited α-amylase and α-glucosidase enzymes with IC₅₀ values ranging from 5.17 μM to 29.84 μM on α-amylase and 7.60 μM to 31.62 μM on α-glucosidase, in comparison to the standard drug Acarbose (α-amylase IC₅₀ = 8.25 ± 0.80 μM; α-glucosidase IC₅₀ = 10.75 ± 1.10 μM). Analogs 8g, 8k, and 8b displayed superior or comparable inhibitory activity compared to the reference drug Acarbose. The inhibition potential of the derivatives can be attributed to their stable contacts with crucial amino acid residues of targeted enzymes, as shown through molecular docking analysis. Moreover, DFT-calculated HOMO–LUMO parameters and electrostatic potential (ESP) maps were used to gain complementary insight into the electronic characteristics, charge distribution, and potential interaction behavior of the synthesized derivatives, which supported the molecular docking observations. Conclusions: Experimental outcomes and in silico support display that these derivatives serve as potential leads for anti-diabetic drug development. These potent pyrimidine-derived pyrazole-based thiadiazole derivatives were comparable to an existing diabetic mellitus inhibitor, specifying potential for further therapeutic development and optimization against diabetic mellitus. Full article

A series of 1,2,3-triazole-linked-thiazolidine-2,4-dione hybrids (SDP1–SDP15) were designed, synthesized, and evaluated for their antidiabetic potential. All structures were characterized by FT-IR and NMR spectroscopy (¹H and ¹³C). All derivatives exhibited significant in vitro inhibition of α-glucosidase (IC₅₀: 24.17–46.41 µg/mL) and α-amylase (23.25–50.66 µg/mL), comparable to the standard drug acarbose (IC₅₀: 25.18 and 32.53 µg/mL) and superior to the reference drug pioglitazone (IC₅₀: 84.24 and 79.74 µg/mL) for α-glucosidase and α-amylase, respectively. Molecule SDP8 emerged as the most potent with an IC50 of 24.17 and 23.25 µg/mL for α-glucosidase and α-amylase, respectively. Further, SDP8 exhibited a higher docking score of −10.7 kcal/mol and −10.4 kcal/mol against α-glucosidase and α-amylase than pioglitazone (−8.1 kcal/mol and −7.7 kcal/mol, respectively), suggesting that interaction with these two enzymes may be the cause for its antidiabetic activity. Furthermore, DFT analysis revealed favorable electronic properties with a low HOMO-LUMO energy gap, whereas ADMET predictions revealed moderate drug-like characteristics with some limitations, such as poor solubility, relatively high lipophilicity, and partial noncompliance with drug-likeness regulations. Overall, these results highlight triazole-linked thiazolidinedione hybrids as promising candidates for further development in T2DM, with SDP8 serving as a preliminary lead requiring additional optimization and validation. Full article

The global rise in metabolic disorders demands novel interventions targeting starch digestion. This study investigated two dietary phenolic acids (caffeic acid (CA) and p-hydroxycinnamic acid (p-HA)) as inhibitors of α-amylase and α-glucosidase through integrated experimental and computational approaches. Molecular docking showed distinct binding modes, and CA formed stable hydrogen bonds with catalytic residues of α-glucosidase, while p-HA interacted mainly with α-amylase via hydrophobic contacts. Enzyme kinetics revealed concentration-dependent mixed-type inhibition, with CA being more potent against α-glucosidase and p-HA against α-amylase. Spectroscopic analysis indicated both acids induced structural changes in the enzymes, with CA causing greater α-helix reduction (Δ7.03% vs. Δ2.10%) by altering the tryptophan microenvironment. Moreover, both compounds significantly suppress glucose absorption in the proximal small intestine in an ex vivo everted gut sac model, with p-HA exhibiting exceptional efficacy in the duodenum. These findings clarify structure–activity relationships and support the potential use of CA and p-HA as local intestinal agents for modulating carbohydrate absorption. Full article