Diabetes mellitus, especially Type 2 Diabetes (T2DM), appears to be a worldwide health challenge marked by progressing hyperglycemia and related complications. Postprandial Hyperglycemia (PPHG) is a critical therapeutic target due to its strong link with cardiovascular risks. Inhibition of carbohydrate-hydrolysing enzymes, α-glucosidase and α-amylase, is an established strategy to mitigate PPHG. Current Inhibitors, including acarbose, miglitol, and voglibose, are effective but limited by gastrointestinal side effects. Isatin (1H-indole-2,3-dione) is a privileged scaffold in medicinal chemistry with diverse biological activities and modifiable sites (N-1, C-3, C-5), enabling optimisation for enzyme inhibition. A comprehensive literature search was conducted up to December 2025 using databases including Google Scholar, Web of Science, PubMed, traditional integrated knowledge resources, local dissertations, and books. The search employed keywords such as "α- glucosidase," "type 2 diabetes," "isatin scaffolds," "standard α-glucosidase enzyme inhibitors," and "isatin derivatives showing α-glucosidase and α-amylase inhibitory activity." This review compiles recent advances in isatin derivatives as potential α-glucosidase and α-amylase inhibitors, highlighting structure-activity relationships, synthetic strategies, including green chemistry and microwaveassisted synthesis, and dual inhibitory activity for improved efficacy and safety. Reported derivatives demonstrate remarkable potency, with some surpassing standard drugs in IC50 values and docking scores, offering promising leads for next-generation antidiabetic therapeutics. Isatin derivatives show strong potential as multifunctional antidiabetic agents by effectively inhibiting α- glucosidase and α-amylase. Their structural versatility enables enhanced enzyme inhibition, supporting their promise as lead compounds for postprandial glucose control.

Twenty-four pinostrobin hydrazone derivatives (TN01-TN24) were synthesized through two continuous steps from pinostrobin, hydrazone, and aldehyde derivatives, well characterized and screened for inhibitory activity against yeast α-glucosidase (Saccharomyces cerevisiae). To further expand the chemical space, a QSAR-guided approach was employed, leading to the identification of four additional candidates (TN25-TN28). Eleven compounds exhibited >80% inhibition at 50 μM, outperforming acarbose, with most displaying IC50 values below 10 μM. Among them, TN27 showed the highest potency with an IC50 of 0.85 μM. Enzyme kinetic analysis confirmed a competitive inhibition mechanism, yielding a dissociation constant (Ki) of 3.56 μM. Molecular docking suggested favorable binding of TN27 within the active site of yeast α-glucosidase from Saccharomyces cerevisiae. To elucidate its binding mechanism, 500 ns molecular dynamics simulations were conducted in three independent replicas. Analysis of converged trajectories enabled end-point binding free energy calculations using MM/GBSA and QM-MM/GBSA methods, along with per-residue energy decomposition. These analyses revealed stable binding patterns driven by hydrophobic interactions and persistent hydrogen bonding with key catalytic residues. Collectively, the integrated experimental and multiscale computational results establish TN27 as a potent α-glucosidase inhibitor and demonstrate an effective strategy for rational lead identification and mechanistic validation.

This study aimed to identify potent drug candidates against diabetes mellitus (DM), particularly through inhibition of the key carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase. For this purpose, a series of novel imidazolone-based chalcone derivatives was synthesized through an efficient and rapid synthetic route. The synthesized analogues were initially monitored and confirmed by thin-layer chromatography (TLC). Their structural characteristics were established using [1]H NMR and [13]C NMR spectroscopy, while high-resolution electron ionization mass spectrometry (HREI-MS) was employed to determine their accurate molecular masses. The synthesized analogues were evaluated for their inhibitory potential against α-amylase and α-glucosidase, and their activities were compared with the standard inhibitor acarbose. Among the synthesized compounds, analogue 5 exhibited the highest inhibitory activity, with IC50 values of 6.80 ± 0.10 µM against α-amylase and 7.10 ± 0.30 µM against α-glucosidase. Enzyme kinetic studies were subsequently performed at different substrate and inhibitor concentrations to investigate the mode and mechanism of enzyme inhibition. To further elucidate the protein-ligand interactions, the most potent analogues were subjected to molecular docking and pharmacophore modeling, which provided insights into their binding orientations and key interactions with active-site amino acid residues. Molecular dynamics (MD) simulations were additionally performed to investigate the stability and dynamic behavior of the selected protein-ligand complexes. Furthermore, density functional theory (DFT) calculations and ADMET analyses were conducted to examine the electronic properties, molecular electrostatic potential, and drug-like and pharmacokinetic characteristics of the potent analogues. Collectively, these experimental and computational investigations provided comprehensive insights into the antidiabetic potential and molecular characteristics of the synthesized imidazolone-based chalcone derivatives.

Diabetes mellitus can cause progressive renal injury characterized by oxidative stress, inflammation, and impaired renal function. This study investigated the kidney- and cell-protective potential of acarbose-guar gum solid dispersion (AGSD-3) using in vitro and in vivo diabetic models. In BHK-21 cells, AGSD-3 showed improved biocompatibility, with higher cell viability (65.54 ± 0.41%) than acarbose (56.67 ± 0.24%) and reduced lactate dehydrogenase release (7.29 ± 0.13%) at 100 µg/mL. Under high-glucose conditions, AGSD-3 significantly reduced lipid peroxidation and enhanced superoxide dismutase, catalase, and glutathione S-transferase activities (p < 0.001). In diabetic rats, AGSD-3 (50 mg/kg) significantly improved renal function, reducing serum creatinine, urea, and uric acid to 0.45 ± 0.02, 36.00 ± 0.96, and 2.00 ± 0.02 mg/dL, respectively, and normalized relative kidney weight. Histopathological findings further supported restoration of renal architecture. AGSD-3 enhanced renal antioxidant status, with increased SOD, catalase, and GST activities, while reducing nitric oxide, xanthine oxidase, and acetylcholinesterase activities (p < 0.001). Furthermore, AGSD-3 reduced TNF-α and IL-6 while increasing IL-10 levels. Overall, AGSD-3 exhibited antioxidant, anti-inflammatory, and renoprotective effects, supporting its potential as an improved acarbose-based formulation for diabetes-associated renal injury.

This study investigated the relationship between the structures of new Copper(II) complexes and their potential hypoglycemic activities, and verified this relationship through molecular docking. Five new Cu(II) metal complexes were formed using three benzotriazole ligands, and their potential hypoglycemic activities were evaluated. The X-ray single crystal diffraction results indicate that complexes 1, 4, and 5 have a one-dimensional chain structure, while complex 2 has a mononuclear structure and complex 3 has a binuclear structure. Complexes 1-5 all exhibited better inhibitory activity against α-amylase than the positive control acarbose (IC50 value was 4.45 ± 0.06 mmol/L). Among them, complexes 1, 3, 4, and 5 had better inhibitory activity against α-amylase, with their IC50 values being 1.60 ± 0.01 mmol/L, 1.55 ± 0.06 mmol/L, 2.52 ± 0.07 mmol/L, and 3.02 ± 0.03 mmol/L, respectively. The results of the α-glucosidase inhibition experiment showed that the IC50 values of complexes 1, 3, and 5 for α-glucosidase were 2.45 ± 0.06 μmol/L, 2.39 ± 0.03 μmol/L, and 3.26 ± 0.10 μmol/L, respectively. At a concentration of 7 μM, the inhibition rates all exceeded 90%. Meanwhile, molecular docking results showed that complexes 1, 3, and 5 had relatively strong binding affinities for α-glucosidase, which is consistent with the results of the enzyme inhibition assays. In addition, complexes 1, 3, and 5 significantly improved the glucose consumption of IR-HepG2 cells, with values 1.88, 1.90, and 1.81 times that of the model group, respectively. This work is based on the precise single-crystal structure of the complexes. It systematically determined the enzyme inhibitory activity, conducted molecular docking simulations, and at the molecular level, revealed and clarified the structure-activity relationship between the complexes and the enzyme active pocket. This provided an intuitive and reliable structural basis for understanding the inhibition mechanism. The results show that complexes have better inhibitory activities against α-amylase and α-glucosidase than the corresponding ligands and metal salts. This indicates that the cooperative effect between Cu(II) and the ligands enhances the potential hypoglycemic activity of the complexes. The enzyme inhibitory activity of the complexes is closely related to the coordination mode and spatial steric hindrance of the metal center.

With the aim of developing novel multi-target agents capable of simultaneously inhibiting α-glucosidase (α-Glu), α-amylase (α-Amy), and protein tyrosine phosphatase 1B (PTP1B), a new library of twenty-four carbazole-5-phenoxymethyl-1,2,4-triazole analogues (7a-7x) was synthesized and subjected to enzyme inhibition screening. The bioassay results demonstrated that all derivatives possessed potent anti-α-glucosidase (IC50: 6.68 ± 0.05 - 35.89 ± 0.68 μM) and anti-α-amylase (IC50: 4.08 ± 0.09 - 21.37 ± 0.72 μM) properties, significantly superior to acarbose (IC50 = 165 ± 4 μM and 20.76 ± 0.29 μM, respectively). Among all tested compounds, 7w displayed the strongest dual inhibition toward α-Glu (IC50 = 6.68 ± 0.05 μM) and α-Amy (IC50 = 4.41 ± 0.15 μM). Meanwhile, its activity against PTP1B (IC50 = 3.49 ± 0.57 μM) was found to be on a par with positive ursolic acid (IC50 = 3.18 ± 0.25 μM). Further mechanistic investigations, including kinetic assays, molecular docking, and multispectral analyses, revealed that compound 7w inhibited α-Glu, α-Amy, and PTP1B activities through binding to the target enzymes, involving non-covalent interactions and altering their secondary structures. Meanwhile, 7w was found to effectively reduce murine post-meal glycemic concentrations and exhibited no apparent cytotoxicity. Collectively, these target compounds hold promise as lead scaffolds in the rational design of new multi-target therapeutics for diabetes mellitus.

The present study investigated chemical composition and in vitro bioactivities of the essential oil (EO) of Macaranga trichocarpa leaves. The EO was analyzed using gas chromatography-mass spectrometry. The results showed the identification of 61 volatile constituents representing 97.54% of the total oil content. Sesquiterpene hydrocarbons were the predominant class (52.58%), with (E)-β-caryophyllene (17.66%), α-curcumene (16.04%), β-pinene (13.83%), linalool (9.52%), and β-caryophyllene epoxide (5.19%), identified as the major constituents. The EO showed weak antioxidant activity in both DPPH and ABTS radical scavenging assays. The EO demonstrated potent α-amylase inhibitory activity (IC50 = 120.70 ± 0.47 µg/mL), comparable to acarbose. Cytotoxicity evaluation using the MTT assay revealed that the EO exerted a dose-dependent inhibitory effect against the human hepatocellular carcinoma (HepG2) cell line. These findings provide the first report on the chemical composition of M. trichocarpa leaf EO, along with preliminary in vitro screening of its enzymatic and cytotoxic properties.

The study investigated how solvent choice affects the extraction of bioactive phytochemicals from Stachys pinardii. Methanol and aqueous extracts of aerial parts were obtained using ultrasound-assisted extraction and analyzed for phytochemical content, antioxidant capacity, and enzyme inhibition. The methanol extract showed higher total phenolic (52.56 mg GAEs/g) and flavonoid contents (18.19 mg REs/g) than the aqueous extract (15.62 mg GAEs/g and 8.25 mg REs/g). Liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis identified verbascoside and chlorogenic acid as major compounds in methanol, while aqueous extract was richer in caffeic acid and hydroxycinnamic derivatives. Despite lower phenolic content, the aqueous extract demonstrated stronger antioxidant activity across 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric ion reducing antioxidant capacity (CUPRAC), and ferric reducing antioxidant power (FRAP) assays, with lower IC50/EC50 values. It also exhibited superior enzyme inhibitory effects, particularly against α-amylase (2.52 mg/mL) and α-glucosidase (1.58 mg/mL), although its inhibitory activity remained lower than that of the standard acarbose. Overall, solvent polarity significantly influences both phytochemical composition and biological activity. The aqueous extract, despite its lower total quantified phenolic content, shows promising multifunctional bioactivity. Further studies should focus on bioactivity-guided fractionation and mechanistic insights into individual compounds.

Untargeted UHPLC-HRMS metabolomics coupled with HPTLC/HPLC bioautography revealed that lactic fermentation and subsequent storage profoundly remodelled the metabolome of red radish (Raphanus sativus var. sativus) and shifted bioactivity-relevant compound pools. Fermentation induced pronounced class-specific changes: organic acids increased approximately 10-fold, phenolic compounds 8-fold and flavonoids 4-fold, whereas glucosinolates decreased to 16% of their initial levels. Discriminant biomarkers of fermentation included phenyllactic acid, hydroxyphenyllactic acid, chlorogenic acid isomers and isorhamnetin derivatives. Antioxidants profiling showed a restructuring of the antioxidant pool - shifting from anthocyanins toward flavonols and phenolic acids, with kaempferol-3-O-rhamnoside, quercetin, and oxygenated lipids emerging as novel antioxidant contributors. α-Amylase inhibitory activity increased throughout fermentation and storage, peaking at 4.08 ± 0.08 mg acarbose equivalents/g DW after storage at 18 °C and correlating with increased flavonoid availability, supporting fermented red radish as a promising functional ingredient with antioxidant and antidiabetic potential.

The divergent total synthesis of nocarterphenyls A-B and 2-dehydroxymethylnocarterphenyl A, as well as the formal synthesis of nocarterphenyl D, have been accomplished in five to six steps. The convergent route featured a novel one-step C-H functionalization of aniline to form the benzothiazole ring, a double Suzuki-Miyaura coupling to construct the thiazole-fused p-terphenyl core, and late-stage dehydrogenative couplings to afford nocarterphenyls divergently. Biological evaluation indicated that these natural products and their derivatives represent a new class of potent α-glucosidase inhibitors. Among all tested compounds, nocarterphenyl derivative 5 exhibited the strongest inhibitory effect, with an IC50 value of 9.82 ± 0.31 μM, which was markedly greater than that of the positive control acarbose (570 ± 4.40 μM). Enzyme kinetic assays demonstrated compound 5 to be a reversible, mixed-type α-glucosidase inhibitor. Circular dichroism (CD) spectroscopy further revealed that the binding of compound 5 induced pronounced conformational alterations and obvious changes in the microenvironment surrounding the secondary structure of α-glucosidase.

Passiflora edulis seeds are frequently discarded as agro-industrial residues despite being a source of bioactive compounds such as piceatannol (PIC). Their valorization through ethanolic extraction aligns with circular economy principles and enables the investigation of antioxidant, anti-inflammatory, and antidiabetic potential relevant to metabolic disorders associated with oxidative stress, inflammation, and impaired glucose homeostasis. Therefore, this study compared the biological activities and toxicological profiles of P. edulis seed ethanol extract (PESE) and PIC using in vitro and in vivo assays, including human and nonhuman models, and hyperglycemia induced during embryogenesis. The zebrafish procedures were approved by the Animal Use Ethics Committee (CEUA; protocol No. 13/2022). LC-MS identified PIC among the main constituents of PESE, which exhibited a high total phenolic content and relevant antioxidant capacity. PIC showed greater antioxidant potency than PESE against DPPH[•], HOCl, and O2 [•-]. It also inhibited α-amylase and α-glucosidase, with IC50 values of 11.8 and 3.1 μg/mL, respectively, outperforming acarbose against α-glucosidase, and activated glucokinase. In contrast, PESE inhibited PTP1B (IC50 = 29.8 μg/mL), an effect not observed with PIC alone. Both samples reduced ROS production in human neutrophils, with PIC displaying high potency in the luminol assay (IC50 = 0.12 μg/mL). In zebrafish embryos, PESE was less embryotoxic than PIC, with LC50 values of 39.3 and 6.2 μg/mL, respectively. In the hyperglycemic zebrafish model, both samples significantly reduced total free glucose and oxidant activity (p ≤ 0.05) and induced distinct antioxidant gene-expression responses: PESE upregulated nfe2l2a, sod1, sod2, and cat, whereas PIC upregulated nfe2l2a, gpx1a, and cat. These findings demonstrate that PESE and PIC act through multiple complementary mechanisms to counteract hyperglycemia and oxidative stress, highlighting the therapeutic potential of an underutilized byproduct while emphasizing the importance of developmental toxicity assessment for the safe advancement of plant-derived agents.

The roots of Croton krabas have traditionally been used as a water decoction for treatment of bloating and flatulence. The preliminary bioactivity screening revealed that the crude n-hexane and EtOAc extracts exhibited significant α-glucosidase inhibitory activity. Accordingly, the first phytochemical investigation of the roots of C. krabas led to the isolation of two previously undescribed clerodane diterpenes (1 and 2), together with eight known compounds (3-10). The structures and stereochemistry were elucidated by extensive analysis of spectroscopic data (UV, IR, [1]H NMR, [13]C NMR, and 2D NMR), mass spectrometry (MS), ECD calculation, and comparison with reported data. The structure of 2, a rare hybrid diterpene ester comprising both clerodane and ent-kaurane units, was further confirmed by alcoholysis and ESI-MS/MS fragmentation analyses. Among these, 12-oxo-hardwickiic acid (7) was obtained as a major clerodane and exhibited potent α-glucosidase inhibitory activity. To enhance its activity, 7 was structurally modified through esterification and reaction with hydrazine hydrate, guided by molecular docking simulations, yielding two esters 2a and 7a and three pyridazines 7b-7d derivatives. A plausible reaction mechanism for the formation of the pyridazine derivatives is also proposed. Isolated clerodanes 2, 6, and 7 exhibited potent α-glucosidase inhibition, surpassing the standard drug acarbose (IC50 = 341.10 μM). Moreover, the clerodane ester derivatives 2a and 7a showed strong inhibitory activity with IC50 values of 27.23 and 14.29 μM, respectively, which were more potent than both parent clerodane and acarbose. In contrast, the pyridazine derivatives 7b-7d (IC50 = 272.40-290.63 μM) reduced activity compared to their parent clerodane, although they remained more active than acarbose. Molecular docking studies revealed that 6, 7, 2a, and 7a-7d blocked substrate from the entrance of α-glucosidase active site. Furthermore, the predicted physicochemical properties of these compounds complied with Lipinski's and Veber's rules, while ADMET analyses indicated favorable pharmacokinetic profiles. These findings suggest that the clerodane ester derivatives 2a and 7a represent promising candidates for the development of α-glucosidase inhibitory agents.

Ardisia crenata Sims is an important medicinal plant in southern China, yet its industrial utilization is severely limited by unsustainable harvesting of wild resources, inconsistent active ingredient quality, and inefficiencies in conventional extraction processes. Endophytic fungi, which can produce bioactive metabolites identical or analogous to those of the host, offer a promising alternative for sustainable biomanufacturing.

Malus micromalus Makino, a fruit crop with a millennium-long cultivation heritage in China, has hitherto received limited systematic investigation regarding its bioactive principles and the mechanistic underpinnings of its glucose-modulating effects. Sixteen compounds were isolated and structurally identified from the fruit. The bioactive components and action modes were systematically explored via network pharmacology, in vitro bioassays, enzyme kinetics, molecular simulation, and in vivo validation. ESR1 and MAPK3 were predicted as potential hub targets involved in insulin resistance and oxidative stress regulation. Oleanolic acid, ursolic acid, and hyperoside exhibited dual functional activities, with potent α-glucosidase inhibitory effects (IC50 = 0.037, 0.038, and 0.047 mM, respectively) stronger than acarbose in this yeast-derived enzyme assay system, plus remarkable DPPH, and ABTS+ radical scavenging capacities. Enzyme kinetic analysis demonstrated a noncompetitive inhibition mode, with unchanged Km value, and dose-dependently decreased Vmax. Molecular docking indicated that OA and UA had high binding affinities with ESR1 and MAPK3. Notably, 100-ns molecular dynamics simulation suggested that OA could form sustained hydrogen bonds with ESR1 and maintain the structural stability of the receptor-ligand complex. Within the in vivo setting, OA treatment at 25 and 50 mg/kg engendered dose-dependent improvements in systemic glucose handling, peripheral insulin sensitivity, and circulating lipid profiles among HFD-induced obese animals. Collectively, this study clarifies the bioactive constituents and metabolic regulatory effects of M. micromalus Makino, and provides scientific evidence for its development as a functional food ingredient for glycemic management. PRACTICAL APPLICATIONS: The present findings offer direct translational value for the functional food sector. The potent α-glucosidase inhibitory activity of oleanolic acid (OA, IC50 = 0.037 mM)-surpassing acarbose by approximately sevenfold-positions M. micromalus fruit extracts as promising candidates for glycemic-management food ingredients. Given its noncompetitive inhibition kinetics, OA retains efficacy irrespective of carbohydrate load, a critical advantage for incorporation into staple foods with variable starch content. From a formulation standpoint, the ethyl acetate fraction enriched in triterpenoids and flavonoids could be developed as standardized extracts for functional beverages, bakery products, or nutraceutical capsules. The established industrial processing of M. micromalus into fruit wine and preserves further supports scalable valorization. However, the poor aqueous solubility of pentacyclic triterpenoids necessitates future work on delivery systems (e.g., nano-emulsions or liposomal encapsulation) to enhance bioavailability and thermal stability during food processing. In addition, the dual antioxidant-hypoglycemic profile of these constituents suggests potential as multifunctional natural preservatives that simultaneously extend shelf life and confer metabolic health benefits. Subsequent studies should evaluate the sensory impact, storage stability, and consumer acceptability of M. micromalus-fortified food prototypes.