Benzimidazole derivatives have emerged as important scaffolds in the development of potent and effective α-glucosidase inhibitors, key targets for managing type 2 diabetes mellitus (T2DM). This review highlights structural innovations and structure-activity relationships (SARs) of diverse benzimidazole-based compounds, including hybrids with Schiff bases, thiosemicarbazones, 1,2,3-triazoles, and oxadiazoles, all exhibiting α-glucosidase inhibitory activity. Notably, numerous derivatives demonstrate superior inhibition compared to the standard reference drug, acarbose.

WEE1 kinase represents a promising therapeutic target in oncology due to its critical role in cell cycle checkpoint regulation. Traditional drug discovery for WEE1 inhibitors has been constrained by the time and resource demands of conventional screening. Here, we integrate machine learning with equilibrium and non-equilibrium thermodynamic analyses to identify potential WEE1 inhibitors from FDA-approved drug libraries. Our approach combines structure-based virtual screening with multi-stage computational validation, employing molecular docking, molecular dynamics simulations, and machine learning-based activity prediction. This strategy revealed several promising candidates, including acarbose and quercetin derivatives, demonstrating binding profiles superior to established kinase inhibitors. Notably, integration of non-equilibrium thermodynamics through steered molecular dynamics provided insights into unbinding mechanisms and energetic barriers absent from traditional equilibrium methods. The machine learning model successfully distinguished active from inactive compounds with high predictive accuracy, enabling efficient prioritization of candidates. This study establishes a computational framework bridging equilibrium thermodynamics, kinetic dissociation analysis, and predictive modelling for accelerated drug repurposing, while highlighting the necessity of experimental validation to confirm computational predictions.

This study was conducted to examine the phytoconstituent, antioxidant, enzyme inhibitory, antimicrobial, and cytotoxic activities of Alkanna orientalis (L.) Boiss. and A. verecunda Hub.-Mor., both from the Boraginaceae family. Root extracts were prepared using methanol. High-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS) analysis results revealed the dominance of caffeic acid derivatives in both species. Both species contained variable amounts of rosmarinic acid, dimers and trimers of caffeic acids, lithospermic acid, salvianolic acid A and C, and sagerinic acid. A. orientalis demonstrated higher total phenolic (96.18 mg gallic acid equivalent (GAE)/g) and flavonoids (6.33 mg rutin equivalent (RE)/g) contents than A. verecunda, leading to increased antiradical (DPPH = 316.74 mg trolox equivalents (TE)/g; ABTS = 491.21 mg TE/g), ions reducing (CUPRAC = 790.46 mg TE/g; FRAP = 523.24 mg TE/g), chelation (7.43 mg ethylenediaminetetraacetate equivalent (EDTAE)/g), and total antioxidant (3.17 mmol TE/g) activities. Anti-acetylcholinesterase activity was comparable in both species (2.98 and 2.92 mg galantamine equivalent (GALAE)/g, p ≥ 0.05). A. orientalis most effectively inhibited α-glucosidase (2.23 mmol acarbose equivalent (ACAE)/g) and α-amylase (0.26 mmol ACAE/g), while A. verecunda showed the highest significant inhibitory effect against butyrylcholinesterase (1.98 mg GALAE/g), anti-tyrosinase (49.75 mg KAE/g), and human carbonic anhydrase isoenzyme II (IC50 0.070 µg/mL). A. orientalis exhibited significant antibacterial activity against Staphylococcus epidermidis ATCC14990, with a minimum inhibitory concentration (MIC) of 0.008 mg/mL and a minimum bactericidal concentration (MBC) of 0.0625 mg/mL. The cytotoxic activity of methanol extracts from A. orientalis and A. verecunda was evaluated on four human cancer cell lines: gastric adenocarcinoma (AGS), ovarian adenocarcinoma (SKOV-3), colon carcinoma (HCT-116), and cervical adenocarcinoma (HeLa), using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Human fibroblasts (HFF-1) were employed as a non-cancerous control line. The findings suggest that the extracts exhibited mild cytotoxic activity on cancer cells while demonstrating no toxicity on normal fibroblasts. A more potent effect was observed for A. orientalis compared to A. verecunda extracts, particularly on gastric cancer AGS cells, where cell viability decreased to 56.84 ± 4.20% at the highest concentration of A. orientalis extract. In conclusion, this study is the first to explore the phytochemical constituents and biological activities of A. verecunda and the roots of A. orientalis. The roots of both species could serve as a novel source of bioactive molecules with potential applications in the pharmaceutical and cosmetic industries.

The prevalence of obesity has risen sharply in recent years, prompting the need for safer and more biocompatible therapeutic alternatives to conventional anti-obesity drugs. In this study, zinc oxide nanoparticles (ZnO NPs) were synthesized using pomegranate husk extract via two green approaches: conventional heating and microwave-assisted synthesis. Structural and morphological characterizations confirmed successful nanoparticle formation. Microwave-assisted ZnO nanoparticles (MA-ZnO NPs) exhibited smaller particle dimensions and narrower polydispersity compared with conventionally synthesized ZnO NPs. Both types of ZnO NPs demonstrated notable antioxidant activity (>62% scavenging in DPPH and ABTS assays) and strong inhibitory effects against pancreatic lipase and α-amylase (>70%), comparable to standard drugs such as orlistat and acarbose. Cytotoxicity assays using Vero cells confirmed high biocompatibility, with >60% cell viability. This work presents a comparative evaluation of two green synthesis methods and highlights the potential of biogenic ZnO NPs as multifunctional agents for oxidative stress reduction and enzyme inhibition in obesity management.

The growing diabetes trend worldwide demands the identification of new α-glucosidase inhibitors for delaying postprandial hyperglycemia. However, the use of existing drugs is often limited by adverse effects, which has increased interest in natural products as safer alternative sources of α-glucosidase inhibitors. I. aquifolium was selected based on reports of flavonoid-rich phytochemistry, leading to the hypothesis that its major flavonoids could act as potential α-glucosidase inhibitors for the management of diabetes. Herein, the virtual α-glucosidase inhibitory potential of eight flavonoid-based phytochemicals of I. aquifolium extracts was investigated through an integrated in silico workflow, which includes molecular docking, DFT analysis, and ADMET profiling. Docking analysis identified IA- 2 (Rutin) and IA- 5 (Kaempferol-3-O-rhamnoglucoside) as the most potent ligands with binding affinities of - 9.59 kcal/mol and - 9.18 kcal/mol, respectively, closely approaching the standard acarbose (-10.96 kcal/mol). The re-docking RMSD of 2.1375 Å fell within the acceptable validation benchmark, supporting the reliability of the docking protocol. The second and third positions were occupied by IA- 1 (Quercetin) and IA- 3 (Quercetin-3-O-hexoside) as potential inhibitors, as they formed hydrogen bonds with hydrophobic contacts. DFT study suggested that all the flavonoids exhibited moderate to high dipole moments (4.88-7.36 Debye) along with the high HOMO-LUMO gaps. Additionally, IA- 7 (Apigenin) showed the highest electrophilicity (3.313) among all the phytochemicals. The pharmacokinetic evaluation of ligands by SwissADME and PkCSM suggested IA- 1 as the most potential hit, and it occupied the main drug-likeness parameters with a bioavailability score of 0.55, whereas low bioavailability scores (0.17) for IA- 2 and IA- 5 indicated their poor permeability through the membrane. The potential toxicity of the ligands through SwissADME predicted that all the ligands have renal and respiratory issues, but IA- 1 showed the highest potential of acute dermal toxicity. MD simulations supported the docking results by showing protein backbone RMSD stabilization at 2.0-2.4 Å and revealing that IA-2 and IA-5 form the most dynamically stable complexes (lowest ligand RMSD, compact Rg, persistent H bonds), while IA-3 and IA-1 display greater ligand flexibility, thereby prioritizing these compounds for experimental validation in a hypothesis-generating context. However, these computational findings do not replace experimental validation and should be interpreted as hypothesis-generating predictions. Overall, the study provides a hypothesis-generating framework, prioritizing IA-2 and IA-5 as potential α-glucosidase inhibitory candidates, with IA-1 emerging as a top-ranked ligand through pharmacokinetic parameters, required further experimental validation.

A new library of quinoline-based hydrazone analogues (7a-7j) was designed and synthesized to evaluate their potential as multifunctional antidiabetic agents. In contrast to earlier quinoline derivatives primarily developed for single-enzyme inhibition, the present series incorporates a quinoline scaffold with a thiocarbohydrazide-derived hydrazone linker and diverse aryl/heteroaryl substituents to investigate a multitarget profile involving α-glucosidase, α-amylase, and PPAR-γ. Biological evaluation showed low-micromolar inhibitory activity against key carbohydrate-metabolizing enzymes. Compounds 7e and 7h exhibited the most potent α-glucosidase inhibition (IC50: 18.55 ± 2.34 and 20.73 ± 0.37 μM, respectively), with activity comparable to acarbose (IC50: 16.53 ± 0.39 μM). Compound 7g showed the strongest α-amylase inhibition (IC50: 7.85 ± 1.92 μM). In addition, compounds 7b and 7f significantly enhanced PPAR-γ transcriptional activity in L6 myotubes, suggesting potential insulin-sensitizing effects. Molecular docking and molecular dynamics simulations supported stable ligand-protein interactions with key catalytic residues across all targets. In silico ADMET analysis indicated acceptable permeability and oral absorption; however, moderate lipophilicity and limited aqueous solubility of some analogues may require further optimization. Overall, these findings highlight quinoline-based hydrazones as promising multitarget scaffolds for further in vivo evaluation.

Because less than 2% of a dose of acarbose is absorbed from the mother's gastrointestinal tract, it is unlikely that any drug reaches the infant through breastmilk.[1]

Annona cherimola is a plant species widely used in Mexican traditional medicine, particularly in the management of diabetes. This study aimed to investigate the antihyperglycemic properties of the petroleum ether extract of A. cherimola leaves (PEEAcL), as well as to evaluate their effects on glycated hemoglobin and toxicity. In addition, the work was directed to determine its potential as an SGLT-1 and α-glucosidase inhibitor. The effect as a potential SGLT-1 and α-glucosidase inhibitor of PEEAcL was evaluated utilizing intestinal glucose absorption (IGA), oral glucose tolerance (OGT), oral sucrose tolerance (OST) and intestinal sucrose hydrolysis (ISH) tests. PEEAcL administered at doses of 200 mg/kg showed significant antihyperglycemic activity after 1 h of treatment, and the maximum effect was seen at 4 h in male and female diabetic mice. In the OST, OLT, and OGT tests, PEEAcL generated a reduction in the postprandial glucose peak at 2 h after the administration of a carbohydrate load, showing an effect comparable to that of acarbose and canagliflozin. In the IGA trial, PEEAcL significantly reduced glucose uptake in the small intestine. Similarly, in the ISH, PEEAcL recorded a significant reduction in glucose concentration in the external aqueous medium. Taken together, these results suggest that the antihyperglycemic effect of PEEAcL could be mediated, at least in part, by inhibition of SGLT-1 and the enzyme α-glucosidase.

Black tea, a tea fully fermented by polyphenol oxidase, is widely recognized for its distinctive flavor and diverse health benefits largely attributed to its various phenolic components. An extensive phytochemical investigation of black tea made from the leaves of Camellia taliensis (Theaceae), a wild tea plant distributed in Yunnan province, China, led to the isolation and characterization of 15 flavan-3-ol derivatives, among which four previously unreported products (1-4), including two flavoalkaloids (1-2), one flavan-3-ol (3) and one nitrogen-containing phenol (4), were identified. When evaluated for α-glucosidase inhibitory activity, 10 of the isolates showed stronger activities than quercetin and acarbose (IC50 = 5.75 and 223.30 µM, respectively), with IC50 values ranging from 0.09 to 3.57 µM. Notably, compound 15 displayed exceptional potency with an IC50 of 0.09 μM, approximately 60-fold lower than that of quercetin. These findings highlight the potential of black tea produced from C. taliensis for the development of functional foods targeting postprandial hyperglycemia management.

Background/Objectives: Pigmented rice is increasingly recognized as a functional food because of its rich phytochemical composition and health-promoting potential. However, local red rice cultivars from the three southern border provinces of Thailand remain insufficiently characterized. This study comparatively evaluated four whole-grain red rice cultivars-Hawm Gra Dang Ngah 59 (HGDN 59), Hawm Mue Lau (HML), Lued Pla Lai (LPL), and Se Bu Kan Tang (SBKT)-for their chemical composition, antioxidant activities, and antidiabetic potential. Methods: Whole-grain rice samples were extracted with 95% ethanol and assessed for extraction yield, total phenolic content, and total flavonoid content. Antioxidant activity was measured using DPPH•, FRAP, and anti-lipid peroxidation assays, while antidiabetic activity was measured using α-amylase and α-glucosidase inhibition assays. LC-MS/MS-based chemical profiling, pathway classification, PCA-based chemical space analysis, molecular docking against α-glucosidase, and physicochemical/ADMET prediction were also performed. Results: Among the tested cultivars, HGDN 59 showed the most favorable overall profile, with the highest phenolic content, strongest antioxidant activity, and marked α-glucosidase inhibitory activity. LC-MS/MS analysis combined with docking-based screening revealed that HGDN 59 contained several abundant compounds, including ent-Epicatechin-(4α→6)-ent-epicatechin, cinnamtannin A1, apiin, and α-tocotrienol. These compounds exhibited strong binding affinities toward α-glucosidase (-10.7 to -9.6 kcal/mol), comparable to or slightly more favorable than acarbose. ADMET prediction indicated that most polyphenolic compounds exceeded Lipinski's rule of five, while α-tocotrienol demonstrated favorable absorption property. Conclusions: This is the first study to suggest that HGDN 59 exhibits potential α-glucosidase inhibitory activity in vitro and may serve as a promising functional food candidate for the dietary management of postprandial glycemic response.

Microbiota-accessible carbohydrates modulate host immunity by shaping gut microbial composition and metabolism. However, their role in modulating the microbiota to influence allergic responses is unclear. Here we show that a widely used antidiabetic agent, the α-glucosidase inhibitor acarbose, redirects dietary carbohydrate utilization by gut bacteria to suppress mast-cell-dependent anaphylaxis in mice, independently of adaptive immune responses. Enhanced carbohydrate availability promoted the proliferation of Parabacteroides distasonis in the mouse gut, leading to increased succinate abundance and intracellular NAD+ levels, and reduced reliance on b-type cytochrome-dependent anaerobic respiration. Direct administration of succinate suppressed systemic anaphylaxis and mast cell degranulation in vitro, implicating succinate as a key effector. A human cohort analysis revealed that patients treated with α-glucosidase inhibitors showed a lower incidence of anaphylaxis than untreated individuals. These findings uncover a previously unrecognized gut-microbiota-mediated pathway linking dietary carbohydrate metabolism to systemic immune regulation.

A series of novel thiazine-thiazolidinone hybrids was synthesized and evaluated for antidiabetic potential. In vitro α-amylase and α-glucosidase inhibition was performed using standard colorimetric assays. Compounds 6 and 8 showed the highest activity, with IC50 values of 3.10 ± 0.10 and 2.70 ± 0.20 μM against α-amylase, and 3.60 ± 0.20 and 3.10 ± 0.20 μM against α-glucosidase, respectively, outperforming acarbose. Preliminary safety assessment, including in vitro cytotoxicity and short-term in vivo evaluation in Wistar rats, indicated no significant toxicity based on hematological and biochemical parameters. Molecular docking revealed favorable binding interactions within enzyme active sites, while molecular dynamics simulations confirmed stable protein-ligand complexes. Pharmacophore modeling identified key structural features contributing to activity, and density functional theory (DFT) analysis provided insights into electronic properties and reactivity. ADMET predictions suggested acceptable pharmacokinetic profiles. Overall, compound 8 emerged as the most promising lead for further optimization as an antidiabetic agent.