Two previously undescribed dihydroflavonol triglycosides, petelotiiosides A and B (1-2), together with two known flavonoid glycosides (3-4) and six known triterpenoid saponins (5-10), were isolated from the seeds of Camellia petelotii (Merr.) Sealy var. petelotii. Their structures were elucidated by HRMS, 1D and 2D NMR, and acid hydrolysis followed by HPLC analysis. Comparison of experimental and calculated electronic circular dichroism spectra established the absolute configurations of 1 and 2 as (2S,3R) and (2S,3S), respectively. Both compounds inhibited lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages, with IC50 values of 13.81 ± 1.73 and 13.48 ± 1.78 μM, respectively, without significant cytotoxicity over the tested concentration range. They also exhibited weak α-glucosidase inhibitory activity, with respective IC50 values of 7.0 ± 0.4 and 16.5 ± 0.7 mM, compared with 0.31 ± 0.08 mM for acarbose. These findings expand the phytochemical profile of C. petelotii seeds and identify two dihydroflavonol triglycosides with inhibitory effects on nitric oxide production in vitro.

A phytochemical investigation of the ethanolic extract of Ardisia sylvestris Pitard leaves led to the isolation and identification of eight compounds, including 3S,5R,6R,9S-tetrahydroxymegastigman-7-ene (1), myricetin-3-O-rutinoside (2), phenyl ethyl-O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside (3), 2-O-(trans-coumaroyl)malic acid 1-methyl ester (4), adenosine (5), gallic acid (6), 5-(8Z-heptadecenyl)resorcinol (7), and mandelic acid (8). Their structures were identified by NMR analysis, supported by MS data where available and comparison with published spectroscopic data. The isolated compounds were evaluated for α-glucosidase inhibitory, acetylcholinesterase (AChE) inhibitory, antioxidant, and antimicrobial activities. Among them, compound 7 showed the most promising biological profile, showing potent α-glucosidase inhibition (IC50 = 7.56 μg/mL), markedly stronger than acarbose (IC50 = 151.09 μg/mL), together with moderate AChE inhibitory activity (IC50 = 14.75 μg/mL). Compound 7 also displayed strong DPPH radical-scavenging activity (IC50 = 10.04 μg/mL), comparable to quercetin, and moderate antibacterial activity against Staphylococcus aureus (MIC = 64 μg/mL). Molecular docking and molecular dynamics simulations revealed favorable binding modes and stable interactions of compound 7 within the active sites of α-glucosidase and AChE. For the antibacterial activity, substrate-similarity-based target prioritization followed by comparative docking highlighted FabI as the highest-priority candidate target for compound 7. These findings identify 5-(8Z-heptadecenyl)resorcinol as a multifunctional bioactive constituent of A. sylvestris and provide complementary structural insights into its interactions with α-glucosidase and acetylcholinesterase.

Herein, a series of novel thiochroman-4-one derivatives bearing sulfonyl hydrazone moiety were rationally designed and synthesized via molecular hybridization strategy. The sulfonyl hydrazone pharmacophore with excellent hydrogen-bonding interaction ability was first introduced into the thiochroman-4-one parent skeleton to construct dual-active functional molecules, aiming to achieve synergistic α-glucosidase inhibition and antioxidant activity for antidiabetic therapy. All target compounds were structurally characterized by [1]H NMR, [1] [3]C NMR, and HRMS. Bioactivity results showed that multiple derivatives exhibited excellent α-glucosidase inhibitory activity and antioxidant capacity, among which compound 5k displayed the optimal comprehensive pharmacological performance with IC50 value of 4.57 µg/mL against α-glucosidase, which was significantly superior to the positive control acarbose (237.48 µg/mL). Molecular docking and molecular dynamics (MD) simulation verified that the optimal compound 5k could stably bind to the active pocket of α-glucosidase through multiple hydrogen bonds and hydrophobic interactions, with lower binding energy and better complex stability. Drug-likeness evaluation demonstrated that all synthesized derivatives complied with Lipinski's rule of five and had favorable pharmacokinetic properties. This work provides a novel structural scaffold for the development of high-efficiency antioxidant, α-glucosidase, and antibacterial inhibitors, and demonstrates its potential as a lead compound for pharmaceutical and agrochemical development.

This study comprehensively evaluated the phytochemical composition and multidimensional biological activities of Sisymbrium altissimum L., a wild edible species belonging to the Brassicaceae family. Methanolic extracts obtained from aerial parts, flowers, fruits, and roots were successively fractionated using solvents of increasing polarity, and essential and fatty oils were characterized by GC-MS and GC-FID analyses. The essential oil composition showed marked organ-dependent variation, with methallyl cyanide dominating fruit (91.9%) and flower (75.9%) oils, while phenylethyl isothiocyanate (48.7%) was the major constituent in roots. Further phytochemical investigation of the biologically active root hexane extract led to the isolation of β-sitosterol, lauric acid, and β-sitosterol-3-O-glucoside. Biological activity assays revealed strong α-glucosidase inhibition, particularly in the root hexane extract (87.92%), exceeding the reference drug acarbose (68.49%), whereas α-amylase inhibition was moderate, with the root ethyl acetate fraction exhibiting the highest activity (40.84%). Cholinesterase inhibition assays demonstrated low to moderate acetylcholinesterase and butyrylcholinesterase inhibitory activities depending on the plant part and extract fraction. Hyaluronidase inhibition was notably high, reaching up to 98.70%, whereas moderate collagenase (27.56%) and elastase (23.98%) inhibition and low tyrosinase activity were observed. Antioxidant activity was prominent in ethyl acetate and n-butanol fractions, with ABTS radical scavenging values approaching those of standard antioxidants. Total phenolic and flavonoid contents correlated with antioxidant capacity, although structural factors also influenced activity. Importantly, all tested extracts and cold-pressed oil exhibited no mutagenic or genotoxic effects in the Ames/Salmonella assay. Overall, these findings provide a comprehensive characterization of S. altissimum and highlight its potential as a source of biologically active natural products.

A new series of coumarin-aniline-triazole hybrids 12a-p was prepared using a multi-step approach. This synthesis involved a Knoevenagel condensation between 2-hydroxybenzaldehyde and diethyl malonate, followed by ester hydrolysis and amide coupling to yield a coumarin-based alkyne, which was then reacted with various 2-azido-N-arylacetamides via a click reaction. All synthesized compounds were evaluated for their potential antidiabetic activities through α-glucosidase inhibition, possessing remarkably superior potency compared to the reference drug acarbose (IC50 = 750.0 ± 0.8 μM), with IC50 values ranging from 1.1 to 44.2 μM. Among them, the 2-methyl derivative 12b emerged as the most potent, exhibiting approximately 750-fold greater activity than acarbose. Kinetic studies established that 12b was a competitive inhibitor (Kᵢ = 1700 nM), and selectivity assays confirmed its excellent specificity for α-glucosidase over α-amylase (no activity was observed up to 100 μM), suggesting a reduced risk of gastrointestinal side effects. Spectral investigations using circular dichroism (CD) spectroscopy revealed that 12b induced significant conformational rearrangements in the enzyme, characterized by a noticeable increase in β-sheet content (from 32.3% to 81.3%), while fluorescence spectroscopy confirmed a 1:1 binding stoichiometry with high affinity (Ka = 1.75 × 10[5] L mol[-1] at 25 °C) and an enthalpy-driven binding mechanism (ΔH = -39.19 kJ mol[-1], ΔS = -31.07 J mol[-1] K[-1]). In vivo studies in a streptozotocin-induced diabetic rat model demonstrated that, while compound 12b at 30 mg/kg exhibited significant antihyperglycemic activity (55% reduction in FBG), its efficacy was slightly lower than that of acarbose (62% reduction in FBG). Additionally, histopathological examination confirmed dose-dependent protective effects against diabetes-induced hepatic and pancreatic damage. Molecular docking and dynamics simulations also provided structural insights into the stable binding of 12b within the α-glucosidase active site (with a mean binding energy of -10.02 kcal/mol), establishing persistent hydrogen-bonding interactions with key residues, particularly ARG439 and LYS155. Collectively, these findings represent compound 12b as a promising lead candidate for further optimization and development as a safe and effective α-glucosidase inhibitor for the management of type 2 diabetes.

In the search for potent bioactive compounds derived from medicinal plants, Garcinia parvifolia from East Kalimantan has demonstrated significant bioactivity consistent with established scientific criteria. Bioassay-guided isolation of the fruit extract resulted in two new depsidones named methyl garcidepsidone B (1) and parvifoliricodone A (6), two known analogues, a phloroglucinol, and a furfural derivative. Their structures were determined by spectroscopic techniques. The isolated compounds were subjected to assessments for their potential antidiabetic effects through an α-glucosidase inhibition assay, anti-tyrosinase activity, and antioxidant properties. Out of the isolated compounds, methyl garcidepsidone B (1) was the most potent inhibitor against α-glucosidase compared with acarbose as a positive standard. In the antioxidant assay, all isolated compounds showed significant free radical scavenging activity against ABTS, with the exception of compound 4. Regarding tyrosinase inhibitory activity, all isolated compounds exhibited low enzyme inhibition activity. Additionally, in silico molecular docking studies showed that compounds 1-3 exhibited favorable conformation and binding affinities within the enzymatic pockets of α-glucosidase. These findings indicate that the indigenous G. parvifolia fruit may serve as a natural source of antidiabetic, antioxidant, and anti-tyrosinase compounds, with potential for further pharmacological investigation.

Current in silico drug discovery workflows largely rely on ligand-based screening and structure-based molecular docking to identify enzyme inhibitors, often overlooking dynamic biological contexts that influence drug efficacy and stability. Integrating multiscale computational modeling with experimental validation at early stages of lead identification can significantly improve predictive accuracy and reduce attrition rates. In this study, we applied an integrated computational-biological framework to identify benzimidazole-based thiophene-derived bis-Schiff base derivatives as potential antidiabetic agents targeting α-amylase and α-glucosidase. Lead compounds were prioritized through molecular docking, pharmacophore modeling, density functional theory (DFT) analysis, quantitative structure-activity relationship (QSAR) modeling, and molecular dynamics (MD) simulations to evaluate binding affinity, electronic features, and protein-ligand stability. The computational predictions were corroborated by in vitro enzyme inhibition assays, identifying compound 1 as the most potent inhibitor with superior activity compared to acarbose. Furthermore, in vivo wound-healing evaluation in rabbit models demonstrated enhanced tissue regeneration and accelerated healing, indicating biological relevance beyond enzymatic inhibition. In silico ADMET analysis predicted favorable pharmacokinetic and low-toxicity profiles for the lead compound. Although demonstrated for α-amylase and α-glucosidase inhibition, the proposed integrative framework is readily adaptable to other enzyme-driven therapeutic discovery pipelines.

The microbiota-gut-brain axis is involved in the pathogenesis of depression; however, whether the cGAS-STING signaling pathway contributes to onset and progression of depression via gut microbiota dysbiosis remains unknown. This study aims to investigate the role of the cGAS-STING signaling pathway in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors. Additionally, it aimed to identify novel downstream signaling factors of this pathway. A comprehensive mechanistic investigation was conducted using CUMS rats, HT22 cells, and cGAS[+]/[-] mice, with behavioral tests to assess depressive-like behaviors. Changes in the gut-brain axis and the underlying molecular mechanisms were systematically evaluated by histopathological staining, transmission electron microscopy, immunohistochemistry, immunofluorescence, Western blotting, co-immunoprecipitation (Co-IP), transcriptomics, metabolomics, and 16S rRNA sequencing. The results showed that in rats, CUMS induced hippocampal and intestinal damage, inflammation, cGAS-STING activation, and SATB2 upregulation, accompanied by intestinal tight junction impairment. Co-IP assays suggested an interaction between SATB2 and STING/IRF3. Additionally, CUMS rats exhibited altered gut microbiota (decreased beneficial genera, increased opportunistic pathogens) and elevated tobramycin, acarbose, and inosine levels. SATB2 was identified as a potential novel downstream molecule of the cGAS-STING axis, potentially associated with depressive-like behaviors via CUMS-induced gut-brain axis dysregulation. This finding provides a basis for antidepressant intervention strategies targeting this pathway.

Type 2 diabetes is a disease that is rapidly expanding across the world with global cases quadrupling since 1990 and now comprising over 800 million people, the majority of whom are in low- and middle-income countries (Zhou et al.Lancet2024, 404, 2077-2093.). The poor control of blood glucose levels that lies at the heart of this disease leads to debilitating complications such as renal failure, vision loss, and amputations and has associations with heart disease and a host of other conditions. Oral drugs that control blood glucose levels and can slow disease progression and reduce the risks are available. Among these are the α-glucosidase inhibitors acarbose and miglitol that function in the gut to slow the breakdown of starch and of oligosaccharides such as sucrose. However, gastrointestinal side effects such as discomfort and diarrhea frequently cause patients to discontinue treatment, highlighting the need for improved, cost-effective alternatives. Our approach has been to develop selective inhibitors of human pancreatic α-amylase (HPA) that shut down digestion of starch while sparing oligosaccharide breakdown, thereby lowering blood glucose without causing gastrointestinal discomfort. In this Account, we present the approaches we have taken to identify potent and selective inhibitors of HPA based upon our earlier determinations of the three-dimensional structure and catalytic mechanism of this key digestive enzyme. Our screens of natural product extract libraries produced two particularly interesting hits. One is the natural product Montbretin A (MbA) isolated from the corms of the common Crocosmia garden flower. Through a series of fragmentation studies, in conjunction with X-ray crystallographic analysis of complexes of MbA with HPA, we identified the core inhibitory component of this (Ki = 8 nM) glycosylated acyl flavonoid comprising a pair of π-stacked phenolic moieties that engage the essential active site carboxylic acids in HPA. Animal studies have shown the efficacy and safety of MbA, and human clinical trials are underway. Based upon this information, simpler inhibitors that retain nanomolar potency have been designed and synthesized. Through a separate screen of marine natural product extracts, we identified helianthamide, from the Caribbean sea anemone Stichodactyla helianthus, as a particularly potent (Ki = 10 pM) and stable 44 amino acid peptidic inhibitor of HPA. The structure of its complex with the highly similar porcine pancreatic α-amylase (PPA) shows it blocking the active site, using two tyrosines and a histidine to engage the catalytic residues, reminiscent of the "phenol sandwich" found with MbA while deriving considerable additional affinity from the burial of surface area. Finally, we used mRNA display methods to screen large cyclic peptide libraries using the RaPID (Random nonstandard Peptide Integrated Discovery) system in collaboration with the Suga lab. Screening this cyclic peptide library, comprising ∼1012 peptides, yielded a 9-amino acid lariat peptide that is a potent (Ki = 7 nM) and selective inhibitor of HPA. Structural studies of the complex revealed once again a motif in which two tyrosines, separated by a proline, engage the active site residues. Thus, through screening of three completely distinct libraries, natural products from terrestrial and marine sources, as well as a large cyclic peptide library, a very similar inhibitory motif has been recovered in each case but from different classes of molecules-essentially a case of convergent inhibitor evolution.

Diabetes mellitus remains a major global health challenge, necessitating the development of new therapeutic agents targeting key enzymes involved in carbohydrate metabolism. In this study, ten novel imidazo-thiazole-thiazolidinone hybrids were designed, synthesized and their structural integrity was confirmed through [1]H NMR and [13]C NMR along with mass determination by HREI-MS. After characterization, each derivative was subjected to in-vitro evaluation using acarbose (reference) to assess their anti-diabetic potential through the inhibition of key enzymes. Compound 3 and 6 with IC50 values 3.20 ± 0.20 μM, 2.10 ± 0.30 μM for α-amylase and 3.70 ± 0.30 μM, 2.60 ± 0.20 μM for α-glucosidase acted as the excellent inhibitors, markedly affecting rate of enzymatic reactions, with kinetic studies revealing their mode of inhibition. The SAR analysis revealed key substituents enhanced ligand-enzyme affinity, supported by molecular docking showing their specific binding. Furthermore, in-vivo cytotoxic assessment in rat models was performed to examine toxicological aspects and biocompatibility of synthesized compounds. Pharmacophore modeling, DFT calculations and MD simulations were also conducted to provide mechanistic insights. Comprehensive ADMET analysis including bioavailability, toxicity prediction, oral suitability and drug-likeness together with in-vivo safety evaluation complemented the in-vitro and computational findings, demonstrating these imidazo-thiazole based thiazolidinone derivatives hold promise as effective therapeutics against diabetes mellitus.

Gut microbiota act as beneficial symbionts of the hosts. Administration of α-glucosidase inhibitors (α-GIs) is considered to promote the microbiota's carbohydrate availability, modulating short-chain fatty acid (SCFA) production. However, it remains unclear whether host-microbiota interaction differs depending on α-GI types (e.g., acarbose versus miglitol) and carbohydrate types co-administered. In this study, we demonstrate that acarbose is transported through bacterial outer membrane porins, LamB and ScrY, and inhibits maltose metabolism in Escherichia coli. Furthermore, studies using Klebsiella pneumoniae reveal that acarbose suppresses utilization of maltose, but not that of sucrose. When co-administered with acarbose in mice, sucrose, relative to maltose, enhances SCFA production, suppresses glucose-dependent insulinotropic polypeptide (GIP) secretion, and protects against high-fat diet-induced obesity, underscoring the importance of sucrose as a microbiota-dependent beneficial factor, but not a culprit in host metabolism. In conclusion, acarbose regulates host metabolic processes partly by modulating gut microbial metabolism in a carbohydrate-type-dependent manner.

Diabetes mellitus is a major global health challenge, highlighting the need for new inhibitors of the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase. In this study, a series of thiazole-based thiazolidinone derivatives (1-10) was designed, synthesized, and structurally characterized using spectroscopic techniques. Among the synthesized compounds, 8 showed the strongest inhibitory activity against α-amylase and α-glucosidase, with IC50 values of 5.50 ± 0.40 and 5.90 ± 0.10 µM, respectively, and compared with 10.80 ± 0.50 and 11.10 ± 0.30 µM for acarbose. Molecular docking suggested that compound 8 can adopt a favorable binding orientation within the active sites of both enzymes through hydrogen-bonding and hydrophobic contacts. Enzyme kinetic studies further characterized its mode of inhibition. DFT calculations were performed to examine the electronic properties, frontier molecular orbitals, and molecular electrostatic potential of selected derivatives. ADMET analysis was also conducted to provide preliminary insight into their predicted pharmacokinetic and toxicity-related properties. Overall, the experimental and computational findings identify compound 8 as a promising lead structure for further investigation as an α-amylase and α-glucosidase inhibitor.

Type 2 diabetes (T2D) is a multifactorial metabolic disease in which hyperglycemia coexists with insulin resistance, β-cell dysfunction, dyslipidemia, and progressive microvascular and macrovascular complications. The structural versatility of the benzothiazole scaffold has enabled the development of a diverse array of preclinical compounds capable of modulating multiple diabetes-relevant targets. This review critically analyzes the available evidence on benzothiazole-derived compounds exhibiting antidiabetic or other diabetes-related pharmacological activities. No lower publication-date limit was imposed, and the literature included in the review ranged from 1997 to March 2026, encompassing in silico, in vitro, ex vivo, and in vivo evidence. The compounds are discussed according to their primary molecular targets, including α-glucosidase and α-amylase, dipeptidyl peptidase-4 (DPP-4), peroxisome proliferator-activated receptor -γ (PPAR-γ), protein tyrosine phosphatase 1B (PTP1B), glycogen phosphorylase, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), aldose reductase, AMPK, and other emerging metabolic targets. Structure-activity relationships (SAR) are highlighted, demonstrating that C-2 functionalization, substitution at the C-5 and C-6 positions, halogenation, the presence of electron-donating or electron-withdrawing groups, and hybridization with thiazolidinedione, rhodanine, triazole, oxadiazole, and other pharmacophores can markedly alter potency, selectivity, and metabolic effects. Various derivatives have matched or outperformed reference agents such as acarbose, glibenclamide, pioglitazone, or aldose reductase inhibitors in preclinical assays. However, a direct comparison between studies is limited by the heterogeneity of models, endpoints, units, and dosing regimens, and clinical efficacy for T2D has not yet been established for this chemical class. Overall, the benzothiazole scaffold emerges not as a universal antidiabetic pharmacophore, but as a highly adaptable platform for the rational design of multitarget compounds.

The potential of plant-based bioactive peptides to be used as an alternative or complementary therapy for the safe management of metabolic diseases such as diabetes is garnering increasing attention. In this in vivo study, the hypoglycemic effect of bromelain hydrolysates of hemp seed cake protein is analyzed in streptozotocin-induced diabetic mice. The results demonstrate that treatment of mice with the hydrolysate at a dose of 200 mg/kg/day for 4 weeks leads to a significant decrease in blood glucose levels (by 39%), serum triglyceride levels (16.44%), total cholesterol (13.50%), and low-density lipoprotein LDL (23.60%) compared to the untreated streptozotocin (STZ) group. The obtained values are comparable to those of the group treated with acarbose, which is used as a reference drug in the study. The applied hydrolysate significantly reduces serum alanine aminotransferase levels (by 39.38%) compared to the values of the untreated STZ group, while the change in superoxide dismutase levels was comparable to that of the group treated with acarbose. This study demonstrates the capacity of the applied hydrolysate to improve hyperglycemic conditions and reveals opportunities for future research into its potential as a functional ingredient.

Inspired by the medicinally relevant stilbene scaffold, a series of six electronically tuned benzylidene-based Schiff base derivatives were designed, synthesized, and characterized by FT-IR, [1]H NMR, [13]C NMR, and ESI-MS analyses. The biological properties of the synthesized compounds were investigated through antioxidant, enzyme inhibitory, and antimicrobial assays, while molecular docking and density functional theory (DFT) calculations were performed to rationalize the experimental findings and structure-activity relationships. Compounds 3 and 6 exhibited the strongest antioxidant activities, particularly in ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal-chelating assays. Compounds 1-3 and 5 demonstrated measurable α-glucosidase inhibitory activity, although they were less potent than acarbose, whereas compounds 1 and 2 showed the highest tyrosinase inhibition within the synthesized series. Antimicrobial evaluation revealed moderate activity across the series, with compound 3 displaying relatively higher antimicrobial activity within the synthesized series. Docking studies demonstrated favorable interactions within enzyme active sites, while DFT calculations provided insights into electronic properties and molecular reactivity. As a result, the investigated substitution patterns were associated with differences in biological activity within the synthesized series, with compound 3 showing relatively favorable activity in selected assays and warranting further investigation.