Synthesis, in vitro Α-Glucosidase, and acetylcholinesterase inhibitory activities of novel Indol-Fused Pyrano[2,3-D]Pyrimidine compounds.

In this study, new indol-fused pyrano[2,3-d]pyrimidines were designed and synthesized. These products were obtained in moderate to good yields and their structures were assigned by NMR, MS, and IR analysis. Afterwards, the biological important of the products was highlighted by evaluating in vitro for α-glucosidase inhibitory activity as well as acetylcholinesterase (AChE) inhibitory activity. Eleven products revealed substantial inhibitory activity against α-glucosidase enzyme, among which, two most potent products 11d,e were approximately 93-fold more potent than acarbose as a standard antidiabetic drug. Besides that, product 11k exhibited good AChE inhibition. The substituents on the 5-phenyl ring, attached to the pyran ring, played a critical role in inhibitory activities. The biological potencies have provided an opportunity to further investigations of indol-fused pyrano[2,3-d]pyrimidines as potential anti-diabetic agents.

Dauresorcinols A and B, two pairs of merosesquiterpenoid enantiomers with new carbon skeletons from Rhododendron dauricum.

Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A-E (1-5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh2(OCOCF3)4-induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1-5 are proposed involving key oxa-electrocyclization and Wagner-Meerwein rearrangement reactions. (+)/(-)-1 and 3-5 showed potent α-glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α-glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α-glycosidase inhibitors.

Bio-MOFs Based on Natural Phenolic, Hematoxylin Leverages Biomedical Applications: Enzyme Inhibition, Antioxidant, and Antibacterial Properties.

Here, using natural hematoxylin (HT) as linker, metal-organic frameworks (MOFs) from Cu(II), Fe(II), and Fe(III) ions was prepared. The SEM images and DLS analyses revealed HT-based MOFs are

Synthesis and Molecular Docking of Curcumin-Derived Pyrazole-Thiazole Hybrids as Potent α-Glucosidase Inhibitors.

α Glucosidase inhibitors are critical for diabetes management, with pyrazoles and thiazoles emerging as effective options. This research highlights curcumin-based pyrazole-thiazole hybrids as potential inhibitors, synthesizing derivatives and evaluating their inhibitory capabilities. The study involved the synthesis of novel compounds using hydrazonoyl halides, confirmed through elemental and spectral analyses. The synthesized derivatives exhibited significant α-glucosidase inhibition, with IC50 values ranging from 3.37 ± 0.25 to 16.35 ± 0.37 µM. Among them, compound 7e demonstrated the strongest inhibition at 3.37 ± 0.25 µM, outperforming the standard drug acarbose (IC50 = 5.36 ± 0.31 µM). In silico assessments and molecular docking using AutoDock Vina revealed strong interactions, particularly with compounds 7b, 7e, 7f, and 7g, indicating their potential as stable and effective inhibitors. The results suggest that the synthesized pyrazole-thiazole hybrids hold promise as novel therapeutic agents for diabetes, warranting further exploration of their substituent effects for optimized inhibitor design.

Carbonylbis(hydrazine-1-carbothioamide) derivatives as a new class of α-glucosidase inhibitors and their mechanistic insights via molecular docking and dynamic simulations.

In the past, efforts have been made to find a cure for diabetes, mainly evaluating new classes of compounds to explore their potency. In this study, we present the synthesis and evaluation of carbonylbis(hydrazine-1-carbothioamide) derivatives as potential α-glucosidase inhibitors, employing both in vivo and in silico investigations. The in vitro experiments revealed that all tested compounds were significantly potent for α-glucosidase inhibition, with the lead compound 3a displaying approximately 80 times higher activity than acarbose. To delve deeper, in silico induced fit docking, pharmacokinetics, and molecular dynamics studies were conducted. Significantly, compound 3a exhibited a docking score of -7.87 kcal/mol, surpassing acarbose, which had a docking score of -6.59 kcal/mol. The in silico ADMET indicated that most of the synthesized compounds have properties conducive to drug development. Molecular dynamics analysis demonstrated that, when the ligand 3a was coupled with the target 3TOP, Cα-RMSD backbone RMSD values below 2.4 Å and "Lig_fit_Prot" values below 2.7 Å were observed. QSAR analysis demonstrates that the "fOC8A" descriptor positively correlates with α-glucosidase inhibition activity, while "lipoplus_AbSA" positively contributes and "notringC_notringO_8B" negatively contributes to this activity.

Screening of potential α-glucosidase inhibitors from astragalus membranaceus by affinity ultrafiltration screening coupled with UPLC-ESI-Orbitrap-MS method.

Astragalus membranaceus is a traditional Chinese medicine with multiple pharmacological activities. Modern pharmacological research has found that Astragalus membranaceus extract has an inhibitory effect on α-glucosidase, however, which component can inhibit the activity of α-glucosidase and its degree of inhibition are unknown. To address this issue, this study used affinity ultrafiltration screening combined with UPLC-ESI-Orbitrap-MS technology to screen α-glucosidase inhibitors in Astragalus membranaceus. Using affinity ultrafiltration technology, we obtained the active components, and using UPLC-ESI-Orbitrap-MS technology, we quickly analyzed and identified them. As a result, a total of 8 ingredients were selected as α-glucosidase inhibitors.

Discovery of N-(phenylsulfonyl)thiazole-2-carboxamides as potent α-glucosidase inhibitors.

In a search for novel nonsugar α-glucosidase inhibitors for diabetes treatment, a series of N-(phenylsulfonyl)thiazole-2-carboxamide derivatives were designed and synthesized, the α-glucosidase inhibitory activities were then evaluated. Several compounds with promising α-glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α-glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 µM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 µM). W24 was identified as a promising candidate in the development of α-glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α-glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol.

Preparation, structural properties, and in vitro and in vivo activities of peptides against dipeptidyl peptidase IV (DPP-IV) and α-glucosidase: a general review.

Diabetes is one of the fastest-growing and most widespread diseases worldwide. Approximately 90% of diabetic patients have type 2 diabetes. In 2019, there were about 463 million diabetic patients worldwide. Inhibiting the dipeptidyl peptidase IV (DPP-IV) and α-glucosidase activity is an effective strategy for the treatment of type 2 diabetes. Currently, various anti-diabetic bioactive peptides have been isolated and identified. This review summarizes the preparation methods, structure-effect relationships, molecular binding sites, and effectiveness validation of DPP-IV and α-glucosidase inhibitory peptides in cellular and animal models. The analysis of peptides shows that the DPP-IV inhibitory peptides, containing 2-8 amino acids and having proline, leucine, and valine at their N-terminal and C-terminal, are the highly active peptides. The more active α-glucosidase inhibitory peptides contain 2-9 amino acids and have valine, isoleucine, and proline at the N-terminal and proline, alanine, and serine at the C-terminal.

Ligand-targeted fishing of α-glucosidase inhibitors from Tribulus terrestris L. based on chitosan-functionalized multi-walled carbon nanotubes with immobilized α-glucosidase.

α-Glucosidase inhibitors in natural products are one of the promising drugs for the treatment of type 2 diabetes. However, due to the complexity of the matrix, it is challenging to comprehensibly clarify the specific pharmacodynamic substances. In this study, a novel high-throughput inhibitor screening strategy was established based on covalent binding of α-glucosidase on chitosan-functionalized multi-walled carbon nanotubes coupled with high-resolution mass spectrometry. The synthesized MWCNTs@CS@GA@α-Glu was characterized by TEM, SEM, FTIR, Raman, and TG. Performance studies showed that the microreactor exhibited stronger thermostability and pH tolerance than that of the free one while maintaining its inherent catalytic activity. Feasibility study applying a model mixture of known α-glucosidase ligand and non-ligands indicated the selectivity and specificity of the system. By integrating ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-QTOF-MS) with ion mobility mass spectrometry (IMS), 15 ligands were obtained and tentatively identified from Tribulus terrestris L., including 8 steroidal saponins, 4 flavonoids, and 3 alkaloids. These inhibitors were further validated by in vivo experiments and molecular docking simulation.

Coumarin linked thiazole derivatives as potential α-glucosidase inhibitors to treat diabetes mellitus.

Diabetes is a leading cause of kidney failure, blindness, heart attacks and lower limb amputation. Prevalence of diabetes is rising globally. α-glucosidase is validated target for controlling hyperglycemia because of its role in catalysing hydrolysis of carbohydrates to glucose in GIT. In an attempt to find novel safe and effective α-glucosidase inhibitors, coumarin linked thiazole was identified as potential scaffold on the basis of its interactions with the active site of α-glucosidase studied in silico. A series of coumarin linked thiazole derivatives were synthesized and analyzed for α-glucosidase inhibitory potential in an in-vitro assay. The synthesized molecules showed potent inhibition of α-glucosidase with IC50 values ranging from 0.14 to 9.38 µM. The most potent compound 2-[(4-bromophenyl) amino)-N-(4- (2-oxo-2H-chromen-3-yl) thiazol-2-yl] acetamide was further docked with α-glucosidase and molecular dynamics studies were carried out for 100 ns which suggested the stability of protein and ligand in the protein active site over the simulation period and role of hydrophobic interactions slightly more than the electrostatic/polar interactions in ligand- receptor stability. In summary, our results demonstrate efficacy of coumarin-linked thiazole as potential leads for further optimization and development.

Rapid screening of α-glucosidase inhibitors in Hypericum perforatum L. using bio-affinity chromatography coupled with UPLC/MS.

α-glucosidase inhibitors (AGIs) are widely used for the treatment of type 2 diabetes, but their side effects have made it to develop novel and alternative AGIs immediately. In this study, the extract of Hypericum perforatum L. (HPE) has been confirmed to have α-glucosidase inhibitory activity in vitro and in vivo. Seven active compounds, rutin, hyperoside, isoquercitrin, avicularin, quercitrin, quercetin, and biapigenin, were screened based on a bio-affinity chromatography column with α-glucosidase enzyme-conjugated solid phase and UPLC/MS, which exhibited excellent α-glycosidase inhibitory effects by the determined IC50 values. The mechanism of α-glycosidase inhibitory activity of biapigenin was studied for the first time. The results showed that biapigenin was a high-potential, reversible, and mixed enzyme inhibitor. Analysis by molecular docking further revealed that hydrophobic interactions were generated by interactions between biapigenin and amino acid residues LYS156, PHE303, PHE314, and LEU313. In addition, hydrogen bonding occurred between biapigenin and α-glucosidase amino acid residues ASP307, SER241, and LYS156. This research identified that biapigenin could be a novel AGI and further applied to the development of potential anti-diabetic drugs. Furthermore, our studies established a rapid in vitro screening method for AGIs from plants.

Inhibition of α-Glycosidase by Lippia dulcis Trevir. (Verbenaceae) Preparations, Quantification of Verbascoside, and Study of Its Molecular Docking.

This study aimed to quantify verbascoside (VEB), perform molecular docking studies of VEB with the α-glucosidase (GL) of Bacillus stearothermophilus, and evaluate the inhibition of the enzyme by L. dulcis preparations. The substrate concentration and presence of reduced glutathione were evaluated for their effect on the in vitro inhibition of the GL enzyme. Assays were also performed in the presence and absence of simulated gastric fluid. The antidiabetic fractions 2 and 3 were the most inhibited GL, but their activity were significantly decreased in the presence of gastric fluid. Chromatographic analyses confirmed the predominant presence of VEB in the samples. The samples had VEB concentrations between 49.9 and 243.5 mg/g. Simulation of the molecular docking of VEB were consistent with its GL-inhibitory activity. It can conclude that the crude ethanol extract and fractions show inhibitory activity against the GL enzyme.

Pyrazole scaffold-based derivatives: A glimpse of α-glucosidase inhibitory activity, SAR, and route of synthesis.

The α-glucosidase is a validated target to develop drugs for treating type 2 diabetes mellitus. The existing α-glucosidase inhibitors have certain shortcomings related to side effects and route of synthesis. Accordingly, it is inevitable to develop new chemical templates as α-glucosidase inhibitors. Pyrazole derivatives have a special place in medicinal chemistry because of various biological activities. Recently, pyrazole-based heterocyclic compounds have emerged as a promising scaffold to develop α-glucosidase inhibitors. This study focuses on the recently reported pyrazole-based α-glucosidase inhibitors, including their biological activity (in vivo, in vitro, and in silico), structure-activity relationship, and ways of synthesis. The literature revealed the development of several promising pyrazole-based α-glucosidase inhibitors and new synthetic routes for their preparation. The encouraging α-glucosidase inhibitory results of the pyrazole-based heterocyclic compounds make them an attractive target for further research. The authors also foresee the arrival of the pyrazole-based α-glucosidase inhibitors in clinical practice.

Design, synthesis, α-glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives.

A new series of indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives 7a-l were designed, synthesized, and screened for their α-glucosidase inhibitory abilities and cytotoxic effects. The results obtained in the α-glucosidase inhibition assay indicated that most of the synthesized derivatives displayed good to moderate inhibitory abilities (Ki values ranging from 14.65 ± 2.54 to 37.466 ± 6.46 µM) when compared with the standard drug acarbose (Ki = 42.38 ± 5.73 µM). Among them, 2-mehoxy-phenoxy derivatives 7l and 7h with 4-nitro and 4-chloro substituents on the phenyl ring of the N-phenylacetamide moiety, respectively, displayed the most inhibition effects. The inhibitory mechanism of these compounds was investigated by molecular docking studies. The in vitro cytotoxicity assay showed that only one compound, 2-methoxy-phenoxy derivative 7k with a 4-bromo substituent on the phenyl ring of the N-phenylacetamide moiety, exhibited moderate cytotoxicity against the human non-small-cell lung cancer cell line A549 and the rest of the compounds show almost no cytotoxicity. Further cytotoxic evaluations were also performed on compound 7k. The in silico pharmacokinetic study predicted that the selected compounds 7l and 7h are likely to be orally active.

Evaluation of α-Glucosidase Inhibition and Antihyperglycemic Activity of Extracts Obtained from Leaves and Flowers of Rumex crispus L.

Among antihyperglycemic drugs used for treating diabetes, α-glucosidase inhibitors generate the least adverse effects. This contribution aimed to evaluate the potential antidiabetic activity of Rumex crispus L. by testing its in vitro α-glucosidase inhibition and in vivo antihyperglycemic effects on rats with streptozotocin (STZ)-induced diabetes. Better inhibition of α-glucosidase was found with the methanol extract versus the n-hexane and dichloromethane extracts. The methanol extract of the flowers (RCFM) was more effective than that of the leaves (RCHM), with an IC50 of 7.3 ± 0.17 µg/mL for RCFM and 112.0 ± 1.23 µg/mL for RCHM. A bioactive fraction (F89s) also showed good α-glucosidase inhibition (IC50 = 3.8 ± 0.11 µg/mL). In a preliminary study, RCHM and RCFM at 150 mg/kg and F89s at 75 mg/kg after 30 days showed a significant effect on hyperglycemia, reducing glucose levels (82.2, 80.1, and 84.1%, respectively), and improved the lipid, renal, and hepatic profiles of the rats, comparable with the effects of metformin and acarbose. According to the results, the activity of R. crispus L. may be mediated by a diminished rate of disaccharide hydrolysis, associated with the inhibition of α-glucosidase. Thus, R. crispus L. holds promise for the development of auxiliary drugs to treat diabetes mellitus.

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.

Identification of Phytochemicals in Bioactive Extracts of Acacia saligna Growing in Australia.

Acacia saligna growing in Australia has not been fully investigated for its bioactive phytochemicals. Sequential polarity-based extraction was employed to provide four different extracts from individual parts of A. saligna. Bioactive extracts were determined using in vitro antioxidant and yeast α-glucosidase inhibitory assays. Methanolic extracts from barks, leaves, and flowers are the most active and have no toxicity against 3T3-L1 adipocytes. Compound isolation of bioactive extracts provided us with ten compounds. Among them are two novel natural products; naringenin-7-O-α-L-arabinopyranoside 2 and (3S*,5S*)-3-hydroxy-5-(2-aminoethyl) dihydrofuran-2(3H)-one 9. D-(+)-pinitol 5a (from barks and flowers), (-)-pinitol 5b (exclusively from leaf), and 2,4-di-t-butylphenol 7 are known natural products and new to A. saligna. (-)-Epicatechin 6, quercitrin 4, and myricitrin 8 showed potent antioxidant activities consistently in DPPH and ABTS assays. (-)-Epicatechin 6 (IC50 = 63.58 µM),D-(+)-pinitol 5a (IC50 = 74.69 µM), and naringenin 1 (IC50 = 89.71 µM) are the strong inhibitors against the α-glucosidase enzyme. The presence of these compounds supports the activities exerted in our methanolic extracts. The presence of 2,4-di-t-butylphenol 7 may support the reported allelopathic and antifungal activities. The outcome of this study indicates the potential of Australian A. saligna as a rich source of bioactive compounds for drug discovery targeting type 2 diabetes.

Towards multi-target antidiabetic agents: In vitro and in vivo evaluation of 3,5-disubstituted indolin-2-one derivatives as novel α-glucosidase inhibitors.

Type 2 diabetes mellitus is a chronic progressive disease that usually requires polypharmacological treatment approaches. Previously we have described a series of 2-oxindole derivatives as GSK3ß inhibitors with in vivo antihyperglycemic activity. α-Glucosidase is another antidiabetic target that prevents postprandial hyperglycemia and corresponding hyperinsulinemic response. Herein we report a study of 3,5-disubstituted indolin-2-one derivatives as potent α-glucosidase inhibitors. These inhibitors were identified via efficient synthesis, in vitro screening, and biological evaluation. The most active compound 5f inhibits yeast α-glucosidase with IC50 of 6.78 µM and prevents postprandial hyperglycemia in rats after maltose and sucrose challenge at 5.0 mg/kg dose. Two lead glucosidase inhibitors, 5f and 5m, are also GSK3ß inhibitors with submicromolar potency. Hence, structure-activity studies elucidate foundation for development of dual GSK3ß/α-glucosidase inhibitors for treatment of type 2 diabetes.

Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against ß-glucosidase.

A series of novel benzimidazole-iminosugars linked a (substuituted) phenyl group on benzene ring of benzimidazole 5(a-p) and 6(a-p) have been rationally designed and conveniently synthesized through Suzuki coupling reaction in high yields. All compounds have been evaluated for their inhibitory activities against ß-glucosidase (almond). Six compounds 5d, 6d, 6e, 6i, 6n, and 6p showed more significant inhibitory activities with IC50 values in the range of 0.03-0.08 µM, almost 10-fold improved than that of the parent analogue 4, and much higher than that of the positive control castanospermine. The additional phenyl ring and the electron donating groups on it would be beneficial for the activity. Compounds 6d, 6n, and 4 had been chosen to be tested for their inhibition types against ß-glucosidase. Interestingly, three compounds have different inhibition types although they had very similar structure. Their Ki values were calculated to be 0.02 ± 0.01 µM, 0.02 ± 0.01 µM, and 0.66 ± 0.14 µM, respectively. The equilibrium dissociation constant (KD) for 6d, 6n, and 4 and ß-glucosidase was 0.04 µM, 0.03 µM and 0.45 µM by the ITC-based assay, respectively. Molecular docking work suggests that such benzimidazole-iminosugars derivatives might bind to the active site of ß-glucosidase mainly through hydrogen bonds, the additional phenyl ring towards the solvent-exposed region played an important effect on their inhibitory activity against ß-glucosidase.

All-cause mortality and cardiovascular events in patients with type 2 diabetes treated with alpha-glucosidase inhibitors: A meta-analysis of randomized controlled trials.

AIM: Alpha-glucosidase inhibitors are approved drugs for treating type 2 diabetes (T2DM); however, their effects on mortality and cardiovascular safety are unclear. This meta-analysis was aimed at evaluating the effects of alpha-glucosidase inhibitors on all-cause mortality and major cardiovascular events (MACE). DATA SYNTHESIS: A Medline, Embase, Cochrane database searching for alpha-glucosidase inhibitors was performed up to July 1st, 2021. All randomized controlled trials (RCT) with a duration ≥52 weeks and comparing the effects of alpha-glucosidase inhibitors with placebo or active drugs were collected. Further inclusion criteria were: RCT reporting MACE within their primary outcome, or as pre-defined secondary outcome; and RCT enrolling at least 100 patients with T2DM. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence intervals were calculated for the aforementioned outcomes. A total of eight RCTs, enrolling 1124 and 908 patients on alpha-glucosidase inhibitors and comparators, respectively, were identified. No trials reported information on MACE. Treatment with alpha-glucosidase inhibitors was not associated with a significant increase of all-cause mortality compared with other therapies or no therapy/placebo (MH-OR 0.76 [0.28; 2.05]). CONCLUSIONS: The evidence of beneficial or detrimental effects of alpha-glucosidase inhibitors on all-cause mortality and cardiovascular events is not sufficient to draw any conclusions.