Potent Α-glucosidase Inhibitors Research Articles

Design, synthesis, and evaluation of novel substituted imidazo[1,2-c]quinazoline derivatives as potential α-glucosidase inhibitors with bioactivity and molecular docking insights.

α-Glucosidase inhibitors are important in the treatment of type 2 diabetes by regulating blood glucose levels and reducing carbohydrate absorption. The present study focuses on identifying new inhibitors bearing imidazo[1,2-c]quinazoline backbone through multi-step synthesis. The inhibitory potencies of the novel derivatives were tested against Saccharomyces cerevisiae α-glucosidase, revealing IC50 values ranging from 50.0 ± 0.12 µM to 268.25 ± 0.09 µM. Among them, 2-(4-(((2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (19e) and 2-(4-((benzo[4,5]imidazo[1,2-c]quinazolin-6-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (27e) emerged as the most potent inhibitors and were further investigated in various assessments. Finally, molecular docking studies were performed to reveal the crucial binding interactions and to confirm the results obtained from structure-activity relationship (SAR) analysis.

Design, synthesis, biological evaluation, and molecular modeling studies of some quinazolin-4(3H)-one-benzenesulfonamide hybrids as potential α-glucosidase inhibitors

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, posing serious health risks and becoming increasingly prevalent. Prolonged hyperglycemia can lead to complications such as nephropathy, neuropathy, retinopathy, cardiovascular damage, and blindness. Controlling hyperglycemia through α-glucosidase inhibitors, which slow down carbohydrate breakdown, is an effective treatment strategy. However, current inhibitors like acarbose, voglibose, and miglitol while used to manage type 2 diabetes, have significant side effects. Therefore, developing new α-glucosidase inhibitors that are more effective and have fewer side effects is crucial. In this study, a series of novel quinazolin-4(3H)-one-benzenesulfonamide hybrid compounds were designed, synthesized, and evaluated for in vitro α-glucosidase inhibitory activity. The compounds showed higher enzyme inhibition potency, with IC50 values ranging between 129.2 ± 0.5 and 558.7 ± 13.7 µM, compared to acarbose (IC50=814.3 ± 13.5 µM). Among the tested compounds, compound 10, bearing a 4-chlorophenyl ring on the nitrogen atom of the sulfonamide group, was the most active, with an IC50 value of 129.2 ± 0.5 µM. Enzyme kinetics analyses and molecular modeling studies were conducted to understand their inhibition mechanisms and interactions with the enzyme. The kinetic studies revealed a mixed-type inhibition model, indicating that the compounds bind to the enzyme-substrate complex with higher affinity than to the free enzyme. Molecular modeling results confirmed these findings. Additionally, in silico prediction studies showed that the selected compounds have favourable physicochemical and drug-like properties. These results suggest these compounds have potential for further optimization and development as effective α-glucosidase inhibitors for diabetes treatment.

Metabolite Profiling and Integrated Network Pharmacology Based Mechanism of Benincasa hispida (Thunb.) Cogn. Fruit Against Non-insulin-Dependent Diabetes Mellitus.

Benincasa hispida (Thunb.) Cogn. (Cucurbitaceae) is an essential food plant in India possessing antihyperglycemic and antihyperlipidemic activities. The objective included comparative estimation of α-glucosidase and α-amylase enzyme inhibition potential of B. hispida fractions prepared by microwave-assisted extraction and prediction of metabolite interaction against non-insulin-dependent diabetes mellitus by metabolite profiling based network pharmacology analysis. A validated microwave-assisted extraction method was employed to obtain different fractions of B. hispida fruits. The invitro enzyme assay was done with p-nitrophenyl-α-D-glucopyranoside and acarbose as standard to evaluate antidiabetic potential. The phytomolecules present in the active fraction wereidentified by UHPLC-QToF-MS/MS analysis. Network pharmacology analysis gave possible gene and disease association, combination synergy network, and predicted probable mechanism of action. The highest enzyme inhibition potential (IC50) was shown by the ethyl acetate fraction (0.546 ± 0.17 mg/mL and 1.134 ± 0.42 mg/mL) compared to acarbose (0.298 ± 0.08 mg/mL and 0.532 ± 0.38 mg/mL), respectively, for α-glucosidase and α-amylase addressing the potential role in ameliorating non-insulin-dependent diabetes mellitus. Metabolite profiling resulted in the identification of 17 metabolites, and a synergy between the identified molecules suggested multimolecule action in the amelioration of non-insulin-dependent diabetes mellitus through insulin resistance pathway, AMPK signaling pathway, PPAR signaling pathway, and PI3K-Akt signaling pathway. Combination synergy of identified molecules was observed through a multitarget approach to manage non-insulin-dependent diabetes mellitus. Polyphenol-enriched fraction of B. hispida fruits and identified phytocompounds ameliorate non-insulin-dependent diabetes mellitus. Thus, enriched extract of B. hispida can be further investigated in order to develop high-quality, safe, and effective products for the management of non-insulin-dependent diabetes mellitus.

Evaluating the antidiabetes and antioxidant activities of halogenated Schiff bases derived from 4-(diethylamino)salicylaldehyde: in vitro antidiabetes, antioxidant and computational investigation

Six Schiff bases with general name 5-(diethylamino)-2-(((halophenyl)imino)methyl)phenol (where halo = 4-fluoro (H1), 2-fluoro (H2), 2-bromo (H3), 4-bromo (H4), 4-chloro (H5) and 3-chloro-4-fluoro (H6)) were prepared by the condensation reaction between 4-(diethylamino)salicylaldehyde and suitable halogenated aromatic amines. The six halogenated Schiff bases were elucidated using different spectroscopic techniques and the structure of H3 and H6 were confirmed using single-crystal X-ray crystallography. The bond lengths of C7–N1, C7–C8 and C8–C9 obtained from structural analysis for both compounds depicted their enol-tautomeric characteristic form. The Hirshfeld analysis revealed that H‧‧‧H intermolecular contacts contributed most towards the Hirshfeld surfaces of both H3 (47.6%) and H6 (39.9%). Quantum chemical calculation studies showed that H1 and H2 have the highest and lowest energy band gap (∆E = 3.80 eV for H1 and ∆E = 3.73 eV for H2), depicting H2 and H1 as the most and least chemically reactive respectively among all the compounds. α-Amylase and α-glucosidase assay were used to evaluate the antidiabetes prowess of the synthesized compounds. All the compounds exhibited lower IC50 values than acarbose (reference drug) in α-amylase assay experiments and H5 with lowest IC50 value of 63.54 μM could be suggested to have the highest α-amylase inhibitory potential among the test samples. For α-glucosidase assay, H1–H6 displayed good antidiabetic potential. However, none of the compounds outshined acarbose with H6 having highest α-glucosidase inhibitory potential when compared to others i.e., IC50 of H6 = 60.89 μM and IC50 of acarbose = 51.42 μM. We measured the antioxidant potential of H1–H6 exploring 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and ferric reducing ability power (FRAP) assays. The DPPH as well as NO radical scavenging assay showed that all the compounds exhibited excellent antioxidant results with some of the compounds surpassing catechin (reference drug). Compound H5 with IC50 values of 30.32 mM and 31.73 mM outshined catechin with IC50 values of 31.17 mM and 140.62 mM for DPPH and NO assays respectively. All the compounds fell within the threshold of Lipinski’s Ro5 projecting them as orally bioavailable and less toxic future therapeutics.

Gas Chromatography-Mass Spectrometry and Fourier Transform Infrared Spectroscopy Analysis of Potential α-Glucosidase Inhibitors from Terminalia catappa Leaf Extracts

Aims: Postprandial hyperglyceamia is often caused by insulin insufficiency or cellular glucose uptake complications, and conventional treatments often yield undesirable side effects. The aim of the current work was to assess the α-glucosidase inhibitory activities of T. catappa leaf extracts and use spectroscopic techniques to partially characterize possible inhibitors. Study Design: Phytochemical screening, enzyme inhibition assay and spectrometric and spectroscopic characterization of bioactive compounds from leaf extract and fractions of T. catappa. Place and Duration of Study: The entire work was carried out at the Department of Applied Chemistry and Biochemistry, University for Development Studies, Ghana within nine months. Methodology: T. catappa leaf extract and fractions were qualitatively screened for phytochemicals and their biological activity assessed in α-glucosidase inhibition assay. The potential enzyme inhibitors were characterized by Gas Chromatography-Mass Spectrometry (GC-MS) and Fourier Transform Infrared (FT-IR) Spectroscopy. Results: Phytochemical screening of the extract and the various solvent fractions revealed the presence of alkaloids, flavonoids, saponins, flavanol glycosides, phenolics, and terpenoids. The α-glucosidase inhibition potential of the crude leaf extract was concentration-dependent with a half-maximal inhibitory concentration (IC50) of 337.5 µg/ml. Solvent fractions from the crude extract demonstrated α-glucosidase inhibitory activity with IC50 values ranging from 170.40 µg/ml for ethyl acetate (EtOAc) fraction to 71.90 µg/ml for n-hexane (n-Hex) fraction. Acarbose, the control drug, demonstrated significant α-glucosidase inhibition activity in a similar pattern with IC50 of 6.16 µg/ml. The enzyme inhibition kinetics parameters, specifically the Michaelis constant (KM) and Maximum reaction velocity (Vmax) values, suggested that the inhibition of α-glucosidase by T. catappa extract followed a competitive mode. GC-MS and FT-IR analysis of the n-Hexane fraction identified the compounds Eugenol, Urs-12-en-24-oic acid, 3-oxo-, methyl ester (+)-, phytol, trans-isoeugenol, α-amyrin, and squalene as the potential antidiabetic agents that might be responsible for reducing postprandial blood glucose levels. Conclusion: These findings show that T. catappa leaf extract contains α-glucosidase inhibitors and therefore serves as a valuable resource in the discovery of natural anti-diabetic agents.

Quinoline-Piperazine Derivatives as Potential α-Glucosidase Inhibitors: Synthesis, Biological Evaluation, and In Silico Studies

α-Glucosidase inhibitors are crucial therapeutic agents for managing postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). This study focuses on designing, synthesizing, and evaluating a new series of quinoline-piperazine-acetamide derivatives as potential α-glucosidase inhibitors. These derivatives introduce a unique combination of a quinoline core with a flexible piperazine linker, as new scaffold for α-glucosidase inhibition. This structural modification is hypothesized to enhance enzyme interaction. The synthesized derivatives were tested in vitro for their inhibitory activity, with compounds 6m (benzyl) and 6f (2-nitrophenyl) showing significant inhibition, having IC50 values of 280.0 µM and 546.2 µM, respectively, compared to the standard drug acarbose (IC50 = 750.7 µM). Molecular docking studies revealed crucial pi-pi stacking and pi-cation interactions with key residues such as His239 and Phe231, along with hydrogen bonding with Lys155, Pro309, and Thr215, which enhanced the inhibitory potency of the active compounds. Furthermore, molecular dynamics simulations confirmed that 6m consistently maintained stability within the active site of α-glucosidase throughout the simulation. These findings suggest that the synthesized compounds hold promise as α-glucosidase inhibitors for adjusting blood sugar control and metabolic health.

Synthesis, highly potent α-glucosidase inhibition, antioxidant and molecular docking of various novel dihydropyrimidine derivatives to treat diabetes mellitus

1,4-dihydropyrimidine-2-thiones were synthesized in five series that include 5-carboxylic acid derivatives of dihydropyrimidine (series A, 6–8), novel 5-carboxamide derivatives of dihydropyrimidine (series B, 9–14), N,S-dimethyl-dihydropyrimidine (series C, 15–20), N-hydrazinyl derivatives of dihydropyrimidine (series D, 21–24) and tetrazolo dihydropyrimidine derivatives (series E, 25–28), and evaluated for anti-diabetic capability. The prepared novel compounds were structurally established by FTIR, 1HNMR, 13CNMR, ESI and HRMS. All of these compounds from series A-E were first time examined for α-glucosidase inhibition as to evaluate their anti-diabetic potential. Most of the compounds for example 8, 11–14, 15, 17–21, 25 and 28 demonstrated greater α-glucosidase inhibitory effects (IC50 = 12.5 ± 0.21 to 47.3 ± 0.23 μM) when compared to deoxynojirimycin as standard (IC50 = 52.02 ± 0.36 μM). Compounds from series B and C found to be highly active however, the compounds from series D found generally less active. The structure–activity relationships demonstrated the importance of C-5 carboxamides, C-5 ethyl ester functionality, and the presence of N,S-dimethyl groups at pyrimidine ring for α-glucosidase inhibition. The docking studies demonstrated that all the active compounds have van der Waal and alkyl bonds interactions with the targeted site of the human lysosomal acid α −glucosidase. All these compounds were also tested for antioxidant potential by DPPH radical scavenging protocol that exhibited significant antioxidant effects (IC50 = 21.4 ± 0.45 to 92.1 ± 0.38 μM) as compared to the standard butylated hydroxyanisol (IC50 = 44.2 ± 0.36 μM). Among all, compound 13, 14 and 19 with potent α-glucosidase inhibition (IC50 = 18.9 ± 0.72, 23.3 ± 0.45 and 21.5 ± 0.16 µM, respectively) along with excellent antioxidant potential in the range of (IC50 = 21.4 ± 0.45 to 31.2 ± 0.23 μM) indicated their ability to use as valuable leads for the development of anti-diabetic drugs with the combined effects of antioxidants.

Identification of new structure of indol-3-acetyl-arylsulfonohydrazide as potent α-glucosidase and α-amylase inhibitors and molecular docking

Herein this work, indole analogs (1-16) were synthesized by treating 2-(1H-indol-3-yl)acetohydrazide with various aryl sulfonyl chloride in pyridine as solvent and screened for α-amylase and α-glucosidase inhibitory activity under positive control of standard drug acarbose (IC50 = 12.80 ± 0.10 μM /12.90 ± 0.10 μM. All analogs of the series appeared with excellent to good inhibitory activity as compared to standard drug. The inhibitory activity range for α-amylase is 0.70 ± 0.01 μM to 19.40 ± 0.40 μM, while for α-glucosidase inhibitory activity is 1.20 ± 0.10 μM to 20.40 ± 0.40 μM respectively. Most of the analogs appeared with excellent inhibitory activity, and some analogs like 5, 6, 7, 8, 9, 10,13 and 14 for both enzymes displayed many folds better inhibitory activity than standard drug acarbose. The influences of substituents on inhibitory activity were superficially resonated via structure activity relationship. Docking studies were established to confirm the binding interaction between analogs and active sites of enzymes.

Novel coumarin-thiazolidine-2,4‑dione hybrids as potential α-glucosidase inhibitors: Synthesis and bioactivity evaluation

To discover novel α-glucosidase inhibitors, a series of coumarin- thiazolidine-2,4‑dione hybrids (BJX1∼20) were synthesized and assessed their inhibitory activities against α-glucosidase. Compared to acarbose (IC50 = 655.01 ± 52.54 μM), coumarin-thiazolidinedione hybrids (BJX1∼20) displayed stronger α-glucosidase inhibitory activity, with IC50 values ranging from 5.12 ± 0.48 to 24.07 ± 1.96 μM. BJX3, BJX9, and BJX15 exhibited strongest inhibitory activities against α-glucosidase and acted as non-competitive inhibitors. The fluorescence quenching experiment revealed that the interaction between BJX3, BJX9, BJX15, and α-glucosidase followed a static binding process. CD spectra and 3D fluorescence spectra analysis revealed that the binding of BJX3, BJX9, and BJX15 to α-glucosidase induced a conformation change of α-glucosidase, thereby inhibiting its activity. Molecular docking simulation revealed the binding mechanism of BJX3, BJX9, and BJX15 with α-glucosidase. In vitro cytotoxicity assay indicated BJX15 (0∼64 μM) showed no obvious cytotoxicity against HEK 293 cells. In vivo experiments in mice demonstrated the ameliorative effect of orally administered BJX15 (50 mg kg-1) on postprandial hyperglycemia.

In Vitro Inhibitory Mechanism of Polyphenol Extracts from Multi-Frequency Power Ultrasound-Pretreated Rose Flower Against α-Glucosidase.

This paper explored the in vitro inhibitory mechanism of polyphenol-rich rose extracts (REs) from an edible rose flower against α-glucosidase using multispectral and molecular docking techniques. Results showed that REs had an inhibitory effect on α-Glu activity (IC50 of 1.96 μg/mL); specifically, the samples pretreated by tri-frequency ultrasound (20/40/60 kHz) exhibited a significantly (p < 0.05) stronger inhibitory effect on α-Glu activity with an IC50 of 1.33 μg/mL. The Lineweaver-Burk assay indicated that REs were mixed-type inhibitors and could statically quench the endogenous fluorescence of α-Glu. REs increased the chance of polypeptide chain misfolding by altering the microenvironment around tryptophan and tyrosine residues and disrupting the natural conformation of the enzyme. Molecular docking results showed that polyhydroxy phenolics had a high fit to the active site of α-Glu, so REs with high polymerization and numerous phenolic hydroxyl groups had a stronger inhibitory effect. Therefore, this study provides new insights into polyphenol-rich REs as potential α-glucosidase inhibitors.

Synthesis and Evaluation of Phenyltriazole-Deoxynojirimycin Hybrids as Potent α-Glucosidase Inhibitors.

1-deoxynojirimycin (DNJ) is a well-known α-glucosidase inhibitor. A series of phenyltriazole-deoxynojirimycin hybrids containing C4 and C6 (4 and 6 methylenes, respectively) linkers were synthesized. These novel compounds were assessed for preliminary glucosidase inhibition and cytotoxicity tests in vitro. Among them, compounds 12-14 and 16-20 (IC50: 105 ± 9-11 ± 1 μM) were more active than deoxynojirimycin (DNJ, IC50 = 155 ± 15 μM). The kinetics of enzyme inhibition measured by using Lineweaver-Burk plots indicated that compounds 18 and 19 were competitive inhibitors. In addition, a molecular docking study of α-glucosidase revealed that the interaction modes and the orientations of compound 18 and DNJ were clearly different. Furthermore, in tissue culture, HL60 cell compounds showed no cytotoxicity at low concentrations. When the concentration reached 50 µM, only compound 20 exhibited cytotoxicity. The structure-activity relationships exhibit that the length of the linker and the nature of 4-position substituents on the phenyl have a significant effect on the inhibitory potency of glucosidases and cytotoxicity.

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.

Impact of Drying Methods on Phenolic Composition and Bioactivity of Celery, Parsley, and Turmeric-Chemometric Approach.

Drying is one of the most commonly used methods for food preservation, and in spice processing, it has a significant impact on quality. In this paper, the influences of drying at room temperature, 60 °C, and 90 °C and freeze-drying on celery and parsley roots and turmeric rhizomes were examined. The highest content of total phenolics was found in celery dried at 60 °C (C60), parsley at room temperature (PRT), and freeze-dried turmeric (TFD) (1.44, 1.58, and 44.92 mg GAE/gdm, respectively). Celery dried at room temperature (CRT), PRT, and TFD showed the highest antioxidant activity regarding the DPPH and ABTS radicals and FRAP. The analysis of color parameters revealed that celery dried at 90 °C (C90); PFD and TFD showed the most similar values to control samples. The drying process was optimized using a combination of standard score (SS) and artificial neural network (ANN) methods. The ANN model effectively evaluated the significance of drying parameters, demonstrating high predictive accuracy for total phenolics, total flavonoids, total flavonols, total flavan-3-ols, IC50ABTS, and FRAP. TFD showed the strongest α-glucosidase inhibitory potential. Also, TFD extract showed good antibacterial activity against Staphylococcus aureus but not against Escherichia coli. C90 and PFD extracts did not show antibacterial activity against the tested microorganisms.

Potent α-glucosidase inhibitors with benzimidazole-propionitrile hybridization; synthesis, bioassay and docking study.

Background: Diabetes is characterized by a lack of insulin and insensitivity to insulin. In 2013, the global diabetes population was 382million, with 90% of them having type 2 diabetes (non-insulin-dependent). It is predicted that this number will increase to 592million by 2035.Aim: Here, we aimed to synthesize a series of benzimidazole-based derivatives B1-B32 with α-glucosidase inhibition potential as antidiabetic agents.Methods: Compounds B1-B32 were prepared in three three-step reactions, and the structures were elucidated using spectroscopic methods, namely 1H NMR, 13C NMR, MS and IR. Enzyme inhibition and kinetic study were done using commercial assay kits, and molecular docking study using autodock4.Results: Bioassay data showed that twenty-four out of the thirty-two tested compounds exhibited IC50 values ranging from 44 to 745μM, surpassing the standard molecule, acarbose (IC50: 750μM). it was determined that the best compound, B10, functions as a competitive inhibitor. Additionally, a molecular docking study provided insights into the interactions between the four most promising compounds (B5, B6, B10 and B28) and the active site residues within the enzyme.Conclusion: The tested compounds are interesting α-glucosidase inhibitors, which indicates the benefit of more bioassay studies, especially in vivo studies.

Design, synthesis and enzymatic inhibition evaluation of novel 4-hydroxy Pd–C-Ⅲ derivatives as α-glucosidase and PTP1B dual-target inhibitors

A library of 4-Hydroxy Pd–C-Ⅲ derivatives (5a-5p and 8a-8h) as α-glucosidase inhibitors was prepared and the activity of these compounds against α-glucosidase was evaluated. The outcomes displayed that most of the derivatives had moderate to potent α-glucosidase inhibition with IC50 values ranging from 66.3 ± 2.4 to 299.7 ± 6.0 μM. Amongst these compounds, 8a had the strongest α-glucosidase inhibition than others with an IC50 value of 66.3 ± 2.4 μM. Therefore, 8a was chosen to detect the inhibitory activities on PTP1B and α-amylase, the results revealed that 8a had the potential to be PTP1B (IC50 = 47.0 ± 0.5 μM) and α-amylase (IC50 = 30.62 ± 2.13 μM) inhibitor. Additionally, the enzyme kinetic study displayed that 8a was a mixed-type inhibitor. Moreover, the results of the spectroscopy experiments proved that 8a could quench the fluorescence intensity of α-glucosidase in a dose-dependent manner, destroy the secondary structure of α-glucosidase and change the conformation of the enzyme. Significantly, the investigation of cellular thermal shift assay exhibited that 8a could target the PTP1B protein, and the in vitro cytotoxicity discovered compound 8a had no significant toxicity to normal HEK-293 cells. Additionally, the results of molecular docking found that 8a could both bind the active sites of the α-glucosidase and PTP1B. Importantly, the in vivo sucrose-loading test displayed 8a had potential to reduce the postprandial blood glucose. All results proved that compound 8a had great potential as a dual-target inhibitor in treating Type 2 diabetes mellitus.

Inhibition of starch hydrolysis during in vitro co-digestion of pasta with phenolic compound-rich vegetable foods

The ability of phenolic compounds to inhibit amylolytic enzymes activities has been investigated, suggesting their possible role in type-2 diabetes management. However, these studies have been carried out with purified enzymes and synthetic substrates and are distant from simulating a real physiological situation. The objective of the present research was to evaluate the ability of phenolic-rich vegetable foods to inhibit starch hydrolysis during in vitro co-digestion with pasta resulting in a potential anti-diabetic effect and mimicking as closely as possible a real scenario. Some tested vegetable foods, such as capers, red-skinned onion, red radish, and olives, determined a decrease in starch hydrolysis by 21.5%–31.7% during in vitro co-digestion with pasta. The quali-quantitative phenolic profiles of in vitro co-digested samples were elucidated and selected standard compounds were tested for their ability to inhibit porcine pancreatic α-amylase and mammalian α-glucosidase. The inhibitory potential of these compounds, especially against α-glucosidase, explained the effect observed during co-digestion experiments. The most active phenolic compounds against α-glucosidase were quercetin-4’-O-glucoside, quercetin-3-O-rutinoside, luteolin-7-O-glucoside and quercetin-3-O-glucoside-4’-O-glucoside with IC50 values of 20.67, 52.23, 68.84 and 87.58 μmol/L, respectively. This is the first report suggesting that these compounds are potent inhibitors of mammalian α-glucosidase. This study indicates that consuming starchy foods (i.e., pasta) with phenolic-rich vegetable foods may result in an inhibition of starch digestion possibly reducing the post-prandial glucose levels.

Antihyperglycemic activity of a novel polyherbal formula (HF344), a mixture of fifteen herb extracts, for the management of type 2 diabetes: Evidence from in vitro, ex vivo, and in vivo studies

Antihyperglycemic effects of a novel polyherbal formula (HF344), comprising fifteen Thai herbal extracts, were elucidated for pharmacological mechanisms and potential for managing type 2 diabetes mellitus, by employing in vitro, ex vivo, and in vivo approaches. LC/MS analysis of HF344 extract revealed several phytoconstituents, with piperine identified as the major active compound. HF344 extract significantly enhanced insulin secretion in RINm5F cells in vitro and inhibited glucose uptake into the everted sacs of the mouse small intestine ex vivo in a concentration-dependent manner compared to the control (p < 0.05). It exhibited potent α-glucosidase inhibition in vitro, with an IC50 of 96.74 μg/mL. Moreover, HF344 extract upregulated mRNA levels of GLUT1 in L6 skeletal myoblasts, suggesting increased glucose uptake into skeletal muscle. In addition, in vivo antihyperglycemic effects were assessed in streptozotocin (STZ)-nicotinamide (NA)-induced diabetic mice. Acute oral toxicity testing confirmed the HF344 extract's safety, with an LD50 exceeding 2000 mg/kg. Oral administration of HF344 extract (500 and 1000 mg/kg) in STZ-NA-induced diabetic mice significantly reduced the area under the fasting blood glucose (FBG)-time curve (AUC) in the oral glucose tolerance test (OGTT) model and treatment for 28-day reduced the FBG levels as compared with control (p < 0.05). This was accompanied by increased serum insulin levels and improved insulin resistance. HF344 extract also demonstrated a concentration-dependent inhibitory effect on malondialdehyde (MDA) production in vitro, with an IC50 of 7.24 μg/mL. Oral treatment with HF344 extract decreased MDA production in the homogenized muscle ex vivo collected from STZ-NA-induced mice. Furthermore, pretreatment with HF344 extract effectively restored the survival of RINm5F cells from STZ-induced damage. These findings suggest that HF344 is a promising polyherbal formula for managing blood glucose levels, enhancing insulin production, and providing antioxidant benefits in T2DM. Further research is required to evaluate the clinical efficacy and safety profiles of HF344.

Phytobioinformatics screening of ayurvedic plants for potential α-glucosidase inhibitors in diabetes management

The enzyme α-glucosidase in the small intestine regulates blood glucose levels and stimulates the hydrolysis of oligosaccharides and polysaccharides, increasing glucose levels in the body. Inhibiting this enzyme slows glucose digestion and absorption and as a result post-prandial blood glucose levels remain low, causing decreased insulin demand. Here, we investigated the ayurvedic antidiabetic plants and virtually screened an in-house library of 478 phytochemicals of these plants against the human α-glucosidase. We identified 11 secondary metabolites, including palmitic acid α-monoglyceride, (+)-(2 R)-6-propionyloxyethyl-4′,5,7-trihydroxyisoflavanone, Abruquinone E, and Aurantiamide Acetate, among others, showed stronger interactions with the receptor than the native ligand N-acetyl cysteine. Surprisingly, except one, all of these metabolites were from Abrus precatorius L. [Fabaceae] affirming its ethnopharmacological use against diabetes. The stability of the interactions between the ligands and receptor protein was evaluated through Molecular Dynamic (MD) simulation trajectories including root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), H bonds, β-factor analysis, and binding energy calculation through MM/GBSA method. The efficacy of top metabolites in inhibiting α-glucosidase is depicted in pharmacophore analysis. A comprehensive pharmacokinetics analysis confirmed the druggability, safety, and efficiency of top drug candidates. Additionally, we predicted the interactions of these top metabolites within the biological system. The medicinal properties described in this study will help develop active drug candidates for therapeutic purposes. Further experiments are recommended to prove the effectiveness of these metabolites in inhibiting the α-glucosidase enzyme for exploring their potential in the treatment of diabetes.

Employing Machine Learning Models to Predict Potential α-Glucosidase Inhibitory Plant Secondary Metabolites Targeting Type-2 Diabetes and Their In Vitro Validation.

The need for new antidiabetic drugs is evident, considering the ongoing global burden of type-2 diabetes mellitus despite notable progress in drug discovery from laboratory research to clinical application. This study aimed to build machine learning (ML) models to predict potential α-glucosidase inhibitors based on the data set comprising over 537 reported plant secondary metabolite (PSM) α-glucosidase inhibitors. We assessed 35 ML models by using seven different fingerprints. The Random forest with the RDKit fingerprint was the best-performing model, with an accuracy (ACC) of 83.74% and an area under the ROC curve (AUC) of 0.803. The resulting robust ML model encompasses all reported α-glucosidase inhibitory PSMs. The model was employed to predict potential α-glucosidase inhibitors from an in-house 5810 PSM database. The model identified 965 PSMs with a prediction activity ≥0.90 for α-glucosidase inhibition. Twenty-four predicted PSMs were subjected to in vitro assay, and 13 were found to inhibit α-glucosidase with IC50 ranging from 0.63 to 7 mg/mL. Among them, seven compounds recorded IC50 values less than the standard drug acarbose and were investigated further to have optimal drug-likeness and medicinal chemistry characteristics. The ML model and in vitro experiments have identified nervonic acid as a promising α-glucosidase inhibitor. This compound should be further investigated for its potential integration into the diabetes treatment system.

Antioxidant, antibacterial, and α-glucosidase inhibition potential of three Allium species (Amaryllidaceae) from Iran

Introduction: Wild species of the genus Allium have high potential for use as medicine due to their essential secondary metabolites with antioxidant activity. This study explored the antioxidant, antibacterial, and α-glucosidase inhibition activities of three Allium species: Allium tripedale, Allium hooshidaryae, and Allium stipitatum. Methods: The antioxidant potentials of the plant methanol extracts were evaluated using the ferric reducing antioxidant power (FRAP) and the 2,2-diphenyl-1picrylhydrazil (DPPH) radical scavenging test. Total phenolic content (TPC), total flavonoid content (TFC) and α-glucosidase inhibition were also evaluated. Antibacterial assessments were done employing disk diffusion and microdilution methods to determine inhibition zone and minimum inhibitory concentration (MIC), respectively against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. Results: Allium hooshidaryae displayed high TPC (70.24 ± 0.0039 mg gallic acid equivalent/g extract), while A. tripedale had the highest TFC (87 ± 0.013 mg Quercetin equivalent/g extract). A. hooshidaryae showed superior antioxidant capacity (DPPH IC50: 724.4 ± 0.31 µg/mL; FRAP: 36.87 mg ascorbic acid equivalent/g extract) and stronger α-glucosidase inhibition (IC50 = 2.59 mg/mL vs. 4.33 mg/mL for A. tripedale and 6.41 mg/mL for A. stipitatum). Qualitative tests confirmed phenolic, flavonoid, and glycoside compounds in all three species. A. stipitatum uniquely contained saponin and tannin. A. hooshidaryae and A. stipitatum inhibited the bacterial strains effectively, especially at the higher concentration (400 µg/mL). A. stipitatum showed inhibition against all strains, particularly against S. aureus (MIC: 12.5 µg/mL). Conclusion: This study highlights the antidiabetic and antibacterial potential of three Allium species, emphasizing their values as rich sources of bioactive compounds.