Yeast Α-glucosidase Research Articles

Rare Sesterterpenoids from the Soil Derived Fungus, Aspergillus variecolor Strain SDG, Therapeutic Potential of Stellatic Acid and Docking Studies.

Ethyl acetate extract of the cultures of the soil-derived filamentous fungus, Aspergillus variecolor SDG strain from Nallamala forest resulted in the isolation of extremely rare sesterterpenoids, stellatic acid (1) and andilesin C (2). We report a thorough chemical characterization of these compounds using various spectroscopic techniques and evaluation of their in vitro preclinical therapeutic potential. Stellatic acid exhibits potent antioxidant activity with an IC50 of 38 µg/mL and significant anticancer activity against HeLa, HepG2, MCF7, and A549 cancer cell lines with an IC50 of 7-12 µM. On the other hand, andilesin C displayed moderate cytotoxicity against DU145 and B16F10 cancer cell lines but lacked antioxidant activity. Furthermore, the potential hypoglycemic property of stellatic acid was evaluated by measuring its inhibitory effect against α-glucosidase. It exhibited tenfold potency against yeast α-glucosidase (IC50 101.73 µg/mL) than mammalian α-glucosidase (IC50 1000.00 µg/mL). Docking studies were also performed to suggest the interaction mode of stellatic acid in the α-glucosidase enzyme active site. Notably, yeast α-glucosidase shows a higher affinity towards stellatic acid than mammalian α-glucosidase (3TOP). Thus, the in vitro preclinical study of stellatic acid suggests its potential efficacy in therapeutic drug development.

Insights into the transglucosylation activity of α-glucosidase from Schwanniomyces occidentalis

The α-glucosidase from Schwanniomyces occidentalis (GAM1p) was expressed in Komagataella phaffii to about 70 mg/L, and its transferase activity studied in detail. Several isomaltooligosaccharides (IMOS) were formed using 200 g/L maltose. The major production of IMOS (81.3 g/L) was obtained when 98% maltose was hydrolysed, of which 34.8 g/L corresponded to isomaltose, 26.9 g/L to isomaltotriose, and 19.6 g/L to panose. The addition of glucose shifted the IMOS synthesis towards products containing exclusively α(1 → 6)-linkages, increasing the production of isomaltose and isomaltotriose about 2–4 fold, enabling the formation of isomaltotetraose, and inhibiting that of panose to about 12 times. In addition, the potential of this enzyme to glycosylate 12 possible hydroxylated acceptors, including eight sugars and four phenolic compounds, was evaluated. Among them, only sucrose, xylose, and piceid (a monoglucosylated derivative of resveratrol) were glucosylated, and the main synthesised products were purified and characterised by MS and NMR. Theanderose, α(1 → 4)-D-glucosyl-xylose, and a mixture of piceid mono- and diglucoside were obtained with sucrose, xylose, and piceid as acceptors, respectively. Maximum production of theanderose reached 81.7 g/L and that of the glucosyl-xylose 26.5 g/L, whereas 3.4 g/L and only 1 g/L were produced of the piceid mono- and diglucoside respectively.Key points• Overexpression of a yeast α-glucosidase producing novel molecules.• Yeast enzyme producing the heterooligosaccharides theanderose and glucosyl-xylose.• Glycosylation of the polyphenol piceid by a yeast α-glucosidase.

Design, synthesis, in vitro, and in silico anti-α-glucosidase assays of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives as new anti-diabetic agents

In this work, a novel series of N-phenylacetamide-1,2,3-triazole-indole-2-carboxamide derivatives 5a–n were designed by consideration of the potent α-glucosidase inhibitors containing indole and carboxamide-1,2,3-triazole-N-phenylacetamide moieties. These compounds were synthesized by click reaction and evaluated against yeast α-glucosidase. All the newly title compounds demonstrated superior potency when compared with acarbose as a standard inhibitor. Particularly, compound 5k possessed the best inhibitory activity against α-glucosidase with around a 28-fold improvement in the inhibition effect in comparison standard inhibitor. This compound showed a competitive type of inhibition in the kinetics. The molecular docking and dynamics demonstrated that compound 5k with a favorable binding energy well occupied the active site of α-glucosidase.

Ent-kaurane glycosides from Stevia rebaudiana and their α-glucosidase inhibition

Phytochemical investigation of the water soluble fraction of the plant Stevia rebaudiana led to isolation of 10 ent-kaurane glycosides, including two new derivatives namely stevibiosides A and B (1 and 2). Their structures were elucidated by extensive analysis of their 1D, 2D NMR, and HRQTOF mass spectra as well as quantum chemical calculations. Conformation studies and DFT-calculated chemical shifts combined with simple (R2, MAE) and DP4+ statistical analyses allow for the complete characterization of compounds 1 and 2. Among isolates, stevibioside A (1) exhibited potent α-glycosidase inhibitory effects with IC50 value of 8.9 ± 0.45 μM. Inhibitory kinetics analysis indicated that 1 had effect with an uncompetitive inhibition type and the Ki value of 2.18 ± 0.81 μM. In addition, docking studies were then used to analysis of the binding modes of the compounds 1 and 2 over the crystallographic structure of yeast α-glucosidase (pdb 3A4A) active site in comparison with acarbose as a standard inhibitor of this enzyme.

Investigating the effect of polyphenols from nuts on human carbohydrate digestion in vitro

Recent studies have documented the importance of postprandial hyperglycaemia in the incidence of chronic diseases, including type 2 diabetes. Inhibition of digestive enzymes, including membrane-bound brush-border α-glucosidases, leads to slowed carbohydrate digestion and absorption, and reduced postprandial glycemia. Nuts are widely eaten around the world and have the potential to inhibit α-glucosidases through their content of polyphenols and other bioactive compounds. According to our recent systematic review(1), no study has investigated the inhibitory effects of nut extracts on human α-glucosidase activities. Almost all studies in this area have been conducted on yeast α-glucosidase, with only a few using rat α-glucosidase. While there is no sequence homology between yeast and human α-glucosidase, there is 74% to 78% sequence homology between rat and human α-glucosidases(1). The lack of studies on the effect of bioactive compounds from nuts on human α-glucosidases, along with the growing attention to nuts as an important component of a healthy diet with the potential to reduce the risk of chronic diseases(2), highlights the need for research to evaluate the inhibitory effect of nut extracts on human α-glucosidases. The aim of the current study is to explore the inhibitory effect of extracts from nuts on human carbohydrate digestive enzymes. Walnuts and almonds were ground and defatted with hexane, extracted in 80% (v/v) acetone, and further purified using solid-phase extraction to obtain phenolic-rich extracts. The Folin–Ciocalteu assay was used to approximate the polyphenol content of the samples. Following our recently published detailed protocol(3), cell-free extracts from human intestinal Caco-2/TC7 cells were used as a source of α-glucosidase in enzyme inhibition assays, with sucrose, maltose and isomaltose as substrates and appropriate controls. The assay products were quantified using high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Glucose production in the presence of various concentrations of phenol-rich nut extracts was compared using a one-way ANOVA and half-maximal inhibitory concentration (IC50) values were calculated. The Folin–Ciocalteu data demonstrate that walnut extracts comprise a relatively high polyphenol content, with 18.1 ± 0.23 mg (epigallocatechin gallate [EGCG] equivalent) per gram of fresh weight, while almond extracts contain 0.87 ± 0.03 mg EGCG equivalent/g of fresh weight. The walnut phenolic-rich extract dose-dependently inhibited human intestinal sucrase and maltase activities (both p<0.01), with IC50 values of 1.67 mg/mL and 2.84 mg/mL, respectively. We demonstrate that phenolic-rich walnut extracts can inhibit human α-glucosidases in vitro and therefore walnuts may contribute to slowing carbohydrate digestion in humans. As such, we plan to assess the effects of walnuts on postprandial glycaemia in vivo.

α-Glucosidase immobilization on calcium-sodium alginate-chitosan gel beads for inhibitory activity evaluation from traditional Chinese medicines

Discovering α-glucosidase inhibitors is one of the effective ways to develop new anti-diabetic drugs. In this study yeast α-glucosidase immobilized in calcium alginate-chitosan gel treated with polyethyleneimine and capillary electrophoresis analysis was used to select enzyme inhibitor compounds in 12 traditional Chinese medicine. The immobilized α-glucosidase shows enhanced tolerance to temperature (70 °C), excellent repeatability (RSD = 1.9%, n = 5), high stability and good reusability (retained 57.8% and 74% of its initial activity after storing at 4 ℃ for 30 days and reusing 10 times, respectively). Moreover, the Michaelis constant of immobilized α-glucosidase and half-maximal inhibitory concentration of acarbose were calculated to be 1.79 mM and 0.70 μM, respectively. These results demonstrate that the immobilized α-glucosidase for inhibitory activity evaluation is feasible. The immobilized α-glucosidase was applied to screen inhibitors from 12 traditional Chinese medicines, and Sanguisorbae Radix the root of Sanguisorba officinalis L. exhibited the strongest inhibitory activity on α-glucosidase.

Anti-enzymatic and DNA docking studies of montelukast: A multifaceted molecular scaffold with in vitro investigations, molecular expression analysis and molecular dynamics simulations

Montelukast, an approved leukotriene receptor 1 (Cys-LT 1) antagonist with anti-inflammatory properties is used for the treatment of asthma and allergic rhinitis. In the present studies, montelukast was subjected to in vitro inhibitory assays followed by kinetic and in silico investigations. Montelukast demonstrated inhibitory activity against yeast α-glucosidase (IC50 44.31 ± 1.21 μM), jack bean urease (JB urease, IC50 8.72 ± 0.23 μM), human placental alkaline phosphatase (hPAP, IC50 17.53 ± 0.19 μM), bovine intestinal alkaline phosphatase (bIAP, IC50 15.18 ± 0.23 μM) and soybean 15-lipoxygenase (15-LOX, IC50 2.41 ± 0.13 μM). Kinetic studies against α-glucosidase and urease enzymes revealed its competitive mode of inhibition. Molecular expression analysis of montelukast in breast cancer cell line MCF-7 down-regulated AP by a factor of 0.27 (5 μM) compared with the 0.26 value for standard inhibitor levamisole (10 μM). Molecular docking estimated a binding affinity ranging −8.82 to −15.65 kcal/mol for the enzymes. Docking against the DNA dodecamer (ID: 1BNA) observed −9.13 kcal/mol via minor groove binding. MD simulations suggested stable binding between montelukast and the target proteins predicting strong inhibitory potential of the ligand. Montelukast features a chloroquinoline, phenyl ring, a cyclopropane group, a carboxylic group and a sulfur atom all of which collectively enhance its inhibitory potential against the said enzymes. These in vitro and computational investigations demonstrate that it is possible and suggested that the interactions of montelukast with more than one targets presented herein may be linked with the side effects presented by this drug and necessitate additional work. The results altogether suggest montelukast as an important structural scaffold possessing multitargeted features and warrant further investigations in repurposing beyond its traditional pharmacological use.

Structure-yeast α-glucosidase inhibitory activity relationship of 9-O-berberrubine carboxylates.

Thirty-five 9-O-berberrubine carboxylate derivatives were synthesized and evaluated for yeast α-glucosidase inhibitory activity. All compounds demonstrated better inhibitory activities than the parent compounds berberine (BBR) and berberrubine (BBRB), and a positive control, acarbose. The structure-activity correlation study indicated that most of the substituents on the benzoate moiety such as methoxy, hydroxy, methylenedioxy, benzyloxy, halogen, trifluoromethyl, nitro and alkyl can contribute to the activities except multi-methoxy, fluoro and cyano. In addition, replacing benzoate with naphthoate, cinnamate, piperate or diphenylacetate also led to an increase in inhibitory activities except with phenyl acetate. 9, 26, 27, 28 and 33 exhibited the most potent α-glucosidase inhibitory activities with the IC50 values in the range of 1.61-2.67μM. Kinetic study revealed that 9, 26, 28 and 33 interacted with the enzyme via competitive mode. These four compounds were also proved to be not cytotoxic at their IC50 values. The competitive inhibition mechanism of these four compounds against yeast α-glucosidase was investigated using molecular docking and molecular dynamics simulations. The binding free energy calculations suggest that 26 exhibited the strongest binding affinity, and its binding stability is supported by hydrophobic interactions with D68, F157, F158 and F177. Therefore, 9, 26, 28 and 33 would be promising candidates for further studies of antidiabetic activity.

Asymmetric Synthesis of Four Stereoisomers of 2,2-Dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane from Ageratina grandifolia and Plausible Absolute Stereochemistry of the Natural Product.

2,2-Dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane is a natural product isolated from Ageratina grandifolia that exhibits inhibitory activity against yeast α-glucosidase. Initially, its structure was proposed to be 4-hydroxy-3-((S)-1'-angeloyloxy-(R)-2',3'-epoxy-3'-methyl)butylacetophenone with an epoxide, but the structure was later revised to 2,2-dimethyl-3R-hydroxy-4S-(1-angeloyloxy)-6-acetylchromane. In this study, we present a total synthesis of 2,2-dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane from A. gradifolia and its stereoisomers. The key features of their synthesis include Sharpless asymmetric dihydroxylation of a readily available benzopyran substrate and subsequent Mitsunobu or Steglich reaction to provide both cis- and trans-isomers with chiral control. The absolute stereochemistry of the natural product was determined to be 2,2-dimethyl-3S-hydroxy-4R-(1'-angeloyloxy)-6-acetylchromane based on optical rotations of the synthesized compounds. The absolute configuration of the synthesized stereoisomers was confirmed by Mosher ester analysis. In addition, we provided ECD spectra for the four stereoisomers, which will allow verification of the absolute configuration of the natural product. Synthesis of all four stereoisomers of 2,2-dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane would facilitate the exploration of their potential biomedical applications.

Phytochemical and functional characterization of fermented Yerba mate using Rhizopus oligosporus

Solid-state fermentation (SSF) was used to enhance the bioactive compounds and biological properties of food materials, such as buckwheat, turmeric, and ginseng. This study was investigated the effects of SSF for up to 10 days using Rhizopus oligosporus on Yerba mate (Ilex paraguariensis St. Hilaire). The total phenolic content of Yerba mate rose to 20% after 1 day fermentation. The saponin contents of Yerba mate rose to 38% after 7 day fermentation. Furthermore, chlorogenic acid, caffeic acid, and caffeine levels were increased up to 27.74% by fermentation, as determined by UPLC-MS analysis. ORAC and FRAP assays showed that the antioxidant activities of Yerba mate were enhanced 1.9- and 1.14-fold after 1 day fermentation. In addition, its inhibitory activities against yeast α-glucosidase and nitric oxide release in LPS-stimulated RAW264.7 cells were higher than in the unfermented Yerba mate. Moreover, taste sensory analysis using an electronic tongue sensory system showed that the flavor of Yerba mate after 1 day fermentation was similar to that of the unfermented Yerba mate. These results suggested that solid fermentation using R. oligosporus is conducive to producing Yerba mate with enhanced biological properties.

α-Glucosidase inhibition of sesquiterpenoids from the heartwood of Mansonia gagei

Nine undescribed sesquiterpenoids, along with ten known compounds, were isolated from the ethyl acetate extract of Mansonia gagei heartwood. Their structures were determined by spectroscopic data analysis (FTIR, 1D, 2D NMR, and HRESIMS), and their absolute configurations were established by ECD calculation. The isolated compounds were evaluated for their inhibitory effect against α-glucosidase from yeast. The results showed that mansonone U, mansonialactam, heliclactone and mansonone S exhibited exceptionally potent activities when compared to the positive control, acarbose, with IC50 values of 12.38 ± 0.71, 0.20 ± 0.05, 13.12 ± 2.85, and 12.05 ± 1.91 μM, respectively. Among them, mansonialactam possessed the most potent inhibitory activity against yeast α-glucosidase, and it showed an uncompetitive inhibition mode.

Indole-carbohydrazide linked phenoxy-1,2,3-triazole-N-phenylacetamide derivatives as potent α-glucosidase inhibitors: design, synthesis, in vitro α-glucosidase inhibition, and computational studies

BackgroundA new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a–o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase.MethodsThe 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted.ResultsAll new derivatives 11a–o (IC50 values = 6.31 ± 0.03–49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound.ConclusionAccording to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

Stilbenoids and Flavonoids from Cajanus cajan (L.) Millsp. and Their α-Glucosidase Inhibitory Activities.

Two new stilbenoids, cajanstilbenoid C (1) and cajanstilbenoid D (2), together with eight other known stilbenoids (3-10) and seventeen known flavonoids (11-27), were isolated from the petroleum ether and ethyl acetate portions of the 95% ethanol extract of leaves of Cajanus cajan (L.) Millsp. The planar structures of the new compounds were elucidated by NMR and high-resolution mass spectrometry, and their absolute configurations were determined by comparison of their experimental and calculated electronic circular dichroism (ECD) values. All the compounds were assayed for their inhibitory activities against yeast α-glucosidase. The results demonstrated that compounds 3, 8-9, 11, 13, 19-21, and 24-26 had strong inhibitory activities against α-glucosidase, with compound 11 (IC50 = 0.87 ± 0.05 μM) exhibiting the strongest activity. The structure-activity relationships were preliminarily summarized. Moreover, enzyme kinetics showed that compound 8 was a noncompetitive inhibitor, compounds 11, 24-26 were anticompetitive, and compounds 9 and 13 were mixed-competitive.

In Vitro and In Vivo Antidiabetic, α-Glucosidase Inhibition and Antibacterial Activities of Three Brown Algae, Polycladia myrica, Padina antillarum, and Sargassum boveanum, and a Red Alga, Palisada perforata from the Persian Gulf.

In recent decades, algae have attracted worldwide attention for their great biological activities, such as antidiabetic and antibacterial properties. We measured antibacterial and α-glucosidase inhibition potential of methanol and 80% methanol extracts of three brown algae species, Polycladia myrica, Padina antillarum, and Sargassum boveanum, and a red alga, Palisada perforata, from the Persian Gulf coasts. Antibacterial activity of the algal extracts was assessed by broth dilution method against three gram-negative and -positive bacteria, including Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa; Staphylococcus epidermidis, Staphylococcus aureus, and Bacillus subtilis, respectively. Furthermore, the yeast's α-glucosidase inhibition of the algal extracts was measured via colorimetric assay. In addition, we investigated the beneficial effect of 80% MeOH extract of S. boveanum on the blood glucose levels in streptozotocin-induced diabetic rats. The MeOH extract of S. boveanum was the best antibacterial extract with MIC = 2.5 mg/mL against all bacterial strains except for E. coli. The MeOH and 80% MeOH extracts of P. myrica and P. antillarum inhibited α-glucosidase at most with IC50 values of 12.70 ± 1.88 µg/mL and 13.06 ± 4.44 µg/mL, respectively. The oral gavage of S. boveanum extract in streptozotocin- (STZ-) induced diabetic rats resulted in decreasing their postprandial blood glucose levels. The algae and acarbose decreased blood glucose levels after sucrose administration in 60 minutes, compared to the non-drug-treated animals, with p values of 0.03 and 0.007, respectively. Overall, due to the in vitro and in vivo antidiabetic potential of S. boveanum, we suggest the alga as a new source for the isolation and identification of potential antidiabetic and antibacterial compounds.

A systematic review of the inhibitory effect of extracts from edible parts of nuts on α-glucosidase activity.

An elevated postprandial glycaemic response is a risk factor for developing type 2 diabetes mellitus (T2DM). Inhibition of digestive enzymes, including membrane-bound brush-border α-glucosidases, leads to slowed carbohydrate digestion and absorption, and reduced postprandial glycaemia. Nuts are eaten widely around the world, and have the potential to inhibit α-glucosidases through their content of polyphenols and other bioactive compounds. We set out to conduct a systematic literature review exploring the inhibitory effect of extracts from edible parts of various nuts on α-glucosidase activity in vitro to ensure, as far as possible, that no papers were missed. After an initial screening, 38 studies were reviewed in full, of which 15 were suitable for the present systematic review. Notably, no studies were found which tested the inhibitory potential of nut extracts against human α-glucosidases. Two studies showed that extracts from almonds and hazelnuts inhibited rat α-glucosidase activity, but the remaining papers reported data on the yeast α-glucosidase enzyme. Where yeast and rat enzymes can be compared, it is clear that nut extracts inhibit yeast α-glucosidase more strongly than mammalian α-glucosidase, which may lead to over-estimation when predicting effects in vivo when using data from the yeast enzyme. In contrast, acarbose is a stronger inhibitor of mammalian α-glucosidase compared to the yeast enzyme. Thus, although the present review indicates that extracts from nuts inhibit yeast α-glucosidase, this cannot be extrapolated to humans in vivo. There is some evidence that extracts from almonds and hazelnuts inhibit rat α-glucosidase, but no information on human enzyme sources. Since most work has been published on the yeast enzyme, future work in vitro must utilise mammalian, and preferably human, α-glucosidases in order to be relevant to human health and disease. This systematic review was registered at INPLASY as INPLASY202280061.

Identification of yeast α-glucosidase inhibitors from Pueraria lobata by ligand fishing based on magnetic mesoporous silicon combined with knock-out/knock-in technology.

In this study, a ligand fishing technique based on magnetic mesoporous silicon was established and used to screen α-glucosidase inhibitors from Pueraria lobata. To clarify quantity-activity relationships in a holistic view, the knock-out/knock-in technology was used to analyse the interactions of several active constituents in P. lobata. Magnetic mesoporous silicon with a large specific surface area and better biocompatibility was synthesised. Subsequently, α-glucosidase was immobilised on -NH2-modified magnetic mesoporous silicon, and the compounds in the crude extract of P. lobata were screened across enzyme binding. The structures of the ligands were elucidated using UPLC-Q-TOF-MS/MS, and their activities were verified by knock-out/knock-in experiments and molecular docking. Daidzein and puerarin showed α-glucosidase inhibitory activities with an IC50 of 0.088 ± 0.003 mg mL-1 and 0.414 ± 0.005 mg mL-1, respectively. Among them, puerarin, which accounted for more than 40% of the total content, showed synergistic effects with other components and was the main contributor to the α-glucosidase inhibitory activity of P. lobata.

Design, synthesis, in vitro, and in silico enzymatic evaluations of thieno[2,3-b]quinoline-hydrazones as novel inhibitors for α-glucosidase

In the development of novel anti-α-glucosidase agents, we synthesized novel thieno[2,3-b]quinoline-hydrazones 9a-n by facile and efficient conventional chemical reactions. These compounds were characterized by IR, 1H NMR, 13C NMR, and elemental analysis. Inhibitory activities of the title compounds were evaluated against yeast α-glucosidase. In particular, compounds 9c, 9d, and 9h exhibited high anti-α-glucosidase activity. Representatively, compound 9c with IC50 = 1.3 µM, was 576-times more potent than positive control acarbose. Molecular docking study of the most active compounds showed that these compounds formed important binding interactions at α-glucosidase active site. Molecular dynamics study of compound 9c was also performed and the obtained results were compared with acarbose. Compounds 9c, 9d, and 9h were also evaluated for in silico druglikeness properties and ADMET prediction. These studies showed that the title most potent compounds could be exploited as drug candidates.

Flavone-1,2,3-triazole derivatives as potential α-glucosidase inhibitors: Synthesis, enzyme inhibition, kinetic analysis and molecular docking study

α-Glucosidase inhibitors are considered prime therapeutics in the management of type-2 diabetes and are preferred due to their localized action ushered by limited side effects. In this regard, nineteen new flavone-1,2,3-triazole derivatives have been designed and synthesized via utilizing an efficient click reaction protocol, and screened for the inhibition of the α-glucosidase enzyme. The reaction conditions were mild, good yielding and required easy work up. All the synthesized flavone-triazole derivatives were found more active against the yeast α-glucosidase with IC50 values ranging from 24.37 ± 0.55–168.44 ± 0.77 μ M as compared to standard inhibitor acarbose (IC50 = 844.81 ± 0.53 μM). The derivatives with 2,5‑dichloro 9k (IC50 = 24.37 ± 0.55 μM) and 4‑chloro 9d (IC50 = 24.77 ± 0.30 μM) substituent bearing an amide linkage were the most active. In the kinetic study of most active derivatives 9k and 9d, they were found to be mixed and uncompetitive inhibitors, respectively. In molecular docking studies, blind docking of the most active compounds was accomplished to find the interactions between the compounds and α-glucosidase that further confirms the mixed or uncompetitive nature of the inhibitors.

Extracts of selected Lamiaceae species as promising antidiabetics: Chemical profiling, in vitro and in silico approach combined with dynamical modeling

Diabetes mellitus has been recognized as one of the most challenging public health problems in the 21st century. The present study aimed to investigate the antidiabetic potential of 18 selected Lamiaceae representatives on yeast α-glucosidase and further translate experimental data into predicted human α-glucosidase inhibition. Since conventional antidiabetic drugs exhibit numerous unavoidable side effects, plant extracts are being increasingly explored as safer alternatives. Plant extracts were prepared by maceration, characterized by liquid chromatography-mass spectrometry (LC-MS), and subjected to in vitro determination of yeast α-glucosidase inhibitory potential, after which the kinetic study of one of the most potent extracts (Mentha × piperita) was performed. Docking simulations were done on both yeast and human α-glucosidase to explore binding modes and energies of the secondary metabolites identified in the examined extracts. Finally, the dynamical model has been constructed (adjR2 = 0.9885) and applied to explore extracts’ inhibition potential onto the human α-glucosidase. The constructed dynamical model revealed, for the first time, that different extracts of Satureja montana represent highly promising candidates for the prevention/treatment of diabetes mellitus. Therefore, the dynamical model described in this study represents a useful tool and a significant advance in the discovery of novel therapeutics with antidiabetic potential in humans.

Design, synthesis, in vitro α-glucosidase inhibition, docking, and molecular dynamics of new phthalimide-benzenesulfonamide hybrids for targeting type 2 diabetes

In the present work, a new series of 14 novel phthalimide-benzenesulfonamide derivatives 4a–n were synthesized, and their inhibitory activity against yeast α-glucosidase was screened. The obtained results indicated that most of the newly synthesized compounds showed prominent inhibitory activity against α-glucosidase. Among them, 4-phenylpiperazin derivative 4m exhibited the strongest inhibition with the IC50 value of 52.2 ± 0.1 µM. Enzyme kinetic study of compound 4m proved that its inhibition mode was competitive and Ki value of this compound was calculated to be 52.7 µM. In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the target compounds over the active site of α-glucosidase. Obtained date of these studies demonstrated that our new compounds interacted as well with the α-glucosidase active site with the acceptable binding energies. Furthermore, in silico druglikeness/ADME/Toxicity studies of compound 4m were performed and predicted that this compound is druglikeness and has good ADME and toxicity profiles.