Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia

Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC₅₀ value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (K_D) value of 5.529 × 10⁻⁵ M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.     

Inhibitory Effect of Fisetin on α-Glucosidase Activity: Kinetic and Molecular Docking Studies

The inhibition of α-glucosidase is a clinical strategy for the treatment of type 2 diabetes mellitus (T2DM), and many natural plant ingredients have been reported to be effective in alleviating hyperglycemia by inhibiting α-glucosidase. In this study, the α-glucosidase inhibitory activity of fisetin extracted from Cotinus coggygria Scop. was evaluated in vitro. The results showed that fisetin exhibited strong inhibitory activity with an IC₅₀ value of 4.099 × 10⁻⁴ mM. Enzyme kinetic analysis revealed that fisetin is a non-competitive inhibitor of α-glucosidase, with an inhibition constant value of 0.01065 ± 0.003255 mM. Moreover, fluorescence spectrometric measurements indicated the presence of only one binding site between fisetin and α-glucosidase, with a binding constant (lgKa) of 5.896 L·mol⁻¹. Further molecular docking studies were performed to evaluate the interaction of fisetin with several residues close to the inactive site of α-glucosidase. These studies showed that the structure of the complex was maintained by Pi-Sigma and Pi-Pi stacked interactions. These findings illustrate that fisetin extracted from Cotinus coggygria Scop. is a promising therapeutic agent for the treatment of T2DM.     

In Vitro Evaluation of the Anti-Diabetic Potential of Aqueous Acetone Helichrysum petiolare Extract (AAHPE) with Molecular Docking Relevance in Diabetes Mellitus

Diabetes mellitus (DM) is a chronic metabolic condition that can lead to significant complications and a high fatality rate worldwide. Efforts are ramping up to find and develop novel α-glucosidase and α-amylase inhibitors that are both effective and potentially safe. Traditional methodologies are being replaced with new techniques that are less complicated and less time demanding; yet, both the experimental and computational strategies are viable and complementary in drug discovery and development. As a result, this study was conducted to investigate the in vitro anti-diabetic potential of aqueous acetone Helichrysum petiolare and B.L Burtt extract (AAHPE) using a 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxy-d-glucose uptake assay. In addition, we performed molecular docking of the flavonoid constituents identified and quantified by liquid chromatography-mass spectrometry (LC-MS) from AAHPE with the potential to serve as effective and safe α-amylase and α-glucosidase inhibitors, which are important in drug discovery and development. The results showed that AAHPE is a potential inhibitor of both α-amylase and α-glucosidase, with IC₅₀ values of 46.50 ± 6.17 (µg/mL) and 37.81 ± 5.15 (µg/mL), respectively. This is demonstrated by a significant increase in the glucose uptake activity percentage in a concentration-dependent manner compared to the control, with the highest AAHPE concentration of 75 µg/mL of glucose uptake activity being higher than metformin, a standard anti-diabetic drug, in the insulin-resistant HepG2 cell line. The molecular docking results displayed that the constituents strongly bind α-amylase and α-glucosidase while achieving better binding affinities that ranged from ΔG = −7.2 to −9.6 kcal/mol (compared with acarbose ΔG = −6.1 kcal/mol) for α-amylase, and ΔG = −7.3 to −9.0 kcal/mol (compared with acarbose ΔG = −6.3 kcal/mol) for α-glucosidase. This study revealed the potential use of the H. petiolare plant extract and its phytochemicals, which could be explored to develop potent and safe α-amylase and α-glucosidase inhibitors to treat postprandial glycemic levels in diabetic patients.     

Discovery of Amide-Functionalized Benzimidazolium Salts as Potent α-Glucosidase Inhibitors

α-Glucosidase inhibitors (AGIs) are used as medicines for the treatment of diabetes mellitus. The α-Glucosidase enzyme is present in the small intestine and is responsible for the breakdown of carbohydrates into sugars. The process results in an increase in blood sugar levels. AGIs slow down the digestion of carbohydrates that is helpful in controlling the sugar levels in the blood after meals. Among heterocyclic compounds, benzimidazole moiety is recognized as a potent bioactive scaffold for its wide range of biologically active derivatives. The aim of this study is to explore the α-glucosidase inhibition ability of benzimidazolium salts. In this study, two novel series of benzimidazolium salts, i.e., 1-benzyl-3-{2-(substituted) amino-2-oxoethyl}-1H-benzo[d]imidazol-3-ium bromide 9a–m and 1-benzyl-3-{2-substituted) amino-2-oxoethyl}-2-methyl-1H-benzo[d] imidazol-3-ium bromide 10a–m were screened for their in vitro α-glucosidase inhibitory potential. These compounds were synthesized through a multistep procedure and were characterized by ¹H-NMR, ¹³C-NMR, and EI-MS techniques. Compound 10d was identified as the potent α-glucosidase inhibitor among the series with an IC₅₀ value of 14 ± 0.013 μM, which is 4-fold higher than the standard drug, acarbose. In addition, compounds 10a, 10e, 10h, 10g, 10k, 10l, and 10m also exhibited pronounced potential for α-glucosidase inhibition with IC₅₀ value ranging from 15 ± 0.037 to 32.27 ± 0.050 µM when compared with the reference drug acarbose (IC₅₀ = 58.8 ± 0.12 μM). A molecular docking study was performed to rationalize the binding interactions of potent inhibitors with the active site of the α-glucosidase enzyme.     

GC/MS Analysis of Essential Oil and Enzyme Inhibitory Activities of Syzygium cumini (Pamposia) Grown in Egypt: Chemical Characterization and Molecular Docking Studies

Syzygium cumini (Pomposia) is a well-known aromatic plant belonging to the family Myrtaceae, and has been reported for its various traditional and pharmacological potentials, such as its antioxidant, antimicrobial, anti-inflammatory, and antidiarrheal properties. The chemical composition of the leaf essential oil via gas chromatography–mass spectrometry (GC/MS) analysis revealed the identification of fifty-three compounds representing about 91.22% of the total oil. The identified oil was predominated by α-pinene (21.09%), followed by β-(E)-ocimene (11.80%), D-limonene (8.08%), β-pinene (7.33%), and α-terpineol (5.38%). The tested oil revealed a moderate cytotoxic effect against human liver cancer cells (HepG2) with an IC₅₀ value of 38.15 ± 2.09 µg/mL. In addition, it effectively inhibited acetylcholinesterase with an IC₅₀ value of 32.9 ± 2.1 µg/mL. Furthermore, it showed inhibitory properties against α-amylase and α-glucosidase with IC₅₀ values of 57.80 ± 3.30 and 274.03 ± 12.37 µg/mL, respectively. The molecular docking studies revealed that (E)-β-caryophyllene, one of the major compounds, achieved the best docking scores of −6.75, −5.61, and −7.75 for acetylcholinesterase, α-amylase, and α-glucosidase, respectively. Thus, it is concluded that S. cumini oil should be considered as a food supplement for the elderly to enhance memory performance and for diabetic patients to control blood glucose.     

Utilization of Cassava Wastewater for Low-Cost Production of Prodigiosin via Serratia marcescens TNU01 Fermentation and Its Novel Potent α-Glucosidase Inhibitory Effect

The purpose of this study was to reuse cassava wastewater (CW) for scaled-up production, via the fermentation of prodigiosin (PG), and to conduct an evaluation of its bioactivities. PG was produced at the yield of high 6150 mg/L in a 14 L-bioreactor system, when the designed novel medium (7 L), containing CW and supplemented with 0.25% casein, 0.05% MgSO₄, and 0.1% K₂HPO₄, was fermented with Serratia marcescens TNU01 at 28 °C in 8 h. The PG produced and purified in this study was assayed for some medical effects and showed moderate antioxidant, high anti-NO (anti-nitric oxide), and potential α-glucosidase inhibitory activities. Notably, PG was first reported as a novel effective α-glucosidase inhibitor with a low IC50 value of 0.0183 µg/mL. The commercial anti-diabetic drug acarbose was tested for comparison and had a lesser effect with a high IC50 value of 328.4 µg/mL, respectively. In a docking study, the cation form of PG (cation-PG) was found to bind to the enzyme α-glucosidase by interacting with two prominent amino acids, ASP568 and PHE601, at the binding site on the target enzyme, creating six linkages and showing a better binding energy score (−14.6 kcal/mol) than acarbose (−10.5 kcal/mol). The results of this work suggest that cassava wastewater can serve as a low-cost raw material for the effective production of PG, a potential antidiabetic drug candidate.     

Personal Glucose Meter for α-Glucosidase Inhibitor Screening Based on the Hydrolysis of Maltose

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K₃[Fe(CN)₆]) to ferrocyanide (K₄[Fe(CN)₆]) and generates the PGM detectable signals. When the α-glucosidase inhibitor (such as acarbose) is added, the yield of glucose and the readout of PGM decreased accordingly. This method can achieve the direct determination of α-glucosidase activity by the PGM as simple as the blood glucose tests. Under the optimal experimental conditions, the developed method was applied to evaluate the inhibitory activity of thirty-four small-molecule compounds and eighteen medicinal plants extracts on α-glucosidase. The results exhibit that lithospermic acid (52.5 ± 3.0%) and protocatechualdehyde (36.8 ± 2.8%) have higher inhibitory activity than that of positive control acarbose (31.5 ± 2.5%) at the same final concentration of 5.0 mM. Besides, the lemon extract has a good inhibitory effect on α-glucosidase with a percentage of inhibition of 43.3 ± 3.5%. Finally, the binding sites and modes of four active small-molecule compounds to α-glucosidase were investigated by molecular docking analysis. These results indicate that the PGM method is feasible to screening inhibitors from natural products with simple and rapid operations.     

α-Glucosidase Inhibitory and Antimicrobial Benzoylphloroglucinols from Garcinia schomburgakiana Fruits: In Vitro and In Silico Studies

α-Glucosidase plays a role in hydrolyzing complex carbohydrates into glucose, which is easily absorbed, causing postprandial hyperglycemia. Inhibition of α-glucosidase is therefore an ideal approach to preventing this condition. A novel polyprenylated benzoylphloroglucinol, which we named schomburgkianone I (1), was isolated from the fruit of Garcinia schomburgkiana, along with an already-reported compound, guttiferone K (2). The structures of the two compounds were determined using NMR and HRESIMS analysis, and comparisons were made with previous studies. Compounds 1 and 2 exhibited potent α-glucosidase inhibition (IC_50s of 21.2 and 34.8 µM, respectively), outperforming the acarbose positive control. Compound 1 produced wide zones of inhibition against Staphylococcus aureus and Enterococcus faecium (of 21 and 20 mm, respectively), compared with the 19 and 20 mm zones of compound 2, at a concentration of 50 µg/mL. The MIC value of compound 1 against S. aureus was 13.32 µM. An in silico molecular docking model suggested that both compounds are potent inhibitors of enzyme α-glucosidase and are therefore leading candidates as therapies for diabetes mellitus.     

On the Inhibitability of Natural Products Isolated from Tetradium ruticarpum towards Tyrosine Phosphatase 1B (PTP1B) and α-Glucosidase (3W37): An In Vitro and In Silico Study

Folk experiences suggest natural products in Tetradium ruticarpum can be effective inhibitors towards diabetes-related enzymes. The compounds were experimentally isolated, structurally elucidated, and tested in vitro for their inhibition effects on tyrosine phosphatase 1B (PTP1B) and α-glucosidase (3W37). Density functional theory and molecular docking techniques were utilized as computational methods to predict the stability of the ligands and simulate interaction between the studied inhibitory agents and the targeted proteins. Structural elucidation identifies two natural products: 2-heptyl-1-methylquinolin-4-one (1) and 3-[4-(4-methylhydroxy-2-butenyloxy)-phenyl]-2-propenol (2). In vitro study shows that the compounds (1 and 2) possess high potentiality for the inhibition of PTP1B (IC₅₀ values of 24.3 ± 0.8, and 47.7 ± 1.1 μM) and α-glucosidase (IC₅₀ values of 92.1 ± 0.8, and 167.4 ± 0.4 μM). DS values and the number of interactions obtained from docking simulation highly correlate with the experimental results yielded. Furthermore, in-depth analyses of the structure–activity relationship suggest significant contributions of amino acids Arg254 and Arg676 to the conformational distortion of PTP1B and 3W37 structures overall, thus leading to the deterioration of their enzymatic activity observed in assay-based experiments. This study encourages further investigations either to develop appropriate alternatives for diabetes treatment or to verify the role of amino acids Arg254 and Arg676.     

Antioxidant,Hypoglycemic and Molecular Docking Studies of Methanolic Extract,Fractions and Isolated Compounds from Aerial Parts of Cymbopogon citratus (DC.) Stapf

Traditionally, Cymbopogon citratus is used to treat a variety of ailments, including cough, indigestion, fever, and diabetes. The previous chemical and bioactive research on C. citratus mainly focused on its volatile oil. In this study, 20 non-volatile known compounds were isolated from the dried aerial part of C. citratus, and their structures were elucidated by MS, NMR spectroscopy, and comparison with the published spectroscopic data. Among them, 16 compounds were reported for the first time from this plant. The screening results for antioxidant and α-glucosidase inhibitory activities indicated that compounds caffeic acid (5), 1-O-p-coumaroyl-3-O-caffeoylglycerol (8), 1,3-O-dicaffeoylglycerol (9) and luteolin-7-O-β-D-glucopyranoside (12) had potent antioxidant capacities, with IC₅₀ values from 7.28 to 14.81 μM, 1.70 to 2.15 mol Trolox/mol and 1.31 to 2.42 mol Trolox/mol for DPPH, ABTS, and FRAP, respectively. Meanwhile, compounds 8 and 9 also exhibited significant inhibitory activities against α-glucosidase, with IC₅₀ values of 11.45 ± 1.82 μM and 5.46 ± 0.25 μM, respectively, which were reported for the first time for their α-glucosidase inhibitory activities. The molecular docking result provided a molecular comprehension of the interaction between compounds (8 and 9) and α-glucosidase. The significant antioxidant and α-glucosidase inhibitory activities of compounds 8 and 9 suggested that they could be developed into antidiabetic drugs because of their potential regulatory roles on oxidative stress and digestive enzyme.     

Anti-Inflammatory,Antidiabetic Properties and In Silico Modeling of Cucurbitane-Type Triterpene Glycosides from Fruits of an Indian Cultivar of Momordica charantia L.

Diabetes mellitus is a chronic disease and one of the fastest-growing health challenges of the last decades. Studies have shown that chronic low-grade inflammation and activation of the innate immune system are intimately involved in type 2 diabetes pathogenesis. Momordica charantia L. fruits are used in traditional medicine to manage diabetes. Herein, we report the purification of a new 23-O-β-d-allopyranosyl-5β,19-epoxycucurbitane-6,24-diene triterpene (charantoside XV, 6) along with 25ξ-isopropenylchole-5(6)-ene-3-O-β-d-glucopyranoside (1), karaviloside VI (2), karaviloside VIII (3), momordicoside L (4), momordicoside A (5) and kuguaglycoside C (7) from an Indian cultivar of Momordica charantia. At 50 µM compounds, 2–6 differentially affected the expression of pro-inflammatory markers IL-6, TNF-α, and iNOS, and mitochondrial marker COX-2. Compounds tested for the inhibition of α-amylase and α-glucosidase enzymes at 0.87 mM and 1.33 mM, respectively. Compounds showed similar α-amylase inhibitory activity than acarbose (0.13 mM) of control (68.0–76.6%). Karaviloside VIII (56.5%) was the most active compound in the α-glucosidase assay, followed by karaviloside VI (40.3%), while momordicoside L (23.7%), A (33.5%), and charantoside XV (23.9%) were the least active compounds. To better understand the mode of binding of cucurbitane-triterpenes to these enzymes, in silico docking of the isolated compounds was evaluated with α-amylase and α-glucosidase.     

Identification of α-Glucosidase Inhibitors from Scutellaria edelbergii: ESI-LC-MS and Computational Approach

The recent study investigated the in vitro anti-diabetic impact of the crude extract (MeOH) and subfractions ethyl acetate (EtOAc); chloroform; n-butanol; n-hexane; and aqueous fraction of S. edelbergii and processed the active EtOAc fraction for the identification of chemical constituents for the first time via ESI-LC-MS analysis through positive ionization mode (PIM) and negative ionization mode (NIM); the identified compounds were further validated through computational analysis via standard approaches. The crude extract and subfractions presented appreciable activity against the α-glucosidase inhibitory assay. However, the EtOAc fraction with IC₅₀ = 0.14 ± 0.06 µg/mL revealed the maximum potential among the fractions used, followed by the MeOH and n-hexane extract with IC₅₀ = 1.47 ± 0.14 and 2.18 ± 0.30 µg/mL, respectively. Moreover, the acarbose showed an IC₅₀ = 377.26 ± 1.20 µg/ mL whereas the least inhibition was observed for the chloroform fraction, with an IC₅₀ = 23.97 ± 0.14 µg/mL. Due to the significance of the EtOAc fraction, when profiled for its chemical constituents, it presented 16 compounds among which the flavonoid class was dominant, and offered eight compounds, of which six were identified in NIM, and two compounds in PIM. Moreover, five terpenoids were identified—three and two in NIM and PIM, respectively—as well as two alkaloids, both of which were detected in PIM. The EtOAc fraction also contained one phenol that was noticed in PIM. The detected flavonoids, terpenoids, alkaloids, and phenols are well-known for their diverse biomedical applications. The potent EtOAc fraction was submitted to computational analysis for further validation of α-glucosidase significance to profile the responsible compounds. The pharmacokinetic estimations and protein-ligand molecular docking results with the support of molecular dynamic simulation trajectories at 100 ns suggested that two bioactive compounds—dihydrocatalpol and leucosceptoside A—from the EtOAc fraction presented excellent drug-like properties and stable conformations; hence, these bioactive compounds could be potential inhibitors of alpha-glucosidase enzyme based on intermolecular interactions with significant residues, docking score, and binding free energy estimation. The stated findings reflect that S. edelbergii is a rich source of bioactive compounds offering potential cures for diabetes mellitus; in particular, dihydrocatalpol and leucosceptoside A could be excellent therapeutic options for the progress of novel drugs to overcome diabetes mellitus.     

Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl]-N-arylacetamides: An In Silico and Biochemical Approach

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC₅₀ values of 30.65, 18.25, 20.76, 35.14, and 24.24 μM, respectively, which were better than the standard drug, acarbose (IC₅₀ = 58.8 μM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.     

Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis,In Vitro α-Amylase Inhibitory Activity,Molecular Docking and Structure–Activity Relationship Analysis

Diabetes mellitus is a major health problem globally. The management of carbohydrate digestion provides an alternative treatment. Flavonoids constitute the largest group of polyphenolic compounds, produced by plants widely consumed as food and/or used for therapeutic purposes. As such, isoxazoles have attracted the attention of medicinal chemists by dint of their considerable bioactivity. Thus, the main goal of this work was to discover new hybrid molecules with properties of both flavonoids and isoxazoles in order to control carbohydrate digestion. Moreover, the trifluoromethyl group is a key entity in drug development, due to its strong lipophilicity and metabolic stability. Therefore, the present work describes the condensation of a previously synthesized trifluoromethylated flavonol with different aryl nitrile oxides, affording 13 hybrid molecules indicated as trifluoromethylated flavonoid-based isoxazoles. The structures of the obtained compounds were deduced from by ¹H NMR, ¹³C NMR, and HRMS analysis. The 15 newly synthesized compounds inhibited the activity of α-amylase with an efficacy ranging from 64.5 ± 0.7% to 94.7 ± 1.2% at a concentration of 50 μM, and with IC₅₀ values of 12.6 ± 0.2 μM–27.6 ± 1.1 μM. The most effective compounds in terms of efficacy and potency were 3b, 3h, 3j, and 3m. Among the new trifluoromethylated flavonoid-based isoxazoles, the compound 3b was the most effective inhibitor of α-amylase activity (PI = 94.7 ± 1.2% at 50 μM), with a potency (IC₅₀ = 12.6 ± 0.2 μM) similar to that of the positive control acarbose (IC₅₀ = 12.4 ± 0.1 μM). The study of the structure–activity relationship based on the molecular docking analysis showed a low binding energy, a correct mode of interaction in the active pocket of the target enzyme, and an ability to interact with the key residues of glycosidic cleavage (GLU-230 and ASP-206), explaining the inhibitory effects of α-amylase established by several derivatives.     

α-Glucosidase Inhibitory Activity of Fermented Okara Broth Started with the Strain Bacillus amyloliquefaciens SY07

In this work, a new strain of Bacillus amyloliquefaciens SY07 isolated from a traditional fermented soybean food was reported to possess remarkable α-glucosidase inhibitor-producing ability. Different culture media were applied for the proliferation of B. amyloliquefaciens SY07, and it was found that fermented okara broth presented the highest α-glucosidase inhibitory activity, while Luria-Bertani medium showed a negative effect. The extract from fermented okara broth acted in a dose-dependent manner to inhibit α-glucosidase activity, with an IC₅₀ value of 0.454 mg/mL, and main inhibitors in the fermentation extract presented a reversible, uncompetitive pattern according to Lineweaver–Burk plots. Moreover, 1-deoxynojirimycin, a recognized α-glucosidase inhibitor, was found in the extract. Results indicated that B. amyloliquefaciens SY07 could utilize okara, a by-product from the soy processing industry, to generate α-glucosidase inhibitors effectively, and be regarded as a novel excellent microbial candidate for safe, economical production of potential functional foods or ingredients with hypoglycemic effect.     

N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides: Molecular Docking,Synthesis, and Biological Investigation as Anticancer Agents

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (¹H and ¹³C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC₅₀ µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.     

Phytochemical Profile,Antioxidant Capacity, α-Amylase and α-Glucosidase Inhibitory Potential of Wild Moroccan Inula viscosa (L.) Aiton Leaves

Medicinal plants offer imperative sources of innovative chemical substances with important potential therapeutic effects. Among them, the members of the genus Inula have been widely used in traditional medicine for the treatment of several diseases. The present study investigated the antioxidant (DPPH, ABTS and FRAP assays) and the in vitro anti-hyperglycemic potential of aerial parts of Inula viscosa (L.) Aiton (I. viscosa) extracts through the inhibition of digestive enzymes (α-amylase and α-glucosidase), responsible of the digestion of poly and oligosaccharides. The polyphenolic profile of the Inula viscosa (L.) Aiton EtOAc extract was also investigated using HPLC-DAD/ESI-MS analysis, whereas the volatile composition was elucidated by GC-MS. The chemical analysis resulted in the detection of twenty-one polyphenolic compounds, whereas the volatile profile highlighted the occurrence of forty-eight different compounds. Inula viscosa (L.) Aiton presented values as high as 87.2 ± 0.50 mg GAE/g and 78.6 ± 0.55mg CE/g, for gallic acid and catechin, respectively. The EtOAc extract exhibited the higher antioxidant activity compared to methanol and chloroform extracts in different tests with (IC₅₀ = 0.6 ± 0.03 µg/mL; IC₅₀ = 8.6 ± 0.08 µg/mL; 634.8 mg ± 1.45 AAE/g extract) in DPPH, ABTS and FRAP tests. Moreover, Inula viscosa (L.) Aiton leaves did show an important inhibitory effect against α-amylase and α-glucosidase. On the basis of the results achieved, such a species represents a promising traditional medicine, thanks to its remarkable content of functional bioactive compounds, thus opening new prospects for research and innovative phytopharmaceuticals developments.     

Barbeya oleoides Leaves Extracts: In Vitro Carbohydrate Digestive Enzymes Inhibition and Phytochemical Characterization

This study investigated the in vitro inhibitory potential of different solvent extracts of leaves of Barbeya oleoides on key enzymes related to type 2 diabetes mellitus (α-glucosidase and α-amylase) in combination with an aggregation assay (using 0.01% Triton X-100 detergent) to assess the specificity of action. The methanol extract was the most active in inhibiting α-glucosidase and α-amylase, with IC₅₀ values of 6.67 ± 0.30 and 25.62 ± 4.12 µg/mL, respectively. However, these activities were significantly attenuated in the presence of 0.01% Triton X-100. The chemical analysis of the methanol extract was conducted utilizing a dereplication approach combing LC-ESI-MS/MS and database searching. The chemical analysis detected 27 major peaks in the negative ion mode, and 24 phenolic compounds, predominantly tannins and flavonol glycosides derivatives, were tentatively identified. Our data indicate that the enzyme inhibitory activity was probably due to aggregation-based inhibition, perhaps linked to polyphenols.     

Flavonoids and Phenols,the Potential Anti-Diabetic Compounds from Bauhinia strychnifolia Craib. Stem.

Bioactive compounds from medicinal plants are good alternative treatments for T2DM. They are also sources of lead molecules that could lead to new drug discoveries. In this study, Bauhinia strychnifolia Craib. stem, a traditional Thai medicinal plant for detoxification, was extracted into five fractions, including crude extract, BsH, BsD, BsE, and BsW, by ethanolic maceration and sequential partition with hexane, dichloromethane, ethyl acetate, and water, respectively. Among these fractions, BsE contained the highest amounts of phenolics (620.67 mg GAE/g extract) and flavonoids (131.35 mg QE/g extract). BsE exhibited the maximum inhibitory activity against α-glucosidase (IC₅₀ 1.51 ± 0.01 µg/mL) and DPP-IV (IC₅₀ 2.62 ± 0.03 µg/mL), as well as dominantly promoting glucose uptake on 3T3-L1 adipocytes. Furthermore, the four compounds isolated from the BsE fraction, namely resveratrol, epicatechin, quercetin, and gallic acid, were identified. Quercetin demonstrated the highest inhibitory capacity against α-glucosidase (IC₅₀ 6.26 ± 0.36 µM) and DPP-IV (IC₅₀ 8.25 µM). In addition, quercetin prominently enhanced the glucose uptake stimulation effect on 3T3-L1 adipocytes. Altogether, we concluded that quercetin was probably the principal bioactive compound of the B. strychnifolia stem for anti-diabetic, and the flavonoid-rich fraction may be sufficiently potent to be an alternative treatment for blood sugar control.     

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P2₁/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO₂ and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO₂/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO₂ group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor.