Bio-Guided Isolation of Alpha-Glucosidase Inhibitory Compounds from Vietnamese Lichen Roccella Montagnei.

A bio-guided isolation was applied to the Vietnamese lichen Roccella montagnei based on alpha-glucosidase inhibition. Six compounds were isolated and structurally elucidated, including a new ortho depside, montagneside A (1), together with five known compounds, sekikaic acid (2), lanost-7-en-3ß-ol (3), ethyl orsellinate (4), D-montagnetol (5), and D-erythrin (6). Their chemical structures were identified by extensive 1D and 2D NMR analysis, high-resolution mass spectroscopy, and comparisons with those reported in the literature. D-Erythrin (6), a major component, was selected for further modification using Smiles rearrangement. Three erythritol derivatives 6a-6c were synthesized. Compounds 1-3, 6, and 6a-6c were evaluated for alpha-glucosidase inhibition. Compounds 2 and 6a-6c showed significant alpha-glucosidase inhibition with IC50 values ranging from 7.9 to 149 µM, respectively. Molecular docking was applied to the most active compound 6a to clarify the inhibitory mechanism.

Two New Benzoquinone Derivatives from Vietnamese Knema globularia Stems.

The chemical investigation of the stems of Knema globularia led to the isolation of two new benzoquinones derivatives, embenones A and B (1 and 2), along with three known compounds (3-5). The structures of the isolated compounds were determined using spectroscopic techniques, including HRESIMS, 1D and 2D NMR, in conjunction with comparison to existing literature data. Compounds 1 and 2 represent new carbon skeletons in nature. Furthermore, all isolated compounds were evaluated for their α-glucosidase inhibitory activity, with compounds 1-3 exhibiting superior potency relative to the positive control (acarbose, IC50 331 µM). Their IC50 values ranged from 1.40 to 96.1 µM.

Two New α-Glucosidase Inhibitory Depsidones from the Lichen Parmotrema cristiferum (Taylor) Hale.

A bioactivity-guided investigation of the lichen Parmotrema cristiferum (Taylor) Hale (Parmeliaceae) led to the isolation of two new depsidones, cristifones A and B (1 and 2). The structures of the isolated compounds were identified by spectroscopic methods and comparison with the literature data. Compound 1 showed the initial combined structures of depsidone and depside cores. The two isolated compounds were then evaluated for α-glucosidase inhibition. Compounds 1 and 2 were confirmed as potent, with IC50 values of 21.5 and 18.4 µM, respectively. Compound 2 was a non-competitive inhibitor against α-glucosidase, as indicated by the intersect in the second quadrant of each respective plot.

Norquandrangularic acid D, a new trinorcycloartane isolated from the leaves of Combretum quadrangulare.

Phytochemical investigation on the leaves of Combretum quadrangulare growing in Vietnam afforded a new trinorcycloartane triterpenoid, norquandrangularic acid D (1), along with three known compounds, betulinic acid (2), luteolin (3), and apigenin (4). Their structures were elucidated using spectroscopic methods and comparison was made with reports in the literature. Compounds 1 and 3 were evaluated for α-glucosidase inhibition. Compound 3 showed significant activity, with an IC50 value of 11.39 µM, (acarbose, used as a positive control, had an IC50 of 367 µM).

New Flavonoid Derivatives from Melodorum fruticosum and Their α-Glucosidase Inhibitory and Cytotoxic Activities.

Three new flavonoid derivatives, melodorones A-C (1-3), together with four known compounds, tectochrysin (4), chrysin (5), onysilin (6), and pinocembrin (7), were isolated from the stem bark of Melodorum fruticosum. Their structures were determined on the basis of extensive spectroscopic methods, including NMR and HRESIMS, and by comparison with the literature. Compounds 1-7 were evaluated for their in vitro α-glucosidase inhibition and cytotoxicity against KB, Hep G2, and MCF7 cell lines. Among them, compound 1 exhibited the best activity against α-glucosidase and was superior to the positive control with an IC50 value of 2.59 µM. On the other hand, compound 1 showed moderate cytotoxicity toward KB, Hep G2, and MCF7 cell lines with the IC50 values of 23.5, 19.8, and 23.7 µM, respectively. These findings provided new evidence that the stem bark of M. fruticosum is a source of bioactive flavonoid derivatives that are highly valuable for medicinal development.

New Benzil and Isoflavone Derivatives with Cytotoxic and NO Production Inhibitory Activities from Placolobium vietnamense.

The phytochemical investigation of Placolobium vietnamense stems led to the isolation of a new isoflavone derivative (1) and three new benzil derivatives (2-4), together with four known pyranoisoflavones (5-8). The structures of all isolated compounds were determined on the basis of extensive spectroscopic analyses, including NMR and HRMS spectral data, as well as comparison of their spectroscopic data with those reported in the literature. The cytotoxicity of all isolated compounds was assessed against the human liver hepatocellular carcinoma (Hep G2) cell line, and compound 1 displayed the most significant cytotoxicity with an IC50 value of 8.0 µM. Furthermore, all isolated compounds were also tested for their inhibitory activity against NO production in RAW 264.7 macrophages. Of these, compound 1 exhibited the strongest inhibitory efficacy against the LPS-induced NO production with the IC50 value of 13.7 µM.

Biological Activities of Lichen-Derived Monoaromatic Compounds.

Lichen-derived monoaromatic compounds are bioactive compounds, associated with various pharmacological properties: antioxidant, antifungal, antiviral, cytotoxicity, and enzyme inhibition. However, little is known about data regarding alpha-glucosidase inhibition and antimicrobial activity. Very few compounds were reported to have these activities. In this paper, a series of monoaromatic compounds from a lichen source were isolated and structurally elucidated. They are 3,5-dihydroxybenzoic acid (1), 3,5-dihydroxybenzoate methyl (2), 3,5-dihydroxy-4-methylbenzoic acid (3), 3,5-dihydroxy-4-methoxylbenzoic acid (4), 3-hydroxyorcinol (5), atranol (6), and methyl hematommate (7). To obtain more derivatives, available compounds from the previous reports such as methyl ß-orsellinate (8), methyl orsellinate (9), and D-montagnetol (10) were selected for bromination. Electrophilic bromination was applied to 8-10 using NaBr/H2O2 reagents to yield products methyl 5-bromo-ß-orsellinate (8a), methyl 3,5-dibromo-orsellinate (9a), 3-bromo-D-montagnetol (10a), and 3,5-dibromo-D-montagnetol (10b). Compounds were evaluated for alpha-glucosidase inhibition and antimicrobial activity against antibiotic-resistant, pathogenic bacteria Enterococcus faecium, Staphylococcus aureus, and Acinetobacter baumannii. Compound 4 showed stronger alpha-glucosidase inhibition than others with an IC50 value of 24.0 µg/mL. Synthetic compound 9a exhibited remarkable activity against Staphylococcus aureus with a MIC value of 4 µg/mL. Molecular docking studies were performed to confirm the consistency between in vitro and in silico studies.

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 (IC50s 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.

Identification of Highly Potent α-Glucosidase Inhibitors from Artocarpus integer and Molecular Docking Studies.

A new natural Diels-Alder adduct (3) was isolated from the leaves and stem bark of Artocarpus integer, along with seventeen known compounds (1, 2, and 4-18). Structural elucidation was conducted using NMR and HR-ESI-MS data, and comparisons were made with previous studies. Deoxyartonin I (3) exhibited the most potent α-glucosidase inhibition (IC50 7.80±0.1 µM), outperforming the acarbose positive control. This was mixed-mode inhibition, as indicated by the intersect in the second quadrant of each respective plot. An in silico molecular docking model and the pharmacokinetic features of 3 suggest that it is a potential inhibitor of enzyme α-glucosidase, and is therefore a lead candidate as a drug against diabetes mellitus.

α-Glucosidase Inhibition by Usnic Acid Derivatives.

This study investigated a set of new potential antidiabetes agents. Derivatives of usnic acid were designed and synthesized. These analogs and nineteen benzylidene analogs from a previous study were evaluated for enzyme inhibition of α-glucosidase. Analogs synthesized using the Dakin oxidative method displayed stronger activity than the pristine usnic acid (IC50 >200 µM). Methyl (2E,3R)-7-acetyl-4,6-dihydroxy-2-(2-methoxy-2-oxoethylidene)-3,5-dimethyl-2,3-dihydro-1-benzofuran-3-carboxylate (6b) and 1,1'-(2,4,6-trihydroxy-5-methyl-1,3-phenylene)di(ethan-1-one) (6e) were more potent than an acarbose positive control (IC50 93.6±0.49 µM), with IC50 values of 42.6±1.30 and 90.8±0.32 µM, respectively. Most of the compounds synthesized from the benzylidene series displayed promising activity. (9bR)-2,6-Bis[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (1c), (9bR)-3,7,9-trihydroxy-8,9b-dimethyl-2,6-bis[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one (1g), (9bR)-2-acetyl-6-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (2d), (9bR)-2-acetyl-6-[(2E)-3-(3-chlorophenyl)prop-2-enoyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo[b,d]furan-1(9bH)-one (2e), (6bR)-8-acetyl-3-(4-chlorophenyl)-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione (3e), (6bR)-8-acetyl-6,9-dihydroxy-5,6b-dimethyl-3-phenyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione (3h), (6bR)-3-(2-chlorophenyl)-8-[(2E)-3-(2-chlorophenyl)prop-2-enoyl]-6,9-dihydroxy-5,6b-dimethyl-2,3-dihydro-1H-[1]benzofuro[2,3-f][1]benzopyran-1,7(6bH)-dione (4b), and (9bR)-6-acetyl-3,7,9-trihydroxy-8,9b-dimethyl-2-[(2E)-3-phenylprop-2-enoyl]dibenzo[b,d]furan-1(9bH)-one (5c) were the most potent α-glucosidase enzyme inhibitors, with IC50 values of 7.0±0.24, 15.5±0.49, 7.5±0.92, 10.9±0.56, 1.5±0.62, 15.3±0.54, 19.0±1.00, and 12.3±0.53 µM, respectively.

Manilkzapotane, a novel dimeric alkylresorcinol derivative from the stem bark of Manilkara zapota.

A novel dimeric alkylresorcinol derivative, manilkzapotane (1), along with seven known compounds, lupeol acetate (2), lupeol (3), arjunolic acid (4), ergosterol peroxide (5), taraxerol (6), hederagonic acid (7), and glochidiol (8) were isolated from the stem bark of Manilkara zapota. Their structures were determined on the basis of spectroscopic data. DFT-NMR chemical shift calculations and a modified probability (DP4+) method were applied to define the relative configuration of 1. To the best of our knowledge, this represents the first isolation of a dimeric alkylresorcinol derivative from the Sapotaceae family.

Alpha-Glucosidase Inhibitory Diterpenes from Euphorbia antiquorum Growing in Vietnam.

Bioactive-guided phytochemical investigation of Euphorbia antiquorum L. growing in Vietnam led to the isolation of five ent-atisanes, one seco-ent-atisane, and one lathyrane (ingol-type). The structures were elucidated as ent-1α,3α,16ß,17-tetrahydroxyatisane (1), ethyl ent-3,4-seco-4,16ß,17-trihydroxyatisane-3-carboxylate (2), ent-atisane-3-oxo-16ß,17-acetonide (3), ent-3α-acetoxy-16ß,17-dihydroxyatisane (4), ent-16ß,17-dihydroxyatisane-3-one (5), calliterpenone (6), and ingol 12-acetate (7). Their chemical structures were unambiguously determined by analysis of one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high resolution mass spectrometry, as well as by comparison with literature data. Among them, 1 is a new compound while 2 is an ethylated artifact of ent-3,4-seco-4,16ß,17-trihydroxyatisane-3-carboxylic acid, a new compound. Isolates were evaluated for alpha-glucosidase inhibition. Compound 3 showed the most significant inhibitory activity against alpha-glucosidase with an IC50 value of 69.62 µM. Further study on mechanism underlying yeast alpha-glucosidase inhibition indicated that 3 could retard the enzyme function by noncompetitive.

Flavones from Combretum quadrangulare Growing in Vietnam and Their Alpha-Glucosidase Inhibitory Activity.

Combretum quadrangulare Kurz is widely used in folk medicine in Eastern Asia and is associated with various ethnopharmacological properties including hepatoprotective, antipyretic, analgesic, antidysenteric, and anthelmintic activities. Previous phytochemical investigations reported the presence of numerous triterpenes (mostly cycloartanes, ursanes, lupanes, and oleananes) along with dozens of flavonoids. However, the extracts of C. quadrangulare and isolated flavonoids have not been evaluated for their alpha-glucosidase inhibition. In the frame of our efforts dedicated to the chemical investigation of Vietnamese medicinal plants and their biological activities, a phytochemical study of the MeOH extract of the leaves of C. quadrangulare using bioactive guided isolation was undertaken. In this paper, the isolation and structure elucidation of twelve known compounds, 5-hydroxy-3,7,4'-trimethoxyflavone (1), ayanin (2), kumatakenin (3), rhamnocitrin (4), ombuin (5), myricetin-3,7,3',5'-tetramethyl ether (6), gardenin D (7), luteolin (12), apigenin (13), mearnsetin (14), isoorientin (15), and vitexin (16) were reported. Bromination was applied to compounds 2 and 3 to provide four new synthetic analogues 8-11. All isolated and synthesized compounds were evaluated for alpha-glucosidase inhibition and antibacterial activity. Compounds 4 and 5 showed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus while others were inactive. All compounds failed to reveal any activity toward extended spectrum beta-lactamase-producing Escherichia coli. Compounds 2, 4, 6-9, and 11-14 showed good alpha-glucosidase inhibition with IC50 values in the range of 30.5-282.0 µM. The kinetic of enzyme inhibition showed that 8 and 11 were noncompetitive type inhibition against alpha-glucosidase. In silico molecular docking model indicated that compounds 8 and 11 were potential inhibitors against enzyme α-glucosidase.

Synthesis, α-glucosidase inhibition, and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic agents.

A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin, a compound with a natural depside structure (1), with a range of hydrazines. The natural product and 12 new analogues (2-13) were investigated for inhibition of α-glucosidase. The N-substituted hydrazide derivatives showed more potent inhibition than the original. The experimental results were confirmed by docking analysis. This study suggests that these compounds are promising molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2 demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2-13 against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.

α-Glucosidase Inhibitory Depsidones from the Lichen Parmotrema tsavoense.

Chemical investigation of the lichen Parmotrema tsavoense led to the isolation of 5 new depsidones, parmosidones F - J (1:  - 5: ). These compounds were structurally elucidated using spectroscopic methods including HRESIMS and 2D NMR data. Compounds 1, 3: , and 4: were evaluated for their inhibition of α-glucosidase. All exhibited potent α-glucosidase inhibitory activity with IC50 values ranging from 10.7 to 17.6 µM, which was much lower than that of the positive control acarbose (IC50 449 µM).

Nervisides I-J: Unconventional Side-Chain-Bearing Cycloartane Glycosides from Nervilia concolor.

Two new cycloartane glycosides, nervisides I-J, were isolated from Nervilia concolor whole plants. Their structures were unambiguously established by interpretation of their HRESIMS and 1D and 2D NMR data. These cycloartanes comprised a stereogenic center at C-24, the R configuration of which was assigned based on DFT-NMR calculations and the subsequent DP4 probability score. These compounds were tested for cytotoxicity against K562 and MCF-7 tumor cell lines, revealing mild cytotoxic activity.

Identification of highly potent α-glucosidase inhibitory and antioxidant constituents from Zizyphus rugosa bark: enzyme kinetic and molecular docking studies with active metabolites.

CONTEXT: Previous studies have shown that extracts of Zizyphus rugosa Lam. (Rhamnaceae) bark contained phytoconstituents with antidiabetic potential to lower blood glucose levels in diabetic rats. However, there has been no report on the active compounds in this plant as potential antidiabetic inhibitors. OBJECTIVE: We evaluated the α-glucosidase inhibitory and antioxidant activities of Z. rugosa extract. Moreover, the active phytochemical constituents were isolated and characterized. MATERIALS AND METHODS: The α-glucosidase inhibition of crude ethanol extract obtained from the bark of Z. rugosa was assayed as well as the antioxidant activity. Active compounds (1-6) were isolated, the structures were determined, and derivatives (2a-2 l) were prepared. All compounds were tested for their α-glucosidase inhibitory (yeast and rat intestine) and antioxidant (DPPH) activities. RESULTS: The active α-glucosidase inhibitors (1-6) were isolated from Z. rugosa bark and 12 derivatives (2a-2 l) were prepared. Compound 2 showed the most powerful yeast α-glucosidase inhibitory activity (IC50 16.3 µM), while compounds 3 and 4 display only weak inhibition toward rat intestinal α-glucosidase. Moreover, compound 6 showed the most potent antioxidant activity (IC50 42.8 µM). The molecular docking results highlighted the role of the carboxyl moiety of 2 for yeast α-glucosidase inhibition through H-bonding. DISCUSSION AND CONCLUSIONS: These results suggest the potential of Z. rugosa bark for future application in the treatment of diabetes and active compounds 1 and 2 have emerged as promising molecules for therapy.

Chemical constituents with their alpha-glucosidase inhibitory activity from the whole plant of Ceratophyllum demersum.

From Ceratophyllum demersum growing in Vietnam, twelve compounds were isolated and structurally elucidated, including six previously undescribed compounds, demersones A-D (1-4), acetylvelutins A and B (8 and 9), together with six known compounds, (+)-cyclocolorenone (5), 1-hydroxycyclocolorenone (6), 10-hydroxycyclocolorenone (7), retusin (10), betulinic acid (11), and lupeol (12). The chemical structures and stereochemistry of 1-12 were identified through analysis of spectroscopic data (1D and 2D NMR and HRESIMS), ECD data, and DFT calculation. Notably, this is the first time that humulene-type (1 and 2), guaiane-type (3), and aromadendrane-type (4-7) sesquiterpenoids have been reported in this genus. Compounds 8 and 9 are the first examples of 8-acetoxyflavones found in nature. Upon evaluation of the alpha-glucosidase of 1-3 and 5-12, it was found that 12 exhibited the highest potential with an IC50 value of 15.4 ± 1.1 µM. The molecular docking of 3 and 8 was further studied.

New α-glucosidase inhibitory xanthones from the fruits of Garcinia schomburgkiana.

Two previously unreported xanthones, xanthoschomes A and B (1 and 2), along with six known xanthones, α-mangostin (3), ß-mangostin (4), γ-mangostin (5), garcinone C (6), 2-(γ,γ-dimethylallyl)-1,7-dihydroxy-3-methoxyxanthone (7), and dulxanthone D (8), have been isolated from the fruits of Vietnamese Garcinia schomburgkiana. The structures of all isolated compounds were fully characterised using spectroscopic data and comparison with the previous literature. All isolated compounds were evaluated for their in vitro α-glucosidase inhibitory activity. Compounds 1-8 demonstrated effective α-glucosidase inhibition, with the IC50 ranging from 2.91 to 26.0 µM, outperforming the standard acarbose (IC50 179 µM). Among these isolated compounds, compound 8 exhibited the highest inhibitory activity against α-glucosidase, with an IC50 value of 2.91 µM.

Alpha-glucosidase inhibitory compounds from Vietnamese lichen Usnea baileyi: in vitro and in silico aspects.

Using a bio-guided isolation on the Vietnamese lichen Usnea baileyi based on alpha-glucosidase inhibition, eleven compounds were isolated and structurally elucidated, namely, protocetraric acid (1), 8'-methylstictic acid (2), stictic acid (3), 4,6-diformyl-8-hydroxy-3-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-7-carboxylic acid (4), vicanicin (5), norstictic acid (6), diffractaic acid (7), barbatic acid (8), atranol (9), 5-chlorohaematommic acid (10), and eumitrin A1 (11). Their chemical structures were identified by extensive 1D and 2D NMR analysis and high-resolution mass spectroscopy and compared with those reported in literature. Protocetraric acid (1) and norstictic acid (6) were selected for further modification to derive new compounds, namely, 1a-1e and 6a. Both isolated and synthesized compounds were assessed for their alpha-glucosidase inhibitory activity. Compounds 1-6, 1a-1e, 6a, and 11 showed significant alpha-glucosidase inhibition with IC50 values ranging from 10.4 to 130 µM. Molecular docking was applied to the most active compounds 1-3, 6, 1a-1e, and 6a to clarify the inhibitory mechanism. Compound 1e was determined to be a mixed inhibitor through a kinetic study.