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.

A new diphenyl ether from the cultured lichen mycobiont of Graphis cf. handelii.

Lichen is well-known for its various purposes. However, understanding the chemical composition and antimicrobial characteristics of Graphis cf. handelii remains insufficient. In this study, a new compound, graphinone A (1), together with three known compounds, handelone (2), 4-O-methylhiascic acid (3), and ethyl orsellinate (4) were isolated and structurally elucidated. Their chemical structures were established using comprehensive spectroscopic data (1D- and 2D-NMR and HRESIMS). Compounds 1-4 were tested for antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and evaluated for the alpha-glucosidase inhibition.

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.

In vitro and in silico studies of alpha glucosidase inhibition and antifungal activity of coffea canephora husk.

The coffea canephora husk, a protected agricultural crop, is abundant in Vietnam. Examining the effects of C. canephora husk compounds on α-glucosidase and antifungal drug activity was the primary objective of this research. A cholestane-type steroid, coffeacanol A (1), was extracted from the ethyl acetate extract. Three cholestane-type derivatives (2-4) and three additional known compounds (5-7) were separated, and we used a variety of chromatographic techniques to identify a total of six substances. We used NMR to determine the chemical structures of these substances. Extensive HR-MS-ESI analysis and NMR experimental data were used to confirm the structure of the novel metabolite (1). The cholestane-type steroid was initially discovered in the Coffea canephora husk, marking the first instance in the coffee plant family to reveal chemical structures (1-7). The inhibition of α-glucosidase was found to be significantly higher in all compounds tested, with the exception of compounds (2) and (5). In vitro, the positive control showed the lowest inhibition, and the range of IC50 values was calculated to be 27.4 to 96.5 µM, which is lower than the IC50 value of 214.50 µM for the acarbose control. With an IC50 value of 27.4 µM, compound (7) showed the greatest capacity to inhibit α-glucosidase among the test compounds. The 3TOP and 2VF5 enzyme crystal structures were used for in silico docking investigations and validations of compounds (1-7). In silico calculations to explain how compound (7) shows high activity in vitro via the enzyme inhibition mechanism by residual amino acids, like Gly 1102 (B chain) and Glu 1095 (B chain), and their relative interaction with compounds (7) and acarbose. Compound (7) exhibited the best antifungal activity against Candida albicans fungus among three fungi, namely Candida albicans, Trichophyton mentagrophytes, and Trichophyton rubrum, with a MIC value of 25 µM. Compound (7) and fluconazole combined to form similar interactions in the contact ligand model, including the functional group, capping group, and linker part, which interacted fully with the 2VF5 enzyme, leading to effective in vitro inhibition.

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.

Correction: Antimicrobial and alpha-glucosidase inhibitory flavonoid glycosides from the plant Mussaenda recurvata: in vitro and in silico approaches.

[This corrects the article DOI: 10.1039/D4RA00666F.].

In vitro and in silico docking and molecular dynamic of antimicrobial activities, alpha-glucosidase, and anti-inflammatory activity of compounds from the aerial parts of Mussaenda saigonensis.

Twelve compounds were isolated from Mussaenda saigonensis aerial parts through phytochemical analysis and the genus Mussaenda is the first place where the compounds 4-6 and 11-12 have been found. Based on the ability to inhibit NO production in RAW264.7 cells, compound 2 has demonstrated the strongest anti-inflammatory activity in vitro with an IC50 of 7.6 µM, as opposed to L-NMMA's IC50 of 41.3 µM. Compound 12 was found to be the most effective inhibitor of alpha-glucosidase enzyme in vitro, with an IC50 value of 42.4 µM (compared to 168 µM for acarbose). Compounds 1-12 were evaluated in vitro for antimicrobial activity using the paper dish method. Compound 11 demonstrated strong antifungal activity against M. gypseum with a MIC value of 50 µM. In silico docking for antimicrobial activity, pose 90 or compound 11 docked well to the 2VF5 enzyme, PDB, which explains why compound 11 had the highest activity in vitro. Entry 2/pose 280 demonstrated excellent anti-inflammatory activity in silico. The stability of the complex between pose 280 and the 4WCU enzyme for anti-inflammatory activity has been assessed using molecular dynamics over a simulation course ranging from 0 to 100 ns. It has been found to be stable from 60 and 100 ns. The Tyr 159 (95%, H-bond via water bridge), Asp 318 (200%, multiple contacts), Met 273 (75%, hydrophobic interaction via water bridge), and Gln 369 (75%, H-bond via water bridge) interacted well within the time range of 0 to 100 ns. It has more hydrophilic or polar pharmacokinetics.

Three new constituents from the stems of Knema globularia and their α-glucosidase inhibitory activity.

Three new metabolites (1-3) were isolated from the stems of Knema globularia, along with five known compounds, including kaempferol (4), quercetin (5), isovanillic acid (6), protocatechuic acid (7), and gallic acid (8). Their structures were deduced using NMR spectroscopic, mass spectrometric analyses, and literature data. The absolute configurations of 1-3 were established by electronic circular dichroism (ECD) spectroscopy. α-Glucosidase inhibitory activities of those compounds were evaluated using a spectrophotometric method, compounds 1-3 showed very strong effects towards α-glucosidase with IC50 values 1.59, 0.58 and 1.37 µM, respectively (the positive control, acarbose, IC50 93.63 µM). Simultaneously, enzyme kinetics study indicated that 2 was a mix-type inhibitor. 2 interacted well in the active site of α-glucosidase enzyme, primarily through hydrogen bonds and hydrophobic interactions.

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.

Antimicrobial and alpha-glucosidase inhibitory flavonoid glycosides from the plant Mussaenda recurvata: in vitro and in silico approaches.

Seven flavonoid glycosides were isolated from the aerial portions of Mussaenda recurvata during a phytochemical analysis. This comprised one novel component, ecurvoside, and six well-studied compounds, namely astragalin, isoquercitrin, nicotiflorin, rutin, hesperidin, and neohesperidin. The chemical structures of compounds were identified using spectroscopic techniques and a comparison with previously published studies. Alpha-glucosidase inhibition testing was carried out on all isolated compounds. The compounds evaluated have IC50 values between 35.6 and 239.1 g mL-1, indicating a moderate degree of inhibition. In vitro antimicrobial activities of compounds 1-7 have screened against the bacteria Pseudomonas aeruginosa (P. aeruginosa), methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus faecalis (Strep. faecalis), and fungi: Candida albicans (C. albicans), Trichophyton mentagrophytes (T. mentagrophytes), and Microsporum gypseum (M. gypseum), where compound 6 showed excellent activity against fungi T. mentagrophytes with an MIC value of 12.5 µM. In accordance with the molecular docking study, ecurvoside (1) or pose 472 interacted well with the 3TOP enzyme: PDB and the molecular dynamic simulations proved that the complex of ecurvoside and 3TOP has a stable simulation time of 50-100 ns and the significant residual amino acids in 3TOP are relative to interactions more than one time such as Asp 960, Glu 961, Lys 1088, Glu 1095, Arg 1097, Gly 1102, Thr 1103, Gln 1109, Glu 1178: A chain and Glu 1095, Thr 1101, and Asp 1107: B chain. The docking studies of compounds 1-7 to the enzyme 2VF5 explain the general mechanism to inhibit bacteria and proved that compound 6 (pose 370) inhibited stronger than compound 7 (pose 362) and compound 5 (pose 280), and compounds 1 to 4 do not interact well with 2VF5.

Globunoids A-D, undescribed bichalconoid and biflavanoids with α-glucosidase and α-amylase inhibitory activities from Knema globularia stems.

A bichalconoid, globunoid A (1) and three biflavanones, globunoids B-D (2-4), previously undescribed, were isolated from the stems of Knema globularia, along with fourteen known analogues 5-18. The chemical structures of 1-4 were elucidated by the comprehensive spectroscopic analysis including UV, IR, HRESIMS, and NMR; the absolute configurations were determined based on their NOESY data, DP4+ statistical analysis, and ECD calculation. Up to now, compounds 2 and 3 represent the first 3,3″-linked biflavanone structures. Among the isolated compounds, 2, 3, and 2,3-dihydrocalodenin B (6) potently inhibited α-glucosidase and α-amylase activities, with IC50 values in the range 1.1-7.5 µM. Furthermore, the most active compound 6 was found to be a non-competitive inhibitor against these two enzymes.

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management.

The spread of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, has strongly motivated the research and development of new anti-TB drugs. New strategies to facilitate drug combinations, including pharmacokinetics-guided dose optimization and toxicology studies of first- and second-line anti-TB drugs have also been introduced and recommended. Liquid chromatography-mass spectrometry (LC-MS) has arguably become the gold standard in the analysis of both endo- and exo-genous compounds. This technique has been applied successfully not only for therapeutic drug monitoring (TDM) but also for pharmacometabolomics analysis. TDM improves the effectiveness of treatment, reduces adverse drug reactions, and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window. Based on TDM, the dose would be optimized individually to achieve favorable outcomes. Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs, aiding in the discovery of potential biomarkers for TB diagnostics, treatment monitoring, and outcome evaluation. This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades. Besides, we discussed the advantages and disadvantages of this technique in practical use. The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted. Lastly, we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies (pharmacometrics, drug and vaccine developments, machine learning/artificial intelligence, among others) to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

Diphenyl ethers from the cultured lichen mycobiont of Graphis handelii Zahlbr.

Purpose: Cultured lichen mycobionts are valuable sources of new natural compounds. Mycobiont of Graphis handelii growing in Vietnam was isolated, cultivated and chemically investigated. The crude extract of this cultured mycobiont showed potent alpha-glucosidase inhibition with an IC50 value of 50 µg/mL. Methods: Multiple chromatographic methods were applied to the extract to isolate compounds. The combination of Nuclear Magnetic Resonance analysis and high-resolution mass spectroscopy determined their chemical structures. Electrophilic bromination/chlorination was applied to obtain new derivatives using NaBr/H2O2 and NaCl/H2O2 reagents. Compounds were evaluated for enzyme inhibitory activities, including alpha-glucosidase inhibition, HIV-1 reverse transcriptase inhibition, SARS-CoV-2 main protease (Mpro) inhibition, anti-inflammatory activity, and cytotoxicity against several cancer cell lines. A molecular docking study for anti-SARS-CoV-2 was conducted to understand the inhibitory mechanism. Results: A new diphenyl ether, handelone (1) and a known compound xylarinic acid A (2) were isolated and elucidated. Four synthetic products 6'-bromohandelone (1a), 2'-bromohandelone (1b), 2',6'-dibromohandelone (1c), and 2',6'-dichlorohandelone (1d) were prepared. Compound 1 showed good activity against Mpro with an IC50 value of 5.2 µM but it showed weak or inactive activity in other tests. Other compounds were inactive in all assays. Conclusion: A new compound, handelone (1) was isolated from the cultured mycobiont of Graphis handelii. From these compounds, four new derivatives were prepared. Compound 1 showed good activity against Mpro with an IC50 value of 5.2 µM but it showed weak or inactive activity in other tests. Other compounds were inactive in all assays.

Antimicrobial sesquiterpenes from the cultured mycobiont Diorygma pruinosum against methicillin-resistant Staphylococcus aureus isolated from Vietnamese street foods.

Traditionally, lichen has been used for many purposes, but there remains a lack of understanding regarding the chemical composition and antimicrobial characteristics of Diorygma pruinosum, a lichen native to Vietnam. In this study, four sesquiterpenes, diorygmones B-E (1-4), one phenolic compound, 3,5-dihydroxy-4-methoxybenzoic acid (5), and one sterol, ß-sitosterol (6), were isolated and structurally elucidated from the cultured mycobiont of the lichen Diorygma pruinosum. Additionally, two compounds, stictic acid (7) and norstictic acid (8), were also isolated from the lichen D. pruinosum. Compounds 2-4 were new compounds. Their chemical structures were established using comprehensive spectroscopic data, and the absolute configurations were confirmed through the analysis of NOESY and electronic circular dichroism (ECD). Moreover, Staphylococcus aureus, a Gram-positive bacterium, has been responsible for various infections, including food poisoning. Herein, we identified and isolated 13 strains of S. aureus from street food sources. Among these strains, one was identified as a multidrug-resistant variant, designated as SAX15, and was subsequently used for further antimicrobial testing. Compounds 1-3 produced zones of inhibition against S. aureus SAX15 (each 5 mm) in comparison to commercial drugs such as penicillin, ciprofloxacin, gentamicin, cefoxitin, and clarithromycin, which displayed inhibitory zones of 7, 5, 10, 9.7, and 7 mm, respectively.

Bio-guided isolation of alpha-glucosidase inhibitory compounds from Vietnamese liverwort Marchantia polymorpha: in vitro and in silico studies.

Bio-guided isolation was applied to Vietnamese Marchantia polymorpha L. to find alpha-glucosidase inhibition. Fifteen compounds were isolated and structurally determined, including two new compounds, marchatoside (7) and marchanol (8), along with thirteen known compounds: marchantin A (1), isoriccardin C (2), riccardin C (3), marchantin K (4), lunularin (5), 3R-(3,4-dimethoxybenzyl)-5,7-dimethoxyphthalide (6), vitexilactone (9), 12-oleanene-3-one (10), 3,11-dioxoursolic acid (11), ursolic acid (12), artemetin (13), kaempferol (14), and quercetin (15). The structures of these compounds were determined through extensive spectroscopic analyses (1D and 2D NMR, HRESIMS, and ECD) and by comparisons to the existing literature. There are five types of carbon skeleton, including bibenzyl (1-5), 3-benzylphthalide (6 and 7), diterpenoid (8 and 9), triterpenoid (10-12), and flavonoid (13-15). Compounds 6-12 were reported for the first time within the genus Marchantia. Compounds 1-12 were evaluated for their alpha-glucosidase inhibition. Among them, 1-5 and 10-12 displayed potent inhibition, with IC50 values ranging from 28.9 to 130.6 µM, compared to the positive control acarbose 330.9 µM. A kinetic study and molecular docking were also performed to understand the mechanism.

Bio-guided isolation of alpha-glucosidase inhibitory compounds from Vietnamese Garcinia schomburgkiana fruits: in vitro and in silico studies.

Garcinia schomburgkiana is an edible tree widely distributed in the southern region of Vietnam. Little is known about the alpha-glucosidase inhibition of the Vietnamese Garcinia schomburgkiana. The aim of the current study was to explore the anti-diabetic potential of G. schomburgkiana fruits. All the fractions of G. schomburgkiana were evaluated for alpha-glucosidase inhibition, followed by bioassay-guided isolation. A new compound, epi-guttiferone Q (1), together with ten known compounds, guttiferones I-K (2-3), hypersampsone I (4), sampsonione D (5), sampsonione H (6), ß-mangostin (7), α-mangostin (8), 9-hydroxycalabaxanthone (9), and fuscaxanthone (10), were isolated and structurally elucidated. The structure of the new metabolite 1 was confirmed through 1D and 2D NMR spectroscopy, and MS analysis. To the best of our knowledge, the metabolites (except 3) have not been isolated from this plant previously. All isolated compounds were evaluated for their alpha-glucosidase inhibition. Compounds 1-6 showed potent activity with IC50 values ranging from 16.2 to 130.6 µM. Compound 2 was further selected for a kinetic study. The result indicated that it was a competitive type. Additionally, in silico docking was employed to predict the binding mechanism of 1-2 and 4-6 in the active site of alpha-glucosidase, suggesting their potential as promising anti-diabetic compounds. Molecular dynamic simulation was also applied to 1 to better understand its inhibitory mechanism.

A New 3-Benzylphthalide from the Moss Erythrodontium julaceum.

From the moss Erythrodontium julaceum Paris growing in Vietnam, julacelide (1), a new 3-benzylphthalide, along with methyl orsellinate (2), ethyl orsellinate (3), 4-O-methylhaematommic acid (4), and zeorin (5), were isolated and structurally elucidated. Their chemical structures were elucidated through extensive 1D and 2D NMR analysis and high-resolution mass spectroscopy as well as through comparisons to the existing literature. Compound 4-O-methylhaematommic acid was a new natural product. The absolute configuration of julacelide was defined using time-dependent density functional theory (TDDFT) calculations. Julacelide was evaluated for α-glucosidase inhibition.

Bioactive-Guided Phytochemical Investigations, In Vitro and In Silico Alpha-Glucosidase Inhibition of Two Vietnamese Medicinal Plants Dicranopteris linearis and Psychotria adenophylla.

Little is known about the chemical and biological profiles of Dicranopteris linearis and Psychotria adenophylla. No previous studies have investigated alpha-glucosidase inhibition using extracts from D. linearis and P. adenophylla. In this paper, bioactive-guided isolation procedures were applied to the plants D. linearis and P. adenophylla based on alpha-glucosidase inhibition. From the most active fractions, 20 compounds (DL1-DL13 and PA1-PA7) were isolated. The chemical structures were elucidated using spectroscopic data and compared with those available in the literature. These compounds were evaluated for alpha-glucosidase inhibition, while a molecular docking study was performed to elucidate the mechanisms involved. Consequently, D. linearis and P. adenophylla might serve as a good potential for developing new antidiabetic preparations.

New Halogenated Flavonoids from Adenosma bracteosum and Vitex negundo and Their α-Glucosidase Inhibition.

Adenosma bracteosum and Vitex negundo are natural sources of methoxylated flavonoids. Little is known about the α-glucosidase inhibition of multi-methoxylated flavonoid derivatives. Eighteen natural flavonoids were isolated from A. bracteosum and V. negundo. Seven halogenated derivatives were synthesized. Their chemical structures were elucidated by extensive NMR analysis and high-resolution mass spectroscopy as well as comparisons in literature. All compounds were evaluated for their α-glucosidase inhibition. Most compounds showed good activity with IC50 values ranging from 16.7 to 421.8 µM. 6,8-Dibromocatechin was the most active compound with an IC50 value of 16.7 µM. A molecular docking study was conducted, indicating that those compounds are potent α-glucosidase inhibitors.

Untargeted Metabolomics Approach for the Differentiation between Panax vietnamensis var. vietnamensis and Panax vietnamensis var. fuscidiscus.

Panax vietnamensis var. vietnamensis (PVV) and Panax vietnamensis var. fuscidiscus (PVF) both belong to Panax vietnamensis species and are chemically and morphologically similar, making it hard to distinguish for the consumer. Herein, 42 PVF and 12 PVV samples were collected in Quang Nam and Lai Chau Province, respectively, and subsequently characterized by ITSr-DNA sequence data to verify their origins. Next, untargeted metabolomics combined with multivariate statistical analysis was developed to differentiate PVV and PVF. The metabolic profiles of PVV and PVF were found to be distinct and classified well using Partial Least-Squares Discriminant Analysis (PLS-DA) in the training set. Among them, seven ginsenosides were of high abundance in PVV, while six were of high abundance in PVF. Next, the test set was used to validate 13 putative differential markers found in the training set, illustrating a complete match with the expression patterns of these ginsenosides in the training set. Finally, PLS-DA and linear Support Vector Machine models both indicated distinct ginsenoside profiles of PVV and PVF without misclassification in the test set. Conclusively, the developed untargeted metabolomics approach might serve as a powerful tool for the authentication of PVV and PVF at the metabolome level.