Morusacerane: A new gammacerane triterpenoid from the trunk of Morus Alba linn. with α-glucosidase inhibitory activity.

This phytochemistry investigation on the trunk of Morus alba L. resulted in the isolation of three triterpenoids, including a new gammacerane triterpenoid - morusacerane (1); along with two known compounds of betulinic acid (2) and ursolic acid (3). The structure elucidation was thoroughly conducted based on 1D, 2D-NMR and HRESIMS spectra, followed by a comparison with existing literatures. The evaluation on α-glucosidase inhibitory exhibited the great potential of the application of these isolated compounds in diabetes treatments. The results show that morusacerane (1), betulinic acid (2), and ursolic acid (3) demonstrate the strong inhibitory with the IC50 values of 106.1, 11.12, and 7.20 µM, respectively. All of these compounds interacted well with the allosteric site enzyme α-glucosidase MAL32 through H-bonds and hydrophobic interaction.

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.

Structural modification of tanshinone IIA and their α-glucosidase inhibitory activity.

α-Glucosidase is one of the therapeutic approaches for treating type 2 diabetes mellitus. Almost 95 % of diabetes patients worldwide have been diagnosed with type 2 diabetes, resulting in 1.5 million fatalities each year. Newly synthesized oxazole-based tanshinone IIA derivatives (1a-n) were designed and evaluated for their inhibitory activity against α-glucosidase enzyme. Eight compounds (1a-d, 1f-g, 1j, and 1m) demonstrated excellent inhibition with IC50 values ranging from 0.73 ± 0.11 to 9.46 ± 0.57 µM as compared to tanshinone IIA (IC50 = 11.39 ± 0.77 µM) and standard acarbose (IC50 = 100.00 ± 0.95 µM). Among this series, 1j bearing two hydroxyls group over the phenyl ring was identified as the most potent α-glucosidase inhibitor with IC50 value of 0.73 ± 0.11 µM. Molecular docking simulations were done for the most active compound to identify important binding modes responsible for inhibition activity of α-glucosidase. In addition, the kinetic study was also performed to understand the mode of inhibition.

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.

Cycloartane-type triterpenoids from the leaves of Sandoricum koetjape and their efficacy on α-glucosidase inhibition activity.

The preliminary α-glucosidase inhibitory activity of the methanol extract of the leaves of Sandoricum koetjape Merr. exhibited promising results. The leaves was extracted with methanol to obtain the methanol extract that was continuedly partitioned with hexane and ethyl acetate. Those fractions were further purified by various chromatographic techniques. The isolation of the potent fractions furnished two new cycloartane-type triterpenoids (1 and 2) along with ten known compounds (3-12). Their chemical structures were unambiguously established by interpretation of NMR (1 D & 2 D) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data. Furthermore, the configurations of two new compounds were determined by using NOESY spectrum as well as comparing their NMR data to the reference. These compounds were evaluated against α-glucosidase. All tested compounds revealed potent activity with IC50 value in the range of 2.17-49.2 µM compared to that of acarbose (IC50 100.6 µM). Compound 10 showed the lowest IC50 value. This compound was reported as a mixed-type inhibitor. Compound 3 possessed the second strong activity with an IC50 value of 14.0 µM and was further investigated on kinetic analysis which revealed as a mixed-type inhibitor with Ki and Ki' values of 59.1 and 155.2 µM, respectively.

Naturally occurring phytic acid: an advanced Brønsted acid catalyst for direct amination reactions of allylic alcohols.

Phytic acid is abundant in various plant-based foods and is considered agricultural waste. Here, we demonstrate the effectiveness of this organophosphorus acid as a sustainable catalyst for the direct amination reactions of allylic alcohols. This approach is successfully performed in air using technical grade solvents, affording allylanilines in moderate to excellent yields. Challenging electron-rich anilines react effectively, and their corresponding Friedel-Crafts side products can be minimised under the optimised reaction conditions. A variety of asymmetrically substituted allylic alcohols are tolerated, while the scope is extended to amide, and C-, O- and S-nucleophiles.

Identification and α-glucosidase inhibitory activity evaluation of two new coumarins derived from Mansonia gagei J. R. Drumm.

Five coumarins were isolated from the heartwood of Mansonia gagei, which included two newly discovered compounds, namely 11-hydroxypopulene E (1) and mansorin D (2), along with three previously identified compounds. The structures were determined through the utilisation of comprehensive spectroscopic data, ECD calculations, and a thorough comparison with existing literature data. The α-glucosidase inhibitory activities of all isolated compounds were assessed in yeast. Out of the compounds tested, compound 2 exhibited the most significant activity, displaying a percentage inhibition of 34.33% at a concentration of 200 µM.

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.

Two new rotenoid glycosides from the rhizomes of Stemona curtisii Hook. f.

Two new rotenoid glycosides named stemonal 11-O-ß-D-glucopyranoside and 6-O-methylstemonal 11-O-ß-D-glucopyranoside together with ten known metabolites were isolated from the rhizomes of Stemona curtisii. The chemical structures of the new compounds were elucidated based on the analysis of their 1D and 2D NMR and HRESIMS, while the sugar unit and absolute configuration were determined by chemical hydrolysis and ECD analysis. Among the tested compounds for anti-α-glucosidase assay, stemonal showed an inhibitory effect (IC50 = 38.67 µM), which is 2.4-fold more potent than acarbose. Cytotoxic evaluation against the lung adenocarcinoma A549 cell line indicated that none of the compounds were strongly active to suppress the cancer cell growth at 100 µM. This work describes the occurrence of rotenoids bearing a sugar moiety, which are reported for the first time in the genus Stemona. The isolated compound's α-glucosidase inhibitory potential provides insight for further investigation of natural rotenoids as anti-diabetic agents.

Synthesis and biological evaluation of 2'-hydroxychalcone derivatives as AMPK activators.

A series of 2'-hydroxychalcone derivatives with various substituents on B-ring were synthesized and evaluated for AMP-activated protein kinase (AMPK) activation activity in podocyte cells. The results displayed that hydroxy, methoxy and methylenedioxy groups on B-ring could enhance the activitiy better than O-saturated alkyl, O-unsaturated alkyl or other alkoxy groups. Compounds 27 and 29 possess the highest fold change of 2.48 and 2.73, respectively, which were higher than those of reference compound (8) (1.28) and metformin (1.88). Compounds 27 and 29 were then subjected to a concentration-response study to obtain the EC50 values of 2.0 and 4.8 µM, respectively and MTT assays also showed that cell viability was not influenced by the exposure of podocytes to compounds 27 and 29 at concentrations up to 50 µM. In addition, compound 27 was proved to activate AMPK via calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß)-dependent pathway without affecting intracellular calcium levels. The computational study showed that the potent compounds exhibited stronger ligand-binding strength to CaMKKß, particularly compounds 27 (-8.4 kcal/mol) and 29 (-8.0 kcal/mol), compared to compound 8 (-7.5 kcal/mol). Fragment molecular orbital (FMO) calculation demonstrated that compound 27 was superior to compound 29 due to the presence of methyl group, which amplified the binding by hydrophobic interactions. Therefore, compound 27 would represent a promising AMPK activator for further investigation of the treatment of diabetes and diabetic nephropathy.

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.

A sulfonamide chalcone inhibited dengue virus with a potential target at the SAM-binding site of viral methyltransferase.

Dengue infection is a global health problem as climate change facilitates the spread of mosquito vectors. Infected patients could progress to severe plasma leakage and hemorrhagic shock, where current standard treatment remains supportive. Previous reports suggested that several flavonoid derivatives inhibited mosquito-borne flaviviruses. This work aimed to explore sulfonamide chalcone derivatives as dengue inhibitors and to identify molecular targets. We initially screened 27 sulfonamide chalcones using cell-based antiviral and cytotoxic screenings. Two potential compounds, SC22 and SC27, were identified with DENV1-4 EC50s in the range of 0.71-0.94 and 3.15-4.46 µM, and CC50s at 14.63 and 31.02 µM, respectively. The compounds did not show any elevation in ALT or Cr in C57BL/6 mice on the 1st, 3rd, and 7th days after being administered intraperitoneally with 50 mg/kg SC22 or SC27 in a single dose. Moreover, the SAM-binding site of NS5 methyltransferase was a potential target of SC27 identified by computational and enzyme-based assays. The main target of SC22 was in a late stage of viral replication, but the exact target molecule had yet to be identified. In summary, a sulfonamide chalcone, SC27, was a potential DENV inhibitor that targeted viral methyltransferase. Further investigation should be the study of the structure-activity relationship of SC27 derivatives for higher potency and lower toxicity.

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 1.61-2.67 µM. 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.

The 8-bromobaicalein alleviated chikungunya-induced musculoskeletal inflammation and reduced the viral load in healthy adult mice.

Chikungunya virus is a re-emerging arbovirus that has caused epidemic outbreaks in recent decades. Patients in older age groups with high viral load and severe immunologic response during acute infection are likely to develop chronic arthritis and severe joint pain. Currently, no antiviral drug is available. Previous studies suggested that a flavone derivative, 8-bromobaicalein, was a potential dengue and Zika replication inhibitor in a cell-based system targeting flaviviral polymerase. Here we characterized that 8-bromobaicalein inhibited chikungunya virus replication with EC50 of 0.49 ± 0.11 µM in Vero cells. The molecular target predicted at viral nsP1 methyltransferase using molecular binding and fragment molecular orbital calculation. Additionally, oral administration of 250 mg/kg twice daily treatment alleviated chikungunya-induced musculoskeletal inflammation and reduced viral load in healthy adult mice. Pharmacokinetic analysis indicated that the 250 mg/kg administration maintained the compound level above EC99.9 for 12 h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug.

Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CLpro through Structure-Based Virtual Screening and Experimental Approaches.

3CLpro is a viable target for developing antiviral therapies against the coronavirus. With the urgent need to find new possible inhibitors, a structure-based virtual screening approach was developed. This study recognized 75 pharmacologically bioactive compounds from our in-house library of 1052 natural product-based compounds that satisfied drug-likeness criteria and exhibited good bioavailability and membrane permeability. Among these compounds, three promising sulfonamide chalcones were identified by combined theoretical and experimental approaches, with SWC423 being the most suitable representative compound due to its competitive inhibition and low cytotoxicity in Vero E6 cells (EC50 = 0.89 ± 0.32 µM; CC50 = 25.54 ± 1.38 µM; SI = 28.70). The binding and stability of SWC423 in the 3CLpro active site were investigated through all-atom molecular dynamics simulation and fragment molecular orbital calculation, indicating its potential as a 3CLpro inhibitor for further SARS-CoV-2 therapeutic research. These findings suggested that inhibiting 3CLpro with a sulfonamide chalcone such as SWC423 may pave the effective way for developing COVID-19 treatments.

Designing Potent α-Glucosidase Inhibitors: A Synthesis and QSAR Modeling Approach for Biscoumarin Derivatives.

Nineteen biscoumarins were synthesized, well-characterized, and evaluated against α-glucosidases in vitro. Of these, six compounds (10, 12, 16, and 17-19) were newly synthesized and not previously reported in the chemical literature. The majority of the synthesized derivatives demonstrated significant inhibitory activity. A quantitative structure-activity relationship (QSAR) model was developed, revealing a strong correlation between the anti-α-glucosidase activity and selected molecular descriptors. Based on this model, two new compounds (18 and 19) were designed, which exhibited the strongest inhibition with IC50 values of 0.62 and 1.21 µM, respectively, when compared to the positive control (acarbose) with an IC50 value of 93.63 µM. Enzyme kinetic studies of compounds 18 and 19 revealed their competitive inhibition with Ki values of 3.93 and 1.80 µM, respectively. Computational studies demonstrated that compound 18 could be inserted into the original binding site (OBS) of α-glucosidase MAL12 and form multiple hydrophobic interactions with nearby amino acids, with the bromo group playing an essential role in enhancing the binding strength and stability at the OBS of the enzyme based on the quantum mechanical calculations using the fragment molecular orbital method. These findings provide valuable insights into the design of potent α-glucosidase inhibitors, which may have potential therapeutic applications in the treatment of diabetes and related diseases.

Discovery of a chalcone derivative as an anti-fibrotic agent targeting transforming growth factor-ß1 signaling: Potential therapy of renal fibrosis.

As a final common pathway of renal injuries, renal fibrosis leads to chronic kidney disease (CKD). Currently, there is no safe and effective therapy to prevent the progression of renal fibrosis to CKD. Inhibition of transforming growth factor-ß1 (TGF-ß1) pathway is proposed as one of the most promising approaches for anti-renal fibrosis therapies. This study aimed to identify novel anti-fibrotic agents using the TGF-ß1-induced fibrosis in renal proximal tubule epithelial cells (RPTEC) and characterize their mechanism of action as well as in vivo efficacy. By screening 362 natural product-based compounds for their ability to reduce collagen accumulation assessed by picro-sirius red (PSR) staining in RPTEC cells, a chalcone derivative AD-021 was identified as an anti-fibrotic agent with IC50 of 14.93 µM. AD-021 suppressed TGF-ß1-induced collagen production, expression of pro-fibrotic proteins (fibronectin and α-smooth muscle actin (αSMA)), and Smad-dependent and Smad-independent signaling pathways via suppression of TGF-ß receptor II (TGFßRII) phosphorylation in RPTEC cells. Furthermore, TGF-ß1-induced mitochondrial fission in RPTEC cells was ameliorated by AD-021 via mechanisms involving inhibition of Drp1 phosphorylation. In a mouse model of unilateral ureteral obstruction (UUO)-induced renal fibrosis, AD-021 reduced plasma TGF-ß1, ameliorated renal fibrosis and improved renal function. Collectively, AD-021 represents a novel class of natural product-based anti-fibrotic agent that has therapeutic potential in the prevention of fibrosis-associated renal disorders including CKD.

A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which currently lacks effective treatments. AMP-activated protein kinase (AMPK) stimulation by chalcones, a class of polyphenols abundantly found in plants, is proposed as a promising therapeutic approach for DM. This study aimed to identify novel chalcone derivatives with improved AMPK-stimulating activity in human podocytes and evaluate their mechanisms of action as well as in vivo efficacy in a mouse model of DN. Among 133 chalcone derivatives tested, the sulfonamide chalcone derivative IP-004 was identified as the most potent AMPK activator in human podocytes. Western blot analyses, intracellular calcium measurements and molecular docking simulation indicated that IP-004 activated AMPK by mechanisms involving direct binding at allosteric site of calcium-dependent protein kinase kinase ß (CaMKKß) without affecting intracellular calcium levels. Interestingly, eight weeks of intraperitoneal administration of IP-004 (20 mg/kg/day) significantly decreased fasting blood glucose level, activated AMPK in the livers, muscles and glomeruli, and ameliorated albuminuria in db/db type II diabetic mice. Collectively, this study identifies a novel chalcone derivative capable of activating AMPK in vitro and in vivo and exhibiting efficacy against hyperglycemia and DN in mice. Further development of AMPK activators based on chalcone derivatives may provide an effective treatment of DN.

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.