New maplexins F–I and phenolic glycosides from red maple (Acer rubrum) bark

Four new gallotannins, maplexins F–I (1–4), two new phenolic glycosides, rubrumosides A–B (5,6), and eleven known compounds were isolated from red maple (Acer rubrum) bark. Their structures were elucidated based on spectroscopic analysis. The maplexins contained three galloylated derivatives attached to different positions of 1,5-anhydro-glucitol and were 10–20 fold more potent α-glucosidase inhibitors than the clinical drug, Acarbose (IC₅₀=7–16 vs 161 μM), in vitro. These results support previous data suggesting that gallotannins are the main contributors to the α-glucosidase inhibitory activities of maple plant part extracts and that three substituents on the 1,5-anhydro-glucitol moiety are important for activity.     

Chemical-epigenetic method to enhance the chemodiversity of the marine algicolous fungus, Aspergillus terreus OUCMDZ-2739

Four new meroterpenoids identified as (R)-4-((2,2-dimethylchroman-6-yl)methyl)-3-(4-hydroxyphenyl)-5-methoxyfuran-2(5H)-one (1), 1-(2,2-dimethylchroman-6-yl)-3-(4-hydroxyphenyl)propan-2-one (2), (R,E)-3-(2,2-dimethylchroman-6-yl)-4-hydroxy-5-((2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl)methylene)furan-2(5H)-one (3), methyl (R)-2-(2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl) acetate (4), along with nine known compounds (5–13) were isolated from a chemical-epigenetic culture of Aspergillus terreus OUCMDZ-2739 with 10 μM trichostatin A (TSA). Under the same condition without TSA, A. terreus OUCMDZ-2739 produced different compounds (14–20), supporting that the chemical-epigenetic modification of fungi could enrich the chemodiversity of the fungal products. The cytotoxicity was observed for compound 8 against K562 cell, 9 against MCF-7 and K562 cells and 12 against MCF-7 cell with IC₅₀ values of 9.5, 10.1, 13.0 and 8.5 μM, respectively. Compounds 3, 8 and 17 exhibited stronger α-glucosidase inhibition than 1-deoxynojirimycin and acarbose (positive controls) with IC₅₀ values of 24.8, 1.2, 61.6, 191.7 and 555.1 μM, respectively. The enzyme kinetics study further indicated that compound 8 was an anticompetitive inhibitor with K_i value of 1.42 μM.     

Antioxidant and α-Glucosidase Inhibitory Compounds of Centella Asiatica

Centella asiatica, as known as Pegagan was previously reported to have anti-hyperglycemic effects in animal diabetic model rats. However, its α-glucosidase activity in vitro assay not yet reported. Our goal in this study is to isolate and identify active compounds as α-glucosidase inhibitor and antioxidant from aqueous ethanol 70% (v/v) extract of C. asiatica. The extract was partitioned by n-hexane, EtOAc, and n-butanol sequentially. Among the fractions tested, EtOAc fraction was showed the highest antioxidant and α-glucosidase inhibitory activities with an IC₅₀ values of 45.42 and 73.17 μg/mL, respectively. The antioxidant activity was conducted by determination of DPPH radical scavenging activity, whereas α-glucosidase inhibitory activity was determined against yeast α-glucosidase. Furthermore, isolation of the ethyl acetate extract yielded two active compounds, which were identified as kaempferol (1) and quercetin (2). Both of the compounds showed good yeast α-glucosidase inhibitory activity with IC₅₀ values of 16.50 and 21.61 μg/mL, respectively. In addition those compounds also could scavenge DPPH radical activity with IC₅₀ values of 9.64 and 11.97 μg/mL, respectively. Due to its ability in reducing α-glucosidase activity and scavenging free radical activity, the C. asiatica appears to be a potential as a good resource for future development of antioxidant and antidiabetic drug.     

A rearranged seco-steroid with new skeleton and five new abnormal progesteroids from Nodulisporium sp.

Abeo-nodulisporisteroid A (1), an abnormal steroid with a rearranged C3 chain at C-9 possibly derived from seco-ring A via Wagner-Meerwein rearrangement and oxidations, was obtained from Nodulisporium sp. together with five related new seco-progesteroids (nodulisporisteroids M-Q, 2–6), which were elucidated by the extensive spectroscopic analysis and X-ray crystallography. A plausible biosynthetic pathway of 1–6 was also proposed. Furthermore, these isolated compounds were also evaluated for cytotoxicities against five human tumour cell lines, antimicrobial activities, and inhibitions against PI3K gamma, Aβ₄₂ aggregation, and α-glucosidase.     

Synthesis, α-glucosidase inhibition and molecular docking studies of natural product 2-(2-phenyethyl)chromone analogues

A series of natural product (2-phenyethyl)chromone analogues (3–34) were designed, synthesized, and screened for their α-glucosidase inhibitory activity. The results indicated that some of the synthesized derivatives displayed inhibitory activities against α-glucosidase with IC₅₀ values ranging from 11.72 ± 0.08 to 85.58 ± 2.30 μM when compared to the standard drug acarbose (IC₅₀ = 832.22 ± 2.00 μM). Among them, compound 4 with a hydroxyl group at the 7-position of chromone and a chloro group at the 4-position of the benzene ring, displayed the most significant inhibitory activity with the IC₅₀ value of 11.72 ± 0.08 μM. The inhibitory mechanism of compound 4 against α-glucosidase was studied by enzyme kinetic, circular dichroism spectra, fluorescence quenching, and molecular docking. Sucrose loading test in vivo further demonstrated that it could decrease blood glucose levels after sucrose administration in normal Kunming mice. In vitro cytotoxicity showed that 4 exhibited low cytotoxicity against normal human cell lines. The ADME study suggested that all compounds are likely to be orally active as they obeyed Lipinski’s rule of five. In summary, our studies showed that these derivatives are a new class of α-glucosidase inhibitors.     

New aeruginazoles,a group of thiazole-containing cyclic peptides from Microcystis aeruginosa blooms

Three related cyclic peptides, aeruginazole DA1497 (1), aeruginazole DA1304 (2), and aeruginazole DA1274 (3), were isolated from the freshwater cyanobacteria, Microcystis aeruginosa, bloom material collected on October 2007 from the Dalton water-reservoir in Northern Israel. Aeruginazoles DA1304 (2), DA1338 (4), and DA1372 (5) were isolated as an inseparable mixture from a bloom material of M. aeruginosa collected from the same water-reservoir on August 2000. Their structures were elucidated using a combination of various spectroscopic techniques, mainly NMR and MS, while the absolute stereochemistry of the chiral centers were determined by Marfey’s method. Aeruginazoles 1–3 were tested in various bioassays (antibacterial, cytotoxicity, and protease inhibition). Aeruginazole DA1497 (1) showed a mild antimicrobial activity against Staphylococcus aureus, but was inactive like the rest of the compounds in all other bioassays.     

Pileamartines A and B: Alkaloids from Pilea aff. martinii with a new carbon skeleton

Two novel alkaloids, with an unprecedented carbon skeleton, pileamartines A (1) and B (2), together with the known alkaloid, julandine (I-a) were isolated from the alkaloidal fraction of Pilea aff. martinii leaves. Their structures were established by spectral data analysis, including MS and 2D NMR. The absolute configurations of 1 and 2 were suggested by comparison of their experimental and calculated electronic circular dichroism spectra. Compound 2 exhibited weak inhibitory activity against the α-glucosidase enzyme with an inhibition of 11% at a concentration of 200?µM. These compounds were not cytotoxic against several cancer cell lines even at a concentration of 150?µM.     

Short synthesis of new salacinol analogues and their evaluation as glycosidase inhibitors

Versatile synthesis of some analogues of the naturally-occurring α-glucosidase inhibitor salacinol (1), involving thioanhydro alditol moieties with erythro, d,l-threo, xylo, ribo, d-arabino and d-manno configurations is described. Nucleophilic attack at the least-hindered carbon atom of an l- or d-protected erythritol cyclic sulfate by the thioanhydro alditol sulfur atom yielded the desired zwitterionic compounds. In addition, the preparation of the cyclic sulfates of 2,4-O-benzylidene-d-erythritol and 2,4-O-isopropylidene-l-erythritol was improved. Enzyme inhibition tests showed that most of the new compounds were weak but specific inhibitors, while good inhibitory activity was found for a six-membered ring analogue (β-glucosidase: K_i=16 μM).     

New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer’s treatment: In silico identification,in vitro and in vivo validation

Neurodegenerative diseases have complex etiology and pose a challenge to scientists to develop simple and cost-effective synthetic compounds as potential drug candidates for such diseases. Here, we report an extension of our previously published in silico screening, where we selected four new compounds as AChE inhibitors. Further, based on favorable binding possess, MD simulation and MMGBSA, two most promising compounds (3a and 3b) were selected, keeping in view the ease of synthesis and cost-effectiveness. Due to the critical role of BChE, LOX and α-glucosidase in neurodegeneration, the selected compounds were also screened against these enzymes.The IC₅₀ values of 3a against AChE and BChE found to be 12.53 and 352.42 μM, respectively. Moderate to slight inhibitions of 45.26 % and 28.68 % were presented by 3a against LOX and α-glucosidase, respectively, at 0.5 mM. Insignificant inhibitions were observed with 3b against the four selected enzymes. Further, in vivo trial demonstrated that 3a could significantly diminish AChE levels in the mice brain as compared to the control. These findings were in agreement with the histopathological analysis of the brain tissues. The results corroborate that selected compounds could serve as a potential lead for further development and optimization as AChE inhibitors to achieve cost-effective anti-Alzheimer’s drugs.     

Phytochemical,Antimicrobial, Antidiabetic,Thrombolytic, anticancer Activities,and in silico studies of Ficus palmata Forssk

Ficus palmata Forssk. (Moraceae family) is medicinally valuable plant that is mostly used as folk medicine for the treatment of different diseases. Phytochemical composition was evaluated by preliminary phytochemical investigation, GCMS analysis, and total bioactive contents (TPC and TFC). The antioxidant, enzyme inhibition, antimicrobial, thrombolytic and anticancer activities were performed for biological evaluation. The extract exhibited the maximum total phenolic (49.24 ± 1.21 mg GAE/g) and total flavonoid contents (29.9 ± 1.13 mg QE/g) which may be correlated to higher antioxidant potential of extract. The GCMS investigation identified the presence of 27 phytocompounds of different classes related to aldehydes, esters of fatty acids, triterpenes, steroids, triterpenoid. The extract possessed the strong α-glucosidase (73.4 ± 4.65 %) and moderate α-amylase inhibition activity (47.1 ± 3.29 %). Significant results were observed in case of antiviral, antifungal, and antibacterial activities. F. palmata extract inhibited the growth of HepG2 cancer cells in a dose-dependent manner. The extract also exhibited moderate in vitro thrombolytic activity. In addition, the phytocompounds identified by GCMS were subjected to in silico molecular docking studies to analyze the binding affinity between phytocompounds and enzymes (α-glucosidase and α-amylase). Moreover, the best docked compounds were selected for ADMET studies which provide information about pharmacokinetics, physicochemical properties, drug-likeness, and toxicity of identified phytocompounds. The outcome of our research revealed that ethanolic extract of F. palmata possessed good antidiabetic, antimicrobial, thrombolytic and anticancer potential. This plant should be further explored to isolate the bioactive compounds for new drug development.     

Dicyanoanilines as potential and dual inhibitors of α-amylase and α-glucosidase enzymes: Synthesis,characterization, in vitro,in silico,and kinetics studies

The present study comprised of the synthesis of dicyanoaniline derivatives of pyridine, thiophene, furan, and substituted phenyl 1–29. All synthetic derivatives were evaluated for their potential to inhibit α-amylase and α-glucosidase enzymes. The synthesized compounds are classified into three categories A, B, and C based on variable substituents at R₁ and R_2, and the structure–activity relationship was discussed accordingly. Amongst twenty-nine derivatives, 1–29, five compounds 2, 9, 18, 23, and 24 displayed excellent inhibition against α-amylase and α-glucosidase enzymes with the IC₅₀ values ranging between 20.33 ± 0.02–25.50 ± 0.06 µM and 21.01 ± 0.12–27.75 ± 0.17 µM, respectively, while other compounds showed moderate to weak inhibition against both enzymes. Acarbose was used as the positive control in this study. The enzyme kinetic studies showed non-competitive and un-competitive types of inhibition mechanism against α-amylase and α-glucosidase enzymes, respectively. In silico studies have demonstrated the involvement of these molecules in numerous binding interactions within the active site of the enzyme.     

New aplysiatoxin derivatives from the Okinawan cyanobacterium Moorea producens

The marine cyanobacterium Moorea producens is a rich source of diverse compounds that possess a variety of biological activities. In the present study, eight new aplysiatoxin derivatives, namely 6, 8–13, and 15, along with aplysiatoxin (1), debromoaplysiatoxin (2), 3-methoxyaplysiatoxin (3), anhydroaplysiatoxin (4), anhydrodebromoaplysiatoxin (5), oscillatoxin B2 (7), and 30-methyloscillatoxin D (14) were isolated and identified from the Okinawan M. producens. In cytotoxicity and diatom growth inhibition tests, the fifteen compounds tested (1–15) showed moderate or no activity at a concentration of 10?μg/mL.     

Alpha-glucosidase inhibitory activity of ethanol extract,fractions and purified compounds from the wood of Albizia myriophylla

Albizia myriophylla Benth. is a medicinal herb which is used as a traditional remedy for various ailments including diabetes in Thailand. In our continued investigation of the biological activity of A. myriophylla, the ethanol extract, fractions and the isolated compounds from the wood of this plant were evaluated for in vitro α-glucosidase inhibition using spectrophotometric method. The plant ethanol extract and its different fractions possessed α-glucosidase inhibitory activity in a concentration-dependent manner. Dichloromethane fraction of the wood ethanol extract exhibited the highest percent inhibition against α-glucosidase (69.30%) among all fractions. Subsequent α-glucosidase inhibition assay proved that indenoic acid (1), 8-methoxy-7, 3′,4′-trihydroxyflavone (2) and 3,4,7,3′-tetrahydroxyflavan (3) were partially rational for antidiabetic effect of this plant species. Among these compounds, 3 (IC₅₀ 98.59 μg/mL) exhibited potent inhibition of α-glucosidase, compared with a positive control acarbose (IC₅₀ 125 μg/mL). The inhibitory effect towards α-glucosidase of compounds 1–3 was reported herein for the first time.     

Synthesis and evaluation of 1-deoxy-8-epi-castanospermine, 1-deoxy-8-hydroxymethyl castanospermine, and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol

A short, versatile, and enantioselective synthesis of 1-deoxy-8-epi-castanospermine (5), 1-deoxy-8-hydroxymethyl castanospermine (6), and (6S,7S,8R,8aR)-8-amino-octahydroindolizine-6,7-diol (7) is achieved from a common template 12. The key step utilized is PET provoked amine radical cyclization of 11 to 12 in excellent diastereoselectivity. The exocyclic double bond at C-8 of the template is functionalized to obtain 5-7 as exclusive diastereomers. 1-Deoxy-8-epi-castanospermine exhibited inhibition of α- and β-galactosidase and β-glucosidase. Compounds 6 and 7 were found to be weak inhibitors of β-glucosidase.     

Chiral 1,4-morpholin-2,5-dione derivatives as α-glucosidase inhibitors: Part 2

A series of chiral 1,4-morpholin-2,5-dione derivatives were synthesized starting from chiral synthons 1 and 2, diastereomeric monolactim ethers derived from l-valine. The compounds investigated, were inactive toward β-glucosidase, α-mannosidase and α-galactosidase but behave as noncompetitive inhibitors against the α-glucosidase (from Saccharomices cervisiae) with some showing a good inhibition ability (0.05 < K_i < 0.18 mM).     

Two new aromatic compounds and a new d-arabinitol ester from the mushroom Hericium erinaceum

Two new aromatic compounds (1, 2), new d-arabinitol ester (3), and two known compounds (4, 5) were isolated from mushroom Hericium erinaceum. The structures of 1–5 were elucidated on the basis of spectral data. Compounds 1, 2, 4, and 5 exhibited α-glucosidasae inhibitory activity.     

Stereoselective synthesis and biological activity of novel spiro-oxazinanone-C-glycosides

The stereoselective synthesis of novel spiro-oxazinanone nucleosides 9 and 10 has been achieved by microwave assisted 1,3-dipolar cycloaddition of exo-glucal (1) and nitrones (2), and followed by reduction, stereospecific recyclization, and catalytic deprotection. The structures of the spironucleosides were determined according to the ¹H NMR, ¹³C NMR, 2D NMR, MS, and X-ray analyses, and the biological activities of the title compounds against glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and cytotoxicity were also evaluated.     

Salarins D-J, seven new nitrogenous macrolides from the madagascar sponge Fascaplysinopsis sp.

Seven new nitrogenous macrolides, designated salarins D-J (4-10), closely related to salarins A-C (1-3), have been isolated from the Madagascar Fascaplysinopsis sp. sponge. The structure and relative stereochemistry of compounds 4-10 were elucidated by interpretation of MS, COSY, HSQC, HMBC, and NOESY spectra. Salarin B's structure (2), based on the structure of salarin J (10), is now amended to also incorporate the C-14 to -17 THF ring system. All compounds were evaluated for their cytotoxicity against K562 and UT-7 human leukemia cells. While salarins D, E, H, and J displayed dose and time dependent inhibition of proliferation, salarins F and I were not active in these assays.     

Synthesis and Bioactivity Evaluation of New 6-Aryl-5-cyano Thiouracils as Potential Antimicrobial and Anticancer Agents

Several novel 6-aryl-5-cyano thiouracil derivatives were synthesized and explored for their activities as antibacterial, antifungal and anticancer agents. The antimicrobial evaluation revealed that compounds 7b and 7c possessed superior antibacterial activity against the Gram positive bacteria S. aureus and B. subtilis compared to the reference drug amoxicillin. Moreover, compound 4i was found to be a broad spectrum antimicrobial agent and it also exhibited the highest antifungal activity against C. albicans, even higher than the reference drug amphotericin B (MIC = 2.34, 3.00 μg/mL respectively). Selected compounds were tested for in vitro cytotoxicity at a single 10^-5 M concentration in accordance to the NCI (USA) protocol. The preliminary screening results showed that most of the compounds had limited cytotoxic activity against renal cancer UO-31 and/or A498 cell lines. Nevertheless, compounds 6d and 6i displayed potent growth inhibitory effect toward non-small cell lung cancer HOP-92 and leukemia MOLT-4 cell lines, respectively.     

Two acridones and two coumarins from the roots of Paramignya trimera

Two acridones, paratrimerins C (1) and D (2), and two coumarins, paratrimerins E (3) and F (4), were isolated from the CHCl₃ and EtOAc extracts of Paramignya trimera (Rutaceae), together with twelve known compounds (5–16). Their structures were elucidated on the basis of spectroscopic data. All isolated compounds possessed significant α-glucosidase inhibitory activity in a concentration-dependent manner, and showed more potent inhibitory activity, with IC₅₀ values ranging from 14.6 to 112.2 μM, than the positive control acarbose (IC₅₀, 214.5 μM). The biosynthesis of the isolated coumarins and acridones was proposed.