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To develop drugs to treat Alzheimer's disease (AD) on the basis of the amyloid cascade hypothesis, the amyloid-β (Aβ) aggregation inhibitory activities of 110 extracts from mushrooms were evaluated by thioflavin T (Th-T) assays. The MeOH extract of Albatrellus yasudae inhibited Aβ aggregation, and the bioactivity-guided fractionation of the extract afforded four novel meroterpenoids, named scutigeric acid (1), albatrelactone methyl ester (2), albatrelactone (3), and 10',11'-dihydroxygrifolic acid (4), together with two known compounds, grifolin (5) and grifolic acid (6). The structures of 1-4 were elucidated using NMR, MS, UV, IR, and induced ECD spectral data. The structure of 1 was determined as a methyl ester (1a) by 2D NMR spectroscopy. Th-T assays showed that compounds 1-4 and 1a possessed inhibitory activities against Aβ aggregation, with IC50 values of 6.6, 40.7, 51.4, 53.3, and 50.3 μM, respectively. Notably, 1 possessed an inhibitory activity against Aβ aggregation comparable to that of myricetin as a positive control. Moreover, 1-6 exhibited inhibitory activities against BACE1, with IC50 values of 1.6, 10.9, 10.5, 34.4, 6.1, and 1.4 μM, respectively.

A series of 2-(N-cyclicamino)chromone derivatives (1a-4c) and 3-(N-cyclicamino)chromone derivatives (5a-8c) were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were studied as part of a structure-activity relationship investigation. Compounds 1a-4c showed no remarkable inhibition for MAO-A or MAO-B, whereas compounds 5a-8c (with a few exceptions) showed significant and selective inhibition of MAO-B. Of these compounds, 7c, 7-methoxy-3-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one inhibited MAO-B the most potently and selectively, having IC50 of 15 nM and an MAO-B selectivity index of more than 6700; c.f, 50 nM and 2000, respectively, for safinamide. The mode of inhibition of 7c to MAO-B was competitive and reversible. Considering the IC50 values and selectivity indices of the other synthetic compounds, the presence of the methoxy group on the chromone ring (R2) of 7c seemed to increase MAO-B inhibition. Molecular docking analysis also supports this hypothesis. Our results suggest that 3-(N-cyclicamino)chromones are useful lead compounds for the development of MAO-B inhibitors.

Cell adhesion plays a crucial role in candidiasis through invasion of the human body and obtaining resistance to drugs by forming biofilms. Cell adhesion thus is a critical target for combating candidiasis by preventing the entry of fungal hyphae into the epithelium. We report here that dehydrocurvularin (1), isolated from the marine-derived fungus Curvularia aeria, exhibited anti-fungal activities for Candida albicans and Candida auris. This compound also prevented the adherence of C. albicans to human adenocarcinoma cells. Real-time RT-PCR analysis showed that exposure to 1 results in decreased expression of HWP1, EFG1, and ECE1, genes involved in Candida adhesion to epithelial cells and hyphal morphogenesis.

A series of 2-(indolylmethylidene)-2,3-dihydro-1-benzofuran-3-ones (aurone-indole hybrids) and 2-(indolyl)-4H-chromen-4-ones (flavone-indole hybrids) were designed, synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 5b and 11b showed potent inhibitory activities against MAO-A, comparable to that of pargyline used as a positive control, and most of the compounds, except for 2a and 10b, showed potent inhibitory activities against MAO-B. Compound 9a was the most potent and highly selective inhibitor of MAO-B (IC50 value for MAO-B: 0.0026 μM, and MAO-A: >100 μM). Comparison of the inhibitory activities of 1a vs. 9a vs. 13a and 1b vs. 7b vs. 11b suggested that methoxy substitution at R1 on the A-rings of flavonoids increases MAO-A inhibition whereas methoxy substitution at R2 increased MAO-B inhibition. Comparison of 4a vs. 10a, 6a vs. 11a, 3b vs. 8b and 4b vs. 9b showed incremental increases in MAO-B inhibitory activity by R2 substitution on the A ring. Comparison of the MAO-B inhibitory effects of the flavone-indole hybrids and aurone-indole hybrids showed that most of the aurone-indole hybrids were stronger inhibitors than the corresponding flavone-indole hybrids. Molecular docking analysis of compounds 1a and 9a with MAO-B further supported the above structural effects of these compounds on MAO-B inhibitory activity. This is the first report identifying aurone-indole hybrids as potent MAO-B inhibitors. The results reported here suggest that 2-(1H-indol-1-ylmethylene)-6-methoxy-3(2H)-benzofuranone (9a) might be a useful lead for the design and development of novel MAO-B inhibitors

The ribosome-targeted antifungal agent hygromycin B (HygB) alters the secondary metabolite profiles of fungi. Hypoxylon truncatum NBRC 32353 fermented in the presence of hygromycin B in barley medium activated secondary metabolite synthesis. A new benzaldehyde derivative truncaaldehyde (1) was obtained, along with thirteen known compounds (2–14). The structures of the new compounds were revealed using NMR and single-crystal X-ray crystallography. The total synthesis of (±)-1 was achieved using a four-step sequence, and chiral separation was accomplished. The isolated compounds were tested for their monoamine oxidase (MAO) -A and -B inhibitory activities, with six compounds ((±)-1, 4, 5, 7, 8, and 10) showing inhibitory activity.

To develop drugs to treat Alzheimer's disease (AD) on the basis of the amyloid cascade hypothesis, the amyloid-β (Aβ) aggregation inhibitory activities of 110 extracts from mushrooms were evaluated by thioflavin T (Th-T) assays. The MeOH extract of

A series of 3-styrylchromone derivatives was synthesized and evaluated for monoamine oxidase (MAO) A and B inhibitory activities. Most of all derivatives inhibited MAO-B selectively, except compound 21. Compound 19, which had a methoxy group at R2 on the chromone ring and chlorine at R4 on phenyl ring, potently inhibited MAO-B, with an IC50 value of 2.2 nM. Compound 1 showed the highest MAO-B selectivity, with a selectivity index of >3700. Further analysis of these compounds indicated that compounds 1 and 19 were reversible and mixed-type MAO-B inhibitors, suggesting that their mode of action may be through tight-binding inhibition to MAO-B. Quantitative structure–activity relationship (QSAR) analyses of the 3-styrylchromone derivatives were conducted using their pIC50 values, through Molecular Operating Environment (MOE) and Dragon. There were 1796 descriptors of MAO-B inhibitory activity, which showed significant correlations (P These data suggest that the 3-styrylchromone derivatives assessed herein may be suitable for the design and development of novel MAO inhibitors.

Thirty-five pyridone derivatives were synthesized, with derivatization conducted on polycyclic pyridone scaffolds, including cis- or trans-oxydecalin and other cyclic structures, by domino-Knoevenagel-electrocyclic reactions. The anti-fungal activities of the synthesized compounds were tested against Candida albicans. Ten compounds inhibited hyphal formation without inhibiting growth. Pyridones with anti-hyphal formation activity (4c, 6d, 12a and 12c) were tested for their ability to inhibit biofilm formation. Compound 6d showed both anti-hyphal and biofilm inhibition activity.

A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors.

The unprecedented tetracyclic coumarin derivatives 1 and 2 and the coumarin dimers 3–5 were isolated from chemically engineered extracts (coumarin dimerization of natural extract) of the marine-derived fungus Eurotium rubrum. The structures of these compounds were established using NMR, MS and IR methods. The absolute configuration of 1 was determined by ECD calculations. The unprecedented tetracyclic coumarin skeleton was generated by domino-Knoevenagel-Diels-Alder reactions. Compounds 1–5 showed tyrosinase inhibitory activity (IC50 = 1.7, 1.2, 4.9, 1.8 and 2.9 μM, respectively). The isolated coumarin derivatives 1–5 were not observed by HPLC analysis in crude extracts of E. rubrum, suggesting that chemically engineered extract generated these new coumarin derivatives with tyrosinase inhibitory activity.

A chemical investigation of the ascomycetes of Daldinia concentrica was performed using silica gel column chromatography, ODS column chromatography, and preparative HPLC. Two new isoindolinone compounds, daldinans B (1) and C (2), two new phthalide compounds, daldinolides A (3) and B (4), and a new naphthoquinone, daldiquinone (5), were isolated together with two known compounds (6 and 7). The structures of 1, 2, and 5 were established using NMR, MS, and IR methods, and the structures of 3 and 4 were determined by derivatization from known compounds (6 and 7). 5 exhibited antiangiogenesis activity against HUVECs (IC50 = 7.5 μM).

A series of eighteen 2-styrylchromone derivatives (see Chart 1 ) were synthesized and evaluated for their monoamine oxidase (MAO) A and B inhibitory activities. Many of the derivatives inhibited MAO-B comparable to pargyline (a positive control), and most of them inhibited MAO-B selectively. Of the eighteen derivatives, compound 9 having methoxy group at R1 and chlorine at R4 showed both the best MAO-B inhibitory activity (IC50 = 17 ± 2.4 nM) and the best MAO-B selectivity (IC50 for MAO-A/IC50 for MAO-B = 1500). The mode of inhibition of compound 9 against MAO-B was competitive and reversible. Quantitative structure–activity relationship (QSAR) analyses of the 2-styrylchromone derivatives were conducted using their pIC50 values with the use of Molecular Operating Environment (MOE) and Dragon, demonstrating that the descriptors of MAO-B inhibitory activity and MAO-B selectivity were 1734 and 121, respectively, that showed significant correlations (P

Metabolites of marine derived fungus Eurotium rubrum MPUC136 differed between cultivation on wheat medium and Czapek-Dox agar medium. Melanin synthesis inhibitory activity of crude extract of culture on wheat medium showed stronger activity than that of crude extract of culture on Czapek-Dox agar medium. A new diketopiperazine compound isoechinulin D (1) and eight reported diketopiperazines (2–9) were isolated from the crude extract of wheat medium. The structure of 1 was established using NMR, MS and IR methods. 2–5 inhibited melanogenesis using B16 melanoma cells (IC50 = 68, 2.4, 83, 9.1 μM each). Structure–Activity-Relationships of diketopiperazines (1–10) indicated the importance of the prenyl groups at C-2, C-5 and C-7, the vinyl group at C-12 to C-25 and the sp2 carbons at C-8 and C-9. Isolated compounds (1–9) were not or slightly observed from the extracts of Czapek-Dox agar medium by HPLC analysis, suggesting that different cultivation processes could affect metabolism and enhance bioactivities.

Three novel diterpenes, phomactins N (1), O (2), and P (3), were isolated from cultures of an unidentified marine-derived fungus. The structures of 1–3 were elucidated from spectroscopic data (NMR, MS, IR) and the absolute configurations of 1–3 were determined by X-ray diffraction analysis.

The natural highly substituted benzophenone childinin E (1) was previously isolated from the fungus Daldinia childiae. Here we describe the total synthesis of childinin E and several derivatives using a linear seven-step sequence. The antifungal properties of the synthesized compounds against Candida albicans were evaluated by an anti-hyphal formation test. Childnin E and two derivatives exhibited anti-hyphal formation activity., 4p. Article number: 152588

Five new labdane-type diterpenoids, sterebins Q1 (1), Q2 (2), Q3 (3), Q4 (4), and R (5), were isolated from Stevia rebaudiana fermented by Saccharomyces cerevisiae. The structures of these compounds were established using NMR, MS, and IR methods and their absolute configurations were determined by the ECD spectra of their benzoate derivatives. Through the structures of these new compounds, it was established that the fermentation process caused selective epoxidation and nucleophilic addition of water. Thus, fermentation is an effective way to develop new natural resources for use as drug candidates by enhancing the diversity of natural compounds.

The diversity of natural compounds is extensive but not unlimited. Fermentation of rhizomes of Atractylodes lancea by marine fungus (Cladosporium cladosporioides) enhanced the diversity of natural compounds. From the fermented rhizomes of A. lancea, two new spirovetivane-type sesquiterpenoids, 2-oxo-12-hydroxy-hinesol (1) and 2-oxo-15-hydroxy-hinesol (2); a new guaiane-type sesquiterpenoid atractylol A (3); and three new eudesmane-type sesquiterpenoids, 14-hydroxy-isopterocarpolone (4), 3α-hydroxy-pterocarpol (5), and (11R)-2, 11, 12-trihydroxy-β-selinene (6), were isolated along with known sesquiterpenoids (7–10). The structures of these compounds were established using NMR, MS, and IR methods. These compounds (1–6) were not observed in A. lancea extracts by TLC and HPLC analysis, suggesting that these compounds were generated during the fermentation process.

Twenty-seven natural product-like polyprenylated phenols and quinones were synthesized and their neuroprotective activity was tested using human monoamine oxidase B (MAO-B) and SH-SY5Y cells. Eight compounds inhibited MAO-B (IC50 values

A new γ-butenolide glycoside, named styphonoloside A (1), was isolated from the root of Styphonolobium japonicum (L.) Schott (= Sophora japonica L.), together with saikoisoflavonoside A (2) and sophoraside A (3). The structure of 1 was characterized as puerol B 2”-O-neohesperidoside based on one- and two-dimensional (1D and 2D) NMR, MS, and electronic circular dichroism (ECD) spectral data. The absolute configuration of the aglycone moiety of 1 was assigned by comparing its experimental ECD spectrum with the calculated ECD spectrum., The distribution of Heterocycles outside Japan is handled by Elsevier.

Five new labdane-type diterpenoids, sterebins Q1 (1), Q2 (2), Q3 (3), Q4 (4), and R (5), were isolated from Stevia rebaudiana fermented by Saccharomyces cerevisiae. The structures of these compounds were established using NMR, MS, and IR methods and their absolute configurations were determined by the ECD spectra of their benzoate derivatives. Through the structures of these new compounds, it was established that the fermentation process caused selective epoxidation and nucleophilic addition of water. Thus, fermentation is an effective way to develop new natural resources for use as drug candidates by enhancing the diversity of natural compounds.

The diversity of natural compounds is extensive but not unlimited. Fermentation of rhizomes of Atractylodes lancea by marine fungus (Cladosporium cladosporioides) enhanced the diversity of natural compounds. From the fermented rhizomes of A. lancea, two new spirovetivane-type sesquiterpenoids, 2-oxo-12-hydroxy-hinesol (1) and 2-oxo-15-hydroxy-hinesol (2); a new guaiane-type sesquiterpenoid atractylol A (3); and three new eudesmane-type sesquiterpenoids, 14-hydroxy-isopterocarpolone (4), 3α-hydroxy-pterocarpol (5), and (11R)-2, 11, 12-trihydroxy-β-selinene (6), were isolated along with known sesquiterpenoids (7–10). The structures of these compounds were established using NMR, MS, and IR methods. These compounds (1–6) were not observed in A. lancea extracts by TLC and HPLC analysis, suggesting that these compounds were generated during the fermentation process.