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Straightforward synthesis of quinazolinones having N-fused medium-sized ring urea was accomplished. Key intermediates were tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates derived from copper-catalyzed domino reaction of tert-butyl [2-(2-iodobenzamido)ethyl]carbamates and cyclic enaminones. Steric hindrance of cyclic enaminones played an important role in the formation of quinazolinone ring. The eleven-membered ring urea moiety was readily achieved by direct cyclization using 1,1′-carbonyldiimidazole (CDI) of diamino intermediate generated by readily reductive amination and deprotection of tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates.

A new variation of Prins cyclization to directly and stereoselectively synthesize cis-2,6-disubstituted tetrahydropyran-4-ones from 3-chlorohomoallylic alcohols and aldehydes catalyzed by perrhenic acid is reported.

The soil-derived fungus Talaromyces thailandensis PSU-SPSF059 produced one new vermistatin derivative, talarostatin, and seven known compounds including two vermistatins, two chrodrimanins, two diphenyl ethers and one penicillide derivative. Extensive spectroscopic analysis was performed to identify their structures. The absolute configuration of talarostatin was determined by comparing the experimental and calculated electronic circular dichroism data. The antimicrobial and cytotoxic activities of the isolated secondary metabolites were also evaluated.

Four new aromatic polyketides including two diphenyl ethers (pseudopithoethers A–B, 1-2), one benzofuranone (pseudopithonone, 3) and one xanthone (pseudopithoxanthone, 4), along with two known compounds (5-6) and one new naturally occurring hydroquinone (α,2,5-trihydroxyacetophenone, 7) were isolated from the marine-derived fungus Pseudopithomyces maydicus PSU-AMF350. Their structures were identified by analysis of spectroscopic data. All isolated compounds were tested for antimicrobial activity. Only compound 7 displayed antibacterial activity against methicillin-resistant Staphylococcus aureus with the MIC value of 128 µg/mL and against S. aureus, Acinetobacter baumannii NPRC005 and A. baumannii NPRC007 with the same MIC value of 200 µg/mL.

Seven new polyketides including a phenol (1), two diphenyl ethers (2 and 3), two depsidones (4 and 5), and two phthalides (6 and 7) were isolated from the fungus Aspergillus unguis PSU-MF16 along with 27 known compounds. Their structures were determined by extensive spectroscopic analysis. The absolute configurations of 1 and 4-7 were established using comparative analyses of calculated and experimental ECD spectra. Among the new metabolites, 2 exhibited the best antimicrobial activity against Staphylococcus aureus, methicillin-resistant S. aureus, and Microsporum gypseum with equal MIC values of 16 μg/mL. In addition, known emeguisin A displayed potent antimicrobial activity against S. aureus, methicillin-resistant S. aureus, and Cryptococcus neoformans with equal MIC values of 0.5 μg/mL, compared with the standard drugs, vancomycin and amphotericin B. The structure-activity relationship study of the isolated compounds for antimicrobial activity is discussed.

Three new compounds including one furanone, one morpholinone and one tetrahydrofuran together with three known compounds were isolated from the broth extract of the marine-derived fungus

Aims This study aimed to isolate actinomycetes from marine environments and examine their antifungal activity against Talaromyces marneffei both in vitro and in vivo. Methods and results Nineteen out of 101 actinomycete extracts were active and further determined for their minimum inhibitory concentrations (MIC). Three extracts of AMA50 that isolated from sediment showed strong antifungal activity against T. marneffei yeast (MICs ≤0·03-0·25 µg ml-1 ) and mould (MICs 0·5-16 µg ml-1 ) forms. The hexane extract from the cells of AMA50 (AMA50CH) exhibited the best activity against both the forms (MIC ≤ 1 µg ml-1 ). Three extracts from AMA50 killed the melanized yeast cells at 0·5 µg ml-1 . The AMA50CH was further tested for protective effects in Caenorhabditis elegans model. At concentrations of 1-8 µg ml-1 , the AMA50CH prolonged survival of T. marneffei-infected C. elegans with a 60-70% survival rate. The composition of AMA50CH was determined by gas chromatography-mass spectrometry. The major components were n-hexadecanoic acid, tetradecanoic acid and pentadecanoic acid. Sequencing analysis revealed that isolate AMA50 belonged to the genus Streptomyces. Conclusions The AMA50CH from Streptomyces sp. AMA50 was the most effective extract against T. marneffei. Significance and impact of the study Talaromyces marneffei is one of the most important thermally dimorphic pathogenic fungi. These results indicated the potency of marine-derived actinomycete extracts against T. marneffei both in vitro and in vivo.

Research background. Lovastatin is a well-known drug used to reduce hypercholesterolaemia. However, the cost of lovastatin production is still high. Therefore, alternative low-cost carbon sources for the production of lovastatin are desirable.Experimental approach. Four different agricultural wastes, namely corn trunks, rice husks, wild sugarcane, and soya bean sludge, were tested separately as substrates to produce lovastatin using a new fungal strain, Aspergillus sclerotiorum PSU-RSPG 178, under both submerged and solid-state fermentation (SSF).Results and conclusions. Of these substrates and cultivation systems, soya bean sludge gave the highest lovastatin yield on dry mass basis of 0.04 mg/g after 14 days of SSF at 25 °C. Therefore, the soya bean sludge was separately supplemented with glucose, wheat flour, trace elements, palm oil, urea and molasses. The addition of the palm oil enhanced the lovastatin yield to 0.99 mg/g. In addition, the optimum conditions, which gave a lovastatin yield of (20±2) mg/g after 18 days of SSF, were soya bean sludge containing 80 % moisture (dry basis) at a ratio of soya bean sludge (g) to mycelial agar plugs of 1:4, and a ratio of soya bean sludge (g) to palm oil (mL) of 1:2. Besides, the lovastatin yields obtained from SSF using fresh or dry soya bean sludge were not significantly different.Novelty and scientific contribution. We conclude that A. sclerotiorum PSU-RSPG 178 has a good potential as an alternative strain for producing lovastatin using soya bean sludge supplemented with palm oil as a carbon source.

One new limonoid, named siamensinolide (1), together with two known limonoids (2 and 3) and eight carbazole alkaloids (4–11) were isolated from the twigs of Chalcas siamensis Tanaka. Their structures were elucidated by spectroscopic methods, mainly 1D and 2D NMR spectroscopy. O-methylclausenolide (2) displayed strong cytotoxicity against A2780 cell lines with the IC50 value of 9.2 µM, while clausenolide (3) exhibited strong antibacterial activity against methicillin-resistant Staphylococcus aureus with the MIC value of 0.5 µg/mL.

One new nonadride enantiomer

One new nonadride enantiomer, ent-epiheveadride, along with five known dioxopiperazine derivatives were isolated from the marine-derived fungus Aspergillus chevalieri PSU-AMF79. Their structures were identified by extensive spectroscopic analysis. The absolute configuration of ent-epiheveadride was determined by comparison of the specific rotation and electronic circular dichroism data with those of related known compounds. It exhibited antifungal activity against Cryptococcus neoformans ATCC90113 flucytosine–resistant and Candida albicans NCPF3153 with the MIC values of 128 and 200 µg/mL, respectively. In addition, the known L-alanyl-L-tryptophan anhydride displayed TMEM16A inhibitory activity with 65.0% inhibition at a concentration of 5 µg/mL.

One new deoxybenzoin, named lakoochanoside A (1), and one new flavan, named lakoochanoside B (2), along with 17 known compounds were isolated and identified from the twigs of Artocarpus lakoocha. The structures of isolated compounds were elucidated by spectroscopic methods, especially 1D and 2D NMR spectroscopy. Cycloartocarpin (14) exhibited strong antibacterial activities against Staphylococcus aureus and methicillin-resistant S. aureus with the same MIC values of 2 μg/mL. It also displayed antimalarial activity against Plasmodium falciparum K1 with an IC50 value of 2.66 μM.

Three new sesquiterpenes (1-3) and one new monoterpene (4) were isolated from the soil-derived fungus Trichoderma reesei PSU-SPSF013 along with five known compounds including hydroheptelidic acid (5), 5-hydroxy-3-hydroxymethyl-2-methyl-7-methoxychromone (6), adenosine (7), uridine (8) and tyrosol (9). Their structures were elucidated by spectroscopic analyses. The absolute configuration of the secondary alcohol moiety in 2 was assigned using Mosher’s method whereas that of 1, 3 and 4 was established by comparison of their specific rotations with those of structurally related compounds. Compounds 3-5 displayed interesting antifungal activity against Cryptococcus neoformans ATCC90113 with the respective MIC values of 8, 8 and 4 μg/mL. Moreover, only 3 was active against C. neoformans ATCC90112 with the MIC value of 32 μg/mL. Interestingly, 4 and 5 were noncytotoxic towards noncancerous Vero cells.

Six new (1–6), together with seven known (7–13), trichothecenes were isolated from the soil-derived Trichoderma brevicompactum PSU-RSPG27. Their structures were established using spectroscopic data. The structure of 1 was confirmed by X-ray data. Trichodermin (7) exhibited the most potent activity against Plasmodium falciparum (K1 strain) with an IC50 value of 0.1 μM, while other trichothecenes (1, 8, 9, and 12) were much less active, with IC50 values in the range of 7.1–9.6 μM. Compound 7 displayed activity against noncancerous Vero cells with an IC50 value of 0.4 μM. The remaining compounds showed moderate to weak activity, with IC50 values in the range of 6.9–15.3 μM. Compounds 7 and 12 were active against human oral carcinoma (KB) cells with IC50 values of 2.4 and 3.7 μM, respectively. Additionally, compounds 7 and 12 displayed antifungal activity against Candida albicans with the respective MIC values of 1 and 2 μg/mL and were active against Cryptococcus neoformans with equal MIC values of 4 μg/mL.

A simple and unified synthesis of four related pyranonaphthoquinone natural products, e.g. 8-O-methylfusarubin, 8-O-methylanhydrofusarubin, fusarubin and anhydrofusarubin, is reported. The key synthetic features include the precedented Diels–Alder cycloaddition to assemble the naphthalene skeleton, selective formylation and acetonylation and intramolecular acetalization to construct the pyran ring. Manipulation of the oxidation state of the naphthoquinone core was performed to construct the two analogues, fusarubin and anhydrofusarubin. This work also highlights an unprecedented directing effect of the hydroxymethylene group in the selective hypervalent iodine-mediated quinone oxidation. The four synthetic compounds were evaluated for their in vitro cytotoxic activities against six human cancer cells. 8-O-Methylfusarubin was the most potent analogue and displayed excellent cytotoxic activity against MCF-7 breast cancer cells with an IC50 value of 1.01 μM with no cytotoxic effect on noncancerous Vero cells, which could potentially be a promising lead compound for anti-breast cancer drug discovery.

Four new aromatic polyketides including two diphenyl ethers (pseudopithoethers A-B

Seven new polyketides including a phenol (

One new 2-oxaspiro[4.5]decane, roussoellide, and one new

One new 2-oxaspiro[4.5]decane, roussoellide, and one new α-pyrenocine, 2',3'-dihydropyrenocine A, together with nine known compounds including known arthropsolide A, and pyrenocines A and E, were obtained from the culture broth of the endophytic fungus Roussoella sp. Their structures were determined using spectroscopic data. The absolute configuration of known arthropsolide A was assigned on the basis of X-ray diffraction data using Cu Kα radiation. Known pyrenocine A displayed weak cytotoxic activity against breast cancer (MCF-7) cells with an IC50 value of 27.1 µM and weak antifungal activity against Microsporum gypseum SH-MU-4 with an MIC value of 615.2 µM.

Two new compounds, one α-pyrone (trichoharzianone) and one decalin (trichoharzianin), along with eight known compounds including three decalins, two δ-lactones, two carboxylic acids and one isochroman were isolated from the marine-derived fungus Trichoderma harzianum PSU-MF79. The structures were determined by spectroscopic methods. The relative configuration of trichoharzianin was assigned based on NOEDIFF data and coupling constants whereas the absolute configurations were established by comparison of electronic circular dichroism data with those of the co-metabolites. Known (-)-massoia lactone exhibited mild antifungal activity against Cryptococcus neoformans ATCC90113 flucytosine-resistant, Candida albicans ATCC90028 and C. albicans NCPF3153 with MIC values of 128, 200 and 200 µg/mL, respectively, and weak cytotoxic activity against HCT-116 and MCF-7 cell lines with the respective IC50 values of 17 and 32 µM. In addition, it was noncytotoxic against noncancerous Vero cells with an IC50 value of >100 µM.

TMEM16A is a Ca2+-activated Cl- channel involved in mucus secretion in inflamed airways and proposed as a drug target for diseases associated with mucus hypersecretion including asthma. This study aimed to identify novel inhibitors of TMEM16A-mediated Cl- secretion in airway epithelial cells from a collection of compounds isolated from fungi indigenous in Thailand and examine its potential utility in mitigating airway mucus secretion using Calu-3 cells as a study model. Screening of > 400 fungal metabolites revealed purpactin A isolated from a soil-derived fungus Penicillium aculeatum PSU-RSPG105 as an inhibitor of TMEM16A-mediated Cl- transport with an IC50 value of ~2 µM. A consistent inhibitory effect of purpactin A on TMEM16A were observed regardless of TMEM16A activators or in the presence of an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a negative regulator of TMEM16A. In addition, purpactin A did not affect cell viability, epithelial barrier integrity and activities of membrane transport proteins essential for maintaining airway hydration including CFTR Cl- channels and apical BK K+ channels. Intriguingly, purpactin A prevented a Ca2+-induced mucin release in cytokine-treated airway cells. Taken together, purpactin A represents the first class of TMEM16A inhibitor derived from fungus, which may be beneficial for the treatment of diseases associated with mucus hypersecretion.

Investigation of the soil-derived fungus

One new limonoid, named siamensinolide (

Secretory diarrhea is one of the most common types of diarrhea with high morbidity and mortality. Previous studies showed that inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels alleviated fluid loss in secretory diarrheas. This study aimed to identify novel CFTR inhibitors from fungal metabolites and explore its underlying mechanisms and potential utility in secretory diarrheas. Electrophysiological analyses in human intestinal epithelial (T84) cells were performed to investigate the effect and mechanism of fungal metabolites on CFTR-mediated Cl- secretion. Anti-diarrheal efficacy and the effect of compound on fluid absorption were investigated in mouse closed-loop models. We found that the screening identified arthropsolide A, a fungal metabolite from an endophytic fungus Roussoella sp. PSU-H51, as an inhibitor of CFTR-mediated Cl- secretion in T84 cells (IC50 ∼0.8 μM). Arthropsolide A inhibited both CFTR and cAMP-activated basolateral K+ channels. Arthropsolide A had no effect on Na+-K+ ATPase activity. Interestingly, the inhibitory effect of arthropsolide A on CFTR was attenuated by cell depolarization and AMPK inhibition independent of multi-drug resistance protein 4, phosphodiesterases, and protein phosphatases. Importantly, arthropsolide A suppressed cholera toxin (CT)-induced Cl- secretion in T84 cells and CT-induced intestinal fluid secretion in mice by ∼75% without affecting intestinal fluid absorption. Taken together, arthropsolide A represents a novel class of fungal metabolites that acts as a potent CFTR inhibitor. Further development of this class of compounds may provide a therapy for secretory diarrheas.

Three new depsides, aspergisides A-C, and one new depsidone, aspergisidone, were isolated from the soil-derived fungus Aspergillus unguis PSU-RSPG204 together with one phthalide derivative and 11 depsidones including emeguisin A, aspersidone and folipastatin. The structures were determined by spectroscopic evidence. Aspersidone and emeguisin A showed remarkably antibacterial activity against Staphylococcus aureus and methicillin-resistance S. aureus with equal MIC values of 0.5 μg/mL. Emeguisin A, which displayed the highest activity with 87.06% inhibition of human colon carcinoma (HCT-116) cell viability, decreased numbers of live cells/numbers of dead cells in a dose-dependent manner with the IC50 values of 34.8–84.7 μM in a 3D culture model depending on durations of incubation. In addition, folipastatin dose-dependently inhibited forskolin-stimulated chloride secretion in human intestinal epithelial (T84) cells with an IC50 value of 0.5 μM. These depsidones were considered to be inactive against noncancerous Vero Cells with the IC50 values of >10 μM.

Three new blennolide derivatives, blennolides L-N (1–3), together with five known metabolites were isolated from the soil-derived fungus Trichoderma asperellum PSU-PSF14. Their structures were determined by analysis of spectroscopic data. Their relative configurations were determined by analysis of NOEDIFF data and confirmed by X-ray crystallography for compound 1 whereas the absolute configurations were established by means of experimental and calculated TDDFT ECD data. Compound 1 displayed antifungal activity against Cryptococcus neoformans ATCC90112 and ATCC90113 flucytosine-resistant with the MIC values of 128 and 64 μg/mL, respectively, and was inactive against noncancerous Vero cell lines.

This study aimed to isolate fungi from leaves, petals, stalks and stamens of Nymphaea lotus and Nymphaea stellata and explore their bioactive potential with respect to antimicrobial activity and their cytotoxicity on human cell lines. The totals of 210 fungal isolates were obtained from 640 segments. The highest isolation rate was found in petal segments (0.44), while stamens yielded the lowest isolation rate (0.13). One hundred and ninety–five fungal extracts were evaluated for their efficiency against ten pathogenic microorganisms by colorimetric broth microdilution tests. Cell hexane extract from Eupenicillium levitum FNL036 (FNL036CH) gave the strongest antifungal activity against Cryptococcus neoformans and Talaromyces marneffei with minimum inhibitory concentration of 0.5 μg/mL and affected cell morphology of the test microorganisms. Moreover, this extract was non–cytotoxic to human embryonic kidney 293 (293T) and human keratinocytes (HaCAT) cell lines with 50% inhibitory concentration (IC50) values above 100 μg/mL. This finding confirmed that fungi derived from these two Nymphaea species were a novel source of bioactive metabolites.

Quinazolinediones were obtained from 2-iodobenzoic acids and carbodiimide derivatives under mild reaction conditions via a copper-catalyzed domino reaction. The absence of an external base was essential to avoid the generation of amide by-products. Both alkyl- and aryl-substituted carbodiimides gave the corresponding quinazolinediones. However, the use of aryl-substituted carbodiimides resulted in low yields due to an undesired elimination process.

The first and convergent total syntheses of polyketide natural products dechlorogreensporones A and D have been accomplished in 17 longest linear steps with 2.8% and 5.4% overall yields, respectively, starting from known methyl 2-(2-formyl-3,5-dihydroxyphenyl)acetate and commercially available R-(+)-propylene oxide and 1,2-epoxy-5-hexene. Our synthesis exploited key Mitsunobu esterification and (E)-selective ring-closing metathesis (RCM) to assemble the macrocycles as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic centers. Both synthetic compounds were found to display significant cytotoxic activity against seven human cancer cell lines with the IC50 ranges of 6.66–17.25 μM.

One new pyrrolidine derivative, asperidine A (1), and two new piperidine derivatives, asperidines B (2) and C (3), were isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 together with two known alkaloids. Compound 3 possessed an unprecedented 7-oxa-1-azabicyclo[3.2.1]octane skeleton with four chiral centers. Their structures were determined by spectroscopic evidence. The absolute configurations of compounds 2 and 3 were established using Mosher’s method and further confirmed for compound 3 by X-ray crystallographic data. Compound 2 dose-dependently inhibited the CFTR-mediated chloride secretion in T84 cells with an IC50 value of 0.96 μM whereas 3 displayed the same activity with the IC50 value of 58.62 μM. Compounds 2 and 3 also significantly reduced intracellular ROS under both normal and H2O2-treated conditions compared with their respective controls in a dose-dependent manner without cytotoxic effect on Caco-2 cells. In addition, compound 3 was inactive against noncancerous Vero cells whereas compound 2 was considered to be inactive with the IC50 value of >10 μM.