Laburnicotides A-F: Acyclic N-Acetyl Oligopeptides from the Nematode-Cyst-Associated Fungus Laburnicola nematophila.

Nematode-associated fungi revealed the potential to produce a broad spectrum of chemical scaffolds. In this study, a mycelial extract of Laburnicola nematophila, a fungal strain derived from the cereal cyst nematode Heterodera filipjevi, was chemically explored and afforded six unprecedentedly reported acylic N-acetyl oligopeptides, laburnicotides A-F (1-6). Structure elucidation of the isolated compounds was established based on comprehensive 1D and 2D NMR spectroscopic analyses together with the acquired HR-ESI-MS spectrometric data. The absolute configuration of amino acid residues in 1-6 was established by performing advanced Marfey's derivatization method. All isolated compounds were assessed for their cytotoxic, antimicrobial, antiviral, and nematicidal activities with no potential activity observed.

Labunicolamine: A Rare Penillic Acid Congener from the Nematode Cyst-Associated Fungus Laburnicola nematophila.

A chemical investigation of a methanol extract derived from a solid-state rice culture of the nematode-cyst associated fungus Laburnicola nematophila K01 led to the isolation and characterization of a previously undescribed penillic acid analogue named laburnicolamine (1). The chemical structure was elucidated through comprehensive 1D and 2D NMR spectroscopic analyses in methanol-d4 and DMSO-d6, alongside with HR-ESI-MS spectrometry. The absolute configuration of 1 was concluded through the electronic circular dichroism (ECD) and time-dependent density functional theory-ECD (TDDFT-ECD) computations compared to its acquired spectrum. Biological assays revealed that compound 1 exhibited no significant cytotoxic, antimicrobial, or nematicidal activity.

Comparative Study of Toxic Terpenoidal Aldehydes and Lactone Derivatives from the European Polypore Bondarzewia mesenterica.

Two unprecedented isomeric secondary metabolites named vibralactones Z5 (1a) and Z6 (1b), in addition to eleven known compounds (2-12), were isolated from solid-state rice culture medium of Bondarzewia mesenterica (Bondarzewiaceae). Chemical structures of the isolated compounds were established via spectral analyses. The new lactone derivatives were weakly active against Staphylococcus aureus without any significant cytotoxicity, while the molecules containing an aldehyde functionality showed significant antimicrobial and cytotoxic effects. For instance, erinacine P (7) and (+)-isovelleral (8) and erinacine P (7) were cytotoxic against all tested cell lines at IC50 values in the ranges of 3.5-14.2 and 2.8-30.2 µM, respectively. In addition, they revealed moderate antimicrobial activity with the lowest minimum inhibitory concentration (MIC) values recorded against Mucor hiemalis (8.3 µg/mL), Pichia anomala, and Rhodotorula glutinis at 16.6 µg/mL.

Omnipolyphilins A and B: Chlorinated Cyclotetrapeptides and Naphtho-α-pyranones from the Plant Nematode-Derived Fungus Polyphilus sieberi.

Chemical exploration for two isolates of the recently described ascomycete species Polyphilus sieberi, derived from the eggs of the plant parasitic nematode Heterodera filipjevi, afforded the identification of many compounds that belong to various metabolite families: two previously undescribed chlorinated cyclotetrapeptides, omnipolyphilins A (1) and B (2), one new pyranonaphthoquinone, ventiloquinone P (3), a 6,6'-binaphto-α-pyranone dimer, talaroderxine D (4) in addition to nine known metabolites (5-13) were isolated from this biocontrol candidate. All isolated compounds were characterized by comprehensive 1D, 2D NMR, and HR-ESI-MS analyses. The absolute configurations of the cyclotetrapeptides were determined by a combination of advanced Marfey's method, ROE correlation aided by conformational analysis, and TDDFT-ECD calculations, while ECD calculations, Mosher's method, and experimental ECD spectra were used for ventiloquinone P (3) and talaroderxine D (4). Among the isolated compounds, talaroderxine D (4) showed potent antimicrobial activities against Bacillus subtilis and Staphylococcus aureus with MIC values of 2.1 and 8.3 µg mL-1, respectively. Additionally, promising inhibitory effects on talaroderxine D (4) against the formation of S. aureus biofilms were observed up to a concentration of 0.25 µg mL-1. Moreover, ophiocordylongiiside A (10) showed activity against the free-living nematode Caenorhabditis elegans.

Lachnuoic Acids A-F: Ambuic Acid Congeners from a Saprotrophic Lachnum Species.

Chemical prospection of an extract derived from a saprotrophic fungus Lachnum sp. IW157 resulted in the isolation and characterization of six unprecedentedly reported ambuic acid analogues named lachnuoic acids A-F (1-6). Chemical structures of 1-6 were determined based on comprehensive 1D and 2D NMR spectroscopic analyses together with HR-ESI-MS spectrometry. The relative configurations of 1-3 were defined by ROESY spectroscopic analyses while their absolute configurations were unambiguously determined by Mosher's esters method. All isolated compounds were subjected to cytotoxic, antimicrobial, antibiofilm and nematicidal activity assays where only lachnuoic acid A (1) revealed potent antimicrobial activity against Staphylococcus aureus and Bacillus subtilis at MIC values of 16.6 and 8.3 µg/mL, respectively.

Cytotoxic Polyhydroxy-Isoprenoids from Neodidymelliopsis negundinis.

Fungal-derived natural products continue to play a pivotal role in the discovery of drug agents for human, veterinary, and general agricultural use. The fungus Neodidymelliopsis negundinis presents a significant saprobic ascomycete whose metabolites remained hitherto unstudied. Herein we report the isolation of eight unprecedented secondary metabolites named neodidymelliosides A and B (1 and 2), neodidymelliol A (3), and neodidymellioic acids A-E (4-8) produced by the submerged cultures of the fungus. Compound 1 proved to be the most active compound, with IC50 values ranging between 4.8 and 8.8 µM against KB3.1 (cervix), PC-3 (prostate), MCF-7 (breast), SKOV-3 (ovary), A431 (skin), and A549 (lung) cell lines. Compound 1 revealed significant inhibition of Staphylococcus aureus and Candida albicans biofilms.

Cytotoxic naphtho- and benzofurans from an endophytic fungus Epicoccum nigrum Ann-B-2 associated with Annona squamosa fruits.

Chemical exploration of the total extract derived from Epicoccum nigrum Ann-B-2, an endophyte associated with Annona squamosa fruits, afforded two new metabolites, epicoccofuran A (1) and flavimycin C (2), along with four known compounds namely, epicocconigrone A (3), epicoccolide B (4), epicoccone (5) and 4,5,6-trihydroxy-7-methyl-1,3-dihydroisobenzofuran (6). Structures of the isolated compounds were elucidated using extensive 1D and 2D NMR along with HR-ESI-MS. Flavimycin C (2) was isolated as an epimeric mixture of its two diastereomers 2a and 2b. The new compounds 1 and 2 displayed moderate activity against B. subtilis, whereas compounds (2, 3, 5, and 6) showed significant antiproliferative effects against a panel of seven different cancer cell lines with IC50 values ranging from 1.3 to 12 µM.

Bioprospection of Tenellins Produced by the Entomopathogenic Fungus Beauveria neobassiana.

Fungi are known as prolific producers of bioactive secondary metabolites with applications across various fields, including infectious diseases, as well as in biological control. However, some of the well-known species are still underexplored. Our current study evaluated the production of secondary metabolites by the entomopathogenic fungus Beauveria neobassiana from Thailand. The fermentation of this fungus in a liquid medium, followed by preparative high-performance liquid chromatography (HPLC) purification, resulted in the isolation of a new tenellin congener, namely pretenellin C (1), together with five known derivatives (2-6). Their chemical structures were elucidated by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy in combination with high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). We evaluated the antimicrobial and cytotoxic activities from all isolated compounds, as well as their inhibitory properties on biofilm formation by Staphylococcus aureus. Generally, tenellins displayed varying antibiofilm and cytotoxic effects, allowing us to propose preliminary structure-activity relationships (SARs). Among the tested compounds, prototenellin D (2) exhibited the most prominent antibiofilm activity, while its 2-pyridone congener, tenellin (4), demonstrated potent cytotoxic activity against all tested cell lines. Given the fact that the biological activities of the tenellins have so far been neglected in the past, our study could provide a good starting point to establish more concise structure-activity relationships in the near future.

Cytotoxic and antimicrobial mycophenolic acid derivatives from an endophytic fungus Penicillium sp. MNP-HS-2 associated with Macrozamia communis.

Macrozamia communis and its associated endophytic fungi are untapped sources of bioactive metabolites with great potential for medicinal exploitation. Chemical investigation of the mycelial extract derived from an endophytic fungus Penicillium sp. MNP-HS-2 associated with M. communis fruit afforded four mycophenolic acid derivatives recognized as previously undescribed natural products (1-4), together with nine known metabolites (5-13). Chemical structures of isolated compounds were determined based on extensive spectroscopic analyses, including 1D/2D NMR and HRESIMS. The absolute stereochemistry of alternatain E (1) was unambiguously established by comparing its experimental and calculated time-dependent density functional theory electronic circular dichroism spectra (TDDFT-ECD). All isolated compounds were assessed for their antimicrobial and cytotoxic activities, where mycophenolic acid methyl ester (7), displayed significant cytotoxic activity against seven different cell lines with IC50 values in the low micromolar to nanomolar range. Mycophenolene A (3) exhibited significant antibacterial activity against Staphylococcus aureus (MIC = 2.1 µg/mL).

Neurite Outgrowth-Inducing Drimane-Type Sesquiterpenoids Isolated from Cultures of the Polypore Abundisporus violaceus MUCL 56355.

Abundisporin A (1), together with seven previously undescribed drimane sesquiterpenes named abundisporins B-H (2-8), were isolated from a polypore, Abundisporus violaceus MUCL 56355 (Polyporaceae), collected in Kenya. Chemical structures of the isolated compounds were elucidated based on exhaustive 1D and 2D NMR spectroscopic measurements and supported by HRESIMS data. The absolute configurations of the isolated compounds were determined by using Mosher's method for 1-4 and TDDFT-ECD calculations for 4 and 5-8. None of the isolated compounds exhibited significant activities in either antimicrobial or cytotoxicity assays. Notably, all of the tested compounds demonstrated neurotrophic effects, with 1 and 6 significantly increasing outgrowth of neurites when treated with 5 ng/mL NGF.

Diaporphasines E and F: New Polyketides from the Saprotrophic Fungus Lachnum sp. IW157 Growing on the Reed Grass Phragmites communis.

Chemical investigation for the mycelial extract of a saprotrophic fungus Lachnum sp. IW157 growing on the common reed grass Phragmites communis afforded the identification of two polyketide metabolites diaporphasines E (1) and F (2). Chemical structures of isolated compounds were unambiguously elucidated based on extensive 1D and 2D NMR spectral analyses in addition to their high-resolution mass spectrometry. The isolated compounds were assessed for their cytotoxicity and antimicrobial and biofilm inhibitory activities. While compound 1 revealed potent cytotoxicity against the tested cell lines L929 and KB3.1 with IC50 values of 0.9 and 3.7 µM, respectively, compound 2 exhibited moderate effects on the formation of S. aureus biofilms at 31.25 µg/mL.

Two new lanostanoid glycosides isolated from a Kenyan polypore Fomitopsis carnea.

Chemical exploration of solid-state cultures of the polypore Fomitopsis carnea afforded two new C31 lanostane-type triterpenoid glycosides, forpiniosides B (1) and C (2) together with two known derivatives, namely 3-epipachymic acid (3) and (3α,25S)-3-O-malonyl-23-oxolanost-8,24(31)-dien-26-oic acid (4). The structures of the isolated compounds were established based on HRESIMS and extensive 1D and 2D NMR experiments. All the isolated compounds were assessed for their antimicrobial and cytotoxic activities. Among the tested compounds, forpinioside B (1) exhibited significant antimicrobial activity against Staphylococcus aureus and Bacillus subtilis at MIC values comparable to gentamycin and oxytetracycline (positive controls), respectively.

Bioactive Naphtho-α-Pyranones from Two Endophytic Fungi of the Genus Polyphilus.

In the course of our survey to study the metabolic potential of two species of a new helotialean genus Polyphilus, namely P. frankenii and P. sieberi, their crude extracts were obtained using different cultivation techniques, which led to the isolation and characterization of two new naphtho-α-pyranone derivatives recognized as a monomer (1) and its 6,6'-homodimer (2) together with two known diketopiperazine congeners, outovirin B (3) and (3S,6S)-3,6-dibenzylpiperazine-2,5-dione (4). The structures of isolated compounds were determined based on extensive 1D and 2D NMR and HRESIMS. The absolute configuration of new naphtho-α-pyranones was determined using a comparison of their experimental ECD spectra with those of related structural analogues. 6,6'-binaphtho-α-pyranone talaroderxine C (2) exhibited potent cytotoxic activity against different mammalian cell lines with IC50 values in the low micromolar to nanomolar range. In addition, talaroderxine C unveiled stronger antimicrobial activity against Bacillus subtilis rather than Staphylococcus aureus with MIC values of 0.52 µg mL-1 (0.83 µM) compared to 66.6 µg mL-1 (105.70 µM), respectively.

Hericioic Acids A-G and Hericiofuranoic Acid; Neurotrophic Agents from Cultures of the European Mushroom Hericium flagellum.

Neurodegenerative diseases are currently posing huge social, economic, and healthcare burdens among the aged populations worldwide with few and only palliative treatment alternatives available. Natural products continue to be a source of a vast array of potent neurotrophic molecules that could be considered as drug design starting points. The present study reports eight new isoindolinone and benzofuranone derivatives, for which we propose the trivial names, hericioic acids A-G (1-7) and hericiofuranoic acid (8), which were isolated from a solid culture (using rice as substrate) of the rare European edible mushroom Hericium flagellum. The chemical structures of these compounds were determined based on extensive 1D and 2D NMR spectroscopy along with HRESIMS analyses. The isolated compounds were assessed for their neurotrophic activity in rat pheochromocytoma cells (PC-12) to promote neurite outgrowth on 5 ng NGF supplementation; all the compounds increased neurite outgrowths, with compounds 3, 4, and 8 exhibiting the strongest effects.

Lasiodipline G and other diketopiperazine metabolites produced by Lasiodiplodia chiangraiensis.

Lasiodiplodia fungi are known to colonize plants as both pathogens and/or endophytes; hence, they can be exploited for their beneficial roles. Many compound classes from the genus have exhibited their potential biotechnological applications. Herein, we report two new metabolites 1 and 2 together with three known cyclo-(D-Ala-D-Trp) (3), indole-3-carboxylic acid (4) and a cyclic pentapeptide clavatustide B (5), isolated from the submerged cultures of a recently described species L. chiangraiensis. Chemical structures of the isolated compounds were determined by extensive NMR spectroscopic analyses together with HRESIMS. The absolute configurations of the new compounds were established based on comparing experimental and calculated time-dependent density functional theory circular dichroism (TDDFT-ECD) spectra. Compound 1 exhibited significant cytotoxic activities against an array of cell lines with IC50 values of 2.9-12.6 µM, as well as moderate antibacterial effects.

Promising anti-Helicobacter pylori and anti-inflammatory metabolites from unused parts of Phoenix dactylifera CV 'Zaghloul': in vitro and in silico study.

CONTEXT: Date palm waste is an agricultural waste that accumulates in massive amounts causing serious pollution and environmental problems. OBJECTIVES: Date palm trees, Phoenix dactylifera Linn CV 'Zaghloul' (Arecaceae) grown in Egypt, leave behind waste products that were investigated to produce compounds with anti-Helicobacter pylori and anti-inflammatory activities. MATERIALS AND METHODS: Chromatographic workup of P. dactylifera aqueous methanol extract derived from fibrous mesh and fruit bunch (without fruit) afforded a new sesquiterpene lactone derivative, phodactolide A (1), along with ten known compounds (2-11), primarily identified as polyphenols. Chemical structures were unambiguously elucidated based on mass and 1D/2D NMR spectroscopy. All isolated compounds were assessed for their activities against H. pylori using broth micro-well dilution method and clarithromycin as a positive control. The anti-inflammatory response of isolated compounds was evaluated by inhibiting cyclooxygenase-2 enzyme using TMPD Assay followed by an in silico study to validate their mechanism of action using celecoxib as a standard drug. RESULTS: Compounds 4, 6 and 8-10 exhibited potent anti-H. pylori activity with MIC values ranging from 0.48 to 1.95 µg/mL that were comparable to or more potent than clarithromycin. For COX-2 inhibitory assay, 4, 7 and 8 revealed promising activities with IC50 values of 1.04, 0.65 and 0.45 µg/mL, respectively. These results were verified by molecular docking studies, where 4, 7 and 8 showed the best interactions with key amino acid residues of COX-2 active site. CONCLUSION: The present study characterizes a new sesquiterpene lactone and recommends 4 and 8 for future in vivo studies as plausible anti-ulcer remedies.

Pro-Apoptotic Activity of the Marine Sponge Dactylospongia elegans Metabolites Pelorol and 5-epi-Ilimaquinone on Human 501Mel Melanoma Cells.

The natural environment represents an important source of drugs that originates from the terrestrial and, in minority, marine organisms. Indeed, the marine environment represents a largely untapped source in the process of drug discovery. Among all marine organisms, sponges with algae represent the richest source of compounds showing anticancer activity. In this study, the two secondary metabolites pelorol (PEL) and 5-epi-ilimaquinone (EPI), purified from Dactylospongia elegans were investigated for their anti-melanoma activity. PEL and EPI induced cell growth repression of 501Mel melanoma cells in a concentration- and time-dependent manner. A cell cycle block in the G1 phase by PEL and EPI was also observed. Furthermore, PEL and EPI induced significant accumulation of DNA histone fragments in the cytoplasmic fraction, indicating a pro-apoptotic effect of both compounds. At the molecular level, PEL and EPI induced apoptosis through the increase in pro-apoptotic BAX expression, confirmed by the decrease in its silencing miR-214-3p and the decrease in the anti-apoptotic BCL-2, MCL1, and BIRC-5 mRNA expression, attested by the increase in their silencing miRNAs, i.e., miR-193a-3p and miR-16-5p. In conclusion, our data indicate that PEL and EPI exert cytotoxicity activity against 501Mel melanoma cells promoting apoptotic signaling and inducing changes in miRNA expression and their downstream effectors. For these reasons could represent promising lead compounds in the anti-melanoma drug research.

Anti-Inflammatory, Antiallergic and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus costaricaensis.

Amid the current COVID-19 pandemic, the emergence of several variants in a relatively high mutation rate (twice per month) strengthened the importance of finding out a chemical entity that can be potential for developing an effective medicine. In this study, we explored ethyl acetate (EtOAc) extract of a marine-derived fungus Aspergillus cosatricaensis afforded three butenolide derivatives, butyrolactones I, VI and V (1-3), two naphtho-γ-pyrones, TMC-256 A1 (4) and rubrofusarin B (5) and methyl p-hydroxyphenyl acetate (6). Structure identification was unambiguously determined based on exhaustive spectral analyses including 1D/2D NMR and mass spectrometry. The isolated compounds (1-6) were assessed for their in vitro anti-inflammatory, antiallergic, elastase inhibitory activities and in silico SARS-CoV-2 main protease (Mpro). Results exhibited that only butenolides (1 and 2) revealed potent activities similar to or more than reference drugs unlike butyrolactone V (3) suggesting them as plausible chemical entities for developing lead molecules.

Anti-Inflammatory, Antiallergic, and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus terreus.

In December 2020, the U.K. authorities reported to the World Health Organization (WHO) that a new COVID-19 variant, considered to be a variant under investigation from December 2020 (VUI-202012/01), was identified through viral genomic sequencing. Although several other mutants were previously reported, VUI-202012/01 proved to be about 70% more transmissible. Hence, the usefulness and effectiveness of the newly U.S. Food and Drug Administration (FDA)-approved COVID-19 vaccines against these new variants are doubtfully questioned. As a result of these unexpected mutants from COVID-19 and due to lack of time, much research interest is directed toward assessing secondary metabolites as potential candidates for developing lead pharmaceuticals. In this study, a marine-derived fungus Aspergillus terreus was investigated, affording two butenolide derivatives, butyrolactones I (1) and III (2), a meroterpenoid, terretonin (3), and 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde (4). Chemical structures were unambiguously determined based on mass spectrometry and extensive 1D/2D NMR analyses experiments. Compounds (1-4) were assessed for their in vitro anti-inflammatory, antiallergic, and in silico COVID-19 main protease (Mpro) and elastase inhibitory activities. Among the tested compounds, only 1 revealed significant activities comparable to or even more potent than respective standard drugs, which makes butyrolactone I (1) a potential lead entity for developing a new remedy to treat and/or control the currently devastating and deadly effects of COVID-19 pandemic and elastase-related inflammatory complications.