New bioactive secondary metabolites from fungi: 2023

ABSTRACT Fungi have been identified as a prolific source of structurally unique secondary metabolites, many of which display promising biological and pharmacological properties. This review provides an overview of the structures of new natural products derived from fungi and their biological activities along with the research strategies, which focuses on literature published in the representative journals in 2023. In this review, a total of 553 natural products including 219 polyketides, 145 terpenoids, 35 steroids, 106 alkaloids, and 48 peptides are presented. By summarising the latest findings, this review aims to provide a guide and inspire further innovation in the fields of the discovery of fungal natural products and pharmaceutical development.


Introduction
Secondary metabolites obtained from natural resources have gained considerable attention due to their potential as key components in new drug development (Evidente 2022).Natural products are usually isolated from various sources such as plants, animals, marine organisms, fungi, bacteria, and others (Hui et al. 2023).They exhibit a wide range of pharmacophores and a high degree of stereochemistry, which are expected to contribute to their strong pharmacological properties (Tammam et al. 2023).Furthermore, with the development and progress of research technology, the investigations on drugs based on natural products are entering a new era (Schor and Cox 2018;Saldívar et al. 2022).Fungi are distributed widespread in nature and have been recognised as one of the important sources of natural products due to their abundant secondary metabolites biosynthetic gene clusters (BGCs) (Hautbergue et al. 2018;Yee et al. 2023).Many fungal-derived natural products possess unique structures and display diverse biological properties (Lin et al. 2021;Holland and Carroll 2023).Since the discovery of penicillin by Alexander Fleming in 1928, many fungal natural products and derivatives have been used as drugs (Molnár et al. 2010), such as lipid-lowering medications (lovastatin), immunosuppressants (cyclosporine and mycophenolic acid), and vasoconstrictors (ergometrine) (Orfali et al. 2021).Therefore, the investigation of fungal secondary metabolites plays an important role in drug development.
Nevertheless, fungal genome research on the identified species suggests that over 80% of their secondary metabolites remain unknown (Simpson 2014), indicating that a large number of compounds are still waiting to be discovered (Rateb and Ebel 2011).Therefore, it is significant to accumulate the chemical structures, bioactivities, and research strategies of the new natural products reported recently.This allows us to summarise research paradigms and propose new breakthrough points in combination with interdisciplinary intersections.Consequently, employing the key words "fungi natural products", "fungi secondary metabolites", "fungal chemistry", and "fungi mycotoxin", this review insights into the literature published in 2023 by searching on PubMed, Web of Science, ACS, RSC, Springer Link, Elsevier, and Wiley databases.Finally, we focus on the representative journals in the field of natural products, including the Journal of the American Chemical Society, Angewandte Chemie International Edition, Chemical Science, Organic Letters, Bioorganic Chemistry, Journal of Natural Products, Journal of Agriculture and Food Chemistry, Chemical Communications, Chinese Chemical Letters, Planta Medica, Journal of Organic Chemistry, and Chinese Journal of Natural Medicine, etc.This review identifies 553 compounds, including 219 polyketides, 145 terpenoids, 35 steroids, 106 alkaloids, and 48 peptides, isolated from the endophytic fungi, marine-derived fungi, solid-associated fungi, animal-derived fungi, and other origin fungi.In this review, we systematically summarise and analyse the structures and biological activities of the new compounds, fungal strain sources and research strategies, aiming to offer new insights into the field of fungal natural products.

Source and strategy of fungi for chemical studies
Figure 1a provides an overview of new compounds isolated from fungi in 2023, categorised by their sources of fungal strains.Based on the literature research results, the fungal sources of all the new compounds reported in 2023 can be divided into four parts, including plants (endophytic fungi and phytopathogenic fungi are both involved), soil, marine, and animals.According to the data from Figure 1, it can be estimated that over one-third of the new compounds reported during 2023 are derived from plants, with an approximately even split between plant and marine sources in the broadest terms, while the remaining compounds originate from fungi isolated from soil, animals and other sources.
Screening bioactive secondary metabolites from such a vast fungal resource for drug research is a challenging task (Newman and Cragg 2020).It is also difficult to elucidate the structure of unknown fungal secondary metabolites due to their complexity and low amounts.Fortunately, advances in high-throughput untargeted metabolomics have led to the development of bioinformatics and cheminformatics tools.Some of the promising strategies for natural product research were conducted in the recent study (Figure 1b) including molecular networking, NMR-guided separation, coculture techniques, and activation of silent BGCs [One Strain Many Compounds (OSMAC) strategy and heterologous expression].However, the largest proportion of new compounds were discovered using traditional strategies (including bioactivity-guided isolation), exceeding 80%.Based on the statistical results from Figure 1b, molecular networking is the most widely used strategy during natural products research, accounting for approximately 10% of the number of new compounds.Scientists prefer traditional strategies such as bio-guided fraction purification to investigate the secondary metabolites of the fungi, with the direct aim of exploring new bioactive natural products and contributing to drug development.Interestingly, almost 70% literatures reviewed herein have proposed the possible biosynthetic pathways of the isolated compounds, highlighting the significance of analysing biosynthetic pathways and expanding databases of BGCs for natural product research.In this review, the biosynthetic pathways of representative compounds for every structural type (except for steroids due to the lack of relevant reports) are summarised.
The overview information of the new compounds including their fungal sources, and strain names, together with the bioactivities and study strategies are summarised and organised in Table 1.With the bioactive compounds numbers attached in parentheses of the line "bioactivities", it is estimated that less than half of the 553 compounds exhibited biological effects, including cytotoxic, anti-inflammatory, antibacterial, anti-viral, anti-fungal, anti-parasitic, antioxidant, and other activities (e.g.organ protection, plant growth regulation, and anti-Alzheimer's, etc).Combined with the evidence from Figure 2a, polyketides play a dominant role, comprising 41% of all new natural products from fungi, followed by terpenoids at 26% (Figure 2a).Alkaloids accounted for the largest proportion of the remaining three structural types, reaching 20%, while steroids and peptides accounted for 7% and 6%, respectively.

General aspects of secondary metabolites
Among the 553 new compounds isolated in 2023, less than half of them (212, approximately 40%) exhibited biological activities, which exposed another difficulty through natural products research as drug candidates due to the low amounts of biologically active natural products synthesised in very complex matrices.In the past year, researches have mainly focused on bioactivities including cytotoxic, antiinflammatory, anti-bacterial, anti-fungal, anti-viral, anti-parasitic, and antioxidant as well as other effects.Among them, compounds with antibacterial activities occupy an advantage in number, followed by those with cytotoxic activities, including each structural type mentioned in the review.Furthermore, the estimation of listed bioactivities (Figure 2b) revealed that the majority of terpenoids exhibit cytotoxic activities, while the number of polyketides with antibacterial activities is the highest.Overall, polyketides are rich and diverse in structure and extensive in biological activity, establishing their priority in this review, followed by terpenoids, steroids, alkaloids, and peptides.Their structural characteristics, biological activities, and strain sources are systematically reviewed herein.

Polyketides
Fungal-derived polyketides and their hybrids play a significant role in expanding the chemical space of total natural products.Totally 219 polyketides (structures are shown in Figures 3-8) were summarised in this section.For instance, trilactones A−H (1−8) were isolated from previously unexplored strains of the fungus Trichocladium crispatum guided by molecular networking separation.Compounds 1 and 7 feature two unconventional bridged tricyclic core skeletons, while 2, 3, 5, and 6 share a unique tetracyclic 9/5/6/6 ring system.Compound 4 exhibits an unusual 9/5/6/10/ 3-fused pentacyclic architecture, and 8 is a dimer connected by an unexpected C-C linkage.Additionally, the antiosteoporosis effects of compounds 1−8 were evaluated in vivo through a zebrafish model.The result suggested that trilactone G (7) significantly maintains bone formation-resorption homoeostasis with a comparable moderating effect to that of the positive control (alendronate) (Han et al. 2023).
Using the genome mining strategy, researches focused on the BGCs of the fungus Trichoderma afroharzianum T-22, a novel highly reducing polyketide synthase (HRPKS) BGC was reported, while five new compounds 44−48 with trans-fused 5,7-bicyclic skeletons were isolated and identified.Further bioactive assay indicated that no antimicrobial or herbicidal activities were detected (Yan et al. 2023).Eight new phenalenones asperphenalenones F−M (49−56) were obtained from the fermentation extract of the endophytic fungus Clonostachys rosea.The structural analysis involved GC-MS analysis of hydrolysis products and determination of optical rotation identified the sugar constituent of glycosylated compounds 53−56 as α-D-mannose.This marks the first reported isolation of glycosides from the rice culture of the endophytic fungus C. rosea.Regarding the antibacterial efficacy, compounds 49, 50, and 52 exhibited significant activities against MRSA and E. faecium, and compound 49 demonstrated the highest potency against both bacterial strains with MIC values of 12.5 and 25 μmol/L, respectively (Yang et al. 2023).Three uncommon caged xanthone [6,6,6,6,6]  discovered from an endolichenic fungus Daldinia pyrenaica 047188.Among them, daldipyrenone A (57) significantly enhanced adiponectin biosynthesis by two-fold compared to the positive control.These compounds were also evaluated for the antimelanogenic activities and the results      showed that 57 displayed a strong antimelanogenic effect in the human melanoma MNT-1 cell lines (EC 50 = 3.36 μg/mL), which was more potent than those of the positive controls arbutin (EC 50 = 54.49μg/mL) and kojic acid (EC 50 = 66.65 μg/mL) (Lee et al. 2023).Three new isocoumarins (61−63) together with one new pyrone derivative (64) were isolated from the fermentation broth of the mangrove endophytic fungus Phomopsis sp.DHS-11.Compounds 61 and 63 exhibited cytotoxic activities against HeLa cells with IC 50 values of 11.49 ± 1.64 μmol/L and 8.70 ± 0.94 μmol/L, respectively.And 64 exhibited cytotoxic activity against human hepatoma cells HepG2 with an IC 50 value of 34.10 ± 2.92 μmol/ L (Guo et al. 2023).Moreover, inspired by OSMAC strategy, two novel dihydroisocoumarin glycosides xylarglycosides A (65) and B (66) were obtained from the fermentation of the fungus Xylaria sp.KYJ-15 on potato and rice solid media.Both compounds exhibited antibacterial activities against Staphylococcus aureus with MICs of 4 and 2 μg/mL, respectively, and showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities comparable to the positive control with IC 50 values of 9.2 ± 0.03 and 13.3 ± 0.01 μmol/L, respectively (Gan et al. 2023).Additionally, combined the OSMAC approach with molecular network-based untargeted metabolomics, two new PKS-NRPS hybrid macrolactone versicolide A (67) and quinazoline (−)-isoversicomide A (68) were isolated from the deep-sea fungus Aspergillus versicolor PS108-62 (Magot et al. 2023).Fruthermore, heterologous expression strategy was used in the investigation of the natural products derived from fungi.The xenoacremones BGC (PKS-NRPS) from the fungus Xenoacremonium sinensis ML-31 was successfully expressed in the Aspergillus nidulans host, leading to the identification of four novel tyrosine-decahydrofluorene analogs, named xenoacremones I−L (69−72) (Liu et al. 2023).
Seven new isocoumarins, named prunolactones A−G (73−79), featuring a unique 6/6/6/6/6/6 spiropentacyclic skeleton, were discovered from the endophytic fungus Phomopsis prunorum, guided by UPLC-QTOF-MS and 1 H NMR spectroscopic analytical techniques.Compounds 75, 76, and 79 exhibited significant pro-angiogenic activities in zebrafish at a concentration of 80 μmol/L (Dai et al. 2023).The fungus Griseofulvania griseomyces yielded six griseofulvin analogues leukomycins A−F (80−85), among which compounds 80 and 83 demonstrated promising anti-inflammatory properties in RAW264.7 macrophages and mice with ulcerative colitis (Liang et al. 2023).Chemical investigation of a lichen-associated fungus named Phaeosphaeria sp.SQ-510 had yielded six skeletally new dimeric spiciferones, phaeosphaerones A−F (86−91).Compounds 86 and 88−91 represented a novel class of chromene-pyrone hybrids featuring a unique ethylidene bridge.The plant-growth regulatory activity of these compounds was evaluated, and the results demonstrated that compounds 86, 87, 90, and 91 inhibited the growth of the weedlike dicot on Arabidopsis thaliana at concentrations of 100 μmol/L.Further studies showed that low concentrations of compound 86 promoted the growth of A. thaliana by increasing fresh weight and/or root elongation, while significant inhibition was observed at high concentrations (Zhai et al. 2023).
Sixteen novel polyketides, ophicirsins A−P (92−107) were discovered from the extract of the endophytic fungus Ophiobolus cirsii LZU-1509.Compounds 96 −100 and 105−107 encompass novel carbon frameworks, while 105 and 106 feature different cyclic ether connected with an aromatic ring system.The antioxidant effects of the isolated compounds were further evaluated using the model of oxidative damaged neuron-like PC12 cells, and compound 106 exhibited excellent protective capacity (nearly rescuing the cell viability completely) for hydrogen peroxide insult.Furthermore, compound 106 displayed a remarkable capacity to scavenge the free radicals of DPPH (Guo et al. 2023).Seven novel tanzawaic acid derivatives, steckwaic acids E−K (108−115), and a novel benzene derivative (115) were extracted from a marine-derived fungus Penicillium steckii SCSIO 41040.Compound 109 was found to suppress the nuclear effect induced by LPS and exhibited inhibitory activity against LPS-induced NF-κB with IC 50 value at 10.4 μmol/L (BAY11-7082 was used as a positive control, IC 50 = 5.0 μmol/L).Furthermore, compound 109 could suppress the RANKL-induced osteoclast differentiation in bone marrow macrophage cells (BMMCs) triggered by NF-κB ligand (RANKL) (Song et al. 2023).
Four structurally unique paraphaeolactones A 1 , A 2 , B 1 , and B 2 (116−119) were isolated from the culture broth of Paraphaeosphaeria sp.KT4192.None of these compounds showed notable antifungal activity against Bipolaris oryzae (Cochliobolus miyabeanus).The WST-1 assay using COLO 201 human colon adenocarcinoma revealed weak cytotoxicities of 118 and 119, with IC 50 values of 260 and 200 μmol/L, respectively (Kanehara et al. 2023).Assisted by a molecular networking-based strategy for natural product dereplication and prioritisation, three unprecedented 1-deoxy-D-glucosamine adducts, glyclauxins A−E (120−125), were obtained from a nestderived fungus Talaromyces sp.CMB-MW102.The author proposed a biogenetic relationship linking all members of the extended duclauxin structure class.However, none of their biological activities were evaluated (Samarasekera et al. 2023).Through genome mining and heteroexpression, a HRPKS gene cluster (cpn) from Calcarisporium arbuscula was successfully identified and activated.Heterologous expression of the cpn cluster in the engineered Aspergillus nidulans A1145 host led to the isolation of four new α-pyrone compounds calcapyrones A−D (126−129).The cpn cluster encodes a HRPKS (cpnA), an O-methyltransferase (cpnB), and a cytochrome P450 (cpnC).First, the HRPKS CpnA synthesised a reduced polyketide chain from one molecule of acetyl-CoA and five molecules of malonyl-CoA to generate intermediate.Then this intermediate is converted to intermediates 128 and 129 catalysed by the O-methyltransferase CpnB.Lastly, the cytochrome P450 CpnC catalysed the regioselective dihydroxylation of intermediates 128 and 129 to form compounds 126 and 127, respectively.It was found that compound 128 showed modest cytotoxic effects against HCT116, HepG2, and B16 cell lines, with IC 50 values of 21.7 ± 0.7, 41.8 ± 0.7, and 38.5 ± 1.0 μmol/L, respectively, while the positive control (cisplatin) showed IC 50 values of 20.8 ± 0.8, 19.3 ± 0.6, and 22.5 ± 1.5 μmol/L, respectively (Dong et al. 2023).A new terrein derivative aspergilethers A (130) was obtained from the endophyte Aspergillus terreus HT5.Notably, structural analysis revealed that 130 had a unique medium aliphatic side chain.However, no phytotoxic activity was detected on 130 (Wang et al. 2023).
Four new 9,11-secosteroid-derived γ-lactones altersteroids A−D (183−186) were isolated from cultures of the ascomycete fungus Aternaria sp.All of the compounds were tested for cytotoxicities against four tumour cell lines.Compound 185 showed moderately cytotoxicity against four types of tumour cells (IC 50 = 4.8−12.7 μmol/L) and induced apoptosis of A549 cells, with a more potent effect than the positive control cisplatin (1.6−25.9μmol/L) (Fu et al. 2023a).Harms et al. discovered that the extracts of the basidiomycete Resupinatus sp.BCC84615 exhibited activity against Bacillus subtilis, which was screened for further chemical investigation.Two novel compounds 187 and 188 were obtained from the culture of this fungus.Both of them exhibited antibacterial activities on B. subtilis and S. aureus at the concentration of 17 μg/mL, and showed weak cytotoxicities against cancer cell lines (Harms et al. 2023).Under the guidance of molecular networking, 21 new p-terphenyl derivatives, asperterphenyls (189-209), were obtained from a spongederived fungus Aspergillus sp.SCSIO41315.These compounds were evaluated their neuraminidase inhibitory activities and antiviral effects.Compound 189 displayed neuraminidase inhibitory activity with an IC 50 value of 1.77 ± 0.53 μmol/L (Wei et al. 2023).
Linear polyketides scytalpolyols A−D (210−213) were isolated from the Scytalidium sp.IQ-074.The inhibitory activities of compounds 210−213 against hPTP1B 1-400 were evaluated.Scytalpolyol B (211) could significantly inhibit hPTP1B 1-400 with an IC 50 value of 27.0 ± 1.7 μmol/L, comparable to that of the positive control ursolic acid (IC 50 = 26.6 μmol/L).This was the first report of a polyenol that acts as an inhibitor of hPTP1B 1-400 (Martinez et al. 2023).A fungal extract from Trichocladium sp.TN09213 RBM-1 was found to inhibit four infectious disease-causing organisms Mycoplasma genitalium, Plasmodium falciparum, Cryptosporidium parvum, and Trichomonas vaginalis with low toxicity to human liver cells.The intensive chemical investigation led to the separation of six new compounds, named xanthoquinodins NPDG A 1 -A 5 (214−218) and B 1 (219).Unfortunately, none of these new compounds were identified as key factors contributing to the antimicrobial activity of crude extracts (Lee et al. 2023).

Terpenoids
Terpenoids, characterised by the isoprene units in their structure, include various subclasses such as sesquiterpenes, diterpenes, and triterpenes.Within this classification, a total of 145 terpenoids are described in detail in this section .
Using the method of liquid chromatograph-mass spectrometer (LC-MS) analysis to screen endophytes from the traditional Chinese medicinal herb Coptis chinensis Franch., the fungus Trichoderma citrinoviride HT-9 has been identified.Further chemical investigation led to the isolation of a novel homotrimeric sorbicillinoid, citrinsorbicillin A (236), together with two new monomers, citrinsorbicillins B (237), and C (238).Compound 236 represented a unique carbon skeleton and exhibited moderate inhibitory activity against human colon cancer H-29 cells (Yin et al. 2023).Antrodizonatins A−L (239−250) are previously undescribed triquinane sesquiterpene glycosides isolated from the fruiting bodies of Antrodiella zonata.All the compounds were evaluated for their antibacterial activities against S. aureus, E. coli, Pseudomonas aeruginosa, and Salmonella enterica.Among them, compounds 239, 243, and 250 exhibited weak inhibitories against the growth of S. aureus with IC 50 values of 35, 34, and 69 μmol/L, respectively (Gao et al. 2023).Based on in vitro antibacterial activity assays against human pathogenic bacteria, a bioactivity-guided fractionation workflow led to the purification of seven novel bioactive eremophilane sesquiterpenes, eremoxylarins D−J (251−257), from an endolichenic fungus Xylaria hypoxylon cultivated in coculture with another endolichenic fungus Dendrothyrium variisporum.Compounds 251, 253, 254, and 256 showed selective activities against MRSA, with MIC values ranging from 0.39 to 12.5 μg/mL.Particularly, eremoxylarin I (256) exhibited the strongest and broadest antibacterial activity among the isolated compounds, and it also exhibited activity against HCoV-229E (IC 50 = 18.1 μmol/L) (Miral et al. 2023).
The deep sea-derived fungus Paraconiothyrium hawaiiense FS482 was shown to produce five novel diterpenoids hawanoids A-E (307-311).The structures of these compounds were elucidated through X-ray crystallographic analysis and NMR spectroscopy.These compounds were tested for inhibitory effects on platelet activating factor (PAF)-induced platelet aggregation.Compounds 309 and 310 showed significant activities with IC 50 values of 7.1 and 8.9 μmol/L, respectively, while compounds 307, 308, and 310 exhibited moderate activities with IC 50 values ranging from 15−67 μmol/L (Chen et al. 2023).
Twelve new austalide meroterpenoids, diaporaustalides A−L (335−346), were isolated from the endophytic fungus Diaporthe sp.XC1211.336 and 340 showed potent proliferation inhibitory effects against LPS-induced B cells, with IC 50 values of 6.7 and 3.8 μmol/L, respectively.Additionally, both compounds decreased the secretion of IL-6 in LPSinduced B cells in a dose-dependent manner (Chang et al. 2023).A drimane meroterpenoid borate, named territrem F (347), along with its diol precursor territrem B (348), were isolated from the fungus Alternaria sp.ZH-15 associated with the soft coral.These compounds featuring a unique borate ring system showed potential as synchronous Ca 2+ oscillation inhibitors.Both compounds showed significant inhibitory activities on spontaneous synchronous Ca 2+ oscillations (SCOs) and epileptic discharges induced by 4-amino-pyridine (Wang et al. 2023).Jiang et al. (2023c) discovered that the culture extract of the fungus Amphichorda felina SYSU-MS7908 displayed moderated cytotoxicity against U87-MG human glioma cells.Then the isolation of four new meroterpenoids amphicordins A−D (349−352) had been reported.Compound 351 possessed a rare benzo[g]chromene (6/6/6) skeleton.However, none of these compounds showed cytotoxic effects.Five new meroterpenoids peniandranoids A−E (353−357) were yielded from the culture extract of the fungus Penicillium sp.sb62.Compound 353 displayed remarkable inhibitory activities towards influenza virus A (H1N1) with an EC 50 value of 19 μg/mL, while 355−357 showed immunosuppressive activities against concanavalin A-induced T cell proliferation with EC 50 values ranged from 4.3 to 27 μmol/L and LPS-induced B cell proliferation with EC 50 values ranging from 7.5 to 23 μmol/L (Chang et al. 2023).
Overall, steroids derived from fungi exhibited obvious bioactivities.For instance, compounds 371 and 373 not only displayed significant antimalarial activities against Plasmodium falciparum K1 (multidrug-resistant strain) but also showed cytotoxicities against Vero cells.Compounds 388−392 and 395 exhibited cytotoxic against HL-60, SD-DHL-2, PKO, HepG2, and A549 cell lines, while compound 397 possessed cytotoxic activity against SU-DHL-2 cells and HL60 cells.Unfortunately, none of the literature mentioned above reported the biosynthetic pathways of the isolated compounds.

Alkaloids
Alkaloids are a class of natural organic compounds that contain nitrogen atoms.This review summarises totally 106 new alkaloids (Figures 16-19) from fungi associated secondary metabolites.
Co-culturing Penicillium janthinellium with Paecilomyces formosus resulted in the discovery of nine new indole-diterpenes, named janthinellumines A-I (400-408).These compounds exhibited a wide range of biological activities, including antiinfluenza A virus, protein tyrosine phosphatase (PTP) inhibitory effects, and anti-Vibrio activities.Specifically, compound 403 displayed significant activity against the strains A/WSN/33 (H1N1) and A/Hong Kong/1/68 (H3N2), with IC 50 values of 3.8 μmol/L and 13.3 μmol/L, respectively.Compounds 400, 403, 404, and 406-408 also showed activities against both strains, with IC 50 values ranged from 7.3 μmol/L to 20.6 μmol/L (Cao et al. 2023).Eleven new indole quinazoline alkaloids aspergillus A-K (409-419) were discovered from the culture extract of the fungus Aspergillus clavatonanicus, which was collected from the gut of centipedes.The myocardial cell protective activities of these compounds were determined, and the results revealed that compounds 409, 410, and 413 could improve the damage caused by cold ischaemia (CI) within 48 hours after CI, and compounds 410 and 413 could also prevent GSK3β induced by cold ischaemia at 12 hours after CI dephosphorylation of Ser9 (Jin et al. 2023).A group of indoloquinazoline alkaloids named clavutoines A-U (420-440) were isolated from the marine-derived fungus Aspergillus clavutus LZD32-24.The inhibitory effects against antiangiogenesis and cytotoxic activities towards human umbilical vein endothelial cells (HUVECs) were evaluated.However, none of the compounds displayed any effects (Guo et al. 2023).
At the same time, metabolic analysis of the endophytic fungus Chaetomium nigricolor F5 was conducted and five new cytochalasins featuring a novel 5/6/5/5/7-fused pentacyclic skeleton, chamisides B-F (447-451) were discovered.Furthermore, these compounds were tested on Arabidopsis thaliana root elongation models.Compound 447 showed moderate inhibition on root elongation (Gu et al. 2023).A bioactive indole alkaloid amoenamide D (452) was isolated from Aspergillus amoenus TJ507 collected from the leaves of Hypericum wilsonii.Compound 452 was found to improve liver ischaemia/reperfusion injury.The experimental results indicated that this compound could reduce hepatocyte apoptosis and liver damage, as well as lower the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in serum.In   MYCOLOGY addition, this compound could reduce the expression of myeloperoxidase (MPO) in liver tissue and alter the localisation of high mobility group protein B1 (HMGB1) (Zhang et al. 2023).The marine-derived fungus Penicillium oxalicum QDU1 was investigated for the production of interconvertible pyridone alkaloids.The researchers isolated and identified 11 new compounds penicipyridones A−K (453−463).The biological activities of these compounds were evaluated.None of them exhibited anti-bacterial or antifungal activity.However, compounds 453, 456, 457, 460, 461, and 463 showed moderate inhibition of NO production by RAW264.7 macrophages, with IC 50 values ranging from 9.2 to 19 μmol/L (Wu et al. 2023).
Two avenualamide pyranone compounds fuligopyrones A and B (468 and 469) were extracted from the fungus Fuligo septica.Although these two compounds have no biological activity, they have unique mechanisms and effects against UV radiation, providing shortterm protection and reducing abiotic stress caused by UV radiation (Minns et al. 2023).Moreover, the first nitrogen-containing phytoactin phytoactinine (470) was isolated from marine fungus Biatriospora sp.CBMAI 1333.At concentrations of 10 and 25 μmol/L, 470 could inhibit cPAF induced IL-8 generation (Oliveira et al. 2023).A novel class of chromenepyrone hybrids named phaeosphaerones A-F (471-476), were isolated from the fungus Phaeosphaeria sp.Compounds 471 and 473-476 possess a unique ethylidene bridge.The plant-growth regulatory activities of compounds 471-476 were evaluated using two herbaceous plants Arabidopsis thaliana and Oryza sativa.The results demonstrated that these compounds exhibited effects in promoting plant growth, with glyphosate and glufosinate used as positive controls in the study (Zhai et al. 2023).Furthermore, four new plant growth inhibitory compounds, colletotriauxins A-D (477-480) were discovered from the phytopathogenic fungus Colletotrichum gloeosporioides NRRL 45420.These compounds inhibited the growth of Lepidium sativum seedlings, with the inhibition of stem growth being stronger than IAA, particularly with compounds 479 and 480 being the most effective.This indicated that 477-480 may be promising herbicide candidates (Zhou et al. 2023).
In summary, the number of alkaloids with cytotoxic activity accounted for the largest proportion in this section.For instance, compounds 445, 465−467, 502, and 503 displayed potent cytotoxicity against HL-60, SMMC-7721, MCF-7, MDA-MB-231, OVCAR3 K562, and H69AR cell lines.Additionally, potential antiplasmodial agents 497−501 displayed significant eliminating activities against chloroquine-sensitive strains (P.f.3D7).Apart from the bioactivies, the biosynthetic pathway of compounds 447−451 (Figure 20) is taken as an example of the biosynthetic process of alkaloids.Compounds 447−449 were derived from a widely accepted PKS-NRPS biosynthetic precursor composed of an octaketide and a phenylalanine.Furthermore, 447−449 might be the key biosynthetic precursors of co-isolated compounds 450 and 451, enabling researches to revisit and update the previously proposed biosynthesis of cytochalasans with a piperidine-2,6-dione ring, such as 450 and 451 (Gu et al. 2023).

Peptides
This section contains 48 new peptides derived from fungi metabolites .For instance, molecular networking-guided isolation of the fungus Aspergillus pseudoviridinutans TW585 resulted in the separation of seven novel cyclic pentapeptides pseudoviridinutans A−F (506−512).These compounds contain the rare amino acid fragment, which has been discovered for the first time in marine-derived fungi.Among them, compound 513 exhibited significant  MYCOLOGY anti-inflammatory effects by inhibiting LPS-induced production of NO (Ding et al. 2023).Tolypocaibolas A (513) and B (514) are two newly discovered compounds isolated from marine-derived fungus Tolypocladium sp.Both compounds displayed moderate selective inhibitions against Gram-positive and acid-fast strains, while maximomycin [(P/M)-3)] exhibited moderate broad-spectrum antibacterial activity (Morehouse et al. 2023).
Persephacin (530) was derived from the endophytic fungus Elsinoe sp.based on the conducting bioactivity tests.It was found that compound 530 demonstrated significant antifungal properties against Aspergillus fumigatus (Du et al. 2023).Three novel cyclic peptides meristosporins A−C (531−533) were successfully isolated and identified from Basidiobolus meristosporus Drechsler, a facultative parasitic fungus found in soil.These compounds were found to contain amino acid residues that are uncommon in this organism.Subsequent bioactivity experiments revealed that 531 and 532 exhibited significant cytotoxic effects on RAW264.7 macrophages and 293T renal epithelial cells (Zhao et al. 2023).The fungus Trichoderma sp.GXIMD 01001 was isolated from sponge samples, and seven novel 18peptide compounds trichorzins A−G (534−540) were identified from this strain.These compounds showed strong cytotoxicity against several human cancer cell lines, including human lung adenocarcinoma A549, human non-small cell lung cancer H1299, human colorectal cancer SW480, and human pancreatic cancer SW1990, with the IC 50 values ranging from 0.46 to 4.7 μmol/L (Lin et al. 2023).From the fungus Trichoderma sp., seven novel 18-residue peptaibols, neoatroviridins E−K (541−547), along with six new 14residue peptaibols, harzianins NPDG J−O (548−553) were isolated.In antimicrobial assessments, compounds 541−547 exhibited moderate inhibitory activities against S. aureus 209P, with MIC values ranging from 8 −32 μg/mL.Moreover, compound 509 exhibited moderate inhibitory effect on C. albicans FIM709, with a MIC value of 16 μg/mL (Cheng et al. 2023).
According to the above analysis, it was found that compound 513 exhibited remarkable antiinflammatory activity, while antifungal agents 516 and 517 had strong inhibitory effects on the growth of Geotrichum citri-aurantii mycelia.And a series of antitumour agents 534−540 significantly exhibited excellent cytotoxicity against several human cancer cell lines.Furthermore, the biosynthetic pathway of compounds 515−520 (Figure 24) is summarised as a case of the biosynthesis of peptides.This BGC contains a typical linear NRPS gene, which encodes six modules containing 18 domains.These modules work together to form the cyclic peptide backbone (Jiang et al. 2023c).

Discussion and conclusions
As described in this review, natural products originating from fungi exhibited a large chemical diversity and significant medicinal values.Despite encountering challenges such as limited yields, complex extracts, missing biological targets, and synthetic hurdles, fungal natural product research has made significant strides.In addition, innovative study strategies such as HPLC-MS/MS-based molecular networking, NMR-guided separations, coculture techniques, and activation of silent BGCs (OSMAC strategy and heterologous expression) have enabled systematic exploration of fungal natural products.These approaches have led to the isolation of new compounds with diverse biological activities.The combination of these new approaches could accelerate the discovery of fungal natural products.For instance, chemical biology can be used to exploit the complex chemical architecture of natural products for the exploration of novel targets.Moreover, detailed biological investigations can facilitate the identification and subsequent screening of active natural compounds possessing diverse chemical structures (Luo et al. 2024).
Furthermore, from the perspective of biological activities, researches have mainly focused on bioactivities including cytotoxic, anti-inflammatory, antibacterial, anti-fungal, anti-viral, anti-parasitic, and antioxidant as well as other effects.As a result, only less than 40% of the reviewed compounds exhibited pharmacological effects.Fortunately, the combination of novel research strategies could not only identify the new action sites for active compounds, but also provide a foundation for quickly obtaining a large number of novel, low-toxicity, and efficient fungal natural products.Moreover, the origin of fungal strains is another important aspect of our concern.Among the 92 strains of fungi described in this review, approximately 37% of them remained unidentified at species levels, indicating the vast diversity of the fungal species and their enormous potential for exploration.Interestingly, more than half of the endophytic fungi were isolated from medicinal plants, which emphasises that the pursuit of excellent pharmacological activity is the ultimate objective and core significance of natural product research.
In this review, we provide an overview of the new natural products derived from fungi reported in the given journals during 2023.A total of 553 novel natural products, including 219 polyketides, 145 terpenoids, 35 steroids, 106 alkaloids, and 48 peptides are characterised by their respective chemical structures and relevant biological activities.With the rapid advancements in multi-omics techniques and artificial intelligence, researchers should combine the different techniques and study strategies to the discovery of candidate compounds from fungi.Additionally, multidisciplinary collaborations such as microbiology, synthetic biology, chemistry, pharmacology, and bioinformatics will expedite the discovery of fungal natural products with therapeutic potential.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Figure 1 .
Figure 1.Number of new compounds derived from fungi in 2023.(a) Divided by sources of fungal strains.(b) Divided by research strategies.

Figure
Figure 2a gives an overview of new chemical structures from fungi reported in the literature published in 2023, categorised on the basis of their structural characteristics and their putative biogenetic origins.According to the related literature published in 2023, there are 553 new compounds derived from fungal

Figure 2 .
Figure 2. Number of new compounds derived from fungi in 2023.(a) Divided by structural types.(b) Separated by both bioactivities and structural conditions.

Table 1 .
Fungal sources of new natural products mentioned in this review along with their bioactivities and study strategies sources.