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Review

Endophytic Fungi: An Effective Alternative Source of Plant-Derived Bioactive Compounds for Pharmacological Studies

1
Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
2
Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
3
New Ruipeng Pet Healthcare Group Co., Ltd., Shenzhen 518000, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
J. Fungi 2022, 8(2), 205; https://doi.org/10.3390/jof8020205
Submission received: 21 January 2022 / Revised: 13 February 2022 / Accepted: 16 February 2022 / Published: 20 February 2022

Abstract

:
Plant-associated fungi (endophytic fungi) are a biodiversity-rich group of microorganisms that are normally found asymptomatically within plant tissues or in the intercellular spaces. Endophytic fungi promote the growth of host plants by directly producing secondary metabolites, which enhances the plant’s resistance to biotic and abiotic stresses. Additionally, they are capable of biosynthesizing medically important “phytochemicals” that were initially thought to be produced only by the host plant. In this review, we summarized some compounds from endophyte fungi with novel structures and diverse biological activities published between 2011 and 2021, with a focus on the origin of endophytic fungi, the structural and biological activity of the compounds they produce, and special attention paid to the exploration of pharmacological activities and mechanisms of action of certain compounds. This review revealed that endophytic fungi had high potential to be harnessed as an alternative source of secondary metabolites for pharmacological studies.

1. Introduction

The term “endophytic fungi” refers to fungi that live in plant tissues throughout the entire or partial life cycle by establishing a mutually beneficial symbiotic relationship with its host plant without causing any adverse effect or disease [1,2]. They are natural components of the plant micro-ecosystem that positively affect the physiological activities of the host plant in several ways, including producing hormones such as indoleacetic acid, biosynthesizing and acquiring nutrients for plant growth and development, secreting stress-adaptor metabolites to protect the host plant from the invasion of herbivores, pathogens, and improving the host’s adaptability to abiotic stressors. In return, plants provide habitats and nutrients for endophytic fungi [3,4]. Endophytic fungi are capable of producing a rich variety of bioactive substances and can produce compounds that are identical or similar to pharmacological activities identified from plants [5]. They produce a range of metabolites of different chemical classes, including alkaloids, flavonoids, steroids, terpenoids, and phenolic compounds. Some compounds show pleiotropic and interesting pharmacological activities, including antimicrobial, antioxidant, anti-diabetic, anti-malarial, and antitumor properties. The discovery of these structurally novel and diverse active compounds provides a valuable resource for studying natural medical products from the microbiome [6,7,8]. In the search for bioactive molecules as pro-drug compounds or in the development of medicines, endophytic fungi can serve as an alternative source for valuable active plant compounds. Endophytic fungi can be harnessed to produce bioactive compounds for human pharmaceutical use when the bioactive secondary metabolites are not commercially available, derived from slow-growing or rare and endangered plants, and difficult to synthesize due to heavy molecular weight or structural complexity. Endophytic fungal secondary metabolites have drawn extensive attention among medicinal plants, mangroves, and marine microorganisms [9,10].
Endophytic fungi are a highly biodiverse and versatile microbial community that seems to be ubiquitous in nature. Studies have shown that almost all plants contain endophytic fungi, including colonized plants in the Arctic and Antarctic regions, deserts, oceans, and tropical rainforests [11,12]. They have been isolated and cultured from the roots and above-ground parts of various plants, including algae, mosses, ferns, gymnosperms, and angiosperms. Evidence from microorganism’s records in the fossil plant tissue indicated that the plant-endophytic fungal interactions have existed for approximately 400 million years, and during this time, endophytic fungi co-evolved unique biosynthetic pathways and metabolic mechanisms to synthesize complex secondary metabolites [13]. To date, only 5% of 1.5 million fungal species on Earth have been described in detail, and out of this percentage (69,000 fungal species), only 16% (11,500 species) have been cultured and studied. About 0.035–5.1 million fungal species have been found on Earth according to results from next-generation sequencing technologies [14]. Approximately 300,000 known species of higher plants exist on Earth, and each of which is a host for one or more obligate endophytic fungi. The high number of bioactive secondary metabolites found in endophytic fungi is due to their rich species diversity [15,16]. Endophytic fungi have been studied for more than 100 years, with the first endophytic strain isolated from the seeds of ryegrass (Lolium temulentum L.) by Vogl et al. in 1898 [17]. Stierle et al. [18] discovered the paclitaxel-producing endophytic fungus (Taxomyces andreanae) from the Pacific yew and then from other plant species successively. This discovery aroused the attention of mycologists and pharmaceutical chemists on endophytic fungi as a new source of bioactive substances and stimulated the interest in endophytic fungi as a sustainable source of plant metabolites. As shown in Table 1, many compounds that were isolated from endophytic fungi were also identified in some plant species as well as exhibited similar biological activity even though there were isolated from different sources, confirming endophytic fungi as an alternative source of bioactive compounds [19,20,21,22,23,24,25,26,27,28,29,30,31,32]. An overview of the recent literature surveys revealed that 51% of the bioactive substances isolated from endophytic fungi were previously unknown, with about 38% being isolated from soil microbiota [19]. Over the past decade, there has been a surge in the number of patents for endophytic fungi with new molecular secondary metabolites, which play a key role in the pharmaceutical industry, phytoremediation, and biomedicine [20,21]. Researchers are now searching for an economical, environmentally safe, and sustainable way to obtain new bioactive secondary metabolites from endophytic fungi.
This article reports 220 new compounds with rare or novel structures or skeleton structures from endophytic fungi from 82 journal articles between 2011 and 2021 and briefly describes the sources of endophytic fungi, chemical structures, and biological activities of these compounds. Among all the new compounds reported in this review, terpenoids (35%) were largest in proportion, followed by alkaloids (26%). The proportion of different types of compounds among all the new compounds are presented in Figure 1. These new compounds were obtained from different species of endophytic fungi, which had diverse chemical skeletons and exhibited diverse and interesting biological activities. Additionally, the most common pharmacological activities these compounds showed were antimicrobial and antitumor activities. However, some of the compounds showed anti-angiogenic, anti-phytotoxic, and α-glucosidase inhibitory effects. Therefore, this review summarized different insights into the prospects and challenges of endophytic fungi as an alternative source of plant-derived bioactive compounds for drug development. In addition, this review will affirm that endophytic fungi produce similar bioactive compounds just as their host plants to give knowledge for the development of drug candidates from endophytic fungi using different strategies, thus making Endophytic fungi a treasure trove of new secondary metabolites.

2. Bioactive New Metabolites Isolated from Endophytic Fungi and Their Biological Activities

2.1. Polyketides

2.1.1. Chromones

The induction of endophyte metabolism by adding Host components was used to add the same phytocomponents (2R, 3R)-3, 5, 7- trihydroxyflavanone 3-acetate in Botryosphaeria ramosa L29 potato dextrose broth culture to induce the production of 5-hydroxy2,3-dihydroxymethyl-7-methoxychromone 1 (Figure 2), 5-hydroxy-3-acetoxymethyl-2-methyl-7- methoxychromone 2 (Figure 2) and 5,7-dihydroxy-3-hydroxymethyl-2-methylchromone 3 (Figure 2), where Compounds 13 displayed acceptable antimicrobial activities against Fusarium oxysporum with MIC values of 50 μg/mL, 50 μg/mL, and 6.25 μg/mL, respectively. These values were superior compared to those of the positive drug—triadimefon—for the antimicrobial test (with an MIC value of 100 μg/mL) [36]. This indicated that the induction of endophytes metabolism to produce bioactive components of interest might be an ideal strategy for easy identification of drug candidates from these microbes; however, there is the need for long-term studies on how specific components influence endophytes metabolism and the bioactive compounds there are linked with. Phaeosphaonesa A 4 (Figure 2), isolated from Phaeosphaeria fuckelii, contains a β-(oxy)thiotryptophan motif structure that is rare in nature. Compound 4 showed stronger inhibition activity of mushroom tyrosinase than the positive control kojic acid (IC50 value of 40.4 μM) at 100 μM concentration, with an IC50 value of 33.2 μM [37]. Two aromatic chromones, Chaetosemins B–C 56 (Figure 2), were isolated from Chaetomium seminudum brown rice cultures, and compounds 56 contained L-cysteine and D-cysteine units, respectively. Compound 5 showed antifungal activity against Magnaporthe oryzae and Gibberella saubinetti, with MIC values of 6.25 μM and 12.5 μM, respectively. Compound 6 showed significant antioxidant activity at a concentration of 50 μM with a DPPH radical scavenging rate of 50.7% [38]. Pestaloficiols M–P 710 (Figure 2), which are new isoprenylated chromone derivatives, were isolated from brown rice culture extract of the plant endophytic fungus Pestalotiopsis fici. The structures of these compounds were elucidated primarily by MS and NMR techniques. Compounds 78 displayed inhibitory effects on HIV-1 replication in C8166 cells, with EC50 values of 56.5 μM and 10.5 μM, respectively (the EC 50 value of the positive control Indinavir Sulfate was 8.2 μM), whereas compounds 910 showed cytotoxic activity against the human tumor cell line HeLa, with IC50 values of 56.2 μM and 74.9 μM, respectively (the positive control 5-fluorouracil has an IC50 of 10.0 μM). Compound 10 exhibited a potent antifungal activity against Aspergillus fumigatus at IC50 = 7.35 μM) [39].

2.1.2. α-Pyrones

Two tetrasubstituted α-pyrone derivatives—Neurospora udagawae udagawanones A-B 1112 (Figure 3)—were isolated from oak endophytic fungi, with both containing unique oxidation functional groups at the C-2 position. Compound 11 exhibited potent antifungal activity against Rhodoturula glutinis with MIC = 66 μg/mL). Additionally, compounds 11 and 13 showed moderate cytotoxic activity against KB3.1 cells with IC50 = 27 μg/mL [40]. The study revealed moderate activity of compounds 11 and 12 against fungi and mammalian cells, and this may be as a result of the method (serial dilution antimicrobial assay) used; therefore, it is suggested that other biological tests be employed to verify these findings. The nigerapyrones A–B 1314 (Figure 3) were obtained from Aspergillus niger MA-132, which was isolated from the mangrove plant Avicennia marina. Compounds 1314 both showed potent antifungal activities against two tumor cell lines (HL60 and A549), with IC50 values ranging from 0.3 to 5.41 μM [41]. The ficipyrones A–B 1516 (Figure 3) were isolated from solid cultures of Pestalotiopsis fici. Compound 15 showed significant antifungal activity against Gibberella zeae CGMCC 3.2873, with an IC50 value of 15.9 μM, but had no activity against Fusarium culmorum CGMCC 3.4595 and Verticillium aiboatrum CGMCC 3.4306 [42]. The endophytic fungus Aspergillus oryzae was isolated from the rhizome of Paris polyphylla in Dali, Yunnan, China, and 4-hydroxy-6-[(2S, 3S)-3-hydroxybutan-2-yI]-3-methyl-2H-pyran-2-one 17 (Figure 3) and (R)-4-hydroxy-6-(l-hydroxy-2-methylpropyl)-3-methyl-2H-pyran-2-one 18 (Figure 3) were obtained from this fungi. However, the biological activities of these compounds were not tested in the study; hence, investigating the biological activities of these compounds is needed, as it may yield a very important source of drug activity [43].The pyran-2-one scaffold compounds 1921 (Figure 3) were isolated by adding 10 mg/L DNA methyltransferase inhibitor 5-aza-2-deoxycytidine to Penicillium herquei liquid cultures, whereas the MTT method was used to measure the cytotoxicity of all compounds in MDA-ME-231 and MV-411 cell lines. Compounds 1921 showed weak cytotoxicity only against the MV4-11 cell line with IC50 values of 90.09 µM, 74.16 µM, and 70.00 µM, respectively [44].

2.1.3. Other Polyketides

The phomaketides A–E 2226 (Figure 4), pseurotins A3 27 (Figure 4), and pseurotins G 28 (Figure 4) were isolated from fermentation broth and mycelial extracts of the marine red algae endophytic fungus Phoma sp. NTOU4195. The mouse macrophages RAW264 were induced using the endothelial progenitor cells of human umbilical cord blood, lipopolysaccharide (LPS), to assess the anti-angiogenic and anti-inflammatory activities of all compounds. Compound 22 showed potent anti-angiogenic activity by inhibiting endothelial cell proliferation, with an IC50 value of 8.1 μM. Compound 24 at the concentration of 20 μM induced effective nitric oxide (NO) inhibition activity against LPS-induced RAW264.7 cells, with an IC50 value of 8.8 μM [45]. There were two tetracyclic polyketide compounds, simplicilone A–B 2930 (Figure 4), containing helical centers obtained from the broth culture of the endophytic fungus Simplicillium sp., which was isolated from the bark of the medicinal plant Duguetia staudtii (Engl. and Diels) Chatrou in the Cameroon region. Compounds 2930 showed weak cytotoxic activities against the KB3.1 cell line, with IC50 values of 1.25 μg/mL and 2.29 μg/mL, respectively, but had no antimicrobial activity against the tested bacteria (Staphylococcus aureus DSM 346 and Bacillus subtilis DSM 10) [46]. 5R-hydroxyrecifeiolide 31 (Figure 4), 5S-hydroxyrecifeiolide 32 (Figure 4), and ent-cladospolide F–H 3335 (Figure 4) were also isolated from the endophytic fungal strain Cladosporium cladosporioides MA-299, which was obtained from the leaves of the mangrove plant Bruguiera gymnorrhiza from Hainan Island, China. Compounds 3135 showed potent antimicrobial activities against Escherichia coli and Staphylococcus aureus, with MIC values ranging from 1.0 to 64 μg/mL. Compound 33 showed moderate inhibition activity against acetylcholinesterase, with an IC50 value of 40.26 μM [47]. The antimicrobial polyketide compound, palitantin 36 (Figure 4), was obtained from Aspergillus fumigatiaffnis and isolated from healthy leaves of Tribulus terrestris L. In addition, compound 36 showed effective antimicrobial activity against the multi-drug-resistant pathogens Enterococcus faecalis UW 2689 and Streptococcus pneumoniae 25697, both with an MIC value of 64 μg/mL [48]. The four polyketide derivatives—isotalaroflavone 37 (Figure 4), (+/−)-50-dehydroxytalaroflavone 3839 (Figure 4), and bialternacin G 40 (Figure 4)—were obtained from the endophytic fungus Alternaria alternata ZHJG5 isolated from the leaves of Cercis chinensis, which was collected from the Nanjing Botanical Garden, Nanjing, China. They exhibited potent antimicrobial activity against Xanthomonas oryzae pv. oryzicola (Xoc) and Ralstonia solanacearum, with MIC values ranging from 0.5 to 64 μg/mL. Compound 37 at the concentration of 200 μg/mL showed a significant protective effect against the bacterial blight of rice caused by Xanthomonas oryzae pv. oryza, with a protection rate of 75.1% [49]. Four polyketide derivatives containing the benzoisoquinoline-9-one moiety structure peyronetides A–D 4144 (Figure 4) were isolated from the mycelial crude acetone extract of Peyronellaea sp. FT431. Compounds 4142 showed moderate to weak cytotoxic activity against human kidney cancer cell line TK10 and human ovarian cancer cell line A2780cisR, with IC50 values ranging from 6.7 to 29.2 μM [50]. The aromatic polyketide compound, (−)alternamgin 45 (Figure 4), was obtained from potato dextrose broth cultures of the endophytic fungus Alternaria sp. MG1 isolated from Vitis quinquangularis. This compound was of particular interest because it had the rare dibenzopyrone functionality of 6/6/6/6/5/6/6/6 heptacyclic backbone. Compound 45 displayed a weak cytotoxic activity against cells from two tested cell lines (Hela and HepG2), both with IC50 values exceeding 20 μM [51].
In summary, Polyketides, such as chromones and α-pyrone, and their derivatives identified from plant sources have also been found in endophytic fungi in recent studies. Chromones and their derivatives isolated from both plant and endophytic fungi sources all showed antimicrobial properties against specific pathogens; therefore, chromones from endophytic fungus can be used in the development of antimicrobials in the place of plant chromones to reduce the depletion of plants’ resources in the ecosystem.

2.2. Alkaloids

2.2.1. Cytochalasin

The methylation-deficient backbone, Phomopsisin A–C 4648 (Figure 5), was obtained from brown rice cultures of Phomopsis sp. sh917, which was isolated from Isodon eriocalyx var. laxiflora stems. Compound 46 contained an unusual 5/6/11/5 tetracyclic ring system 2H-isoxazole moiety and showed significant inhibition activity against LPS-induced NO production in RAW264.7 cells, with an IC50 value of 32.38 μM, which was more potent than the positive control L-NMMA (IC50 value of 42.34 μM) [52]. The highly oxidized cytochalasin alkaloids—armochaetoglobins S–Z 4957 (Figure 5) and 7-O-acetylarmochaetoglobin S 50 (Figure 5)—were identified and isolated from Chaetomium globosum TW1-1. The effects of all compounds on five tested human cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW-480) were measured using the MTT method. Compounds 5657 showed potent cytotoxic activities, with IC50 values ranging from 10.45 to 30.42 µM [53]. Furthermore, diaporthichalasins D–H 5862 (Figure 5) were obtained from solid cultures of the endophytic fungus Diaporthe sp. SC-J0138 isolated from the leaves of the pteridophyte Cyclosorus parasiticus, and the MTS method was used to evaluate the cytotoxic activities of these compounds on four human cancer cell lines (A549, HeLa, HepG2, and MCF-7). Compound 58 exhibited significant cytotoxic activity against all tested human cancer cell lines; compounds 5962 exhibited selective cytotoxic activities against some cell lines [54]. Cytochrysins A–C 6365 (Figure 5) were obtained from rice cultures of Cytospora chrysosperma HYQZ-931, an endophytic fungus isolated from the desert plant Hippophae rhamnoides. Compound 63 showed significant antimicrobial activity to Enterococcus faecium, with an MIC value of 25 μg/mL. Compound 65 showed potent antimicrobial activity to Staphylococcus aureus, with an MIC value of 25 μg/mL [55].

2.2.2. Indole Alkaloids

Six prenylated indole alkaloids, asperthrins A–F 6671 (Figure 6), were derived from the marine endophytic fungus Aspergillus sp. YJ191021. Compound 66 showed moderate antimicrobial activity against Vibrio anguillarum, with an MIC value of 8 μg/mL. Additionally, the compounds 66 and 69 showed potent–weak anti-inflammatory activities against propionibacterium acnes-induced human mononuclear cell line (THP-1), with IC50 values of 1.46 μΜ and 30.5 μΜ, respectively, while compound 66 showed higher anti-inflammatory activity than the positive control Tretinoin at an IC50 value of 3.38 μM [56]. The α-pyrone meroterpenoid-type alkaloid, oxalicine C 72 (Figure 6), was obtained from Penicillium chrysogenum XNM-12, which was isolated from the marine brown algae Leathesia nana. Compound 72 showed potent antimicrobial activity against the phytopathogenic fungus Ralstonia solanacearum, with an MIC of 8 μg/mL [57]. Scalarane 73 (Figure 6) was isolated from Hypomontagnella monticulosa Zg15SU through the potato dextrose liquid culture. Compound 73 showed potent cytotoxic activity against cancer cell lines Panc-1, NBT-T2, and HCT116, with IC50 values of 0.05, 0.75, and 0.05 μg/mL, respectively [58]. Asperlenines A–C 7476 (Figure 6) were isolated from Aspergillus lentulus DTO 327G5 cultures, and the antimicrobial activity of all compounds was evaluated using the broth-microdilution method against five tested agricultural pathogens (Xanthomonas oryzae pv. Oryzae, Xanthomonas oryzae pv. Oryzicola, Rhizoctonia solani, Fusarium oxysporum, and Colletotrichum gloeosporioides). Compounds 7476 showed moderate to weak antimicrobial activities against Xanthomonas oryzae pv. Oryzae and Xanthomonas oryzae pv. Oryzicola, with MIC values ranging from 25 to 100 μg/mL [59].

2.2.3. Diketopiperazine Derivatives

The thiodiketopiperazine alkaloid, phaeosphaones D 77 (Figure 7), featuring an unusual β-(oxy) thiotryptophan motif, was obtained from endophytic fungus Phaeosphaeria fuckelii isolated from the medicinal plant Phlomis umbrosa. Compound 77 showed stronger mushroom tyrosinase inhibition activity than the positive control kojic acid (IC50 value of 40.4 μM), with an IC50 value of 33.2 μM. [60]. The oxepine-containing diketopiperazine-type alkaloids, varioloids A-B 7879 (Figure 7), were obtained from Paecilomyces variotii EN-291, which was isolated from the marine red alga Grateloupia turuturu. Compounds 7879 showed potent antifungal effects against Fusarium graminearum, with MIC values of 8 μg/mL and 4 μg/mL, respectively [61]. Aspergiamides A–F 8085 (Figure 7) were isolated from the endophytic fungus Aspergillus sp. 16-5 of mangroves, and all compounds were evaluated for their inhibition activities against protein-tyrosine phosphatase 1B (PTP1B) and α-glucosidase. Compounds 80 and 81 showed potent to moderate α-glucosidase inhibition activities, with IC50 values of 18.2 µM and 40.7 µM, respectively. Compounds 8085 did not show significant PTP1B inhibition activities (<10% inhibition) at 100 µg/mL [62]. Five sulfide diketopiperazines derivatives, penicibrocazines A–E 8690 (Figure 7), were obtained from the endophytic fungus Penicillium brocae MA-231 isolated from the mangrove plant Avicennia marina. The antimicrobial effects of all compounds were evaluated by the agar diffusion method against five tested pathogens (Aeromonas hydrophilia, Escherichia coli, Staphylococcus aureus, Vibrio arveyi, and V. parahaemolyticus). Compounds 8690 showed potent antimicrobial activities against S. aureus, with MIC values ranging from 0.25 to 32 μg/mL [63]. Spirobrocazines A–C 9193 (Figure 7) were isolated from the mangrove-derived Penicillium brocae MA-231. Compounds 9193 contained a 6/5/6/5/6 cyclic system with a rare spirocyclic center at C-2. All compounds showed moderate antimicrobial activities against S. aureus, Aeromonas hydrophilia, and Vibrio harveyi, with MIC values ranging from 16 to 64 μg/mL [64].

2.2.4. Other Types of Alkaloids

The quinazoline alkaloid (-)-(1R,4R)-1,4-(2,3)-indolmethane-1-methyl-2,4-dihydro-1H-pyrazino-[2,1-b]-quinazoline-3,6-dione 94 (Figure 8) was obtained from the endophytic fungus Penicillium vinaceum X1, which was isolated from corms of Crocus sativus (Iridaceae). The in vitro cytotoxicity of compound 94 was evaluated against three human tumor cell lines (A549, LOVO, and MCF-7), to which compound 94 showed weak cytotoxic activities against all human tumor cell lines, with IC50 values of 76.83, 68.08, and 40.55 μg/mL, respectively [65]. The enantiomeric bromotyrosine alkaloids S-Acanthodendrilline 95 (Figure 8) and R-Acanthodendrilline 96 (Figure 8) were isolated from the ethyl acetate extract of the sponge endophytic fungus Acanthodendrilla sp. The cytotoxic activities of compounds 9596 against human non-small cell lung cancer H292 and normal human immortalized fibroblast HaCaT cell lines were evaluated using the MTT method. Compound 95 (IC50 value of 58.5 µM) was approximately three times more potent than compound 96 (IC50 value of 173.5 µM) against the H292 cell line. Compounds 9596 exhibited efficient and selective cytotoxic activities against H292 and HaCaT cell lines, with IC50 values ranging from 58.5 to 173.5 µM and >400 µM, respectively [66]. Three phenylpyridone derivatives, citridones E–G 9799 (Figure 8), were obtained from the endophytic fungal strain Penicillium sumatrense GZWMJZ-313 9, which was isolated from the leaves of Garcinia multiflora. These compounds showed moderate to weak antimicrobial activities against Staphylococcus aureus ATCC6538, Pseudomonas aeruginosa ATCC10145, and Escherichia coli ATCC11775, with MIC values ranging from 32 to 128 μg/mL [67]. Two isoprenylisoindole alkaloids, diaporisoindoles A-B 100101 (Figure 8), were obtained from the endophytic fungus Diaporthe sp. SYSU-HQ3, which was isolated from a fresh branch of the mangrove plant Excoecaria agallocha. Compound 100 showed potent inhibition activity against Mycobacterium tuberculosis protein-tyrosine phosphatase B, with an IC50 value of 4.2 µM [68].
In a nutshell, anti-angiogenic and anti-inflammatory activities were the main activities of alkaloids in both plants and endophytic fungi. In addition, phomaketides and their derivatives that were isolated from fungal endophytes possess antimicrobial activity just as those isolated in plants; therefore, alkaloids producing endophytic fungi can be used in the development of anti-angiogenic, anti-inflammatory, and antimicrobial drugs for both human and animal use.

2.3. Terpenoids

2.3.1. Sesquiterpenoids and Their Derivatives

The 1-methoxypestabacillin B 107 (Figure 9) was obtained from brown rice cultures of endophytic fungus Diaporthe sp. SCSIO 41011 isolated from the stem of the mangrove plant Rhizophora stylosa. Compound 107 was evaluated for the reversal of HIV incubation period and anti-influenza A virus activities, to which compound 107 did not show antiviral activity. However, its structure could serve as the backbone for the synthesis of more potent antiviral compounds [69]. The eremophilane-type sesquiterpenoids rhizoperemophilanes A-N 102115 (Figure 9) were isolated from the ethyl acetate extract of Rhizopycnis vagum Nitaf22. Compound 111 contained a C-4/C-11 epoxide, and compound 115 had a 3-nor-eremophilane lactone-lactam skeleton. All compounds were evaluated for their cytotoxic activities against five tested human cancer cells (BGC823, Daoy, HCT116, HepG2, and NCI-H1650) and inhibition activities against radicle growth in rice seedlings. Compound 115 showed high selective cytotoxicity against NCI-H1650 and BGC823 cell lines, with IC50 values of 15.8 µM and 48.2 µM, respectively, while no significant cytotoxic activity was observed for other compounds at IC50 > 50 μm. Compounds 106107 and 113114 showed strong phytotoxic activities against radicle growth in rice seedlings at a concentration of 200 µg/mL, where the inhibition exceeded 50% [70]. The bisabolane-type sesquiterpene, trichoderic acid 116, (Figure 9) and acorane-type sesquiterpene, 2β-hydroxytrichoacorenol 117 (Figure 9), were obtained from Trichoderma sp. PR-35 culture, an endophytic fungus isolated from stems of Paeonia delavayi. Compounds 116117 were tested for antimicrobial activity against two pathogens (Escherichia coli, and Shigella sonnei) using an agar diffusion method. Compounds 116117 showed moderate to weak antimicrobial activities, with MIA values ranging from 50 to 175 µg/mL [69]. The ring flores aurantii alkane-type sesquiterpene, cyclonerotriol B 118 (Figure 9), and the α-pinene skeleton-containing sesquiterpene, 3β-hydroxy-β-acorenol 119 (Figure 9), were obtained from Fusarium proliferatum AF-04 isolated from Chlorophytum comosum roots via a combination of high-performance liquid chromatography (HPLC) and a bioassay-guided method. Compounds 118119 showed weak antimicrobial activities (MIC values > 100 μg/mL) against Bacillus subtilis, Clostridium perfringens, E. coli, and methicillin-resistant Staphylococcus aureus (MRSA) [71]. The aromatic bisabolene-type sesquiterpene (7S, 8S)-8-hydroxysydowic acid 120 (Figure 9) was obtained from the brown rice culture of the endophytic fungus Aspergillus sydowii EN-434 isolated from the marine red alga Symphyocladia latiuscula from Qingdao, China. Compound 120 showed potent DPPH radical scavenging activity, with an IC50 value of 113.5 μmol/L [72]. The ophiobolane sesquiterpenes ophiobolins P–T 121125 (Figure 9) were isolated from the acetone extract of the endophytic fungus Ulocladium sp. using the one-strain many-compound (OSMAC) strategy. Compounds 121125 were evaluated for their cytotoxicity and antibacterial activities against two tested human cancer cell lines (KB and HepG2 cell lines) and three tested pathogens (Bacillus subtilis, MRSA, and Bacille Calmette-Guerin). Compounds 121125 showed moderate antimicrobial activities against B. subtilis and multi-drug-resistant S. aureus, with MIC values ranging from 15.6 to 62.5 μM. Compound 125 showed moderate antimicrobial activity against Bacille Calmette-Guerin, with an MIC value of 31.3 μM. Additionally, compound 125 showed potent cytotoxic activity against the HepG2 cell line, with an IC50 value of 0.24 μM, which was stronger than the positive control etoposide (IC50 value of 2.02 μM) [73]. The daucane-type sesquiterpenes trichocarotins I-M 126130 (Figure 9) were obtained from Trichoderma virens QA-8 isolated from the roots of Artemisia argyi H. Lév. and Vaniot, and these compounds showed significant antimicrobial activities against E. coli EMBLC-1, with MIC values ranging from 0.5 to 16 μg/mL [74].

2.3.2. Diterpenoids

The ring diterpene diaporpenoid A 131 (Figure 10), containing a 5/10/5-fused tricyclic ring system, was isolated from the MeOH extract obtained from cultures of the mangrove endophytic fungus Diaporthe sp. QYM12. Compound 131 showed significant anti-inflammatory activity by inhibiting LPS-induced NO production in a mouse macrophage cell line RAW264.7, with an IC50 value of 21.5 μM [75]. The pimarane-type diterpene Libertellenone M 132 (Figure 10) was isolated from the marine source endophytic fungus Phomopsis sp. S12. Compound 132 inhibited pro-inflammatory cytokines IL1β and IL-18 mRNA expression in colon tissue, significantly reduced the cleavage of pro-caspase1, and dose-dependently inhibited the NF-κB nuclear translocation in macrophages. Clinical indications of acute colitis induced by 3% dextran sulphate sodium in mice were attenuated by intravenous administration of different doses of compound 132 (10 or 20 mg/kg), which is a potent inhibitor of NLRP3 inflammatory vesicles and may be a new medicine for treating acute colitis [76]. Three pimarane-type diterpenoids—pedinophyllol K 133 (Figure 10), pedinophyllol L 134 (Figure 10), and libertellenone T 135 (Figure 10)—were isolated from the endophytic fungal Phomopsis sp. S12 culture using the OSMAC strategy. The anti-inflammatory activities of all compounds were assessed using an LPS-induced inflammation model of mouse macrophage RAW264.7. Compound 135 dose-dependently inhibited the expression of inflammatory factors IL-1β and IL-6 at the mRNA level. Additionally, the anti-inflammatory activity of compounds 133134 was similar to that of compound 135 in terms 0f IL-6 inhibition [77]. Two tetranorlabdane diterpenoids botryosphaerins G–H 136137 (Figure 10) were obtained from the ethyl acetate extract of Botryosphaeria sp. P483 isolated from the branches of the herb Huperzia serrata (Thunb.) Trev. and tested for their antifungal activities against Gaeumannomyces graminis, Fusarium solani, and Pyricularia oryzae by the disk diffusion method. Compound 137 showed effective antifungal activity at a concentration of 100 μg/disk with an inhibitory zone diameter of 9 mm. (The inhibitory zone diameter of positive control carbendazim was 15–18 mm.) Compounds 136137 were evaluated for their nematicidal activities against Panagrellus redivivus and Caenorhabditis elegans and showed weak nematicidal activities, with 30% and 28% fatality rates at a 24h action concentration of 400 mg/L, respectively [78]. The isopimarane diterpene sphaeropsidin A 138 (Figure 10) was isolated from the ethyl acetate extract of the endophytic fungus Smardaea sp. AZ0432 of Ceratodon purpureus. The in vitro cytotoxic activities of compound 138 against five human cancer cell lines (NCI- H460, MDA-MB-231, MCF-7, PC-3M, and SF-268) and human embryonic lung fibroblast cell line WI-38 were evaluated using the resazurin colorimetric assay. The results showed that compound 138 showed a high cell selectivity when it was applied at a concentration of 10 μM for 72 h and inhibited the migration of MDA-MB-231 cells by 50% at a subcytotoxic concentration of 1.5 μM [79]. (10S)-12,16-epoxy-17(15→16)-abeo-3,5,8,12,15-abietapentaene-2,7,11,14-tetraone 139 (Figure 10) was obtained from the cultures of the endophytic fungus Pestalotiopsis adusta isolated from stems of the medicinal plant Clerodendrum canescens. The cytotoxicity of compound 139 to the HL-60 tumor cell line was evaluated using the MTT assay, by which compound 139 showed moderate cytotoxic activity, with an IC50 value of 12.54 μM [80]. (The IC50 value of the positive control cisplatin was 9.20 μM.) The trichodermanin A 140 (Figure 10), a diterpene containing a 6-5-6-6 ring system, was obtained from the endophytic fungus Trichoderma atroviride S361 of Cephalotaxus fortunei and was not tested for any biological activities [81]. Therefore, further studies are needed to identify the potential biological activity of this compound in the future. The new tetranorlabdane diterpenoids, asperolides A–C 141143 (Figure 10), were isolated from the ethyl acetate extract of the marine brown alga Aspergillus wentii EN-48 and the cytotoxic activities of compounds 141143 to seven tested human cancer cell lines (NCI-H460, MDA-MB-231, HeLa, MCF-7, SMMC-7721, HepG2, and SW1990) were evaluated using the MTT method. Compounds 141143 showed moderate cytotoxic activities, with IC50 values ≤ 10 Μm [82].

2.3.3. Triterpenoids

The 24-homo-30-nor-cycloartane triterpenoid 154 (Figure 11) was isolated from the endophytic fungus Mycoleptodiscus indicus FT1137. Compound 154 showed no activity against the human ovarian cancer cell line A2780 at a concentration of 20 μg/mL [83]. Three Lanostane-type triterpenes—sclerodols A–B 144145 (Figure 11) and lanosta-8,23-dien-3β,25-diol 146 (Figure 11)—were obtained from Eucalyptus grandis cultures derived from the endophytic fungus Scleroderma UFSMSc1, and the antifungal activities of compounds 144146 against Candida albicans and Candida parapsolosis were evaluated by the agar diffusion method. Compounds 144146 showed moderate to weak antifungal activities, with MIC values ranging from 12.5 to 50 μg/mL. The antifungal effects of these compounds against C. albicans were associated with the inhibition of the selenocysteine methyltransferase (SMT) activity [84]. Fusidic acid 147 (Figure 11) was obtained from the cultures of the endophytic fungus Acremonium pilosum F47, isolated from the stem of Mahonia fortunei using the bioactivity-guided assay, and the antimicrobial activities of compound 147 against four human pathogens were tested (S. aureus ATCC 6538, B. subtilis ATCC 9372, P. aeruginosa ATCC 27853, and E. coli ATCC 25922) and evaluated. Compound 147 showed effective antimicrobial activities against S. aureus ATCC 6538 and B. subtilis ATCC 9372. The acetylation of the C-16 hydroxyl group of compound 147 was essential for antimicrobial action [85]. Two new ring A-cleaved lanostane-type triterpenoids, glometenoid A–B 148149 (Figure 11), were obtained from the ethyl acetate extract of the mason pine endophytic fungus Glomerella sp. F00244. The cytotoxic activity of compounds 148149 against the human ovarian cancer cell line HeLa was tested using the MTT assay. Compound 148 showed weak cytotoxic activity at a concentration of 10 μM with 21% inhibition [83]. Nine highly oxygenated schitriterpenoids—kadhenrischinins A–H 150157 (Figure 11) and 7β-schinalactone C 158 (Figure 11)—were isolated from Penicillium sp. SWUKD4.1850, and compounds 154157 contained a unique 3-one-2-oxabicyclo [1,2,3]-octane motif. All compounds were tested for their cytotoxic activities against the HepG2 tumor cell lines using the MTT assay, and these compounds showed weak cytotoxic activities, with IC50 values ranging from 14.3 to 40 μM [86]. Two tetracyclic triterpenoids—integracide E 159 (Figure 11) and isointegracide E 160 (Figure 11)—were isolated from the mycelia of Hypoxylon sp. 6269. Compound 159 showed weak inhibition activity against the HIV-1 integrase, with an IC50 value of 31.63 μM [87]. The tetracyclic triterpenoids, integracides H–J 161163 (Figure 11), were obtained from the endophytic fungus Fusarium sp., which was isolated from the roots of Mentha longifolia L. (Labiatae) and were evaluated for antileishmanial activity against L. donovani promastigotes. Compound 161 showed significant antileishmanial activity, with an IC50 value of 4.75 μM, exceeding the positive control Pentamidine (IC50 value of 6.35 μM) [88]. The tetracyclic triterpenoids, integracides F–G 164165 (Figure 11), were obtained from the endophytic fungus Fusarium sp. of Mentha longifolia L. (Labiatae). Compounds 164165 were evaluated for their antileishmanial and cytotoxic activities to BT-549 and SKOV-3 cells and Leishmania donovani promastigotes. Compounds 164165 showed significant cytotoxic activities against SKOV-3 and BT-549 cell lines, with IC50 values ranging from 0.16 to 1.97 μg/mL and 0.12 to 1.76 μg/mL, respectively. (The IC50 value of the positive control Pentamidine was 2.1 μg/mL.) Compounds 164165 showed potent antileishmanial activities against L. donovani promastigotes, with IC50 values of 3.74 μg/mL and 2.53 μg/mL, respectively [89].

2.3.4. Meroterpenoids

Guignardones P–S 166169 (Figure 12) were obtained from Guignardia mangiferae A348 cultures, and the cytotoxic activities of compounds 166169 against three human cancer cell lines (SF-268, MCF-7, and NCI-H460) were tested using an MTT assay. Compounds 167 and 169 only showed weak cytotoxic activities against MCF-7 cell lines, with IC50 values ranging from 83.7 to 92.1 µM [90]. Six 3, 5-demethylorsellinic acid-based meroterpenoids emeridones A–F 170175 (Figure 12) were isolated from Emericella sp. TJ29 cultures. Compound 171 possessed a 2,6 dioxabicyclo [2.2.1] heptane and a spiro [bicycle [3.2.2] nonane-2,1′-cyclohexane] moiety. The cytotoxic activities of all compounds against five human cancer cell lines (HL-60, SMMC7721, A549, MCF-7, and SW-480) were tested using the MTT assay, and compounds 172, 173, and 175 showed moderate cytotoxic activities against all tested cell lines, with IC50 values ranging from 8.19 to 18.8 µM [91]. Phyllomeroterpenoids A–C 176178 (Figure 12) were isolated from the crude extract of Phyllosticta sp. J13-2-12Y fermentation broth. Compounds 176178 showed moderate antimicrobial activities against Staphylococcus aureus 209P, Candida aureus 209P, and Candida albicans FIM709, with MIC values ranging from 32 to 128 μg/mL [92]. Austin 179 (Figure 12) was obtained from the ethyl acetate extract of Talaromyces purpurogenus H4 and Phanerochaete sp. H2 co-cultures, which showed moderate trypanocidal activity against T. cruzi at a concentration of 100 μg/mL, with an IC50 value of 36.6 µM. Notably, neither of the two endophytic fungi produced compound 179 when cultured separately under similar conditions [93].
To sum up, Meroterpenoids and their derivatives, which are mainly known for their antifungal properties in most plants species, have been found in endophytic fungi. However, recent studies have also reported anti-oxidative, anti-inflammatory, and anti-cancer activities from these compounds. Therefore, these microorganisms can be used in the development of drugs candidates for human, animal, and other agricultural activities.

2.4. Lactones

Helicascolide F 180 (Figure 13) was obtained from Talaromyces assiutensis JTY2 isolated from Ceriops tagal leaves. The cytotoxic activities of compound 180 against three human cancer cell lines (HeLa, MCF-7, and A549) were tested using an MTT assay, in which compound 180 showed a moderate cytotoxic effect on all tested cell lines, with an IC50 value range of 14.1–38.6 μM [94]. Two β-lactones, polonicin A–B 181182 (Figure 13), were obtained from the brown rice culture of the endophytic fungus Penicillium polonicum in the fruit of Camptotheca acuminata. Compound 181 showed effective glucose uptake activity at a concentration of 30 μg/mL on rat skeletal myoblast cell line L6, which enhanced 1.8-fold compared to that of the control. Compound 182 was used to assess its effect on GLUT4 translocation by using the fluorescent protein, IRAP-mOrange, which is stably expressed in L6 cells. It showed a 2.1-fold increase in fluorescence intensity on L6 cell membranes compared to the untreated controls [95]. The spirodilactone compound chaetocuprum 183 (Figure 13) was obtained from cultures of the endophytic fungus Chaetomium cupreum of wild Anemopsis californica from New Mexico, U.S.A. Compound 183 showed a weak antimicrobial activity against S. aureus, with an MIC value of 50 μg/mL [96]. A phytotoxic bicyclic lactone, (3aS,6aR)-4,5-dimethyl-3,3a,6,6a-tetrahydro-2H-cyclopenta [b] furan-2-one 184 (Figure 13), was obtained from the fermentation broth of Xylaria curta 92092022. Compound 184 contained a rare 5/5 rings-fusion system and was tested for antimicrobial activities against four pathogens (Pseudomonas aeruginosa ATCC 15442, Staphylococcus aureus NBRC 13276, Aspergillus clavatus F318a, and Candida albicans ATCC 2019) and the phytotoxicity against lettuce seedlings. Compound 184 showed moderate antimicrobial activities against Pseudomonas aeruginosa ATCC 15442 and Staphylococcus aureus NBRC 13276 at a concentration of 100 μg/disk, with inhibitory zone diameters of 13 mm and 12 mm, respectively. At the concentration of 25 μg mL −1, compound 184 showed 50% inhibition on lettuce roots with a root length of 1.6 ± 0.3 cm (3.2 ± 0.5 cm for the control). At a concentration of 200 μg mL −1, compound 184 strongly inhibited lettuce seed germination, with 90% inhibition [97]. Lasiodiplactone A 185 (Figure 13) was obtained from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1 and contained a unique tetracyclic system (12/6/6/5) of RAL 12 (12-membered β-resorcylic acid lactone) with a pyran ring and a furan ring. Compound 185 showed significant anti-inflammatory activity by inhibiting the LPS-induced NO production in RAW 264.7 cells, with an IC50 value of 23.5 μM, which was stronger than the positive control indomethacin (IC50 = 26.3 μM). Additionally, compound 185 showed potent α-glucosidase inhibition activity, with an IC50 value of 29.4 μM, which was superior to the commonly used clinical drug acarbose (IC50 = 36.7 μM) [98]. (+)-phomalactone 186 (Figure 13), hydroxypestalopyrone 187 (Figure 13), and pestalopyrone 188 (Figure 13) were isolated from the endophytic fungus Aspergillus pseudonomiae J1 cultures and evaluated for in vitro anti-trypanosomal activity against the Trypanosoma cruzi Y strain using an anti-epimastigote assay. Compounds 186188 showed moderate to weak anti-trypanosomal activities, with IC50 values of 0.86 μM, 88.33 μM, and 580.19 μM, respectively [99].
In summary, this review reported that fungal endophytes could produce Lactones and their derivatives through their metabolic activities. In addition, these compounds possessed biological activities, such as antimicrobial, anti-cancer, allelopathic, and anti-inflammatory; thus, fungal endophytes that produce these compounds may be utilized in the pharmacological setup as alternatives to plant-derived compounds.

2.5. Anthraquinones, Quinones, and Related Glycosides

6,8-di-O-methylbipolarin 189 (Figure 14), aversin 190 (Figure 14), and 6,8-di-O-methylaverufin 191 (Figure 14) were obtained from rice cultures of the marine red algae endophytic fungus Acremonium vitellinum from Qingdao, China. Compounds 189191 showed moderate insecticidal activities against the third-instar larvae of Helicoverpa armigera, with LC50 values of 0.72 mg/mL, 0.78 mg/mL, and 0.87 mg/mL, respectively. (The LC50 value for the positive control, matrine, was 0.29 mg/mL.) Additionally, the molecular mechanism of the insecticidal activity of compound 191 was investigated based on transcriptome sequencing. The identification of 5,732 differentially expressed genes was performed, of which 2,904 genes were downregulated and 2,828 genes were upregulated. The upregulated genes were primarily involved in cell autophagy, apoptosis, DNA mismatch repair, and replication [100]. A new quinone, identified as 1,3-dihydroxy-4-(1,3,4-trihydroxybutan-2-yl)-8-methoxy-9H-xanthen-9-one 192 (Figure 14), was obtained from Phomopsis sp. isolated from the rhizome of Paris polyphyllavar. in Yunnan, China. Compound 192 showed significant cytotoxic activities against A549 and PC3 cell lines, with IC50 values of 5.8 μM and 3.6 μM, respectively [101]. The anthraquinone derivative eurorubrin 193 (Figure 14) was obtained from the ethyl acetate extract of the endophytic fungus Eurotium cristatum EN-220 of the seaweed Sargassum thunbergii and tested for its antimicrobial activities against three tested pathogens (E. coli, Physalospora obtuse, and Valsa mali), including its fatal activity against brine shrimp larvae. Compound 193 only showed a weak antimicrobial activity against E. coli, with an MIC value of 64 μg/mL. At the concentration of 10 μg/mL, compound 193 showed moderate fatal activity against brine shrimp larvae, with a fatality rate of 41.4% [102]. Isorhodoptilometrin-1-methyl ether 194 (Figure 14), emodin 195 (Figure 14), and 1-methyl emodin 196 (Figure 14) were obtained from cultures of the endophytic fungus Aspergillus versicolor of the red seaweed Halimeda opuntia. Compounds 194196 were evaluated for their inhibiting activities against the hepatitis C virus NS3/4A protease, where Compounds 195196 showed weak inhibition activities, with IC50 values ranging from 22.5 to 40.2 μg/mL [103]. The quinone altersolanol A 197 (Figure 14) was isolated from the endophytic fungus Stemphylium globuliferum of the medicinal plant Mentha pulegium (Lamiaceae). Compound 197 inhibited the proliferation of K562 and A549 cells in a time-dependent, dose-dependent manner and caused apoptosis by cleaving Caspase-3 and Caspase-9 and decreasing anti-apoptotic protein expression [104].
Anthraquinones, quinones, and related glycosides are known for their anti-viral and anti-apoptotic activity both in vitro and in vivo. Interestingly, these compounds have been identified and isolated from fungal endophytes by various studies and have similarly shown anti-viral and anti-apoptotic activities. Thus, endophytes that produce these compounds may serve as cheap and environmentally friendly alternative sources for the development of antimicrobial drugs instead to plant sources.

2.6. Steroids

Phomosterols A–B 198199 (Figure 15) were isolated from the endophytic fungus Phoma sp. SYSU-SK-7 of mangrove plants. Compounds 198199 had an unusual aromatic B ring skeleton and showed significant inhibition activities against LPS-induced NO production in RAW 264.7 cells, with IC50 values of 13.5 μM and 25.0 μM, respectively. Additionally, compounds 198199 showed potent α-glucosidase inhibition activities with IC50 values of 51.2 μM and 46.8 μM, respectively, exceeding the positive control 1-deoxynojirimycin (IC50 value of 62.8 μM) [105]. The ergosterol derivative fusaristerol A 200 (Figure 15) was obtained from the endophytic fungus Fusarium sp., which was isolated from the root of Mentha longifolia L. This compound showed significant antimicrobial activity against Candida albicans, with an MIC value of 8.3 μg/disc. Additionally, compound 200 showed moderate cytotoxic activity against human colorectal cancer cell line HCT 116, with an IC50 value of 0.21 μΜ, compared to the positive control adriamycin (IC50 value of 0.06 μΜ) [106]. (5,6,15,22E)-6-ethoxy-5,15-dihydroxyergosta-7,22-dien-3-one 201 (Figure 15) and (14,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione 202 (Figure 15) were isolated from the endophytic fungus Phomopsis sp. of Aconitum carmichaeli in Yunnan, China. Compounds 201202 were analyzed against six tested pathogenic fungi (Candida albicans, Aspergillus niger, Fusarium avenaceum, Pyricularia oryzae, Hormodendrum compactum, and Trichophyton gypseum) using a broth microdilution assay. Compounds 201202 showed weak antifungal activities against C. albicans and F. avenaceum, with MIC values ranging from 64 to 128 μg/mL [107].
To summarize, endophytic fungi are alternative sources of steroids and their derivatives; thus, they may be harnessed for the production of various drugs since they have shown antimicrobial and anticancer activity in previous studies.

2.7. Other Types of Compounds

Four lignans, terrusnolides A–D 203206 (Figure 16), were obtained from the endophytic fungus Aspergillus sp. isolated from the root of Tripterygium wilfordii. Compounds 203206 showed significant inhibition of LPS-induced IL-1β, TNF-α, and NO production in RAW264.7 cells, with IC50 values ranging from 16.21 to 35.23 μΜ, 19.83 to 42.57 μΜ, and 16.78 to 38.15 μΜ, respectively, which were comparable to the positive control indomethacin (IC50 value of 15.67–21.34 μΜ) [108]. The indene derivative methyl 2-(4-hydroxybenzyl)-1,7-dihydroxy-6-(3-methylbut-2-enyl)-1H-indene-carboxylate 207 (Figure 16) obtained from the endophytic fungus Aspergillus flavipes Y-62 isolated from Suaeda glauca Bunge in Zhoushan, Zhejiang, China, showed weak antimicrobial activities against Pseudomonas aeruginosa, Klebsiella pneumonia, and Staphylococcus aureus, with MIC values ranging from 32 to 128 μg/mL [109]. The polychlorinated triphenyl diether simatorone 208 (Figure 16) was isolated from Microsphaeropsis sp. cultures, and its antimicrobial activities against three pathogens (Escherichia coli, Bacillus megaterium, and Microbotryum violaceum) were evaluated using an agar diffusion assay. Compound 208 showed effective antimicrobial activities against B. megaterium and E. coli with inhibitory zone diameters of 14 mm and 18 mm, respectively [110]. Two alkylated furan derivatives—5-(undeca-3′,5′,7′-trien-1′-yl) furan-2-ol 209 (Figure 16) and 5-(undeca-3′,5′,7′-trien-1′-yl) furan-2-carbonate 210 (Figure 16)—were obtained from the methanol extract of the endophytic fungus Emericella sp. XL029 isolated from Panax notoginseng leaves in Hebei, China. Compounds 209210 both showed potent antifungal activities against six tested plant pathogenic fungi (Rhizoctorzia solani, Verticillium dahliae Kleb, Helminthosporium maydis, Fusarium oxysporum, Fusarium tricinctum, and Botryosphaeria dothidea), with MIC values ranging from 25 to 3.1 μg/mL [111]. The new azaphilone, isochromophilone G 211 (Figure 16), was obtained from the endophytic fungus Diaporthe perseae sp. isolated from Pongamia pinnata (L.) Pierre. Compound 211 showed significant DPPH and ABTS radical scavenging activities, with IC50 values of 7.3 μmol/mL and 1.6 μmol/mL, respectively [112]. The furan derivative, 3-(5-oxo-2,5-dihydrofuran-3-yl) propanoic acid 212 (Figure 16), was obtained from the endophytic fungus Aspergillus tubingensis DS37 isolated from Decaisnea insignis (Griff.) Hook & Thomson, and showed significant inhibition activities against Fusarium graminearum and Streptococcus lactis, with MIC values of 16 μg/mL and 32 μg/mL, respectively [113]. The pyrrolidinone derivative, nigrosporamide A 213 (Figure 16), was isolated from the endophytic fungus Nigrospora sphaerica ZMT05 of Oxya chinensis Thunberg and showed a three-fold higher α-glucosidase inhibition activity than the positive control acarbose (IC50 value of 446.7 µM) with an IC50 value of 120.3 µM. Compound 213 has the potential to be a lead compound for the development of α-glucosidase inhibitors [114]. The production of the terrein derivative asperterrein 214 (Figure 16) was induced by co-culturing endophytic fungi Aspergillus terreus EN-539 and Paecilomyces lilacinus EN-531 of the marine red alga Laurencia okamurai. Compound 214 showed weak antimicrobial activities against Physalospora piricola and Staphylococcus aureus, with MIC values ranging from 32 to 64 μg/mL. Additionally, compound 214 was not detected in the sterile cultures of the two fungi alone [115]. The endophytic fungus Lachnum palmae of Przewalskia tangutica was isolated to halogenated dihydroisocoumarins palmaerones A–F 215220 (Figure 16) under the guidance of UPLC-ESIMS. The antimicrobial activities of all compounds against five tested pathogens (Cryptococcus neoformans, Penicillium sp., Candida albicans, Bacillus subtilis, and Staphylococcus aureus) were evaluated using the broth microdilution method. Compounds 215220 showed potent to weak antimicrobial activities against all tested pathogens, with MIC values ranging from 10 to 55 μg/mL. Additionally, compounds 215 and 219 showed moderate inhibition of LPS-induced NO production in RAW264.7 macrophages, with IC50 values of 26.3 μM and 38.7 μM, respectively [116].
Over the past few years, plants have been a major source of numerous compounds that possess biological activities; however, this review revealed that most of these compounds were also produced by various endophytes, especially fungi. Therefore, the isolation and development of these compounds as novel drug candidates would be of great importance to the pharmacological industry since endophytes are easy to manage, keep, and work with compared with plants. Thus, we conclude that endophytic fungi may serve as alternative sources of bioactive compounds of pharmacological interest.
All the information about the new compounds have been summarized below in Table 2.

3. Future Prospects and Challenges of Using Endophytic Fungi as an Alternative Source of Plant Bioactive Compounds

Endophytic fungi are hidden and subtle dwellers in several plant tissues and intercellular spaces and can produce diverse chemical structures and efficient, low-toxic new secondary metabolites that were initially thought to be produced by the host plants. The current reports on the biosynthesis of plant metabolites by endophytic fungi, in conjunction with recent research advances in fermentation culture, extraction, isolation, and structure identification techniques, permit us to rapidly uncover new valuable compounds. Generally, fungi are chemically diverse, easily cultured, and biologically active modalities that have great flexibility to be regulated by adding precursors, elicitors, and specific enzymes to effectively increase the quantity and yield of bioactive compounds. Table 3 represents the culture conditions and specific bioactive secondary metabolites and yields produced by various endophytic fungi. Endophytic fungi can convert active compounds of the host plant into more potent derivatives. This makes endophytic fungi an alternative and sustainable source of plant bioactive compounds [117,118]. The search for new compounds in endophytic fungi requires specific theories and ingenious bioprospecting strategies. Along with the continuously growing literature reports, the most promising host plants can be selected. It includes the selection of (A) plants from special habitats or growing in biodiversity-rich areas, including mangrove plants in tropical marine intertidal zones, and (B) medicinal and indigenous plants with ethnopharmacological uses, including Camptotheca acuminata and Ageratina adenophora. These selection criteria provide a reference for the current and future screening of host plants for endophytic fungi with new bioactive compounds [119,120]. This review has summarized 220 new compounds obtained between 2011 and 2021 from endophytic fungi using different culture methods, including the common culture, co-culture with bacteria or other fungi, and the addition of metal ions. These new compounds have unique molecular structures, and these rare structures allow these compounds to possess diverse biological activities, including significant antimicrobial and cytotoxic activities and α-glucosidase inhibition. These compounds have the potential to be modified as pro-drug molecules or directly developed as drugs for treating certain diseases. However, most of the current studies on the activity of new compounds with endophytic fungal sources are limited to in vitro studies; therefore, animal experiments and human intervention clinical trials are needed to further investigate the in vivo activities and mechanisms of action of the new compounds.
Unfortunately, endophytic fungi as new sources of bioactive secondary metabolites encounter various limitations, including the attenuated yield of secondary metabolites due to long-term storage and repeated passages under laboratory culture conditions, silencing of biosynthetic gene clusters or low level of expression (activation of gene clusters depends on environmental factors). Thus, the ability of endophytic fungi to produce new compounds of interest has been underestimated [129]. The expression could be upregulated by physicochemical and genetic manipulation techniques to increase the production of specific metabolites in endophytic fungi and to produce analogs of new active secondary metabolites. Methods including the OSMAC strategy (activation of silent biosynthetic gene clusters mediated by changes in medium composition, temperature, and aeration efficiency to produce desired metabolites), co-culture (mimicking natural ecosystems and triggering silent gene clusters to promote metabolite secretion and enhance bioactive metabolite production by microbial interaction-induced stress responses), and chemical epigenetic modification methods have been used to isolate new compounds. It was found that the addition of micromolar or even nanomolar small-molecule chemicals to cultures inhibits or activates relevant enzymes and remodels the fungal epigenome to increase the diversity of its secondary metabolites, including DNA methyltransferases (DNMTs) and histone deacetylase inhibitors (HDACs) [130,131]. The addition of epigenetic modifiers (5 μM SAHA and 10 μM AZA) to the endophytic fungus Xylaria psidii isolated from leaves of Vitis vinifera showed elevated resveratrol concentrations of 52.32 μg/mL and 48.94 μg/mL, respectively, by HPLC analysis (control concentration was 35.43 μg/mL). The treatments with 5 μM SAHA and 10 μM AZA showed stronger antioxidant activity with 30.92% and 33.82% DPPH radical scavenging, respectively, compared to the wild strain (19.26%) [132]. Unlike the chemical epigenetic modification methods reported, introducing exogenous substances as precursors into the cultures, including methyl jasmonate, causes the production of new compounds containing their structural units [133]. However, the addition of host plant components to the culture to induce the production of new compounds has rarely been reported. Additionally, it is necessary to elucidate the pathways by which endophytic fungi biosynthesize secondary metabolites, including the enzymes and genes involved via “omics” techniques—genomics, transcriptomics, and metabolomics—in regulating and manipulating the biosynthetic process to increase the number of new compounds [134].

4. Conclusions

Pharmaceutical chemists are turning their focus on the development of safe, efficient, and low-toxic new drugs from natural sources. Endophytic fungi may serve as renewable sources of novel bioactive compounds with pharmacological activities, as the number of new compounds to be isolated in the future tends to increase exponentially and rapidly. In addition, numerous studies have also reported that these bioactive compounds isolated from the endophytic fungi are also present in plants and have similar biological activities as the compounds from plant sources. Therefore, we conclude that endophytic fungi may be the best alternative for harnessing pharmacological bioactive compounds for the development of drugs for both human and animal use. Hence, there is a need for the identification of more compounds with pharmacological activity from endophytic fungi and elucidate their mechanisms of action through biological, pharmacodynamic, biochemical, bioinformatics, and pre-clinical approaches.

Author Contributions

J.W. (Juan Wen) and S.K.O. drafted the manuscript; S.K.O., S.W., Y.R. and J.W. (Juan Wen) generated the figures and tables; S.K.O., Y.H., J.W. (Jianchen Wang) and L.X. discussed literatures; J.W. (Juan Wen) designed the work, drafted and revised the manuscript, Y.H. supervised and funded the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Sichuan Province Science and Technology Support Program (Grant No. 2020YFS0337).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. The proportion of different types of compounds among all new compounds.
Figure 1. The proportion of different types of compounds among all new compounds.
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Figure 2. Chemical structures of chromones.
Figure 2. Chemical structures of chromones.
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Figure 3. Chemical structures of α-pyrone compounds.
Figure 3. Chemical structures of α-pyrone compounds.
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Figure 4. Chemical structures composition of other polyketides.
Figure 4. Chemical structures composition of other polyketides.
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Figure 5. Chemical structures composition of cytochalasins.
Figure 5. Chemical structures composition of cytochalasins.
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Figure 6. Chemical structures of indole alkaloids.
Figure 6. Chemical structures of indole alkaloids.
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Figure 7. Chemical structures of diketopiperazine derivatives.
Figure 7. Chemical structures of diketopiperazine derivatives.
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Figure 8. Chemical structure of other types of alkaloids.
Figure 8. Chemical structure of other types of alkaloids.
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Figure 9. Chemical structures of sesquiterpenoids and derivatives.
Figure 9. Chemical structures of sesquiterpenoids and derivatives.
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Figure 10. Chemical structures of diterpenoids and derivatives.
Figure 10. Chemical structures of diterpenoids and derivatives.
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Figure 11. Chemical structures of terpenoids.
Figure 11. Chemical structures of terpenoids.
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Figure 12. Chemical structures of Meroterpenoids.
Figure 12. Chemical structures of Meroterpenoids.
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Figure 13. Chemical structures of Lactones.
Figure 13. Chemical structures of Lactones.
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Figure 14. Chemical structure of anthraquinones, quinones, and related glycosides.
Figure 14. Chemical structure of anthraquinones, quinones, and related glycosides.
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Figure 15. Chemical structures of steroids.
Figure 15. Chemical structures of steroids.
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Figure 16. Chemical structures of other new compounds.
Figure 16. Chemical structures of other new compounds.
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Table 1. Several endophytic fungi of host plants have been reported to produce compounds with similar activity.
Table 1. Several endophytic fungi of host plants have been reported to produce compounds with similar activity.
No.Endophytic FungusHost PlantRegions/CountriesCompoundBiological ActivityRef.
1Lophiostoma sp.Eucalyptus exsertaGuangzhou, China.ScorpinoneAntibacterial[22]
2Mycosphaerella sp.Myrciaria floribundaAmazon rainforest, Brazil.MyriocinAntifungal[23]
3Mucor sp.Centaurea stoebeIdaho, USATerezine EAntifungal and cytotoxicity[24]
4Aspergillus calidoustusAcanthospermum australeJalapao State Park, Tocantins, Brazil.Ophiobolin K
6-epi-ophiobolin K
Antifungal, trypanocidal and cytotoxicity[25]
5Phomopsis sp.Garcinia kola (Heckel) nutYaounde, CameroonCytochalasins HAntibacterial and cytotoxicity[26]
6Aspergillus nidulansNyctanthes arbor-tristis LinnKarachi, PakistanSterigmatocystinAntiproliferative activity[27]
7Trichoderma asperellum and Trichoderma brevicompactumVinca herbaceaHamedan, Iran4b-hydroxy-12,13-epoxytrichothec-9-eneAntimicrobial
and antiproliferative activity
[28]
8Phyllosticta elongataCipadessa bacciferaWestern Ghats, IndiaCamptothecinAnticancer agent[29]
9Fusarium verticillioidesHuperzia serrataGucheng Mountain, Sichuan, ChinaHuperzine ATreatment of Alzheimer’s disease[30]
10Fusarium solaniCassia alataBangladeshNapthaquinones
Azaanthraquinones
Cytotoxicity, antimicrobial and
antioxidant activity
[31]
11Fusarium sp. and
Lasiodiplodia theobromae
Avicennia lanataTerengganu, MalaysiaAnhydrofusarubin
dihydrojavanicin
Antitrypanosomal[32]
12Corynespora cassiicolaGongronema latifoliumNigeriaCorynesidone DAnti-inflammatory/anticancer agent[33]
13Pestalotiopsis theaeCamellia sinensis TheaceaeHangzhou, Chinapunctaporonin HAntibacterial and cytotoxicity[34]
14Phialocephala fortiniiPodophyllum peltatumTamilnadu, IndiaPodophyllotoxinAntiviral, antioxidant, and antirheumatic activities[35]
Table 2. Brief summary of new compounds.
Table 2. Brief summary of new compounds.
CompoundMolecular FormulaColor and MorphologyEndophytic FungusHost PlantSite and NationPharmacological ActivityRef.
Polyketides Chromones
1C12H13O6colorless powderBotryosphaeria ramosa L29leaf of Myoporum bontioidesLeizhou Peninsula, ChinaDisplayed acceptable antimicrobial activities against Fusarium oxysporum[36]
2C14H15O6white powder
3C11H11O5
4C17H19N3O3S2yellow crystalsPhaeosphaeria fuckeliiPhlomis umbrosaMount Hua, ChinaMushroom tyrosinase inhibitory activity[37]
5C15H16O7Syellow powderChaetomium seminudum Showed antifungal activity (5–6); Exhibited radical scavenging activity against DPPH; Showed significant antioxidant activity ((5)[38]
6C16H18O7S
7C16H24O5colorless oilPestalotiopsis fici W106-1Camellia sinensisHangzhou, ChinaDisplayed inhibitory effects on HIV-1 replication in C8166 cells ((7–8); Showed low to moderate cytotoxic activity (9–10); Displayed significant antifungal activity (9)[39]
8
9C32H54O6
10C32H54O6Na
Polyketides α-pyrones
11C11H14O4colorless crystalsNeurospora udagawaeshoot of Quercus macranthera Exhibited moderate antifungal (vs. Rhodoturula glutinis) activity and cytotoxicity against KB3.1 cells (12) [40]
12C10H10O4colorless oil
13C28H42O4 colorless amorphous powderAspergillus niger MA-132Avicennia marina Hainan Province, ChinaShowed potent antifungal and cytotoxic activities [41]
14
15C14H22O5 yellow oilPestalotiopsis fici branches of Camellia sinensis (Theaceae) Hangzhou, China Displayed significant antifungal against Gibberella zeae [42]
17C10H14O4 yellow oilAspergillus oryzaeParis polyphylla var. yunnanensis Dali, Yunnan Province, China The biological activities of compounds 17–18 were not tested [43]
18
19C11H16O4yellow gumPenicillium herqueCordyceps sinensisXiahe, ChinaWeak cytotoxic activity[44]
20 C12H16O5
21
Polyketides: Other polyketides
22 C22H35ClO7white powderPhoma sp. NTOU4195Pterocladiella capillaceaTaiwan, ChinaShowed potent anti-angiogenic activity (22); Exhibited inhibition of nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells (24)[45]
23
24
25
26
27C22H34O6
28C22H26NO8
29C24H35NO5colorless oilSimplicillium subtropicum SPC3 fresh bark of Duguetia staudtiiCameroon Weak cytotoxic activity [46]
30C24H35NO6
31C12H20O3colorless oilCladosporium cladosporioides MA-299leaves of the mangrove plant Bruguiera gymnorrhizaHainan Island, ChinaShowed potent antimicrobial((vs. Escherichia coli and Staphylococcus aureus) activity and moderate inhibition activity against acetylcholinesterase (33)[47]
32
33C12H22O4pale yellow powder
34C14H24O5pale yellow oil
35C12H20O4colorless crystals
36C14H20O5colorless powderAspergillus fumigatiaffnisTribulus terestris Weak antimicrobial activities[48]
37C14H12O6Nawhite amorphous solidAlternariaalternata ZHJG5leaf of Cercis hinensisNanjing, ChinaExhibited potent antimicrobial activity; Showed significant protective effect against the bacterial blight of rice (37)[49]
38C14H12O5Nawhite powder
39C14H12O5Na
40C29H22O12Na
41C24H27NO5brown solidPeyronellaea sp. FT431healthy leaf of a Hawaiian indigenous plant, Verbena sp.Lyon, FranceShowed weak to moderate cytotoxic activity (41–42)[50]
42C24H26O7
43C24H26O7
44C18H20O5
45C29H22O9red wine colored lump crystalAlternaria sp. MG1Vitis quinquangularis Showed weak cytotoxicity[51]
Alkaloids Cytochalasin
46C22H32N2O5white amorphous solidPhomopsis sp. sh917Fresh stems of I. eriocalyx var. laxifloraKunming, ChinaSignificant inhibitory activity against NO production in LPS-induced RAW264.7 cells (46)[52]
47C22H33NO4
48
49C32H40N2O6colorless amorphous powderChaetomium globosum TW1-1Armadillidium vulgareHubei Province, ChinaShowed potential cytotoxic activities against cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW-480)[53]
50 C32H38N2O6
51
52C32H40N2O6
53C32H38N2O5white amorphous powder
54C32H83N2O6
55 C32H36N2O4
56 colorless amorphous powder
57C34H42N2O7Na
58C28H37NO3white amorphous solidDiaporthe sp. SC-J0138Cyclosorus parasiticus (Thelypteridaceae)Guangdong Province, ChinaShowed significant cytotoxic activities against four human cancer cell lines (A549, HeLa, HepG2, and MCF-7) (58); Exhibited selective cytotoxic activity (59–62)[54]
59 C28H37NO
60
61C28H37NO4
62
63 C25H37NO4colorless crystalCytospora chrysosperma HYQZ-931Hippophae rhamnoides Exhibited significant antibacterial activity (63,65)[55]
64white amorphous powder
65C26H41NO5
Alkaloids Indole alkaloids
66C26H28N3O4brilliant yellowish powderAspergillus sp. YJ191021 Zhejiang Province, China Exhibited moderate antibacterial activity (66); Displayed notable anti-inflammatory; Exhibited notable cytotoxicity (66–69) [56]
67C26H29N3O5white powder
68C27H31N3O6Na
69C27H31N3O6
70C28H31N3O6
71C26H31N3O6
72C30H33NO7white amorphous powderPenicillium chrysogenum XNM-12Leathesia nanaShandong Province, ChinaExhibited moderate antibacterial effects against Ralstonia solanacearum[57]
73C23H38N1NaO3amorphous powderHypomontagnella monticulosa Zg15SUfresh rhizome of Zingiber griffithii BakerIndonesiaShowed potent cytotoxic activity[58]
74C20H22N2NaO4yellowish powderAspergillus lentulus DTO 327G5CaenagrionShanghai, ChinaDisplayed weak to moderate antibacterial activity[59]
75C19H21O4N2 white powder
76C24H25N3NaO3
Alkaloids Diketopiperazine derivatives
77C20H27N3O3S2Nawhite solid powderPhaeosphaeria fuckeliiPhlomis umbrosaMount Hua, ChinaShowed strong inhibitory effects on mushroom tyrosinase [60]
78C26H29N3O5 colorless oilPaecilomyces variotii EN-291Grateloupia turuturu Qingdao Province, China Exhibited potent antifungal effects [61]
79C22H23N3O4
80C21H25O3N3yellow powderAspergillus sp. 16-5cleaf of S. apetalaHainan Island, ChinaShowed potent to moderate α-glucosidase inhibitory activity (80–81)[62]
81C21H23O4N3white powder
82C21H23O3N3yellow powder
83C21H25O3N3
84C22H27O3N3
85C18H15O4N3white powder
86C19H24N2O6Scolorless crystalsPenicillium brocae MA-231Avicennia marina Displayed moderate to high activities against Staphylococcus aureus[63]
87C19H22N2O5Syellowish solid
88C20H26N2O6S2colorless crystals
89C20H26N2O6S2colorless solid
90C20H24N2O6S2
91C19H18N2O4Scolorless crystalsPenicillium brocae MA-231 Showed moderate antimicrobial activities against S. aureus and Aeromonas hydrophilia [64]
92C19H16N2O4S
93C18H14N2O4
Alkaloids: Other types of alkaloids
94C21H16N4O2colorless needlesPenicillium vinaceum (X17)corm of Crocus sativusShanghai, ChinaShowed weak cytotoxic activities against three human tumor cell lines (A549, LOVO, and MCF-7)[65]
95C14H16Br2N2O5 colorless amorphous powderAcanthodendrilla sp. ThailandExhibited efficient and selective cytotoxic activities against two human tumor cell lines (H292 and HaCaT)[66]
96
97C19H20NO3colorless needles crystalPenicillium sumatrense GZWMJZ-313leaf of Garcinia multifloraGuizhou, ChinaShowed moderate to weak antimicrobial activities against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli[67]
98C20H24NO3 white powder
99C20H21NO3
100C25H29O5N white powderDiaporthe sp. SYSUHQ3fresh branch of the mangrove plant Excoecaria agallocha Showed potent inhibition activity against Mycobacterium tuberculosis protein-tyrosine phosphatase B[68]
101C25H29O5N
Terpenoids Sesquiterpenoids and their derivatives
102C15H22O3Nacolorless oilRhizopycnis vagum Nitaf22Nicotiana tabacum Exhibited high selective cytotoxicity against NCI-H1650 and BGC823 cell lines (115); Showed strong phytotoxic activities against radicle growth in rice seedlings (106–107, 113–114)[70]
103C15H23O3
104C15H22O4Nacolorless amorphous solid
105C15H20O3Nacolorless oil
106C15H24O3Na
107C15H22NaO3
108C15H21O4
109C15H25O4
110C15H22O3Na
111C15H19O5colorless amorphous solid
112C15H13O5brown amorphous solidRhizopycnis vagum Nitaf22
Rhizopycnis vagum Nitaf22
Nicotiana tabacum
Nicotiana tabacum
Exhibited high selective cytotoxicity against NCI-H1650 and BGC823 cell lines (115); Showed strong phytotoxic activities against radicle growth in rice seedlings (106–107, 113–114)[70]
113C15H14O4Nayellowish oil
114C17H18NO4greenish-yellow amorphous solid
115C14H15NO4light-yellowish amorphous solid
116C15H22O3 colorless oilTrichoderma sp. PR-35healthy stem of Paeonia delavayi Yunnan Province, ChinaShowed moderate to weak antimicrobial activities against Escherichia coli and Shigella sonnei[69]
117C15H26O2
118C15H28O3Nacolorless oilFusarium proliferatum AF-04 Lanzhou, ChinaDisplayed weak antimicrobial against Bacillus subtilis, Clostridium perfringens, E. coli, and MRSA[71]
119C15H26O2Na
120C15 H 20 O5colorless oilAspergillus sydowii EN-434SymphyocladialatiusculaQingdao Province, ChinaExhibited radical scavenging activity against DPPH[72]
121C25H37O4amorphous powderUlocladium sp. Yunnan Province, ChinaShowed moderate antimicrobial activities against B. subtilis and multi-drug-resistant S. aureus (121–125); Exhibited high selective cytotoxicity against the HepG2 cell line (125)[73]
122
123C26H38O4Na
124C26H40O5Na
125C25H34O3Na
126C15H26O3colorless crystalsTrichoderma virens QA-8fresh inner root tissue of the grown medicinal herb Artemisia argyi H. Lév. and VaniotHubei Province, China Showed significant antimicrobial activities against E. coli [74]
127amorphous powder
128colorless oil
129C15H24O2
130C15H26O3colorless waxy solid
Terpenoids Diterpenoids
131C20H32O6Nacolorless oilDiaporthe sp. QYM12healthy leaves of Kandelia candelHainan Province, ChinaShowed significant anti-inflammatory effects through the inhibition of NO production[75]
132C21H28O6colorless crystalsPhomopsis sp. S12seed of Illigera rhodantha Showed excellent inhibitory effects on the production of IL-1β and IL-18; Effects on the NF-κB signaling pathway[76]
133C20H26O5colorless needle crystalPhomopsis sp. S12seed of Illigera rhodantha Exhibited anti-inflammatory activity against the production of IL-1b and IL-6 induced by lipopolysaccharide (LPS) in macrophages[77]
134C20H28O4colorless oil
135C20H26O6
136C16H20O5colorless needlesBotryosphaeria sp. P483Chinese Herbal Medicine Huperzia serrataKunming, ChinaShowed effective antifungal antifungal activities against Gaeumannomyces graminis, Fusarium solani, and Pyricularia oryza (136); Showed weak nematicidal activities[78]
137C16H20O6colorless solid
138C20H28O6white amorphous solidSmardaea sp. AZ0432photosynthetic tissue of the moss Ceratodon purpureusChiricahua Mountains of southeastern Arizona, USAExhibited selective cytotoxicity[79]
139C20H16O5yellowish needlesPestalotiopsisadustaFresh, healthy stems of Clerodendrum canescensYandang, Zhejiang Province, ChinaDemonstrated cytotoxic activities against the HL-60 tumor cell line[80]
140C20H34O2colorless needlesTrichoderma atroviride S361Cephalotaxus fortuneiJiande, Zhejiang, ChinaBioactivity tests were not performed[81]
141C16H16O5colorless needlesAspergillus wentii EN-48unidentified marine brown algal species of the genus SargassumQingdao Province, ChinaShowed moderate cytotoxic activities against seven human tumor cell lines (NCI-H460, MDA-MB-231, HeLa, MCF-7, SMMC-7721, HepG2, and SW1990)[82]
142C16H16O5
143C16H24O5
Terpenoids Triterpenoids
144C30H48Ocolorless solidScleroderma UFSMSc1Eucalyptus grandis Showed moderate to weak antifungal activities against Candida albicans and Candida parapsolosis[84]
145
146
147C29H46O5 white powderAcremonium pilosum F47pedicel of the Chinese medicinal plant Mahonia fortuneiQingdao Province, ChinaDisplayed effective antimicrobial activities against S. aureus and B. subtili[85]
148C30H50O6yellow amorphous powderGlomerella sp. F00244stem of mason pineFujian Province, ChinaShowed weak cytotoxic activity (148)[83]
149C31H52O6white amorphous powder
150C30H40O6yellowish needle crystalsPenicillium sp. SWUKD4.1850healthy branches of Kadsura angustifoliaYunnan Province, ChinaExhibited moderate in vitro cytotoxic activities[86]
151C30H40O6white needle crystals
152C30H40O6white amorphous solid
153C30H41O6
154C32H44O7white amorphous powder
155C30H42O6white powder
156C34H46O8 yellow amorphous solid
157C31H44O6
158C30H46O6white amorphous powder
159C32H50O5 white amorphous powderHypoxylon sp. 6269Artemisia annua Weak inhibition activity against the HIV-1 integrase (159) [87]
160C29H44O4
161C36H55O7white amorphous powder
Fusarium sp.roots of Mentha longifoliaSaudi ArabiaShowed significant antileishmanial activity (161)[88]
162C32H51O5
163C39H55O7
164C34H53O6colorless powderFusarium sp.roots of Mentha longifoliaSaudi ArabiaDisplayed potent cytotoxic activity towards BT-549 and SKOV-3; Showed potent antileishmanial activities against L. donovani promastigotes[89]
165C42H68O7white amorphous powder
Terpenoids Meroterpenoids
166C18H26O5colorless crystalGuignardia mangiferae A348Medicinal Plant Smilax glabraLuofu Mountain Natural Reservation, Guangdong Province, China Showed weak cytotoxic activities against MCF-7 cell lines(167,169)[90]
167C17H22O4
168C18H28O5white powder
169C17H24O4
170C25H30O5colorless amorphous powderEmericella sp. TJ29root of the plant Hypericum perforatumthe Shennongjia areas of Hubei Province, ChinaShowed moderate cytotoxic activities against five human tumor cell lines (HL-60, SMMC7721, A549, MCF-7, and SW-480) (172, 173, 175)[91]
171C27H34O6white powder
172C26H32O6colorless crystals
173C25H30O6colorless crystals
174C25H32O6white powder
175C25H28O6colorless crystals
176C31H35O9yellowish oilPhyllosticta sp. J13-2-12Yleaf of Acorus tatarinowiiGuangxi Province, ChinaExhibited moderate antimicrobial activities against Staphylococcus aureus 209P, Candida aureus 209P, and Candida albicans FIM709[92]
177C31H37O9
178C31H34O9
179C27H32O9 white powderCo-culture Talaromyces purpurogenus H4 and Phanerochaete sp. H2Handroanthus impetiginosusAlfenas, Minas Gerais, Brazil.Showed moderate trypanocidal activity against T. cruzi[93]
Lactones
180C13H22O3colorless gumTalaromyces assiutensis JTY2leaf of Ceriops tagalSouth China Sea, ChinaShowed moderate cytotoxic activities against three human cancer cell lines (HeLa, MCF-7, and A549)[94]
181C21H34O5yellow oilPenicillum polonicumfruits of Camptotheca acuminata DecneWuhan, ChinaShowed effective glucose uptake activity on rat skeletal muscle myoblast L6 (181); Significantly promoted GLUT4 translocation in L6 cells[95]
182C16H28O5light red oil
183C24H33NO8colorless crystalChaetomium cupreumAnemopsis californicaNew Mexico, U.S.A.Showed weak antimicrobial activity against S. aureus[96]
184 Xylaria curta 92092022 Taiwan, ChinaShowed moderate antimicrobial activities against Pseudomonas aeruginosa and Staphylococcus aureus; Displayed strongly inhibited lettuce seed germination[97]
185C24H34O5white powderLasiodiplodia theobromae ZJ-HQ1healthy leaves of the marine mangrove Acanthus ilicifoliusSouth China Sea, ChinaExhibited inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells; Showed moderate inhibitory activity against α-glucosidase[98]
186C8H10O3 Aspergillus pseudonomiae J1Euphorbia umbellata (Pax) Bruyns (Euphorbiaceae)Bahia, BrazilShowed moderate to weak anti-trypanosomal activity[99]
187C10H12O4
188C10H12O3
Anthraquinones, quinones, and related glycosides
189C20H19O7Brilliant yellowish oilAcremonium vitellinumAcanthus ilicifolius LinnQingdao Province, ChinaShowed moderate insecticidal activities against the third-instar larvae of Helicoverpa ar-migera[100]
190C20H16O7yellow solid
191C22H21O7
192C18H18O8Nayellow amorphous powderPhomopsis sp.Paris polyphyllavarYunnan Province, ChinaShowed significant cytotoxic activities against A549 and PC3 cell lines[101]
193C21H20O10red amorphous powderEurotium cristatum EN-220Sargassum thunbergiiQingdao Province, ChinaShowed weak antimicrobial activity against E. coli only; Showed moderate fatal activity against brine shrimp larvae[102]
194C18H15O6orange yellow powderAspergillus versicolorHalimeda opuntiaSouth Sinai, EgyptWeak inhibitory activity against hepatitis C virus NS3/4A protease[103]
195C12H11O4red powder
196C16H11O5orange powder
197C16H21O7red powderStemphylium globuliferumhealthy stems of Mentha pulegiumBeni Mellal, MoroccoShowed significant inhibition of proliferation of K562 and A549 cells[104]
Steroids
198C27H40O3white crystalsPhoma sp. SYSU-SK-7 Guangdong Province, ChinaExhibited inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophage cells; Showed moderate inhibitory activity against α-glucosidase[105]
199C28H41O3white solid
200C38H64O4white amorphous powderFusarium sp.Mentha longifoliaEgyptShowed moderate cytotoxic activity against human colorectal cancer cell line HCT 116[106]
201C28H40O4 Phomopsis sp.Aconitum carmichaeliHuize County, Yunnan Province, ChinaShowed weak antifungal activities against C. albicans and F. avenaceum[107]
202C30H48O4
Other types of compounds
203C20H22O3yellow oilAspergillus sp.root of Tripterygium wilfordiiWuhan, ChinaShowed significant inhibition of LPS-induced IL-1β, TNF-α, and NO production in RAW264.7 cells[108]
204C24H26O6
205C24H26O6colorless oil
206C23H24O6
207C23H24O5brown powderAspergillus flavipes Y-62stems of plant Suaeda glauca BungeZhoushan coast, Zhejiang province, ChinaExhibited antimicrobial activities against the Gram-negative pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae[109]
208C23H21O5white powderMicrosphaeropsis sp. Showed effective antimicrobial activities against B. megaterium and E. coli[110]
209C15H20O2brown amorphous powderEmericella sp. XL029leaf of Panax notoginsengShijiazhuang, Hebei province, ChinaShowed potent antifungal activities against six tested plant pathogenic fungi (Rhi-zoctorzia solani, Verticillium dahliae Kleb, Helminthosporium maydis, Fusarium oxysporum, Fusarium tricinctum, and Botryosphaeria dothidea)[111]
210C16H20O4
211C18H18O6Clyellow powderDiaporthe perseae sp.stem of Chinese mangrove Pongamia pinnataHainan city, ChinaShowed significant DPPH and ABTS radical scavenging activities[112]
212C7H7O4colorless flake crystalAspergillus tubingensis DS37Decaisnea insignis (Griff.) Hook. f. and Thomson Showed significant inhibition activities against Fusarium graminearum and Streptococcus lactis[113]
213C13H15NO4Naamorphous powderNigrospora sphaerica ZMT05Oxya chinensisThunberGuangdong Province, China.Showed significant α-glucosidase inhibitory activity[114]
214C9H14O2colorless oilCo-culture Aspergillus terreus EN-539 & Paecilomyces lilacinus EN-531Laurencia okamuraiQingdao, ChinaShowed weak antimicrobial activities against Physalospora piricola and Staphylococcus aureus[115]
215 C11H11BrO4white amorphous powderLachnum palmaePrzewalskia tangutica Exhibited potent to weak antimicrobial activities against Cryptococcus neoformans, Penicillium sp., Candida albicans, Bacillus subtilis, and Staphy-lococcus aureus (215–220); Showed moderate inhibitory effects on NO production in LPS-induced RAW 264.7 cells (215,219)[116]
216
217C12H13BrO4
218C10H9BrO4
219C11H11BrO5
220C11H11ClO4
Table 3. Culture conditions and yields of bioactive secondary metabolites produced by endophytic fungi.
Table 3. Culture conditions and yields of bioactive secondary metabolites produced by endophytic fungi.
No.Endophytic FungusHost PlantCulture ConditionsSecondary MetabolitesYieldRef.
1Hansfordia biophilaHedychium acuminatum RoscoeInoculated in potato glucose broth (PDB) medium and shaken at 120 rpm at 25 °C for 7 days.Tannin41.6 μm·mL−1[121]
2Aspergillus terreusFicus elasticaInoculated into PDB medium and incubated at 30 °C for 20 days on a rotatory shaker incubator at 140 rpm.Camptothecin320 μg/L[122]
3Guignardia mangiferae HAA11Taxus x mediaInoculated into (PDB) medium and incubated at 200 rpm at 28 °C for 5 days.Paclitaxel720 ng/L[123]
4Papulasora sp.S6Phellodendron amurense RuprMutagenesis by UV, X-ray rays, and NaNO2, inoculated in PDB medium, and shaken at 100 rpm at 28 °C for 7 days.Berberine12.28 mg/L[124]
5Actinoplanes teichomyceticus Improvement of the output of teicoplanin by genome shuffling; Inoculated teicoplanin medium and cultured at 28 °C for 15–20 days.Teicoplanin3016 μm·mL−1[125]
6Phialocephala fortiniiPodophyllum peltatumInoculated in Sabouraud’s dextrose agar (SDA) and cultured at 23 °C for 4–6 weeks.Podophyllotoxin189 µg/L[126]
7Entrophospora infrequens
RJMEF001
Nothapodytes foetidaInoculated into wheat bran containing Sabouraud’s broth, and incubation was carried
out at 28 ± 2 °C for 28 days.
Camptothecin503 ± 25 μg/100 g dry cell mass (in Sabouraud broth)[127]
8Epicoccum nigrum
SZMC 23769
Hypericum perforatumFungal isolates were grown in potato dextrose broth (PDB) for 7 days at 25 °C.Hypericin, Emodin117.1 μg/mL, 87.7 μg/mL[128]
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Wen, J.; Okyere, S.K.; Wang, S.; Wang, J.; Xie, L.; Ran, Y.; Hu, Y. Endophytic Fungi: An Effective Alternative Source of Plant-Derived Bioactive Compounds for Pharmacological Studies. J. Fungi 2022, 8, 205. https://doi.org/10.3390/jof8020205

AMA Style

Wen J, Okyere SK, Wang S, Wang J, Xie L, Ran Y, Hu Y. Endophytic Fungi: An Effective Alternative Source of Plant-Derived Bioactive Compounds for Pharmacological Studies. Journal of Fungi. 2022; 8(2):205. https://doi.org/10.3390/jof8020205

Chicago/Turabian Style

Wen, Juan, Samuel Kumi Okyere, Shu Wang, Jianchen Wang, Lei Xie, Yinan Ran, and Yanchun Hu. 2022. "Endophytic Fungi: An Effective Alternative Source of Plant-Derived Bioactive Compounds for Pharmacological Studies" Journal of Fungi 8, no. 2: 205. https://doi.org/10.3390/jof8020205

APA Style

Wen, J., Okyere, S. K., Wang, S., Wang, J., Xie, L., Ran, Y., & Hu, Y. (2022). Endophytic Fungi: An Effective Alternative Source of Plant-Derived Bioactive Compounds for Pharmacological Studies. Journal of Fungi, 8(2), 205. https://doi.org/10.3390/jof8020205

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