The cytochalasin alkaloids are a class of structurally related fungal metabolic products. To date, more than 300 cytochalasin analogs have been isolated from many genera of ascomycetes and basidiomycetes, including Aspergillus, Chaetomium, Penicillium, Phomopsis, Phoma, Spicaria, Xylaria, and so on (Wei et al., 2017). Structurally, cytochalasins are characterized by a highly substituted perhydroisoindol-1-one moiety which is fused with a 9- to 15-membered macrocyclic ring. Many of cytochalasins exhibit a wide range of biological activities, such as cytotoxic, antimicrobial, and phytotoxic properties (Wei et al., 2017; Xu et al., 2017). 14 cytochalasins (Figure 1) isolated from fungal endophytes were reported to possess moderate to potent antifungal activity. Cytochalasin D (1) was produced by various endophytic fungi Xylaria sp., which were isolated from leaves of guarana plant (Elias et al., 2018). 1 showed fungistatic activity against the phytopathogen Colletotrichum gloeosporioides, which causes the anthracnose disease, with an MIC of 2.46 mM. Commercial fungicides captan and difenoconazole were applied as positive controls (MICs 16.63 and 0.02 mM, respectively) (Elias et al., 2018). Bioassay-guided separation of Xylaria sp. XC-16, an endophyte from Toona sinensis led to the discovery of five agriculturally active cytochalasin alkaloids, including a new compound cytochalasin Z₂₈ (2) (Zhang Q. et al., 2014). Compound 2 showed potent fungicidal effect (MIC = 12.5 μM) against the phytopathogen Gibberella saubinetti, which was better than that of the positive control hymexazol (MIC = 25 μM) (Zhang Q. et al., 2014). Chemical investigation of the biocontrol potential endophytic fungus Aspergillus capensis CanS-34A in Brassica napus has resulted in the isolation and identification the antifungal metabolite rosellichalasin (3) (Qin et al., 2019). 3 inhibited the plant pathogenic fungi Botrytis cinerea, Monilinia fructicola, Sclerotinia sclerotiorum, and S. trifoliorum with the EC₅₀ values of 36.8, 87.1, 5.3, and 41.1 μM, respectively. Thus, S. sclerotiorum was the most sensitive target fungus (Qin et al., 2019). A new chaetoglobosin, penochalasin K (4) possessing a rare six-cyclic 6/5/6/5/6/13 fused ring system, was isolated from the solid culture of the mangrove endophytic fungus Penicillium chrysogenum V11 (Zhu et al., 2017b). Compound 4 displayed potent selective activities against C. gloeosporioides and Rhizoctonia solani, with MIC values of 6.13 and 12.26 μM, respectively, which were about ten-fold and two-fold better than that of the positive control carbendazim (Zhu et al., 2017b). Five metabolites, chaetoglobosins A (5), B (6), E (7), F (8), and penochalasin G (9), were obtained from endophytic Chaetomium globosum, isolating from the seeds of Panax notoginseng (Li et al., 2016). Some of them exhibited remarkable inhibition against phytopathogenic fungi causing root rot disease. For example, chaetoglobosin E (7) and penochalasin G (9) indicated potent inhibition against Epicoccum nigrum with the MICs < 2 μM (Li et al., 2016). A new chaetoglobosin named penochalasin J (10), as well as two known chaetoglobosins, chaetoglobosin C (11) and armochaetoglobosin I (12), were isolated from the mangrove endophytic fungus P. chrysogenum V11 (Huang et al., 2016). Compound 10 showed more potent antifungal activity against plant pathogen C. gloeosporioides with an MIC value of 25.08 μM, than the positive control carbendazim (MIC = 65.38 μM). Simultaneously, compounds 11 and 12 remarkably inhibited R. solani, with MIC values of 23.66 and 12.11 μM, respectively (Huang et al., 2016). Chaetoglobosins V (13) and G (14) were isolated from the culture of the endophytic fungus C. globosum, associated with the leaves of Ginkgo biloba tree (Xue et al., 2012). Compounds 13 and 14 exhibited potent antifungal activity against Alternaria solani, with MICs of 47.3 μM, while 14 also possessed potent activity against A. alternate, with an MIC of 47.3 μM (Xue et al., 2012). In total, the above results indicated that cytochalasin alkaloids could be used as fungicides or as leads of new fungicides to the related phytopathogenic fungi.

Except for the cytochalasins, alkaloids also include indoles, diketopiperazines, cyclopeptides, amides, and other N-containing compounds (Figure 2). Two prenylated tryptophan analogs, a previously reported 14-hydroxyterezine D (15) and a new terezine E (16), were isolated from an endophytic Mucor sp. from the medicinal plant Centaurea stoebe (Abdou et al., 2018). Both 15 and 16 exerted weak antifungal efficacy against Aspergillus terreus, with MICs of 127.8 and 111.2 μM, respectively (Abdou et al., 2018). Chemical investigation of the endophytic fungus C. gloeosporioides from the leaves of Michelia champaca resulted in the isolation of one new indole alkaloid, 2-phenylethyl 1H-indol-3-yl-acetate (17) (Chapla et al., 2014). 17 exhibited moderate activity against Cladosporium cladosporioides and C. sphaerospermum at 5 μg, which was comparable to that observed for the positive control nystatin (Chapla et al., 2014). Three prenylated indole diketopiperazine alkaloids, 12β-hydroxy-13α-methoxyverruculogen TR-2 (18), fumitremorgin B (19), and verruculogen (20), were isolated from Aspergillus fumigatus LN-4, an endophytic fungus isolated from the stem bark of Melia azedarach (Li et al., 2012). Compounds 18-20 showed broad-spectrum anti-phytopathogenic activities against eight fungi (B. cinerea, A. solani, A. alternata, C. gloeosporioides, Fusarium solani, F. oxysporum f. sp. niveum, F. oxysporum f. sp. vasinfectum, and G. saubinettii), with MIC values of 13.7-100 μM, which were comparable to the positive controls carbendazim and hymexazol (Li et al., 2012). Two quinolinones 3-O-methylviridicatin (21) and viridicatol (22), together with a new isoquinolone alkaloid named 5-hydroxy-8-methoxy-4-pheny lisoquinolin-1(2H)-one (23) were isolated from the fermentation of an endophytic fungus Penicillium sp. R22 in Nerium indicum (Ma et al., 2018). Compounds 21-23 exhibited weak to moderate antifungal activities against Alternaria brassicae, A. alternate, B. cinerea, and Valsa mali with MIC values of 124.3, 123.3, and 116.8 μM, respectively (Ma et al., 2018). A new fusaric acid derivative, atransfusarin (24), and (3R,6R)-3-benzyl-6-isopropyl-4-methylmorpholine-2,5-dione (25) were isolated from the culture of an endophyte Alternaria atrans MP-7, associated with the medicinal plant Psidium guajava (Yang Z. et al., 2019). Compound 25 exhibited potent antifungal activities against A. solani, C. gloeosporioides, and Phyricularia grisea with MICs of 6.25 μM, better than that of a broad-spectrum fungicide carbendazim. In contrast, 24 only exerted weak activities against B. cinerea and A. solani (MIC = 50 μM) (Yang Z. et al., 2019). A new pyrrolidinone derivative, named nigrosporamide A (26), was obtained from an endophytic fungus Nigrospora sphaerica ZMT05, which was isolated from Oxya chinensis Thunberg (Zhu et al., 2017a). 26 exhibited higher antifungal activity against C. gloeosporioides with an MIC value of 25.14 μM, than the positive control triadimefon (MIC = 272.39 μM) (Zhu et al., 2017a). It should be pointed out that the MIC of the positive control triadimefon (272.39 μM) seems to be outside the error measurements, probably because triadimefon is insensitive to C. gloeosporioides. As we discussed above, other appropriate positive controls should be rechose. From the culture extracts of the endophytic fungus Phoma sp. isolated from the plant Salsola oppositifolia, a new pyridione epoxide derivative, (+)-flavipucine (27), was isolated and characterized (Loesgen et al., 2011). This metabolite showed strong antifungal inhibition down to 7.81 ppm (Inhibitory concentration, 90% of growth inhibition) against Phytophthora infestans and down to 31.3 ppm against Septoria tritici (Loesgen et al., 2011). Two cyclic pentapeptides 28 and 29 were isolated from Cryptosporiopsis sp., an endophytic fungus from Zanthoxylum leprieurii (Rutaceae) (Talontsi et al., 2012). Compounds 28 and 29 exhibited motility inhibitory and lytic activities against Plasmopara viticola zoospores, a grapevine downy mildew pathogen, at 17.7-44.3 μM. Moreover, both of them also displayed potent inhibitory effects against mycelial growth of Pythium ultimum, Aphanomyces cochlioides, and R. solani (Talontsi et al., 2012). A metabolite cercosporamide (30) was isolated from the endophytic fungus Cadophora orchidicola from Kalimeris indica (Wang et al., 2019). Antifungal assay revealed that 30 had potent growth inhibition against five plant pathogens, Pestalotia diospyri, B. cinerea, Fusarium oxysporum, Sclerotium rolfsii, and Penicillum digitatum, with EC₅₀ values of 16.0 × 10^–3, 1.8, 2.8, 2.89, and 20.2 μM, respectively (Wang et al., 2019). Two new solanapyrone analogs, solanapyrones N (31) and O (32), and the known solanapyrone C (33), were isolated from Nigrospora sp. YB-141, an endophytic fungus obtained from Azadirachta indica (Wu et al., 2009). Compound 32 was regarded as an inseparable mixture of (E)-32 and (Z)-32. Compound 31 showed moderate activity against Penicillium islandicum at equivalent concentration of 98.6 μM compared with the positive control nystatin (Wu et al., 2009). Bipolamide B (34), a new triene fatty acid amide, was discovered from the endophytic fungus Bipolaris sp. MU34 of Thai medicinal plants Gynura hispida (Siriwach et al., 2014). Compound 34 showed weak to meoderate broad-spectrum antifungal activities against C. cladosporioides, C. cucumerinum, Saccharomyces cerevisiae, Aspergillus niger, and Rhizopus oryzae, with MICs of 82.9, 165.8, 165.8, 331.6, and 331.6 μM, respectively (Siriwach et al., 2014). An endophytic Xylaria sp. with broad antimicrobial activity was isolated from Ginkgo biloba L. Bioactivity-guided fractionation led to the identification of 7-amino-4-methylcoumarin (35) (Liu et al., 2008). Antimicrobial assay showed that 35 inhibited the growth of the tested 13 pathogens including Penicillium expansum (MIC, 228.6 μM) and A. niger (142.8 μM) (Liu et al., 2008).

Terpenoids produced by fungi are one of the most numerous and structurally diverse secondary metabolites with a wide array of pharmacological properties (Figure 3). The coculture of the phytopathogenic Nigrospora oryzae and endophytic Irpex lacteus from the same host Dendrobium officinale afforded a new tremulane sesquiterpene 5-demethyl conocenol C (36), conocenol B (37), and a new squalene irpenigirin B (38) (Wu et al., 2019). The new compounds 36 and 38 were active against C. gloeosporioides, with MICs of 31.7 and 13.4 μM, while 36 showed antifungal activity against Didymella glomerata with an MIC of 3.9 μM (Wu et al., 2019). It was also found that the mutually antagonistic relationship between the phytopathogens and endophytes can lead to the production of antibiotics, which inhibit the growth of phytopathogens and hinder certain phytotoxins (Wu et al., 2019). A new natural sesquiterpene 5-(hydroxymethyl)-2-(2′,6′,6′-trimethyltetrahydro-2H-pyran-2-yl)phenol (39) was characterized from endophytes belonging to the Lophodermium sp., which were isolated from the needles of superior Pinus strobus (eastern white pine) trees (Sumarah et al., 2011). 39 was antifungal against the rust Microbotryum violaceum with an MIC of 2 μM (Sumarah et al., 2011). Trichothecium roseum LZ93, an endophyte from medicinal plant Maytenus hookeri, was found to antagonize various phytopathogens in vitro. Chemical investigation of this fungal strain afforded a trichothecene, trichothecin (40), with weak to moderate inhibition on phytopathogenic fungi Typhula incarnate (MIC, 150.6 μM), Gaeumannomyces graminis (MIC, 90.4 μM), Phytophthora infestans (MIC, 90.4 μM), A. solani (MIC, 15.1 μM), and Phyricularia oryzae (MIC, 60.2 μM) (Zhang et al., 2010). A monosesquiterpene rhinomilisin B (41), a new dimeric sesquiterpene divirensol H (42), and an unprecedented trimeric sesquiterpene trivirensol A (43), were purified from T. virens FY06, an endophyte derived from Litchi chinensis Sonn (Hu et al., 2019). Compounds 41-43 exhibited moderate to potent activities on Penicillium italicum, F. oxysporum, F. graminearum, Colletotrichum musae, and C. gloeosporioides. 41 showed potent inhibitory activity against C. musae, with an MIC value of 37.4 μM, which was superior to that of the positive control triadimefon (273.0 μM). Moreover, 42 was more active toward F. oxysporum, C. gloeosporioides, C. musae, P. italicm, and F. graminearum, which were 8, 8, 3.2, 8, and 24 times as high as those of triadimefon (Hu et al., 2019). Interestingly, as metabolites of the endophytic fungus from L. chinensis, all the isolated sesquiterpenes presented potent antifungal activities against C. gloeosporioides. The phytopathogenic fungus C. gloeosporioides can cause anthracnose in L. chinensis, indicating that the metabolites produced by endophytes from its host may play a defensive role by inhibiting invasive phytopathogens. Two tetranorlabdane diterpenoids, botryosphaerin H (44) and 13,14,15,16-tetranorlabd-7-en-19,6β:12,17-diolide (45), were isolated from the endophytic fungus Botryosphaeria sp. P483 of the Chinese herbal medicine Huperzia serrata (Chen et al., 2015). Compounds 44 and 45 showed strong antifungal activities against G. graminis, F. moniliforme, F. solani, F. oxysporum and Pyricularia oryzae at 100 μg/disk (Chen et al., 2015). Three diterpenes, conidiogenones C (46), D (47), and G (48), were isolated from an endophytic fungus Leptosphaeria sp. XL026 derived from the leaves of Panax notoginseng (Chen et al., 2019). Compounds 46 and 48 showed moderate antifungal activity against Rhizoctonia cerealis, as well as 47 against Verticillium dahlia, with an MIC value of 41.4 μM (Chen et al., 2019). A nordammarane triterpenoid helvolic acid (49) was obtained from Aspergillus fumigatus, an endophytic fungus associated with Melia azedarach (Li et al., 2012). 49 exhibited broad-spectrum and potent antifungal activities against B. cinerea, A. solani, A. alternata, C. gloeosporioides, F. solani, F. oxysporum, F. oxysporum, and G. saubinettii, with MIC values of 11.0-88.1 μM (Li et al., 2012).

Polyketides are a large class of structurally diverse natural products that exhibit a wide range of bioactivities. These metabolites are generally biosynthesized by polyketide synthases, and simultaneously, some of them possess hybrid chemotypes derived from different biosynthetic pathways. In this review, chromones, quinines, macrolides, benzopyrones, unsaturated lactones, and phenols are all classified into polyketides (Figures 4–6). The culture of the fungus Botryosphaeria dothidea KJ-1, isolated from the stems of white cedar (Melia azedarach L.), yielded a perylenequinone derivative stemphyperylenol (50) (Xiao et al., 2014b). 50 displayed potent antifungal activity against A. solani with an MIC of 1.57 μM, compared to the commercially available fungicide carbendazim (Xiao et al., 2014b). Cultivation of the newly discovered fungal strain Edenia gomezpompae, an endophyte obtained from the leaves of Callicarpa acuminata (Verbenaceae), afforded three new naphthoquinone spiroketals, preussomerins EG₁ (51), EG₂ (52), and EG₃ (53) (Macías-Rubalcava et al., 2008). Spiroketals 51-53 displayed significant growth inhibition against four economically important phytopathogens (Phythophtora capsici, P. parasitica, F. oxysporum, and A. solani), with IC₅₀ values ranging from 57.5 to 447.4 μM (Macías-Rubalcava et al., 2008). Fonsecinone A (54), a dimeric naphtha-γ-pyrone, was characterized from the culture of Aspergillus sp. KJ-9, an endophytic fungus residing in the stem bark of Melia azedarach (Xiao et al., 2014a). Compound 54 had marked inhibition of G. saubinetti, Magnaporthe grisea, B. cinerea, and A. solani, with MICs in the range of 6.25-50 μM, which were better than or similar to that of hymexazol (MIC 50 μM) (Xiao et al., 2014a). An anthraquinone, macrosporin (55), was isolated from the mangrove endophytic fungus Phoma sp. L28 (Huang et al., 2017). 55 possessed broad-spectrum antifungal activities against F. oxysporum, F. graminearum, C. musae, P. italic, R. solani, and C. gloeosporioides, with MIC values ranging from 13.2 to 252.1 μM. It should be pointed out that the inhibitory activity of 55 against F. oxysporum (MIC = 13.2 μM) was higher than that of the positive control carbendazim (MIC = 32.7 μM) (Huang et al., 2017). Then, from the same host plant (semi-mangrove plant Myoporum bontioides), an endophytic fungus Alternaria sp. R6 was isolated. A racemic new cyclopentenone derivative, (±)-(4S^∗,5S^∗)-2,4,5-trihydroxy-3-methoxy-4-methoxycarbonyl-5-methyl-2-cyclopenten-1-one (56), and a new xanthone 4-chloro-1,5-dihydroxy-3-hydroxymethyl-6-methoxycarbonyl-xanthen-9-one (57), were characterized from this fungal strain (Wang et al., 2015). In comparison to the positive control triadimefon (MIC 510.64 μM), compounds 56 and 57 exhibited inhibitory activities against F. graminearum with MICs of 215.52 and 107.14 μM, respectively, while 57 also showed potent antifungal activity against C. musae with an MIC of 214.29 μM (Wang et al., 2015). Cryptosporiopsis sp., an endophytic fungus from the medicinal plant Zanthoxylum leprieurii, was the source of new polyketides, cryptosporiopsin A (58), ponchonin D (59), hydroxypropan-2′,3′-diol orsellinate (60), and (-)-phyllostine (61) (Talontsi et al., 2012). Compounds 59-61 exhibited motility inhibitory and zoosporicidal activities against P. viticola zoospores at 28.6-71.4 μM. Meanwhile, they also displayed mycelial growth of P. ultimum, A. cochlioides, and R. solani with MICs of 20-40 μg/disk (Talontsi et al., 2012). An endophytic fungus, Epicoccum sp. CAFTBO, obtained from the cocoa tree Theobroma cacao was found to produce three new unprecedented polyoxygenated polyketides, epicolactone (62), epicoccolides A (63) and B (64) (Talontsi et al., 2013). Compounds 62-64 significantly inhibited the growth of three notorious crop-devastating phytopathogens P. ultimum, A. cochlioides, and R. solani with MICs of 20-80 μg/disk (Talontsi et al., 2013). Two chlorine-substituted azaphilones, chaetomugilins A (65) and D (66), were isolated from endophytic C. globosum of Panax notoginseng (Li et al., 2016). Compounds 65 and 66 had moderate activity against E. nigrum with the MIC values of 17.8 and 36.9 μM, respectively (Li et al., 2016). Viburspiran (67), a structurally novel maleic anhydride natural products with an additional ethylene bridge, was isolated the fungal endophyte Cryptosporiopsis sp. from Viburnum tinus (Saleem et al., 2011). 67 was active against Microbotryum violaceum and B. cinerea, with inhibition radius of 6 and 10 mm at 50 μg substance/filter disk (Saleem et al., 2011). A new macrocyclic metabolite, chaetoglobosin X (68), was isolated from an endophytic fungus C. globosum obtained from the medicinal plant Curcuma wenyujin (Wang Y. et al., 2012). 68 possessed reasonably potent fungistatic activities on Exserohilum turcicum, F. oxysporum, and Curvularia lunata with an MIC of 7.5 μM and showed moderate activity against F. graminearum and F. moniliforme with an MIC of 15.1 μM (Wang Y. et al., 2012). Two benzopyran derivatives, 2-methyl-5-methoxy-benzopyran-4-one (69) and (2′S)-2-(propan-2′-ol)-5-hydroxy-benzopyran-4-one (70), were isolated from the isolate of Curvularia sp., which was obtained from the leaves of a native plant Ocotea corymbosa (Teles et al., 2005). Compounds 69 and 70 exhibited moderate antifungal activity against C. sphaerospermum and C. cladosporioides with a detection limit of 10 μg (Teles et al., 2005). Two new chromones, phomochromones A and B (71 and 72), and one new natural cyclopentenone derivative, phomotenone (73), was obtained from Phomopsis sp., an endophyte isolated from Cistus monspeliensis (Ahmed et al., 2011). Compounds 71-73 showed moderate antifungal properties toward Microbotryum violaceum, with the radius of the inhibition zone of 8, 5, and 8 mm, respectively, at concentration of 50 μL of 1 mg/mL (Ahmed et al., 2011).

5-carboxy-6-hydroxy-3-methyl-3,4-dihydroisocoumarin (74) was produced from the endophyte Xylaria sp., associated with leaves of Casearia sylvestris (Chapla et al., 2018). 74 exhibited potent antifungal activities against two phytopathogenic fungi C. cladosporioides and C. sphaerospermum at 10 μg (Chapla et al., 2018). Bioassay-guided fractionation of the endophytic fungus Phoma sp. ZJWCF006 in the Chinese medicinal plant Arisaema erubescens afforded a new α-tetralone derivative, (3S)-3,6,7-trihydroxy-α-tetralone (75) (Wang L. W. et al., 2012). 75 showed selective growth inhibition against F. oxysporium and R. solani with EC₅₀ values of 2.1 and 0.3 mM, respectively, whereas no obvious activity was observed against C. gloeosporioides and Magnaporthe oryzae (Wang L. W. et al., 2012). Three known isobenzofuranones including diaporthelactone (76), 7-hydroxy-4,6-dimethy-3H-isobenzofuran-1-one (77), and 7-methoxy-4,6-dimethyl-3H-isobenzofuran-1-one (78) were obtained from the mangrove endophytic fungus Phomopsis sp. A123 from the foliage of Kandelia candel (Zhang W. et al., 2014). Compounds 76 and 77 displayed antifungal activity against A. niger with MICs of 243 and 485 μM, respectively, while 78 inhibited the growth of A. alternaria with an MIC of 500 μM (Zhang W. et al., 2014). Chemical and biological study on an unidentified Ascomycete, an endophyte isolated from Meliotus dentatus, led to the isolation of 5-methoxy-7-hydroxyphthalide (79) and (3R,4R)-cis-4-hydroxymellein (80) (Hussain et al., 2009). Compounds 79 and 80 showed antifungal activity against Microbotryum violaceum with the radius of zone of inhibition of 7 and 8 mm at a concentration of 50 μL of 1 mg/mL (Hussain et al., 2009). An antifungal strain Verticillium sp. from the roots of Rehmannia glutinosa yielded 2,6-dihydroxy-2-methyl-7-(prop-1E-enyl)-1-benzofuran-3(2H)-one (81) (You et al., 2009). 81 clearly inhibited biomass accumulation at a low concentration of 4.4 μM on the pathogens Septoria sp. and Fusarium sp. The growth of the producing strain Verticillium sp. itself was also inhibited to some degree by 81 (You et al., 2009). Pestafolide A (82), a novel reduced spiro azaphilone derivative, and pestaphthalides A (83) and B (84), two new isobenzofuranones, were isolated from Pestalotiopsis foedan, an endophyte from an unidentified tree (Ding et al., 2008). 82 displayed antifungal activity against A. fumigatus, affording a zone inhibition of 10 mm at 100 μg/disk, whereas 83 and 84 showed activity against C. albicans and G. candidum, with the zone inhibition of 13 and 11 mm, respectively (Ding et al., 2008). Griseofulvin (85) was produced by Nigrospora sp. LLGLM003, an endophytic fungus of the medicinal plant Moringa oleifera Lam (Zhao et al., 2012). In vitro antifungal assay indicated that 85 displayed potent inhibition of the test eight plant pathogenic fungi; of particular note was the antifungal activity against B. cinerea and Colletotrichum orbiculare with the EC₅₀ of 0.6 and 1.4 μM, respectively (Zhao et al., 2012). Four new metabolites, pestalotheols E-H (86-89), containing a reduced tetrahydro-2H-furo[3,2-g]chromene unit, were isolated from a fungal endophyte, an unidentified Ascomycete from the tree Arbutus unedo (Qin et al., 2011). Compounds 86-89 showed antifungal activity against Microbotryum violaceum, with the radius of the inhibition zone of 6, 8, 6, and 7 mm, respectively, at 50 μg of test substance/test filter disk (Qin et al., 2011). Phytochemical studies of the active constituents of the endophytic fungus Phomopsis sp. led to the isolation of two new pyrenocine derivatives pyrenocine K (90) and M (91) (Hussain et al., 2012a). Both compounds also showed antifungal activity against M. violaceum in an agar diffusion assay, with inhibition zone of 5 mm at a concentration of 0.05 mg (Hussain et al., 2012a). A new fungal polyketide, koningiopisin C (92), was characterized from the culture broth of the fungus Trichoderma koningiopsis YIM PH 30002 from the medicinal plant Panax notoginseng (Liu et al., 2016). 92 exhibited antifungal activity against Plectosphaerella cucumerina with an MIC of 57.1 μM (Liu et al., 2016). The endophyte Drechslera sp. strain 678 was isolated from the roots of an Australian native grass Neurachne alopecuroidea, which demonstrated efficacy against several plant pathogens (d’Errico et al., 2020). Metabolomic analysis revealed the presence of two major bioactive metabolites, an alkynyl substituted epoxycyclohexenone derivative (5-hydroxy-1-(3-oxo-but-1-ynyl)-7-oxa-bicyclo[4.1.0]hept-3-en-2-one) (93) and monocerin (94). 93 and 94 were active against B. cinerea and S. sclerotiorum at 10 and 100 μg (d’Errico et al., 2020). A new epoxydon derivate epoxydine B (95), along with two related metabolites, epoxydon (96) and (4R,5R,6S)-6-acetoxy-4,5-dihydroxy-2-(hydroxymethyl)cyclohex-2-en-1-one (97), were obtained from an endophytic fungus, Phoma sp., isolated from the plant Salsola oppostifolia (Qin et al., 2010). Compounds 95-97 were biologically active exhibiting antifungal activity against M. violaceum at a concentration of 0.05 mg (Qin et al., 2010). A new α-pyrone (2H-pyran-2-one), ficipyrone A (98), was isolated from solid cultures of the plant endophytic fungus Pestalotiopsis fici from the tea plant Camellia sinensis (Liu et al., 2013). 98 displayed weak antifungal activity against Gibberella zeae, with an IC₅₀ value of 15.9 μM, compared with the positive control ketoconazole (IC₅₀ 6.02 μM) (Liu et al., 2013). Structural elucidation of the metabolites produced by the endophytic Phomopsis sp. revealed four new α-pyrone derivatives, phomopsinones A-D (99-102) (Hussain et al., 2012b). 99 showed potent antifungal activity against B. cinerea (inhibition zone of 17 mm), P. oryzae (25 mm), and Septoria tritici (20 mm), while 102 was active against B. cinerea (10 mm) and S. tritici (10 mm) (Hussain et al., 2012b). The fermentation of the endophytic fungus Nigrospora sp. YB-141 isolated from A. indica yielded two lactones, nigrosporalactone (103) and phomalactone (104) (Wu et al., 2009). Compounds 103 and 104 were active against B. cinerea with MIC values of 200.3 and 405.8 μM (Wu et al., 2009). Preliminary screening for antimicrobial activity of the endophytic fungi from Cinnamomum mollisimum yielded a polyketide, 5-hydroxyramulosin (105), which was identified as the major constituent of the bioactive fungal extracts (Santiago et al., 2012). 105 inhibited the fungal pathogen A. niger with the IC₅₀ value of 7.9 μM (Santiago et al., 2012).

Five new polyoxygenated cyclohexenoids, phomopoxides B (106), C (107), D (108), F (109), and G (110), were isolated from an endophytic fungal strain Phomopsis sp. YE3250 from the medicinal plant Paeonia delavayi (Huang et al., 2018). Compounds 106-110 were active against five pathogenic fungi (C. albicans, A. niger, P. oryzae, F. avenaceum, and Hormodendrum compactum) with MICs of 46.5-372.1 μM (Huang et al., 2018). Investigatation of the metabolites produced by the endophytic Fusidium sp., isolated from the leaves of Mentha arvensis, found two new bicyclic fusidilactones D (111) and E (112) (Qin et al., 2009). Both compounds had only moderate activity toward Microbotryum violaceum, with the radius of the inhibition zone of 7 and 10 mm, respectively (Qin et al., 2009). Through screening antifungal activity of endophytic fungi and subsequent bioassay-guided fractionation, sporothriolide (113) was isolated from the selected endophyte Nodulisporium sp. A21 in Ginkgo biloba (Cao et al., 2016). 113 was validated to be potently antifungal against the mycelia growth of R. solani, S. sclerotiorum and inhibit conidium germination of M. oryzae in vitro and in vivo (Cao et al., 2016). The screening of fungal extracts of Lophodermium sp. isolated from P. strobus resulted in the discovery of a new aliphatic polyketide, (2Z,4E)-6(acetyloxy)-5-formyl-7-oxoocta-2,4-dienoate (114) (Sumarah et al., 2011). 114 was antifungal against M. violaceum with MIC of 2 μM (Sumarah et al., 2011). Terrein (115) was isolated from the endophytic fungus Aspergillus terreus JAS-2 associated with medicinal plant Achyranthus aspera (Goutam et al., 2017). In antifungal assay, 10 μg/μL concentration of 115 showed inhibition of Bipolaris Sorokiniana (57.14%), A. flavus (52.5%), and A. alternata (91.25%) as compared to control (Goutam et al., 2017). Six new halogenated cyclopentenones, including four chlorinated, bicolorins A (116), B (117), D (118), and E (119), and two brominated bicolorins G (120) and H (121), were isolated from the endophytic fungus Saccharicola bicolor of Bergenia purpurascens (Zhao et al., 2020). Compounds 116-121 possessed weak to moderate activity against five pathogenic fungi-Uromyces viciae-fabae, Pythium dissimile, G. zeae, A. niger, and S. sclerotiorum, with MICs of 26.8-380.9 μM. 117 and 118, in particular, exhibited moderate activity against P. dissimile with the MICs of 33.0 and 44.7 μM, respectively, compared with the positive control cycloheximide (MIC 30.6 μM). Additionally, 118 was proven to be potently antifungal against S. sclerotiorum in vivo, indicating its potential as a candidate of new natural fungicides (Zhao et al., 2020). A new dibenzo-α-pyrone rhizopycnin D (122) and a known congener TMC-264 (123) were isolated from the endophytic fungus Rhizopycnis vagum Nitaf22 obtained from Nicotiana tabacum (Lai et al., 2016). Both compounds inhibited the spore germination of M. oryzae with IC₅₀ values of 33.9 and 34.1 μM, respectively (Lai et al., 2016).

A new furan derivative named 3-(5-oxo-2,5-dihydrofuran-3-yl) propanoic acid (124) was isolated from an endophytic Aspergillus tubingensis of Decaisnea insignis (Figure 7; Yang X. F. et al., 2019). 124 exhibited potent antifungal activity against F. graminearum with MIC value of 102.6 μM (Yang X. F. et al., 2019). Piliformic acid (125), derived from octanoate that originates from a fatty acid synthase, was obtained from endophytic fungi Xylaria sp., which were isolated from leaves of guarana plant (Elias et al., 2018). 125 had antifungal activity against C. gloeosporioides with an MIC of 2.92 μM (Elias et al., 2018). The endophytic fungus Aspergillus sp. from Moringa oleifera produced one phenolic acid, ferulic acid (126), which showed a weak antifungal activity at 500 μg/mL against A. niger with an inhibition zone diameter of 2 mm (Abonyi et al., 2018). Cordycepsidone A (127), a depsidone metabolite, was isolated from Cordyceps dipterigena, an endophytic fungus from Desmotes incomparabilis antagonistic to the phytopathogen Gibberella fujikuroi (Varughese et al., 2012). 127 showed a moderate to potent growth inhibitory activity against G. fujikuroi (MIC, 23.3 μM) and Pythium ultimum (MIC, 3.4 μM) (Varughese et al., 2012). An endophyte Botryosphaeria rhodina was isolated from the stems of the medicinal plant Bidens pilosa and was chosen for further chemical study due to its potent antifungal effects (Abdou et al., 2010). Bioactivity-guided fractionation of this strain yielded two new depsidones, botryorhodine A (128) and B (129), which were significantly active against A. terreus with MICs of 26.03 and 49.70 μM (Abdou et al., 2010). A new tridepside, colletotric acid (130), was characterized from C. gloeosporioides, an endophytic fungus colonized inside the stem of Artemisia mongolica (Zou et al., 2000). 130 inhibited the growth of the crop pathogenic fungus Helminthosporium sativum with an MIC of 95.4 μM (Zou et al., 2000). From an isolate of Aspergillus from a healthy plant of oilseed rape (Brassica napus), two chlorinated diphenyl ethers, penicillither (131) and methyl dichloroasterrate (132), were characterized (Qin et al., 2019). Both of them inhibited four plant pathogenic fungi (B. cinerea, M. fructicola, S. sclerotiorum, and S. trifoliorum) with the EC_50s of 21.7-151.2 μM (Qin et al., 2019).

Griseofulvin (85), a secondary metabolite possessing spirocyclic benzofuran-3-one skeleton, was initially isolated from the fungus Penicillium griseofulvum in 1939 by Oxford et al. (Petersen et al., 2014). Then, this polyketide has also been found to be produced by several Ascomycetes including Penicillium sp., Aspergillus sp., and Xylaria sp. (Zhao et al., 2012). Griseofulvin has a rich chemical diversity, and until now, more than 400 griseofulvin analogs have been isolated and synthesized (Figure 8; Petersen et al., 2014). Griseofulvin was one of the first antifungal metabolic products in filamentous fungi, offered in vitro fungistatic effect against dermatomycoses. Recently, it has gained renewed attention due to many reports of antifungal properties against plant pathogenic fungi. Zhao et al. reported that griseofulvin, produced by an endophyte Nigrospora sp., displayed clear growth inhibition of the test eight plant pathogenic fungi (B. cinerea, Colletotrichum orbiculare, F. oxysporum f.sp. cucumerinum, F. oxysporum f.sp. melonis, Pestalotia diospyri, Pythium ultimum, R. solani, and S. sclerotiorum) (Zhao et al., 2012). Among them, it exhibited potent activity against B. cinerea and C. orbiculare with the EC₅₀ values of 0.6 and 1.4 μM, respectively (Zhao et al., 2012). It should be pointed out that, its dechlorinated derivative, dechlorogriseofulvin, only showed weak activity, indicating that the chlorine played a decisive role in the antifungal activity. Tang et al. reported that griseofulvin isolated from Penicillium brasilianum displayed strong inhibitory effect on the growth of A. solani with an MIC of 3.13 μM (Tang et al., 2015). These impressive activities make this compound suitable candidate for biopesticide discovery and trigger the following synthesis studies, including semisynthesis from griseofulvin and de novo synthesis.

Bai et al. designed and synthesized 22 griseofulvin derivatives from commercially available griseofulvin (Bai et al., 2019). In vitro antifungal assay indicated that griseofulvin and its derivatives possessed remarkable activities against five phytopathogenic fungi (Cytospora sp., C. gloeosporioides, B. cinerea, A. solani, and F. solani) (Bai et al., 2019). Of significance was that, compounds numbered 6a-6f were found to have significant potential, which were superior to commercial fungicides hymexazol and thiophanate-methyl. The three-dimensional quantitative structure-activity relationship analysis revealed that the modification of the 4’ position, for example, the suitable bulky and electronegative acyl-substituted groups at the 4’ position, can significantly improve the antifungal activity, even up to 10-fold higher than inhibitory effect of the parent compound griseofulvin (Bai et al., 2019). Kartsev et al. carried out the synthetic studies of griseofulvin derivatives (Kartsev et al., 2019). As a result, a total of 42 new griseofulvin derivatives were designed and synthesized. These newly synthesized griseofulvin derivatives exhibited potent antifungal activity against A. niger, A. ochraceus, A. fumigatus, A. versicolor, Penicillium funiculosum, P. ochrochloron, P. verucosum var. cyclopium, Trichoderma viride. All compounds showed higher activity than the commercial antifungal drugs ketoconazole (7-42 times) and bifonazole (3-16 fold) (Kartsev et al., 2019). Interestingly, the synthesized compounds were more active than the parent compound griseofulvin (up to 4 times). Therefore, in conclusion, griseofulvin especially its derivatives can be further used for the development of new agricultural fungicides.

Trichothecenes, a group of sesquiterpene-based fungal metabolites with a common tricyclic 12,13-epoxytrichothec-9-ene core, are found to be produced by various microorganisms such as Fusarium sp., Myrothecium sp., Spicellum sp., Stachybotrys sp., Cephalosporium sp., Trichoderma sp., and Trichothecium sp. Based on the substitution pattern, trichothecenes are classified into different families of nivalenols, neosolaniols, isotrichodermins, calonectrins, trichothecins, and trichobreols (Figure 9; Takahashi-Ando et al., 2020). Trichothecenes are well-known as mycotoxins, causing significant negative effects on agriculture and human health. Initial study of trichothecenes was focused on the phytotoxicity and mammalian intoxications, and later emphasis was on exploring their complementary bioactivities. Some related compounds exhibited potent antitumor effect and have been used for clinical trials (Li et al., 2017). Meanwhile, trichothecenes showed varied role in the field of agriculture and may act as bio-control agents, strengthen the defense system of the plants against pathogens (Kumari et al., 2016). Previous structure–activity relationships study revealed that a slight modification of trichothecenes could dramatically decrease the toxicity but still retain its bioactivity (Li et al., 2017). In this case, there seems to be a special significance to search for new trichothecenes with agricultural applications.

Yamazaki et al. reported three new antifungal trichothecenes, trichobreols A-C, from the NaI-containing fermentation of the marine-derived Trichoderma cf. brevicompactum (Yamazaki et al., 2020a). Then, from the same fungus, another two new trichothecenes, trichobreols D and E, were obtained (Yamazaki et al., 2020b). Trichobreols showed good antifungal activity, especially toward yeast-like pathogenic fungi. Moreover, five semisynthetic derivatives were prepared from trichobreol A to evaluate the structure–activity relationship of antifungal trichothecenes. The results indicated that the substituents at C-3 and C-4 positions were responsible for the potency of antifungal activity (Yamazaki et al., 2020b). Li et al. reported three new macrocyclic trichothecenes possessing rare 6’-ketal moieties, roridoxins A-C, from the insect-associated fungus Myrothecium roridum (Li et al., 2019). Roridoxins A and C were found to possess potent antifungal activity against Alternaria tenuissima, A. niger, Pyricularia grisea, and F. oxysporum (Li et al., 2019). These findings suggested that trichothecenes are also promising leads which are applicable for the development of new agrochemicals.