Phytotoxic Secondary Metabolites from Fungi

Fungal phytotoxic secondary metabolites are poisonous substances to plants produced by fungi through naturally occurring biochemical reactions. These metabolites exhibit a high level of diversity in their properties, such as structures, phytotoxic activities, and modes of toxicity. They are mainly isolated from phytopathogenic fungal species in the genera of Alternaria, Botrytis, Colletotrichum, Fusarium, Helminthosporium, and Phoma. Phytotoxins are either host specific or non-host specific phytotoxins. Up to now, at least 545 fungal phytotoxic secondary metabolites, including 207 polyketides, 46 phenols and phenolic acids, 135 terpenoids, 146 nitrogen-containing metabolites, and 11 others, have been reported. Among them, aromatic polyketides and sesquiterpenoids are the main phytotoxic compounds. This review summarizes their chemical structures, sources, and phytotoxic activities. We also discuss their phytotoxic mechanisms and structure–activity relationships to lay the foundation for the future development and application of these promising metabolites as herbicides.


Introduction
Phytotoxic secondary metabolites from fungi (or called fungal phytotoxins) are toxic compounds to plants produced by fungi, especially by plant fungal pathogens responsible for serious diseases of agrarian and forest plants causing significant economical losses [1]. Fungal phytotoxins play an important role in the development of plant disease symptoms, inclduing leaf spots, wilting, chlorosis, necrosis, and growth inhibition and promotion [2,3]. Their chemical and biological characterizations as well as the structure-activity relations and modes of action can help us to deeply investigate plant-pathogen interactions.
Fungal phytotoxins are either host specific (HST) or non-host specific (NHST) toxins. Hosts specific phytotoxins (or called host-selective toxins) are active only towards plants that are hosts of the toxin-producing fungi, and are essential for pathogenicity [4]. Host specific toxins are mainly produced by plant pathogenic fungi of Alternaria, Colletotrichum, and Helminthosporium [5,6]. In some cases, host sensitivity is mediated by gene-for-gene interactions, and phytotoxin sensitivity is mandatory for disease development [7]. Contrarily, non-host specific phytotoxins (or called non-host-selective toxins) are primary determinants of host range and not essential for pathogenicity, although they may contribute to virulence. These phytotoxins have a broader range of activity, causing symptoms not only on hosts of the pathogenic fungi, but also on other plant species [8].
Fungal phytotoxins belong to different classes such as polyketides, phenols and phenolic acids, terpenoids, nitrogen-containing metabolites based on their biosynthetic pathways and structural characters. To our knowledge, there are no detailed reviews about the phytotoxic secondary metabolites from all fungal species to be published. This review describes fungal phytotoxic metabolites, their structures, isolated fungi and phytotoxic activities. Furthermore, the probable roles played by fungal phytotoxins in the induction of plant disease symptoms, structure-activity relationships, phytotoxic mechanisms, as well as the potential applications in agriculture are also discussed.

Polyketides
Polyketides are an extremely important class of bioactive secondary metabolites. They are produced by repetitive Claisen condensations of an acyl-coenzyme A (CoA) starter with malonyl-CoA elongation units in a fashion reminiscent of fatty acid biosynthesis. The biosynthesis of polyketides from acyl-CoA thioesters is catalyzed by polyketide synthase (PKS), a multi-enzyme complex that is highly homologous to fatty acid synthase (FAS). The diverse structures of polyketides can be explained as being derived from poly-β-keto chains, formed by the coupling of acetic acid units via condensation reactions. Although sharing a similar synthetic process, PKSs can be classified into three types, namely type I PKS, type II PKS, and type III PKS. Type I PKSs are multifunctional peptides containing linearly arranged and covalently fused domains. The type I PKSs can be further classified into iterative type I PKSs (iPKSs) and modular type I PKSs (mPKSs). Type II PKSs are multi-enzyme complexes composed of monofunctionall proteins. Type III PKSs are simple homodimers that use CoA rather than acyl carrier protein (ACP) as an anchor for chain extension. In addition, both type II and type III PKSs are iterative [29]. Most fungal phytotoxic metabolites belong to polyketides. They are mainly divided into aromatic and aliphatic polyketides.

Aromatic Polyketides
Aromatic polyketides are characterized by their polycyclic aromatic structures. The biosynthesis of aromatic polyketides is usually accomplished by the type II polyketide synthases (PKSs), which produce highly diverse polyketide chains by sequential condensation of the starter units with extender units, followed by reduction, cyclization, aromatization and tailoring reactions [29]. Many fungal phytotoxic polyketides belong to aromatic polyketides that mainly include benzopyrones, dibenzopyrones, benzophenones, naphthopyrones, azaphilones, naphthalenes, anthraquinones, perylenequinonoids, and aromatic macrolides.
Monocerin (6) was isolated from Eserohilum turcicum (syn. Drechslera turcica), the leaf pathogen of the noxious weed Johnson grass (Sorghum halepense). This metabolite possessed non-specific phytotoxic activity to inhibit root and shoot growth of Johnson grass and cucumber seedlings [34].
The structures of the fungal phytotoxic benzo-γ-pyrones (chromenones) are shown in Figure 2. Chloromonilinic acids B (13), C (14), and D (15) were isolated from the liquid cultures of Cochliobolus australiensis, the leaf pathogen of the weed buffelgrass (Pennisetum ciliare). These three chloromonilinic acids were toxic to buffelgrass in a seedling elongation assay, with significantly delayed germination and dramatically reduced radicle growth [40]. Coniochaetone A (16) and rabenchromenone (17) were isolated from the culture filtrates of Fimetariella rabenhorstii, an oak-decline-associated fungus in Iran. They were toxic by causing a necrosis diameter in the range of 0.2-0.7 cm with a leaf puncture assay on tomato and oak leaves [41].
Many fungal dibenzo-α-pyrones possess a wide spectrum of biological activities such as cytotoxic, phytotoxic, and antimicrobial activities [42]. The structures of phytotoxic dibenzoα-pyrones produced by the fungi from the genera Alternaria are shown in Figure 3. Both alternariol (18) and alternuisol (22) were isolated from the cultures of Alternaria sp., the pathogen of the invasive weed Xanthium italicum. They inhibited shoot and root growth of Pennisetum alopecuroides and Medicago sativa by seedling growth assay [43]. Further stud-ies on the mode of action showed that alternariol (18) and alternariol-9-methyl ether (also called AME, 19) from Alternaria alternata inhibited the photosynthetic electron transport chain in isolated spinach chloroplasts [44].

Benzophenones
Benzophenones share a common phenol-carbonyl-phenol skeleton. They are considered as the derivatives of xanthones [45]. The A-ring is derived from the shikimic acid pathway, and the B-ring is derived from the acetate-malonate pathway [46]. The structures of phytotoxic benzophenones from fungi are shown in Figure 5. Two benzophenones named daldinalds A (25) and B (26) were isolated from Daldinia concentrica. Both metabolites showed inhibition on the root growth with a rice seedling assay [47].
Moniliphenone (27) and rabenzophenone (also called chloromoniliphenone, 28) were isolated from the culture filtrates of Fimetariella rabenhorstii, an oak-decline-associated fungus in Iran. They were active by causing a necrosis diameter in the range of 0.2-0.7 cm with leaf puncture assay on tomato and oak leaves [41]. These two benzophenones were also isolated from the solid culture of Alternaria sonchi, the leaf pathogen of sowthistles (Sonchus spp.). Both metabolites were toxic to the leaves of couch-grass (Elytrigia repens) and sowthistle (Sonchus arvensis) by a punctured leaf disc assay [48].

Azaphilones
Azaphilones (or called azaphilonoids) are a structurally variable family of fungal polyketide metabolites possessing a highly oxygenated pyranoquinone bicyclic core, usually known as isochromene, and a quaternary carbon center. They belong to a large group of fungal pigments, which turn red in the presence of primary amines due to an exchange of the pyran oxygen for nitrogen, arising from their affinity of the 4H-pyran nucleus to undergo substitution with primary amines to form the corresponding vinylogous γ-pyridones. Some fungal azaphilones showed phytotoxic activities. However, most of azaphilones have not been screened for their phytotoxic activities [52]. The structures of phytotoxic azaphilones from fungi are shown in Figure 7. Acetosellin (37) was isolated from the mycelia of Cercosporella acetosella, the pathogen of leaf spots of the cosmopolitan weed (Rumex acetosella). It inhibited root elongation of Lepidium sativum and Zea mais at 6.4 × 10 −4 M [53].
Ascochitine (38) was produced as a main phytotoxin from Ascochyta fabae and A. pisi, two pathogens that caused the so called 'brown spots' disease in broad bean and necrotic lesions on pea leaflets [54]. This compound was later isolated from the cultures of Phoma clematidina, the pathogen of leaf spot-wilt disease of Clematis sp. This metabolite was toxic to the leaves of Clematis sp. by leaf disc assay [55].
Lunatoic acid A (41) was isolated from Cladosporium oxysporum DH14, the fungus residing in the gut of locust (Oxya chinensis). This metabolite exhibited significant inhibition against radicle growth of Amaranthus retroflexus seedlings [24]. Spiciferinone (42) was isolated from the culture filtrates of Cochliobolus spicifer, the pathogen of leaf spot disease in Gramineae. This metabolite was phytotoxic to wheat cotyledons by using protoplast viability assay [56].

Naphthalene Derivatives
Phytotoxic fungal naphthalene derivatives include naphthols, naphthoquinones, and naphthalenones. One naphthol and seven naphthoquinones with phytotoxicity were found in fungi. Their structures are shown in Figure 8.
Agropyrenal (43), a naphthol, was isolated from the liquid cultures of Ascochyta agropyrina var. nana. When the leaves of several weed plants (i.e., Mercurialis annua, Chenopodium album and Setaria viridis) were assayed, agropyrenal (43) was proved to be phytotoxic by causing the appearance of necrotic lesions [57].
Further, 2-hydroxyjuglone (48) was isolated from the culture broth of Ceratocystis fimbriata f.sp. platani, the canker pathogen of plane tree (Platanus orientalis). This compound induced large necrotic lesions in stem explants of plane tree as was observed in vivo [60].
Lentiquinone A (49) was isolated from Ascochyta lentis, the pathogen of lentil (Lens culinaris). It exhibited a strong phytotoxicity to the punctured leaves and seed germination of host and non-host plants [61].

Anthraquinones
Anthraquinones are a group of polyketides containing eight C2 units, which generates in turn with three aldol type condensations of the carbon skeleton of anthraquinones except for the two carbonyl oxygens of the central ring [74]. The structures of fungal phytotoxic anthraquinones are shown in Figure 11. Two anthraquinones, namely altersolanols A (73) and J (74), were isolated from the pathogen Phomopsis foeniculi (teleomorph: Diaporthe angelicae) of fennel (Foeniculum vulgare). They showed a modulated phytotoxicity on the detached tomato leaves [75]. Altersolanol A (73) was also isolated from Alternaria porri. This compound inhibited growth of lettuce and stone-leek seedlings [76].
Neoanthraquinone (75) was isolated from Neofusicoccum luteum, the causal agent of Botryosphaeria dieback in Australia. Neoanthraquinone (75) showed the obvious toxic effect by causing severe shriveling and withering on grapevine by leaf assay [37].
Catenarin (78) was produced by the necrotrophic fungus Pyrenophora tritici-repentis (anamorph: Drechslera tritici-repentis), the causal agent of tan spot foliar pathogen of wheat. Catenarin (78) induced necrosis on the leaves of wheat. It also infected wheat kernels by causing a red discoloration known as red smudge [79].
Dothistromin (85) was isolated as the main phytotoxin produced by Dothistroma pini, the pathogen by causing necrotic disease characterized by the formation of red bands on the infected needles of Pinus radiata and other pines [82].
Lentiquinones B (88) and C (89) were isolated from Ascochyta lentis, the pathogen of lentil (Lens culinaris). Both compounds caused severe leaf necrosis when applied to the punctured leaves of host and non-host plants. [61].
Rhodolamprometrin (99) was isolated from Fusarium proliferatum ZS07, the endophytic fungus residing in the gut of long-horned grasshopper (Tettigonia chinensis). This compound exhibited inhibitory activity on the radicle growth of Amaranthus retrofleus seeds to show its potential as a biocontrol agent in agriculture [22].

Perylenequinonoids
Perylenequinonoids are a class of aromatic polyketides characterized by a pentacyclic conjugated chromophore. Fungal perylenequinones are the photoactivated phytotoxins which act by absorbing light energy and generating reactive oxygen species that damage host plant cells [92]. The structures of phytotoxic perylenequinonoids from fungi are shown in Figure 12. Alterlosins I (103) and II (104) were isolated from the cultures of Alternaria alternata, the pathogen of spotted knapweed (Centaurea maculosa), a major weed pest in rangelands of the northwestern United States and southwestern Canada. Both metabolites induced necrotic lesions on knapweed by a leaf puncture assay. Alterlosin I (103) induced larger necrotic lesions compared to the small flecks induced by alterlosin II (104) [93].
Calphostin C (107) was isolated from plant pathogen Cladosporium cladosporioides. This metabolite was a protein kinase C (PKC) inhibitor by competing at the binding site for diacyglycerol and phorbol esters. Specific inhibitor of PKC would be very useful for calphostin C (107) as the pharmacological tool and potential drug [95].
Cercosporin (108) was isolated from cultures of Cercospora nicotianae, and was tested for toxic effects on suspension-cultured cells of tobacco. Cercosporin (108) was toxic to tobacco cells only when it was incubated under the light [96]. It was found that cercosporin (108) can be produced by a few pathogenic fungi in the genus Cercospora. It was toxic to plants by the generation of activated oxygen species, particularly singlet oxygen. Cercospora fungi penetrate host tissues through the stomata and colonize the intercellular spaces. Production of the membrane-damaging cercosporin (108) would allow for cell breakdown and leakage of nutrients required by the fungi for growth and sporulation in the host plant [97]. Isocercosporin (109) was isolated from Scolecotrichum graminis, the causal fungus of a leaf streak disease of orchardgrass. This metabolite was higher toxic than cercosporin (108) by lettuce seedling growth assay [98].
Elsinochrome A (110) was isolated from Stagonospora convolvuli, the biocontrol fungus to bindweed (Convolvulus arvensis). This metabolite showed inhibition on the root elongation of tomato by seedling growth assay, and toxic to bindweed and grapevine leaves by leaf-wounded assay [99].

Aromatic Macrolides
Aromatic macrolides are a class of fungal polyketides possessing a macrolide core structures fused into an aromatic ring. The typical metabolites are benzenediol lactones. They have various biological activities such as phytotoxic, cytotoxic, and nematicidal activities. The structures of phytotoxic aromatic macrolides from fungi are shown in Figure 13. Curvularin (113) and α,β-dehydrocurvularin (114) were isolated from the cultures of Curvularia intermedia, the leaf pathogen of Pandanus amaryllifolius. Both metabolites were toxic to lettuce (Lactuca sativa) and bentgrass (Agrostis stolonifera) with seed germinatin assay [100]. In addition, α,β-dehydrocurvularin (114) was isolated from the culture filtrates of Alternaria zinnia, the fungus causing leaf necrosis of Xanthium occidentale. It was toxic to the test plants by using leaf puncture assay [101]. α,β-Dehydrocurvularin (114) was also isolated from Nectria galligena, the apple canker pathogen in Chile. This compound significantly reduced elongation and epicotyl growth of lettuce seedlings [102].

Simple Furan and Furanone Analogues
The structures of phytotoxic furan and furanone analogues from fungi are shown in Figure 14. (−)-Botryodiplodin (122) was isolated from the cultures of Botryodiplodia thebromae, the pathogen of soybean charcoal rot disease. (−)-Botryodiplodin (122) was a simple lactol analogue which was toxic to soybean and duckweed (Lemna pausicostata) [106]. This compound has been synthesized by using stereoselective radical cyclizations of acyclic esters and acetals [107].
Nigrosporione (127) was isolated from Neofusicoccum luteum, the causal agent of Botryosphaeria dieback in Australia. It showed the phytotoxic effect by causing severe shriveling and withering on grapevine by leaf assay [37].
Papyracilic acid (128) was a 1,6-dioxaspiro [4,4]nonene isolated from the solid culture of Ascohyta agropyrina var. nana, the leaf pathogen of quack grass (Elytrigia repens). This compound was toxic to host plant and a number of non-host plants of the fungus. It was considered as the potential mycoherbicide for control of E. repens [110]. Penicillic acid (129) from Malbranchea aurantiaca showed significant inhibition of radicle growth of Amaranthus hypochondriacus seedlings with IC 50 value of 3.86 µM [111].
Quercilactone A (130) was isolated from Raffaelea quercivora, the pathogen of Japanese oak wilt disease. This compound exhibited weak phytotoxic activity by inhibiting root growth of lettuce seedlings [66].
Sapinofuranones A (131) and B (132), belonging to 5-substituted dihydrofuranones, were isolated from liquid cultures of Sphaeropsis sapinea, the pathogen to cause a wide range of disease symptoms on conifers such as Cupressus macrocarpa and C. sempervirens. Both metabolites were diastereomers of each other. Bioassay of sapinofuranones A (131) and B (132) gave epinasty and brown discoloration on petioles of tomato leaves, sapwood stain on inner cortical tissues of the stem of cypress seedlings, and yellowing and needle blight on pine seedlings [112].

Aromatic-Free Pyrones
Phytotoxic aromatic-free pyrones include α-pyrones and γ-pyrones. Most of them belong to α-pyrones. The structures of phytotoxic aromatic-free α-pyrones from fungi are shown in Figure 15. ACRL toxins I (140), II (141), III (142), IV (143), and IV' (144) were isolated from the culture broth of Alternaria citri, the fungal pathogen causing brown spot disease of rough lemon (Citrus jambhiri) and Rangpur Lime (Citrus limonia). They were toxic to the host plants rough lemon and Rangpur Lime by leaf puncture assay and electrolyte leakage assay. These ACRL toxins were considered as the host-specific phytotoxins [118,119]. Alternaric acid (145) was isolated from the culture filtrates of Alternaria solani, the pathogen of early blight and collar rot diseases on tomato plants. Alternaric acid (145) was toxic to tomato seedlings [120].
Simple α-pyrones are often lactone derivatives of fatty acids. Diplopyrone (147) was a phytotoxic metabolite of Diplodia corticola [122] and Diplodia mutila [123], which were phytopathopagenic fungi causing different forms of cork oak canker on Quercus suber with heavy economic losses. Diplopyrone (147) was toxic to the cuttings of cork oak and tomato by causing necrosis and wilting. The absolute configuration of diplopyrone (147) was determined by vis-à-vis comparison of experimental and simulated spectra [124].
Pestalopyrone (152) was a pentaketide phytotoxin isolated from Pestalotiopsis guipinii, the pathogen to cause twig of hazelnut (Corylus avellana). This compound was toxic to a few non-host plants such as Cirsium arvense, Sonchus oleraceus, and Chenopodium album by causing extensive necrosis on the test plant leaves [127].
Solanapyrones A (160) and B (161) were isolated from the culture filtrates of Alternaria solani, the causal organism of early blight disease of tomato and potato. Both metabolites induced leaf necrotic lesion of the host plants [132]. Solanapyrone A (160) was later isolated from the culture filtrates of Ascochyta rabiei grown in the Czapek-Dox medium supplemented with seed aqueous extract of host plant chickpea. Solanapyrone A (160) was toxic to the cultured cells of chickpea [133].
Three phytotoxic aromatic-free γ-pyrones ( Figure 16) namely spiciferones A (162), B (163) and C (164) were isolated from the fungus Cochliobolus spicifer. Among them, spiciferone A (162) was the most toxic to wheat cotyledon protoplasts, spiciferone C (164) was the least, and spiciferone B (163) had no activity. This indicated that the substitution on the γ-pyrone ring of spiciferone A (162) affected its phytotoxicity, and the methyl at C-2 was also essential to its phytotoxicity [134,135].

Furopyran and Pyranopyran Analogues
Phytotoxic furanpyran and pyranpyran analogues from fungi with their structures are shown in in Figure 17. Three dihydrofuropyran-2-ones afritoxinones A (165) and B (166), and oxysporone (167) were isolated from Diplodia africana, the causal agent of branch dieback on Juniperus phoenicea. Three compounds showed phytotoxic activity on host (Phoenicean juniper) and non-host plants (holm oak, cork oak and tomato) by cutting and leaf puncture assays. Among them, oxysporone (167) was the most phytotoxic compound [136]. Biscopyran (168) was a phytotoxic hexasubstituted pyranopyran isolated from the liquid culture filtrates of Biscogniauxia mediterranea, the pathogen of cork oak (Quercus suber). This compound caused epinasty on cork oak cuttings, and wilting on non-host tomato [137].
Luteopyroxin (170) was isolated from Neofusicoccum luteum, the causal agent of Botryosphaeria dieback in Australia. This compound showed the phytotoxic effect by causing severe shriveling and withering on grapevine by leaf assay [37].

Macrolide Analogues
Phytotoxic aromatic-free macrolides from fungi with their structures are shown in Figure 18. Brefeldin A (171) was a bicyclic lactone isolated from the culture filtrates of Alternaria zinnia, which was used as the biocontrol agent of Xanthium occidentale (Compositae). Brefeldin A (171) was toxic to a series of the tested plants such as Chenopodium album, Cirsium arvense, Mercurialis annua, Nicotiana tabacum, Sonchus oleraceus, and Xanthium occidentale at 10 −4 M by leaf pucture assay [101]. Cladospolides A (172) and B (173) were isomers isolated from the culture broth of Cladosporium cladosporioides. Cladospolide A (172) inhibited root elongation of lettuce and rice seedlings. However, cladospolide B (173) promoted root elongation of lettuce seedlings. It was interesting that these isomers had different plant growth regulatory activities [139]. Cladospolide C (174), a diastereomer of cladospolide A (172), was isolated from the culture filtrate of Cladosporium tenuissimum. Cladospolide C (174) inhibited shoot elongation of rice seedlings [140].
Cladospolide B (173) and myxotrilactone A (180) were isolated from the solid-substrate cultures of the endolichenic fungus Myxotrichum sp. Both compounds significantly inhibited shoot elongation of Arabibopsis thaliana by seedling growth assay [141].
Luteoxepinone (179) was isolated from Neofusicoccum luteum, the causal agent of Botryosphaeria dieback in Australia. It showed the phytotoxic effect by causing severe shriveling and withering on grapevine by leaf assay [37].
Putaminoxin (187) was isolated from the liquid culture filtrates of Phoma putaminum, the causal agent of leaf necrosis of Erigeron annuus. Putaminoxin (187) was toxic to a wide range of host and non-host plants with leaves of E. annuus being most sensitive [148]. Putaminoxin C (188) was isolated from the liquid culture filtrates of Phoma putaminum. This compound showed toxic effects similar to putamnoxin (187) [149].
Pyrenophorin (189) was isolated from the cultures of Pyrenophora avenae. It depressed radical growth of oat (Avena sativa) seedlings [150]. (−)-Dihydropyrenophorin (190) was isolated from the liquid culture of Drechslera avenae, the causal agent of leaf blotch of oats. This compound caused sunken lesions on oats and a variety of other plants at 3.2 × 10 −4 M [151]. Pyrenophorol (191) was later isolated from D. avenae and was toxic to oats [152].
Seiricuprolide (192) was isolated from Seiridium sp., the pathogen causing canker disease of cypress. It showed minor inhibition to the test plants by cutting assay [153].

Sorbicillinoids
Sorbicillinoids (also called vertinoids) belong to hexaketide metabolites in which the cyclization has taken place on the carboxylate terminus. They have a variety of biological activities including cytotoxic, antioxidant, antiviral, antimicrobial and phytotoxic activity [154,155]. Four phytotoxic sorbicillinoids ( Figure 19) named bisvertinolone (193), demethyltrichodimerol (194), trichodimerol (195), and trichotetronine (also called bislongiqinolide 196) were isolated from the rice solid cultures of Ustilaginoidea virens (teleomorph: Villosiclava virens), the pathogen of rice false smut disease. These compounds were evaluated for their phytotoxic activity, and showed strong inhibition against the radicle and germ elongation of rice and lettuce seedlings. Among these compounds, bisvertinolone (193) displayed the strongest inhibition [156].

Linear Polyketides
The structures of phytotoxic linear polyketides from fungi are shown in Figure 20. Three AF-toxins have been reported as AF-toxins I (197), II (198), and III (199), which were produced by Alternaria alternata, the pathogen of black spot of strawberry. They were host-specific toxins. AF-toxin I (197) also showed toxicity towards pear. AF toxin III (199) was highly toxic towards strawberry and less toxic to pear, while AF-toxin II (198) was toxic to pear [4,157]. Depudecin (200) was isolated from the weed pathogen Nimbya scirpicola. This metabolite produced necrotic lesions on kuroguwai, cowpea, and kidney bean by leaf-puncture assay, and inhibited the root elongation of lettuce seedlings. It did not show significant effects on the other test plants, which indicated that depudecin (200) was a host specific toxin [158].
Three host-specific toxins namely drechslerols A (201), B (202), and C (203) were successively isolated from the culture filtrate of Drechslera maydis, the pathogen of leaf blight disease of Costus speciosus. They all caused necrotic and chlorotic lessions on the leaves of C. speciosus, and inhibited root growth of wheat seedlings [159][160][161].
Three host-specific toxins namely PM-toxins A (204), B (205), and C (206) were isolated from the corn pathogen Phyllosticta maydis. They belonged to the linear polyketides with phytotoxicity toward the tissues and mitochondria obtained from susceptible corn varieties [162].
Spencer acid (207) was a diacrylic acid derivative isolated from Spencermartinsia viticola, the causal agent of Botryosphaeria dieback on grapevine in Australia. It exhibited strong phytotoxicity on Vitis lambrausca and V. vinifera cv. Shiraz by grapevine leaf assay [163].

Phenols and Phenolic Acids
Phenols and phenolic acids are mixed biosynthetic origins. Most phenol and phenolc acid derivatives are of polyketide origin such as salicylaldehyde analogues. Other biosynthetic origins include shikimic acid and mevalonic acid pathways [164]. The structures of phytotoxic phenols and phenolic acids from fungi are shown in Figure 21.
Agropyrenol (208) was a dihydroxypentenyl substituted salicyladehyde isolated from the liquid cultures of Ascochyta agropyrina var. nana. When the leaves of several weed plants (i.e., Mercurialis annua, Chenopodium album, and Setaria viridis) were assayed, agropyrenol (208) was proved to be phytotoxic to cause the appearance of necrotic lesions by leaf puncture assay [57].
Ascosalitoxin (209) was a trisubstituted salicylic aldehyde which belonged to the methylated hexaketide via polyketide biosynthetic pathway [165]. This metabolite was isolated from Ascochyta pisi var. pisi to show phytotoxic activities on the leaves and pods of pea and bean, as well as on tomato seedlings [166].   Moreover, 2,4-dihydroxy-3,6-dimethylbenzaldehyde (210) isolated from Leptosphaeria maculans was virulent on canola. This metabolite had strong root and hypocotyl growth inhibition on lettuce seedlings [167].
p-Hydroxybenzoic acid (213) was isolated from Alternaria dauci, which was the causal agent of Alternaria leaf blight. It showed an important phytotoxic activity when tested in the leaf-spot assay on parsley (Petroselinum crispum), in the leaf infiltration assay on tobacco (Nicotiana alata) and marigold (Tagetes erecta), and in the immersion assay on parsley and parsnip (Pastinaca sativa) leaves. It might play an important role in the pathogenicity of the fungus [169].
Diorcinol (or called 3,3 -dihydroxy-5,5 -dimethyldiphenyl ether, 224) was isolated from Diplodia corticola, an oak pathogen. This metabolite was toxic to the leaves of Quercus afares, Q. suber, Q. ilex and Celtis australis at 1 mg/mL by causing necrotic lesions [175]. Diorcinol (224) was also isolated from the endophytic fungus Epichloe bromicola obtained from Elymus tangutorum grass. It displayed obvious inhibition on the root and shoot growth of Lolium perenne and Poa crymophila seedlings, and was as active as the positive control glyphosate [176].
p-Methoxyphenol (235) was isolated from the culture filtrates of Ascochyta lentis var. lathyri, the causal agent of Ascochyta blight of grass pea (Lathyrus sativus). p-Methoxyphenol (235) caused clear necrosis on leaves of seven test plants, and inhibited seed germination and rootlet elongation of the parasitic weed Phelipanche ramosa [178].
Phomozin (237) was an ester of orsellinic acid and dimethylglyceric acid. It was isolated from Phomopsis helianthi which was the causal agent of leaf necrosis and steam cankers of sunflowers. Phomozin (237) was thought as a host-specific phytotoxin by leaf puncture assay and cutting test [179].
Stemphol (249) was isolated from Stemphylium botryosum, the pathogen of oilseed rape. This metabolite was toxic to the cells of oilseed rape and chickpea by using cell viability assay [184].

Sesquiterpenoids
Many sesquiterpenoids from fungi showed phytotoxic activities. Their structures are shown in Figure 23. Two drimane-type sesquiterpenoids, named altiloxins A (257) and B (258), were isolated as the main phytotoxins from Phoma asparagi, the causal agent of stem blight disease on saparagus. When tested on root elongation of the non-host lettuce seedlings, both compounds showed a weak inhibitory activity. Meanwhile, in the same assay carried out on the host plant at 10 µg/mL, they inhibited the root elongation of 48.2% and 48.5%, respectively [187].   Aspterric acid (259) was previously found from Aspergillus terreus to inhibit the pollen development of Arabidopsis thaliana. However, the mode of action was not clear [188]. This compound was later found to inhibit dihydroxy acid dehydratase (DHAD), which is an essential and highly conserved enzyme among plant species that catalyses β-dehydration reactions to yield α-keto acid precursors to isoleucine, valine and leucine. DHAD along with other two enzymes: acetolactate synthase (ALS) and actohydroxy acid isomeroreductase (KARI) are three enzymes in the plant branched-chain amino acid (BCAA) biosynthetic pathway, which is essential for plant growth [189].
Prehelminthosporol (295) was isolated from Dreschlera sorokiana (syn. Helminthosprorium sativum, Bipolaris sorokiniana). This metabolite was a plant growth regulator that promoted shoot growth of rice seedlings but inhibited the coleoptile growth of wheat seedlings [201]. Prehelminthosporol (295) and dihydroprehelminthosporol (296) were isolated from the culture filtrates of Bipolaris species which was the pathogen of Johnson grass (Sorghum halepense), one of the worst weeds in tropical and subtropical areas of the world. Both metabolites were toxic towards sorghum (Sorghum bicolor) in leaf spot assay [202]. Prehelminthosporolactone (297) was latter isolated from the the culture filtrates of Bipolaris species to show toxic to the leaves of sorghum and sicklepod (Cassia obtusifolia) [203].
Pyrenophoric acid (313) and pyrenophoric acids B (314) and C (315) were isolated from seed pathogen Pyrenophora semeniperda of cheatgrass (Bromus tectorum). Three metabolites showed phytotoxic activity by reducing coleoptile elongation of cheatgrass seedlings [209,210]. Among three metabolites, pyrenophoric acid B (314) was the most phytotoxic to use the abscisic acid (ABA) biosynthesis pathway at the level of alcohol dehydrogenase ABA2 to reduce seed germination of cheatgrass [211].
Seiricardines A (319), B (320), and C (321) were separately isolated from the culture filtrates of Seiridium cardinale, S. cupressi, and S. unicorne, that all were associated with canker disease of cypress (Cupressus sempervirens) in the Mediterranean area [213,214]. The solution of seiricardine A (319) at 0.3 mg/mL was absorbed by severed twigs of cypress to cause the leaf yellowing and browning. Subperidermal injection of the solution of seiricardine A (319) at 0.1 mg/mL into young cypress trees caused necrotic lesions on the stem and a diffuse yellowing of adjacent twigs [213]. Seiricardines B (320) and C (321) were epimeric diastereomers. They showed similar phytotoxic activity to sericardine A (319) [214].
Sorokinianin (322) was isolated from the culture broth of Bipolaris sorokiniana, the pathogen of barley. This compound inhibited germination of the seeds of barley (Hordeum vulgare) [215].
Chenopodolin (331) was an unrearranged ent-pimaradiene diterpene isolated from the pathogen Phoma chenopodiicola, which was proposed for the biological control of Chenopodium album, a common worldwide weed of arable crops such as sugar beet and maize. At concentration of 2 mg/mL, the compound caused necrotic lesions on the leaves of Mercurialis annua, Cirsium arvense, and Setaria viride [220].
Fusicoccn A (332) and dideacetylfusicoccin A (333) were diterpene glycosides produced by the plant pathogenic fungus Fusicoccum amygdali (syn. Phomopsis amygdali) with a unque O-prenylated glucose moiety. They stimulated seed germination of the parasitic weeds Orobanche spp. [221]. Further mechanism investigation showed that fusicoccn A (332) binded to a hydrophobic cavity in plant 14-3-3 proteins and stabilized the interaction with the C-terminal phosphorylated domain of plasma membrane H + -ATPase, thereby promoting stomatal opening and eventually leading to plant death [222].

Triterpenoids
Phytotoxic triterpenoids are mainly isolated from the fungi of Basidiomycetes. Their structures are shown in Figure 26. Three lanostane triterpenoids namely aeruginosols A (361), B (362) and C (363) were isolated from the fruiting bodies of Stropharia aeruginosa. Among them, aeruginosol C (362) showed root growth inhibitory activity on lettuce seedlings [238].

Meroterpenoids
Meteroterpenoids are natural products that are partially derived from terpenoid biosynthetic pathways. Phytotoxic meteroterpenoids usually contain monoterpene, sesquiterpene, and diterpene biosynthetic pathways.

Meroterpenoids Containing Monoterpene Biosynthetic Pathways
The structues of fungal phytotoxic meroterpenoids contain monoterpene biosynthetic pathways are shown in Figure 27. Foeniculoxin (367), a geranylhydroquinone, was isolated from Phomopsis foeniculi which was the fungal pathogen (Phomopsis foeniculi) of fennel (Foeniculum vulgare subsp. vulgare) to cause the necrosis of stems, leaves and inflorescences leading to a marked decrease in fruit production [242]. Guignardone A (368) was isolated from the culture filtrates of Macrophomina phaseolina which was the charcoal rot pathogen of many crops. It was toxic to the non-host plant tomato leaf puncture assay. However, it did not show phytotoxic activity to the host plant soybean [243].
Phyllostictones A-C (369-371), and E (372) were isolated from the endophytic fungus Phyllosticata capitalensis derived from the plant Cephalotaxus fortune. These three compounds inhibited shoot and root growth of Lactuca sativa and Lolium perenne seedlings [21].
Phomentrioloxin (373), a phytotoxic geranylcyclohexenetriol, was isolated from the liquid culture of Phomopsis sp. (teleomorph: Diaporthe gulyae) which was isolated from symptomatic saffron thistle (Carthamus lanatus). Phomentrioloxin (373) causes the appearance of necrotic spots when applied to the leaves of both host and non-host plants. It also caused growth and chlorophyll content reduction of the fronds of Lemna minor and inhibition of tomato rootlet elongation [244]. The structure-activity relationship study showed that the hydroxy groups at C-2 and C-4 appeared to be important features for the phytotoxicity, as well as an unchanged cyclohexentriol ring and the unsaturations of the geranyl side chain [245].
Phomentrioloxins B (374) and C (375) were isolated from Diaporthe gulyae, the pathogen of sunflower (Helianthus annuus) by causing stem canker. Phomentrioloxin B (374) showed small but clear necrotic spots on a number of plant specices when assayed at 5 mM on punctured leaf disks of weedy and crop plants [125].

Meroterpenoids Containing Sesquiterpene Biosynthetic Pathways
The structures of fungal phytotoxic meroterpenoids contain sesquiterpene biosynthetic pathways are shown in Figure 28. 4β-Acetoxytetrahydrobotryslactone (376) was isolated from the culture broth of Botrytis cinerea. This lactone compound showed a phytotoxic effect on Phaseolus vulgaris when tested up to 250 µg/mL by leaf disk assay. It was specu-lated that the biosynthetic origin of this compound belonged to sesquiterpene-polyketide pathway [246]. Four meroterpenoid quinones cochlioquinons A (377) and B (378), isocolioquinone A (379), and stemphone (384) were isolated from the cultures of Bipolaris bicolor, the pathogen of gramineous plants such as rice and millet. They inhibited the root growth of the seedlings of finger millet and rice [247]. Their absolute configurations were further elucidated by spectroscopic data interpretation, single-crystal X-ray diffraction analysis, chemical transformations, and biosynthetic considerations [248]. They belonged to polyketidesesquiterpenoid hybrid compounds biosynthesized through type I polyketide gene cluster by genome sequence analysis of Bipolaris sorokiniana [249].
Phyllostictone D (382) was isolated from the endophytic fungus Phyllosticata capitalensis derived from Cephalotaxus fortune. This compound inhibited shoot and root growth of Lactuca sativa and Lolium perenne seedlings [21].

Meroterpenoids Containing Diterpene Biosynthetic Pathways
The structures of fungal phytotoxic meroterpenoids contain diterpene biosynthetic pathways are shown in Figure 29. Three meroterpenoids namely colletotrichin (also called colletotrichin A, 386), colletotrichin B (387) and colletotrichin C (388) were isolated from the cultures of Colletotrichum nicotianae. Their structures all contained a norditerpene and a polysubstituted γ-pyrone. When applied to tobacco leaves, these compounds induced symptoms similar to those of the tobacco anthracnose caused by C. nicotianae [121]. They were also toxic to lettuce and rice seedlings [251].

Cyclic Peptides
Cyclic peptides are cyclic compounds formed mainly by the amide bonds between either proteinogenic or non-proteinogenic amino acids. Phytotoxic cyclic peptides from fungi mainly include ester bond-containing cyclic peptides (or called cyclic depsipeptides) and ester bond-uncontaining cyclic peptides.

Cyclic Depsipeptides
Cyclic depsipeptides (CDPs) are cyclopeptides in which amide groups are replaced by corresponding lactone bonds due to the presence of a hydroxylated carboxylic acid in the peptide structure [252]. The structures of phytotoxic cyclic depsipeptides from fungi are shown in Figure 30. AM-toxins I (389), II (390) and III (391) belong to cyclic tetradepsipeptides. They were host-specific phytotoxins isolated from Alternaria mali, the pathogen of apple blotch disease [253,254]. It was found that AM-toxin I (389) inhibited photosynthetic O 2 evolution in a host-specific manner [255].
Destruxin congeners are cyclic hexadepsipeptides belonging to host-specific phytotoxins. Destruxin A (392) was isolated from the culture broth of Alternaria linicola, the seed-borne pathogen of linseed (Linum usitatissimum). The infected seeds caused poor germination and damping-off of the seedlings. Alternaria linicola also caused leaf spotting on seedling and adult plants, and a form of head blight in the seed capsules which resulted in a loss of yield and reduction in oil quality [256]. Three cyclic hexadepsipeptides, namely destruxin B (393), desmethyldestruxin B (395) and homodestruxin (396), were isolated from the culture filtrates of Alternaria brassicae, the pathogen responsible for the balck spot of canola. They were assayed on the leaves of host and non-host plants. Dextruxin B (393) induced symptoms ranging from severe chlorosis and necrosis to almost no visible chlorosis. Dextruxin B (393) was proved as the host specific phytotoxin [257]. Both destruxin B (393) and homodestruxin B (396) could be transformed to hydroxydestruxin B (394) and hydroxyhomodestruxin B (397), respectively by host plants. The hydroxylated products (394 and 397) were less phytotoxic than their corresponding destruxins. It was considered as the detoxification strategy of canola against Alternaria fungi [258].
Two destruxin E derivatives, namely destruxin E chlorohydrin (398) and [β-Me-Pro]destruxin E chlorohydrin (399) from Beauveria feline were screened to have phytotoxic activity against the radicle growth of Amaranthus retroflexus seedlings. The structure-activity study showed that chlorine atom played an important role for their phytotoxic activity [28].
Phytotoxic enniatin derivatives included enniatins A (400), A1 (401), B (402), and B1 (403). They belong to the class of cyclodepsipeptides found in various Fusarium species, and consist of alternating residues of D-2-hydroxyisovaleric acid and a branched chain N-methyl L-amino acid, linked by peptide and ester bonds. Enniatins are host non-specific toxins which caused wilt and necrosis during infection of the host, probably related to their ionophoric properties [259]. Enniatins from Fusarium tricinctum reduced the growth of germination of wheat seeds [260]. Enniatins might act synergistically as a phytotoxin complex, which caused wilt and necrosis of plant tissue [261]. Enniatin B (402) and acetamido-butenolide (515) isolated from Fusarium avenaceum, the pathogen of spotted knapweed (Centaurea maculosa), also acted synergistically to cause necrotic lesions on the leaves of different plant species [262].
Two bicyclic lipopeptides, gramillins A (404) and B (405), were isolated from Fusarium graminearum. They were produced in planta in maize silks by promoting fungal virulence on maize, but had no discernible effect on wheat head infection. Leaf infiltration of the gramillins induced cell death in maize, but not in wheat. This indicated that gramillins were host-specific phytotoxins which were deployed as the virulence agents by F. graminearum in maize [263].
Phomalide (406) was a host-selective phytotoxin isolated from the virulent isolates of Leptoshphaeria maclans. It was a cyclic pentadepsipetide with three α-mino acids and two α-hydroxy acids. Phomalide (406) caused disease symptoms (necrotic, chlorotic, and reddish lesions) on canola, but not on either brown or white mustard [264].
Roseotoxin B (407) was isolated from Trichothecium roseum, the pathogen of apple pathogen. This metabolite was able to penetrate apple peel and produced chlorotic lesions by using kinetic fluorescence imaging method. It was the direct evidence of phytopathogenic activity of reseotoxin B (407) of Trichothecium roseum on apple [265].
Phomalirazine (412) was isolated from Leptosphaeria maculans, the pathogen of canola. This compound was to toxic to canola and brown mustard by leaf puncture assay [270].
HV-toxin M (437) was another host specific phytotoxin isolated from the culture broth of Helminthosporium victoriae, the causal agent of victoria blight disease of oat [281].
Phomopsin A (438) was a cyclic tripeptide with a tripeptide side chain isolated from Phomopsis leptostromiformis. This compound inhibited seedling growth of lupinis [282,283].
Ustiloxins A (442), B (443) and G (444) were isolated from Ustilaginoidea virens (teleomorph: Villosiclava virens), the pathogen of rice false smut disease. They showed strong inhibition on the radicle and germ elongation of rice seedlings. When their concentrations were at 200 µg/mL, the inhibitory ratios of radicle and germ elongation were more than 90% and 50%, respectively, the same effect as that of positive control (glyphosate). They also induced abnormal swelling of the roots and germs of rice seedlings [267].

Noncyclic Oligopeptides
Fungal phytotoxic noncyclic oligopeptides are linear compounds composed of several amino acids (Figure 33). AS-I toxin (446) was a phytotoxic tetrapeptide (Ser-Val-Gly-Glu) isolated from the culture filtrates of Alternaria alternata, the pathogen of sunflower (Helianthus annuus) by causing leaf necrotic spots. AS-I toxin (446) was toxic to sunflower. Nontoxic or very slight toxic effects were observed on the other tested plants which indicated that AS-I toxin (446) was a host-specific phytotoxin [288]. Depsilairdin (447) produced by Leptosphaeria maculans possessed a tripeptide coupled with a sesquiterpene moiety. Depsilairdin (447) caused disease symptoms similar to those caused by the pathogen. Plant leaves of brown mustard treated with depsilairdin (447) showed strong necrotic and chlorotic lesions, but such symptoms were not observed in canola at a wide concentration range from 1 µM to 1 mM [289].

Cytochalasin Congeners
Cytochalasins belong to class of perhydroisoindolylamcrocylclic lactones. The structures of phytotoxic cytochalasin congeners from fungi are shown in Figure 34. Cytochalasin B (448) was isolated from the culture filtrates of the plant pathogens Drechslera wirrenganensis and D. campanulata, and was toxic to the leaves of faba bean by leaf puncture assay [290]. Cytochalasins C (449) and D (450) were isolated from the endophytic fungus Xylaria cubensis associated with Eugenia brasiliensis (Myrtaceae). Both cytochalasins showed phytotoxic activity on wheat coleoptiles [291]. Cytochalasin D (450) was also isolated from the culture filtrates of Ascochyta rabiei (teleomorph: Didymella rabiei), the pathogen of chickpea. This metabolite was toxic to the leaflet cells of chickpea [292].
Three cytochalasins named phomacins D (455), E (456) and F (457) were identified from the wheat pathogen Parastagoospora nodorum by genomics-driven discovery. Both phomacins D (455) and E (456) obviously inhibited wheat seed germination at 100 µg/mL. Phomacin F (457) just had week inhibitory activity on wheat seed germination. Interestingly, phomacin D (455) did not show any inhibition of seed germination against the dicots Arabidopsis thaliana and Lepidium sativum, which indicated that seed germination inhibition of phomacin D (455) could be specific to monocots [294].
Pyrichalasin H (458) was isolated from the cultures of Pyricularia grisea, the causative fungus of blast disease in crabgrass (Digitaria sanguinalis). This compound strongly inhibited growth of rice seedlings at 1 µg/mL [295].

Lactams
The structures of phytotoxic lactams from fungi are shown in Figure 35. Cichorine (459), zinnimidine (485) and Z-hydroxyzinnimidine (486) were isolated from the fungus Alternaria cichorii, the pathogen of foliar blight disease of Russian knapweed (Acroptilon repens). These compounds were toxic to the leaves of Russian knapweed by in vitro leaf puncture assay [185].
Four oxazatricycloalkenones phyllostictines A (467), B (468), C (469) and D (470) isolated from Phyllosticta cirsii showed phytotoxic to Cirsium arvense. Phyllostictine A (467) was proved to be highly toxic. Phyllostictines B (468) and D (470) were slightly less toxic compared to phlyllostictine A (467), wheras phyllostictine C (469) was almost not toxic, that showed a clear structure-activity relationship between the phytotoxic activity and the structural features characterizing phyllostictine group. Phyllostictine A (467) should be potential mycoherbicide for Cirsium arvense biocontrol [300]. Porritoxin (471) was first identified as a benzoxazocine derivative from the culture broth of Alternaria porri, the causal pathogen of black spot disease in stone-leek and onion [301]. The structure of porritoxin (471) was then corrected as isoindol-1-one congener [302]. This compound inhibited shoot and root growth of lettuce seedlings at 10 µg/mL [301]. Another isoindo-1-one, namely porritoxin sulfonic acid (472) was later isolated from A. porri. Structure-phytotoxicity investigation showed that the N-alkyl and hydroxyl groups contributed to the phytotocitiy, but that this activity became weak with sulfonation [286].
Triticones A (481) and B (482) were two spirocyclic γ-lacams isolated from Drechslera tritici-repentis, the causal agent of reddish brown spots on wheat (Triticum vulgare). Two compounds in mixture showed phytotoxicity on the leaves and protoplasts of wheat [314].

Indole Derivatives
The structures of phytotoxic indole derivatives from fungi are shown in Figure 36. Chlamydosporin (487) was isolated from the endophytic fungus Fusarium chlamydosporum residing in the roots of Suaeda glauca. This indole derivative exhibited significant phytotoxic activity against the radicle growth of Echinochloa crusgalli seedlings with the inhibition rate of more than 80%, even at concentration of 1.25 µg/mL [316]. Colletophyrandione (488) was a tetrasubstituted indolyllidenepyrandioine isolated from the culture filtrates of Colletotrichum higginsianum. It was toxic to four plant species Sonchus arvensis, Helianthus annuus, Convolulus arvensis, Ambrosia artemisiifolia by leaf puncture assay [317].
Crypticin C (489) was isolated from the culture filtrates of Diaporthella cryptica, the emerging hazelnut pathogen. This compound was active in the tomato cutting assay [173].

Pyridine Derivatives
The structures of phytotoxic pyridine derivatives from fungi are shown in Figure 37. Ascosonchine (491) was the enol tautomer of 4-pyridylpyruvic acid with herbicidal activity produced by Ascohyta sonchi, the leaf pathogen of Sonchus arvensis, a perennial herbaceous weed occurring throughout the temperate regions of the world. Ascosonchine (491) was toxic to Sonchus arvensis and showed selective herbicidal properties [319]. Fusaric acid (also called 5-butylpicolinic acid, 492) was isolated from Fusarium oxysporum. It was toxic to tobacco leaves by pucture assasy [320]. Fusaric acid (492) was produced by several Fusarium species which commonly infected cereal grains and other agricultural commodities [321]. Both fusaric aicd (492) and 9,10-dehydrofusaric acid (493) were isolated from Fusarium nygamai, which caused large leaf and stem necrosis on the host Striga hermonthica. These two compounds showed a wide chlorosis and necrosis in the punctured aera of tomato leaves as well as a strong inhibition on root elongation of tomato seedlings [322].
Luteoethanones A (502) and B (503), two 1-substituted ethanones, were isolated from Neofusicoccum luteum, the causal agent of Botryosphaeria dieback on grapevine. Both metabolites caused large necrotic spots, severe shriveling, and distortion of the leaf lamina of grapevine by leaf detached assay [39].
Solanapyrone C (528) has been isolated from the culture filtrate of Alternaria solani, the causal organism of early blight disease of tomato and potato [132], and the culture filtrates of Ascochyta rabiei, the pathogen of chickpea [133]. Solanapyrone C (528) was toxic to the leaves of the host plants.

Other Nitrogen-Containing Metabolites
The structures of other fungal phytotoxic nitrogen-containing metabolites are shown in Figure 39. Brasicicolin A (529) was isolated from Alternaria brassicola, the dark leaf spot pathogen of Brassica species. Brasicicolin A (529) was a polyester of mannitol esterified with two α-isocyanoisopentanoyl, two α-hydroxyisopentanoyl and two acetyl residues. It was a mixture of diastereomers due to the epimerizable protons adjacent to the isocyano group. Brasicicolin A (529) was host specific phytotoxin by causing chlorosis and necrosis on the leaves of brown mustard (Brassica juncea cv. Cutlass, susceptible) at 0.5 mM, but no detectable damage on the leaves of white mustard (Sinapis alba cv. Ochre, resistant) [335]. Maculansin A (530) was isolated from Leptosphaeria maculans (anamorph: Phoma lingam) cultured in potato dextrose broth (PDB) at high temperature. The structure of maculansin A (530) was similar to that brasicicolin A (529). Maculansin A (530) was more toxic to resistant plant (brown mustard) than to susceptible plant (canola) [167].
(S)-Ornidazole (531), a nitroimidazole, was isolated from the solid culture of Penicillium purpurogenum derived from soil. This compound inhibited root and hypocotyl growth of radish seedlings at 100 µM [26].
β-Nitropropionic acid (532) was isolated from Septoria cirsii, the pathogen of weed Canada thistle (Cirsium arvense) growing in virturally all temperate areas of the world. This compound inhibited seed germination and root elongation, and caused the typical symptoms of chlorosis and necrosis on the leaves of Canada thistle and other test plants [336].
Two isoquinoline derivatives named pyrenolines A (533) and B (534) were isolated from the cultures of Pyrenophora teres, the pathogen of barley. Both compounds were toxic to both monocots and dicots by leaf puncture assay [337].

Miscellaneous
The structures of miscellaneous phytotoxic metabolites from fungi are shown in Figure 40. Crypticin A (535), a phenylpropanoid, was isolated from the culture filtrates of Diaporthella cryptica, the pathogen of hazelnut. This compound was also called 2-hydroxy-3-phenylpropanoate methyl ester. It was found to be inactive at 1 mg/mL on the leaves of cork oak, grapevine, hazelnut, and holm oak by leaf puncture assay [173]. Two cyclohexene epoxides named (+)-epiepoxydon (536) and PT-toxin (544) were isolated from Pestalotiopsis longiseta and P. theae. They induced leaf necrosis on the test leaves [338].
Phaseocyclopentenones A (540) and B (541) are penta-and tetrasubstituted cyclopentenones isolated from the culture filtrates of Macrophomina phaseolina, the charcoal rot pathogen of many crops. Both compounds were toxic to the non-host plant tomato (Solanum lycopersicum) by leaf puncture assay and seedling cutting assay. However, they did not show phytotoxic activity to the host plant soybean (Glycine max) [243].
Phenylacetic acid (542) was isolated from the liquid culture filtrates by Biscogniauxia mediterranea, the pathogen of cork oak (Quercus suber). This compound caused epinasty on cork oak cuttings, and wilting on non-host tomato [137].
Stagonosporyne G (545) was an oxygenated acetylenic cyclohexanoid isolated from the Parastagonospora nodorum SN15, the pathogen of wheat. This compound displayed a significant phytotoxic activity by killing Arabidopsis thaliana seedlings [339].

Conclusions and Future Perspectives
Due to long-term co-evolution of pathogenic fungi and their host plants, the fungus has evolved strategies for successful infection of host. Among these strategies is the production of phytotoxins. Fungal phytotoxins play an important role in the process of pathogenesis as the mediators of virulenece [12]. They are either host specific or non-host specific. This is why many phytotoxins have been identified from phytopathogenic fungi. In fact, fungal phytotoxins play diverse roles in plant disease, from impacting symptom expression, disease progression, to being required for pathogenesis. Some phytotoxins are directly toxic by killing plant cells and allowing for infection of dead cells. Others interfere with the induction of defense responses, or induce programmed cell death-mediated defense responses in order to generate necrosis required for pathogenicity [7,167,335].
In recent years, more and more phytotoxic metabolites have been discovered from other fungi such as plant and animal endophytic fungi, soil-derived fungi, and marinederived fungi [21-24,27,28]. Most of these phytotoxic metabolites are non-host specific. They are suitable for development of herbicides with a broad spectrum. In addition, the phytotoxins from weed pathogens are a very promising source of specific herbicide development for weed control [25, 340,341]. An example of success is the discovery of ophiobolins which have shown their potential as herbicides [229,230].
Transformation of phytotoxin-resistant genes from the fungus into plants is another strategy. Aspterric acid (259) is a fungal phytotoxin. Aspterric acid-producing fungi have the self-resistance gene, astD, which was validated to be insensitive to aspterric acid (259). The fungal self-resistance gene astD has been deployed as a transgene in the establishment of plants to create aspterric acid-resistant crops. Aspterric acid (259) should be a promising lead for development as a broad-spectrum commercial herbicide [189].
The current review describes the phytotoxic activities of secondary metabolites from fungi. In fact, many fungal phytotoxins have other biological activities in addition to their phytotoxic activity. For example, emodin (86) exhibits antioxidant [342], antitumor [343], phytotoxic [86], insecticidal [344], antimicrobial [344], and acetylcholinesterase (AChE) and glutathione S-transferase (GST) inhibitory [344] activities. In addition, many other isolated fungal metabolites have not been evaluated for their phytotoxic activities due to either the lack of phytotoxic assays or not enough of the compounds could be isolated to perform toxicity assays. These metabolites remain to be further tested for their phytotoxicities. For example, herbarin (47) is a naphthoquinone congener. It was previously isolated from a few fungal species such as Anteaglonium sp. FL0768 [345] and Corynespora sp. BA-10763 [346], and later showed obviously phytotoxic activity [59].
In addition to their potential as herbicides, fungal phytotoxins have other potential applications in agriculture [1]. As different fungal species produce specific phytotoxins, this characteristic could be used to develop rapid, simple and specific methods to recognize plant diseases such as the development of practical kits (i.e., rapid test strip) to be used directly in the field by farmers. Furthermore, phytotoxins could be used to select plant varieties resistant to disease instead of using whole plant-pathogen systems. In this way, the disease resistance breeding can be accelerated.