Nidulantes of Aspergillus (Formerly Emericella): A Treasure Trove of Chemical Diversity and Biological Activities

The genus Emericella (Ascomycota) includes more than thirty species with worldwide distribution across many ecosystems. It is considered a rich source of diverse metabolites. The published classes of natural compounds that are discussed here are organized according to the following biosynthetic pathways: polyketides (azaphilones, cyclopentenone pigments, dicyanides, furan derivatives, phenolic ethers, and xanthones and anthraquinones); shikimate derivatives (bicoumarins); mevalonate derivatives (meroterpenes, sesquiterpenes, sesterterpenes and steroids) and amino acids derivatives (alkaloids (indole-derivatives, isoindolones, and piperazine) and peptides (depsipeptides)). These metabolites produce the wide array of biological effects associated with Emericella, including antioxidant, antiproliferative, antimalarial, antiviral, antibacterial, antioxidant, antihypertensive, anti-inflammatory, antifungal and kinase inhibitors. Careful and extensive study of the diversity and distribution of metabolites produced by the genus Emericella (either marine or terrestrial) revealed that, no matter the source of the fungus, the composition of the culture medium effectively controls the metabolites produced. The topic of this review is the diversity of metabolites that have been identified from Emericella, along with the contextual information on either their biological or geographic sources. This review presents 236 natural compounds, which were reported from marine and terrestrial Emericella. Amongst the reported compounds, only 70.2% were biologically assayed for their effects, including antimicrobial or cytotoxicity. This implies the need for substantial investigation of alternative activities. This review includes a full discussion of compound structures and disease management, based on materials published from 1982 through December 2019.


Introduction
Fungi are ubiquitous cosmopolitan organisms, accounting for the second largest group of organisms after insects [1]. Inter alia, until the discovery of antibiotics, fungi have been known for decades as harmful entities, spoiling foods and causing health hazards; today they are considered as antimicrobials that act against bacteria, which has been saving millions of lives. Views on fungi have changed to consider their beneficial effects, which have appeared in bread preparation, cheese manufacturing and fermentation [1][2][3][4]. The number of fungal strains is roughly estimated to be six per plant species. Consequently, the total number of fungi is tentatively estimated as 1.5 million species, of which only 100,000 species have been identified [4]. The classified fungal species population on earth is tentatively estimated to be 150,000, which indicates that only 10% have been scientifically investigated [5,6]. Kirk et al. (2008) deduced that the fungal population is growing at a rate of 1200 species per year [7]. Consequently, more time is required to describe the remaining fungal species. Fungi include marine and terrestrial, endophytic and saprophytic and pathological and mutualistic species [8].
Endophytic fungi spend part or all of their lives colonizing the tissues of their hosts [2,3]. They can be categorized into obligate or facultative. The fungi that depend on taking nutrients from their surroundings are termed as obligate [8,9]. Conversely, facultative fungi live outside the host body during a definite stage of their lives and are mostly associated with plants from the neighboring soil environment and atmosphere [10]. Their relationships range from symbiotic to pathogenic. The host organisms supply the nutrients to the endophytic microorganisms, and in return, they produce secondary products as growth and competitiveness factors for the host in its environment [11]. Recently, they have been identified as a fruitful scaffold for bioactive natural compounds, thus demonstrating possible leads for new phytopharmacological agents [10,12]. Marine fungi produce interesting metabolites, which has attracted particular attention among those seeking new pharmaceuticals [13]. The marine sediment offers a wealth of secondary metabolites with exceptional structures and interesting biological effects [14].
Natural products represent eighty percent of all pharmaceuticals. For example, of the seventy thousand reported compounds of polyketide origin, more than twenty developed substances are now available in medical markets. This hit rate of less than one percent is notably higher than that for screening of synthetic pharmaceutical agents, which is less than 0.001% [15]. Researchers have considered such fungal applications since the discovery of penicillin and the trend has only increased with time. Currently, more than thirty-five launched pharmaceutics were originally discovered from fungi [16]. These drugs were employed to manage certain diseases including bacterial and fungal infections, to serve as immunosuppressants, and as other therapeutic agents. Those that have been processed in clinical studies include plinabulin and diketopiperazine derivatives [17]. It is well-known that the antimicrobial agent cephalosporin C, which was originally discovered in July 1945, was developed from the marine fungus Acremonium strictum W. Gams (1971) [18]. Despite these momentous discoveries, however, the number of active marine fungal products has increased only slowly. An interesting method of engaging the fungal warehouse is the One Strain-Many Compounds Approach (OSMAC), which includes managing the culture conditions such as media composition, temperature pH and oxygen source [19][20][21][22].
Genus Emericella (E.) includes more than thirty species and is named after the sexual phase (teleomorph) of this fungal strain, which ranges from saprobes to pathogenic or endophytic organisms on living host organism [23]. It forms white cleistothecia surrounded by Hülle cells and produces purple ascospores. Conidiophores usually have short brown stripes, bear both metulae and phialides and produce columns of dark green conidia [24,25]. The white cleistothecia surrounded by Hülle cells are characteristic of Emericella. A published taxonomical study of Emericella species resulted in transferring them to a subgenus of Aspergillus named "Nidulantes". The subgenus Nidulantes consists of five sections (Nidulantes, Versicolores, Usti, Terrei and Flavipedes). This is based on the fact that the majority of the Emericella have a sexual stage, and that their morphological features are similar to

Azaphilones
Azaphilones (isochromenes) are fungal metabolites with a pyrone-quinone skeleton and a highly oxygenated bicyclic structure. They have the ability to react with amines to form red or purple vinylogous c-pyridones due to the exchange of pyrane oxygen for nitrogen. This class of natural substances is responsible for the characteristic colors of the mycelia. Azaphilones play an important role as a taxonomically important marker in some fungal species. For instance, sassafrins were firstly found in Creosphaeria sassafras, and were fortunately not produced by any other species of the Xylariaceae [27]. Azaphilones are products of many species that belong to the basidiomycetous and ascomycetous species. They exhibit a variety of pharmacological effects, including antimicrobial, antiviral, cytotoxic, anticancer and anti-inflammatory effects. Several biological effects have been assigned to the reactions of azaphilones with the N-containing moieties, like proteins, nucleic acids and amino acids, resulting in the formation of vinylogous γ-pyridones [28].

Cyclopentenone Pigments
Two new yellow-colored compounds, falconensones A and B (18,19), were reported from the dichloromethane extract of E. falconensis (NHL 2999 = ATCC 76117), isolated from Venezuelan soil and/or E. fruticulosa, which have been isolated from Venezuelan soil. Compounds 18 and 19 have cyclopent-2-en-1-one connected through conjugated pentaene with acetate residue [34]. Further investigations on the same strain by the same research group led to the identification of three more falconensins, namely E-G (5-7) [30]. They then studied the absolute stereochemistry of falconensin A (1). Hydrogenation of 1 resulted in a hexahydro derivative, which upon methanolysis gave a ketodiol, which was elucidated by extensive interpretation of different spectroscopic measurements including 1D and 2D NMR. An advanced Mosher's approach was employed to identify the absolute stereochemistry of ketodiol [31]. The Mosher's reagent [α-methoxy-α-(trifluoromethyl) phenylacetic acid (MTPA)] is used in measuring the chirality of the secondary alcohols, by generating the magnetic anisotropy effect of the ring current, which is induced under the external magnetic field [31]. The MTPA esters of ketodiol were prepared and the NMR assignment between these (R)-and (S)-MTPA esters was estimated. The absolute stereochemistry at C-8 was assigned as an S configuration, which is consistent with the outcome application of the octant rule to ketodiol. Conclusively, falconensins A-D had the same configuration by the comparison of their circular dichroism (CD) data. A positive cotton effect indicates an Rconfiguration at C-7 [30,31]. Further investigation of the same strain by the same scientists led to the isolation of a new azaphilone derivative, falconensin H (8). The absolute configuration around C-7 has been decisively recognized by measuring the optical rotations and CD measurements. Unfortunately, falconensins A-H showed no effect [32].
Falconensone A (18) displayed an apoptotic effect on HL60 leukemia cells, while 19 and the 4'-nor-methyl derivative of falconensone A exhibited less potency [35]. The synthetic products, p-bromophenylhydrazone and dioxime derivatives of 18, displayed higher potency than the corresponding non-synthetic falconensones A and B [36]. The initiation of cell death programming by the falconensones is associated with their inhibition of cell growth. The synthetic derivatives of falconensone A (i.e., falconensone A dioxime and falconensone A p-bromophenylhydrazone) have potent inhibitory effects on HL60 cell growth. They displayed inhibitory effects much greater than that exhibited by falconensone A. Unfortunately, 19 showed no measurable effect on cell growth. The proliferation effect of falconensone A and its derivatives on HL60 cell growth was inhibited at 1 and 10 µM. The acute growth inhibition by falconensone A p-bromophenyl-hydrazine was 55% continuously from 54 to 149 h; however, falconensone A dioxime and falconensone A inhibited cell growth gradually, exhibiting 35% and 23% cell growth inhibition at 54 and 149 h, respectively. These reported results indicate that 18 and its derivatives had antiproliferative effects. Moreover, the percentage of viable cells was >94% under all conditions for four days. Thus, the inhibition of cell growth cannot be attributed to necrotic cell death [35,36].
Furthermore, 18, its dioxime and 19 elevated the generation of intracellular ROS (reactive oxygen species), while the p-bromophenylhydrazone of 18 is inactive [37]. These effects recommend that only 18 and its derivatives (i.e., p-bromophenylhydrazone and dioxime) would be considered as apoptotic agents. The active generation of ROS in cells may be induced only by 18 and its dioxime derivative. It was also proposed that the Me-4' in the cyclopentenone ring in 18 may be essential for the induction of apoptosis. Thus, 18 and its derivatives may be clinically useful in the management of some leukemia types. Retinoic acid (RA) is a physiological compound that induces HL60 cells to change into granulocyte-like cells and undergo apoptosis. Falconensones induce differentiation of HL60 cells into monocyte/macrophage-like cells, and those combinations of falconensone A and RA synergistically induced differentiation. The structural similarity between RA or fenretinide and the falconensones, particularly between 4-HPR and falconensone A p-bromophenylhydrazone, led researchers to test falconensones, which could induce apoptosis of HL60 cells [35][36][37]. Fifteen falconensins were evaluated for their inhibitory impact on the enhancement of ear edema in mouse ears by 12-O-tetradecanoyl-phorbol-13-acetate [38]. These azaphilonoidal derivatives displayed inhibitory effects comparable with indomethacin. All the tested compounds, except 17, inhibited the effect of inflammation with inhibitory doses (ID 50 ) of 0.373, 0.553, 0.417 and 0.908, for falconensins E, K, M and indomethacin, respectively [35][36][37][38].

Phenolic Ethers
E. violacea IFO 8106 displayed toxigenicity against experimental animals through the production of phenolic metabolites [43,44]. The ethyl acetate extract of the mycelia, which were grown on sterilized rice, exhibited a lethal effect on mice upon intraperitoneal injection (500 mg/kg). Violaceol I (39) and II (40) (Figure 2) were isolated by employing silica gel column chromatography, together with another non-toxic phenolic compound, which was identified as violaceic acid (41). The aldehydic moiety was identified based on the appearance of a singlet at δ H 9.65 ppm in the 1 H NMR spectrum and a doublet at δ C 190.6 ppm in 1 H single-frequency off-resonance decoupling (SFORD) mode. 3,3'-dihydroxy-5,5'-dimethyldiphenyl ether (42) was previously reported from E. rugulosa [43].

Xanthones and Anthraquinones
Xanthones are natural metabolites characterized by having dibenzo-γ-pyrone derivatives. They are typically polysubstituted and occur as either partial or fully aromatized derivatives. Xanthones may be divided into different subclasses based upon their structural features: xanthone monomers and dimers/heterodimers. The notably wide array of xanthones' bio-activities could be attributed to the production of several chemical classes, such as fully aromatic-, dihydro-, tetrahydro-and hexahydro-xanthones resulting from the oxidation of the C-ring [45,46].
Sterigmatocystin (43) was reported from E. striata and E. venezualensis, and also was known as a precursor of aflatoxin B1 [47,48]. Sterigmatocystin is polyketide, which produced by numerous species, including Emericella and Aspergillus. Its pathway is obeyed by the normal polyketide-derived compounds through polyketide synthases. Moreover, the gene (pksST) encoding the sterigmatocystin polyketide synthase in A. nidulans has been cloned, sequenced, and characterized.
Investigation of Emericella sp. 25379 led to the identification of 15-chlorotajixanthone hydrate (66) and 14-methoxytajixanthone (56). In addition, shamixanthone (45) and tajixanthone hydrate (46) ( Figure 4) were also obtained [58]. The activation of the calmodulin sensitive cAMP phosphodiesterase (PDE1) was inhibited by 45, 46, 52 and 66 in a dose concentration-related manner [52].   (52), were obtained from the marine fungus Emericella sp. SCSIO 05240, which was isolated from deep sea sediment [60]. X-ray crystallographic analysis of ruguloxanthone B (54) was performed, aiming at the identification of its stereochemistry. All the isolated compounds were assayed for antibacterial, antifungal and antitumor activities. Compounds 74 and 77 showed weak antibacterial effects against all pathogens. The inhibition zones of 74 and 76 against the six pathogens were in a range between 4 and 6 mm, while that of the positive control ciprofloxacin was in a range between 35 and 40 mm. Compound 77 displayed weak antifungal activity against all agricultural pathogens with inhibition zones of 3-4 mm, while that for the positive control, carbendazim, was 40-45 mm. No effects were observed against the ten tested human tumor cell lines [61].
Chromatographic purification performed on the extract obtained from Emericella sp. SCSIO 05240, which was isolated from deep sea sediments [62], resulted in the identification of a new emerixanthone E (79) and four known metabolites, orange yellow powder (80), citreorosein (81) (   (78) and tajixanthone methonate (52), were obtained from the marine fungus Emericella sp. SCSIO 05240, which was isolated from deep sea sediment [60]. X-ray crystallographic analysis of ruguloxanthone B (54) was performed, aiming at the identification of its stereochemistry. All the isolated compounds were assayed for antibacterial, antifungal and antitumor activities. Compounds 74 and 77 showed weak antibacterial effects against all pathogens. The inhibition zones of 74 and 76 against the six pathogens were in a range between 4 and 6 mm, while that of the positive control ciprofloxacin was in a range between 35 and 40 mm. Compound 77 displayed weak antifungal activity against all agricultural pathogens with inhibition zones of 3-4 mm, while that for the positive control, carbendazim, was 40-45 mm. No effects were observed against the ten tested human tumor cell lines [61].

Bicoumarins
Coumarins consist of a benzopyrone nucleus, which could consist of benzo-α-pyrones to benzoɤ-pyrones. They are found in many plants and help defend against herbivores. They also have an appetite-suppressing effect, which may reduce their consumption by animals. They have various biological effects, including bacteriostatic and anti-tumor effects [66]. Chromatographic purification performed on the extract obtained from Emericella sp. SCSIO 05240, which was isolated from deep sea sediments [62], resulted in the identification of a new emerixanthone E (79) and four known metabolites, orange yellow powder (80) Arugosins A-C (84-86), G and H (87,88) and epiisoshamixanthone (89) were obtained from the endophytic fungal strain Emericella sp. [63]. Moderate cytotoxic activities against several tumor cell lines were observed for 84 and 85 [64].

Bicoumarins
Coumarins consist of a benzopyrone nucleus, which could consist of benzo-α-pyrones to benzo-γ-pyrones. They are found in many plants and help defend against herbivores. They also have an appetite-suppressing effect, which may reduce their consumption by animals. They have various biological effects, including bacteriostatic and anti-tumor effects [66].
Three rare bicoumarins, desertorins A-C (95-97) ( Figure 5), were reported as the mycelia of E. desertorum, which was isolated from Egyptian desert soils. Desertorin A (95) was isolated from acetone extract, while desertorins B and C (96 and 97) were isolated from acidic dichloromethane extract. These metabolites have unsymmetrical 4-methoxy coumarin dimers. Restriction of rotation around the biphenyl linkage is the reason for their optical activity. The final structure was supported by hydrolytic degradation of the prepared diacetylbiphenyl derivatives [67]. In addition, the structure of desertorins C was confirmed by synthesizing its racemic mixture [67].

Meroterpenes
Meroterpenes are natural products, categorized as polyketide-terpene hybrids with often-potent bioactivities. These compounds have unusual molecular architectures. Thus, they have received high levels of attention from either chemists or pharmacologists, particularly for their biological effects (e.g., anti-inflammatory, cytotoxic and antimicrobial) [68].
(HK-ZJ) ( Figure 6) [69]. These compounds are meroterpenoids and isolated from the Aspergillus and Penicillium genera. These derivatives have noteworthy levels of toxicities against insects and also block the nicotinic acetylcholine of cockroaches [70].
breast cancer cell lines.
Diasteltoxins A−C (130−132) and asteltoxin (133) (Figure 9) were reported from marine E. variecolor XSA-07-2 [73]. Compounds 131−133 displayed inhibitory effects against H1299 and MCF7, while they displayed observed inhibitions against thioredoxin reductase (TrxR). Two closely asteltoxin-similar compounds 134 and 135 were isolated from E. variecolor IFM42010 (an asteltoxin-generating fungal species). Both structures have β-ketolactone moieties; surprisingly they have different stereochemistry at carbon-4 ( Figure 9) [74]. The bioassay-directed fractionation of the extract of plant-derived fungus Emericella sp. TJ29 yielded three new terpenoidal polyketide hybrid meroterpenoids (emervaridones A−C (136−138)) and two new polyketides (varioxiranediols A and B (139 and 140)), in addition to 99, 105 and 106 [75]. Compound 105 is a unique carbo-skeleton that bears an emervaridone-type carbocyclic moiety. Compounds 136 and 139 exhibited activity against five drug-resistant microbial pathogens with MIC values in the micrograms per milliliter range. Compound 84 showed inhibition effects against extended spectrum β-lactamases (ESBL)-producing Escherichia coli, which is comparable to that of the clinically used antibiotic amikacin, with an MIC value of 2 µg/mL. Both 136 and 139 showed low toxicities to mammalian cells [75]. (139 and 140)), in addition to 99, 105 and 106 [75]. Compound 105 is a unique carbo-skeleton that bears an emervaridone-type carbocyclic moiety. Compounds 136 and 139 exhibited activity against five drug-resistant microbial pathogens with MIC values in the micrograms per milliliter range. Compound 84 showed inhibition effects against extended spectrum β-lactamases (ESBL)-producing Escherichia coli, which is comparable to that of the clinically used antibiotic amikacin, with an MIC value of 2 µg/mL. Both 136 and 139 showed low toxicities to mammalian cells [75].  [75]. All the isolated compounds showed moderate antimicrobial activities against 3 fungal stains and two bacterial strains with MIC ranges of 25-50 µg/mL, and compounds (141-144) were also effective against P. parasitica and B. subtilis with MIC values in the range of 50-100 µg/mL. It was published that this type of metabolites plays a vital role in protecting its host from parasites, as well as from other predators such as bacteria, fungi and animals [76].

Indole-Derivatives
Paxilline (186) was first published from Penicillium paxili, which was isolated from insectdamaged pecans. Paxilline was also isolated from Acremonium lorii as a biosynthetic precursor of loritrem B, which induces a neurotic syndrome affecting sheep. On theses bases, a further investigation was reported, which was interested in detecting the paxilline in 19 Emericella species, and was found in E. desertorum, E. foveolata, and E. striata [93]. A derivative of paxilline (l'-0acetylpaxilline, 187), was isolated from the mycelium of E. striata. Paxilline induced tremors in cockerels and mice after oral administration (25 mg/kg). Deep investigation indicated that it had an

Sesterterpenes
Sesterterpenes are a group of pentaprenyl terpenoidal derivatives whose structures are derivable from geranyl farnesyl diphosphate. They are a small group of terpenoids obtained from different sources: terrestrial fungi, lichens, higher plants, insects and sponges. Sesterterpenoids exhibit diverse biological effects such as anti-inflammatory, cytotoxicity, anti-tumor and antimicrobial activities [82].
Emericellenes A−E (163-167), unique sesterterpenes (Figure 11), were reported from the Emericella sp. AST0036 isolated from the leaves of Astragalus lentiginosus [83]. From a biosynthesis point of view, metabolites 163-167 may be derived from geranylfarnesyl biphosphate; moreover, they represent an unprecedented class of sesterterpenes bearing an emericellane-type bicyclic system. 163-167 are found to be non-toxic to a set of several cell lines.

Indole-Derivatives
Paxilline (186) was first published from Penicillium paxili, which was isolated from insect-damaged pecans. Paxilline was also isolated from Acremonium lorii as a biosynthetic precursor of loritrem B, which induces a neurotic syndrome affecting sheep. On theses bases, a further investigation was reported, which was interested in detecting the paxilline in 19 Emericella species, and was found in E. desertorum, E. foveolata, and E. striata [93]. A derivative of paxilline (l'-0-acetylpaxilline, 187), was isolated from the mycelium of E. striata. Paxilline induced tremors in cockerels and mice after oral administration (25 mg/kg). Deep investigation indicated that it had an effect on the electromyographic (EMG) characteristics of smooth muscle in the reticulorumen of conscious sheep [93].
Emindoles  are indoloditerpenes, identified from the mycelium of E. purpurea [100]. The common feature among these metabolites is the presence of 1,1-dimethyl-2propenyl residues at C-2 or N-1 in the indole moiety. Those metabolites are entirely biosynthesized from geranylgeraniol and a tryptophan biosynthetic pathway [100,101].
Six isoindoline-containing meroterpenes, emericellolides A−C (205−207) and emeriphenolicins E−G (208−210), were obtained from a culture of the endophytic fungus E nidulans HDN12-249. This fungus was isolated from the leaves of Tamarix chinensis, which was collected from Laizahau Bay [102]. Compounds 204−207 have a unique macrolide carbo-skeleton of an unusual L-glutamate fragment, an isoindolone and a sesquiterpene moiety, while the structures of emeriphenolicins E−G (208−210) had two farnesyl groups attached to one isoindolone unit (Figure 13), which are rare isoindolone-derived meroterpenoids. The cytotoxic effects of compounds (208−210) were assessed against HeLa, A549 and HCT-116, human cancer cell lines, with adriamycin as a positive control. Compound 205 showed cytotoxic effects with IC50 values of 4.7, 12.04 and 33.05 µM, respectively. However, the rest of the compounds were not active (IC50 > 50 µM) [102].

Piperazines
Piperazines are an organic substance that consists of a six-membered ring with two nitrogen atoms at opposite positions in the ring. They are a big class of chemical compounds with different pharmacological properties, which contains a piperazine group [103]. Epidithiodioxopiperazine is a group of alkaloids with an amazing array of molecular structure and potent bio-activities [104][105][106].
A macrocyclic epidithiodioxopiperazine, emestrin (211), was reported from E striata . This strain was isolated from the seeds of Cuminum cymium, which were collected from Nepal ( Figure 15) [104,105]. The chemical structure was obtained by interpretation of the spectral data of 1 H-, 13 C-NMR and MS. An X-ray was performed after obtaining crystals of emestrin from methanol, which were grown in an acetone-methanol solution as prisms. The planarity between the two aromatic rings was not so good, because of the formation of the 15-member ring [106]. Six isoindoline-containing meroterpenes, emericellolides A−C (205−207) and emeriphenolicins E−G (208−210), were obtained from a culture of the endophytic fungus E nidulans HDN12-249. This fungus was isolated from the leaves of Tamarix chinensis, which was collected from Laizahau Bay [102]. Compounds 204−207 have a unique macrolide carbo-skeleton of an unusual L-glutamate fragment, an isoindolone and a sesquiterpene moiety, while the structures of emeriphenolicins E−G (208−210) had two farnesyl groups attached to one isoindolone unit (Figure 13), which are rare isoindolone-derived meroterpenoids. The cytotoxic effects of compounds (208−210) were assessed against HeLa, A549 and HCT-116, human cancer cell lines, with adriamycin as a positive control.

Piperazines
Piperazines are an organic substance that consists of a six-membered ring with two nitrogen atoms at opposite positions in the ring. They are a big class of chemical compounds with different pharmacological properties, which contains a piperazine group [103]. Epidithiodioxopiperazine is a group of alkaloids with an amazing array of molecular structure and potent bio-activities [104][105][106].
A macrocyclic epidithiodioxopiperazine, emestrin (211), was reported from E striata . This strain was isolated from the seeds of Cuminum cymium, which were collected from Nepal ( Figure  15) [104,105]. The chemical structure was obtained by interpretation of the spectral data of 1 H-, 13 C-NMR and MS. An X-ray was performed after obtaining crystals of emestrin from methanol, which were grown in an acetone-methanol solution as prisms. The planarity between the two aromatic rings was not so good, because of the formation of the 15-member ring [106]. Further investigation of a filtrate of the same culture led to the identification of violaceic acid. Emestrin (211) inhibited the growth of Gibberella zeae and Penicillium expansum (1.0 µg per disc) with 12 and 10 mm inhibition circle diameters, respectively. The MIC values of 80 against G. zeae and P. expansum were 10 and 2.5 µg/mL, respectively [105,106].
Emeheterone (213) was the first pyrazinone derivative that has been derived from two aromatic amino acid moieties. It was isolated from the dichloromethane extract of E heterothallica, strain ATCC 16824, along with dithiosilvatin (214) and a dihydroisocoumarin (Stellatin, 215) [108].

Cyclic Peptides and Depsipeptides
Peptides are a chain of amino acids linked by amide bonds. They include, but are not limited to, dipeptides, tripeptides and tetrapeptides. A polypeptide is a long, continuous, and unbranched peptide chain [113]. Depsipeptides are basically peptides, where some of the cyclic peptide amide functions are replaced by the corresponding esters [113]. Cyclic peptides are mainly isolated from terrestrial microorganisms and marine organisms [112].

Cyclic Peptides and Depsipeptides
Peptides are a chain of amino acids linked by amide bonds. They include, but are not limited to, dipeptides, tripeptides and tetrapeptides. A polypeptide is a long, continuous, and unbranched peptide chain [113]. Depsipeptides are basically peptides, where some of the cyclic peptide amide functions are replaced by the corresponding esters [113]. Cyclic peptides are mainly isolated from terrestrial microorganisms and marine organisms [112].
Unguisins A-C (228-230) were reported as the first cyclic heptapeptides of the gamma aminobutyric acid (GABA) skeleton, isolated from the marine-derived fungus E. unguis, which was isolated from a Venezuelan cannonball jellyfish, Stomolopus meliagris [114,115]. 228 and 229 ( Figure 15) displayed moderate effects against Staphylococcus aureus, but no activity against Vibrio parahaemolyticus. Furthermore, the exogenous addition of L-leucine to the culture resulted in the production of unguisin D (231), which was detected by ion trap mass chromatography (LC-QIT-MS) [116]. Cyclic peptides are bio-synthesized through either ribosomal or nonribosomal mechanisms. The high content of D-amino acids in unguisins A and B strongly supports the indication of a nonribosomal origin for these metabolites. Fungi utilize GABA as a carbon and nitrogen source, and it is associated with some of the major features of the cell cycle, including sporulation, differentiation and development. The presence of GABA in (228-230) induces an enhanced conformational mobility relative to the cyclic peptides derived solely from R-amino acids. Such conformation-biological activity dependence strengthens the occurrence of GABA in 228-230 [114][115][116].

Conclusions and Future Prospective
In terms of the genus Emericella, a careful review of the major carbon skeletons revealed the involvement of one or several biosynthetic pathways involved in the production of diverse metabolites. It proved to be a productive genus, as 236 metabolites have been isolated and classified into polyketides (azaphilones, cyclopentenone pigments, dicyanides, furan derivatives, phenolic ethers, xanthones and anthraquinones); Shikimate derivatives (bicoumarins); Mevalonate derivatives (meroterpenes, sesquiterpenes, sesterterpenes and steroids) and amino acids derivatives (alkaloids (indole-derivatives, isoindolones and piperazine) and peptides (depsipeptides)).
Among the 236 secondary metabolites isolated, almost 30% were not examined for their biological impacts and 43% showed weak to absent activities in the conducted bioassay (mainly antimicrobial and cytotoxicity assays). However, there are several bright and motivating examples encouraging more bio-investigation of the Emericella isolates. Stromemycin (a xanthone derivative) was patented for its metalloproteinase-inhibiting effect. Falconensins E, K and M displayed inhibitory effects against the enhancement of ear edema in mice, which was comparable with indomethacin. Tajixanthone hydrate and 14-methoxy tajixanthone-25-acetate have been shown to be active as doxorubicin toward KATO3 and BT474. Ruguloxanthone A and 15-chlorotajixanthone hydrate displayed a potent inhibition of the calmodulin-sensitive cAMP phosphodiesterase (PDE1). This effect is comparable with that of chlorpromazine, a well-known Calmodulin (CaM) inhibitor. As far as reported, neither clinical trials nor randomized control trials (RCTs) have been conducted on these compounds.
It is interesting to note the high conjugation system that was observed amongst the yellowcolored cyclopentenone derivatives. This is an important observation, which aims at encouraging researchers to recall these compounds as antioxidants and anti-tumour. Moreover, indoloterpenes are well-known biologically active compounds (chiefly isolated from plant families such as Apocynaceae) formed from tryptophan and terpenoid substrates. The presence of tryptophan derivatives (e.g., Emindoles) could lead to the discovery of an agent that improves cognition and reduces insomnia and depression. It is also noteworthy that nine peptides were reported as having Unguisin C (230) allowed the replacement of D-alanine with L-serine, leading to a peptide with more hydrophilicity, based on the oxidation of the methyl group in alanine to produce serine [116]. Unguisines 228-230 are the first naturally occurring compounds incorporating GABA in a cyclic peptide structure.
Incorporation of the cyanobacterium Scytomena ocellatum, with added elicitors (e.g., fungal wall polysaccharides), led to increasing the production of tolytoxin [120]. The marine fungus Phomopsis asparagi cultured in the presence of the spongal product jasplakinolide, which redirected its synthetic pathway to yield chaetoglobosins. Mixed cultivation of the marine-derived fungus Libertella sp. with a marine strain with α-proteobacterium, closely related to Thalassospira lucentensis, yielded new cytotoxic diterpenoids. Desferritriacetylfusigen (234) was one of the natural group of a cyclic triester of the three molecules of N-acetyl-N-(cis-5-hydroxy-3-methylpent-2-enoyl)-N-hydroxy-L-ornithine, which are known for their antibiotic effects. These compounds are detected in most fungal species [121,122]. Echinocandin E (235) was identified from E. quadrilineata and was reported for the first time as producing echinocandin B (236) [123].
Based on the scientific literature published on the genus Emericella and some other fungal species [124][125][126][127][128], fungal metabolites could replace some conventional shelf drugs that are common in the market with extremely few drawbacks, for example cordycepin (a nucleoside obtained from Cordyceps militaris) replaces glyophosate and benzoic acid. Cordycepin showed a maximum inhibition on the germination and growth of Raphanus sativus (radish) (IC 50 = 0.052-0.078 mg/mL).

Conclusions and Future Prospective
In terms of the genus Emericella, a careful review of the major carbon skeletons revealed the involvement of one or several biosynthetic pathways involved in the production of diverse metabolites. It proved to be a productive genus, as 236 metabolites have been isolated and classified into polyketides (azaphilones, cyclopentenone pigments, dicyanides, furan derivatives, phenolic ethers, xanthones and anthraquinones); Shikimate derivatives (bicoumarins); Mevalonate derivatives (meroterpenes, sesquiterpenes, sesterterpenes and steroids) and amino acids derivatives (alkaloids (indole-derivatives, isoindolones and piperazine) and peptides (depsipeptides)).
Among the 236 secondary metabolites isolated, almost 30% were not examined for their biological impacts and 43% showed weak to absent activities in the conducted bioassay (mainly antimicrobial and cytotoxicity assays). However, there are several bright and motivating examples encouraging more bio-investigation of the Emericella isolates. Stromemycin (a xanthone derivative) was patented for its metalloproteinase-inhibiting effect. Falconensins E, K and M displayed inhibitory effects against the enhancement of ear edema in mice, which was comparable with indomethacin. Tajixanthone hydrate and 14-methoxy tajixanthone-25-acetate have been shown to be active as doxorubicin toward KATO3 and BT474. Ruguloxanthone A and 15-chlorotajixanthone hydrate displayed a potent inhibition of the calmodulin-sensitive cAMP phosphodiesterase (PDE1). This effect is comparable with that of chlorpromazine, a well-known Calmodulin (CaM) inhibitor. As far as reported, neither clinical trials nor randomized control trials (RCTs) have been conducted on these compounds.
It is interesting to note the high conjugation system that was observed amongst the yellow-colored cyclopentenone derivatives. This is an important observation, which aims at encouraging researchers to recall these compounds as antioxidants and anti-tumour. Moreover, indoloterpenes are well-known biologically active compounds (chiefly isolated from plant families such as Apocynaceae) formed from tryptophan and terpenoid substrates. The presence of tryptophan derivatives (e.g., Emindoles) could lead to the discovery of an agent that improves cognition and reduces insomnia and depression. It is also noteworthy that nine peptides were reported as having cyclic heptapeptides containing GABA in the ring, which opens the door to the discovery of new antifungal agents. Other carbon skeletons such as phenols, meroterpenes and ethers were published from the genus Emericella, and there is still potential to find new carbon skeletons and/or biological rules, proving the value of analyzing fungi to promote drug discovery.
Funding: This research received no external funding.