The Chemistry and Pharmacology of Fungal Genus Periconia : A Review

: Periconia is ﬁlamentous fungi belonging to the Periconiaceae family, and over the last 50 years, the genus has shown interest in natural product exploration for pharmacological purposes. Therefore, this study aims to analyze the different species of Periconia containing natural products such as terpenoids, polyketides, cytochalasan, macrosphelides, cyclopentenes, aromatic compounds, and carbohydrates carbasugar derivates. The isolated compound of this kind, which was reported in 1969, consisted of polyketide derivatives and their structures and was determined by chemical reaction and spectroscopic methods. After some years, 77 compounds isolated from endophytic fungus Periconia were associated with eight plant species, 28 compounds from sea hare Aplysia kurodai, and ten from endolichenic fungi Parmelia sp. The potent pharmacological agents from this genus are periconicin A, which acts as an antimicrobial, pericochlorosin B as an anti-human immunodeﬁciency virus (HIV), peribysin D, and pericosine A as cytotoxic agents, and periconianone A as an anti-inﬂammatory agent. Furthermore, information about taxol and piperine from Periconia producing species was also provided. Therefore, this study supports discovering new drugs produced by the Periconia species and compares them for future drug development.


Introduction
Periconia is filamentous fungi belonging to the Periconiaceae Family (Ascomycetes), and according to Index Fungorum [1], there are 202 epithets with 12 varieties. However, only 40 species of the Periconia genus are currently recognized [2][3][4]. This genus has spread as endophytes and saprobes in plants with multiple habitats and has been shown to be plant pathogens. Leukel [5] reported that Milo disease, found in crops, can be caused by one species of Periconia, P. circinata (L. mangin). Interestingly, these fungi can live in the gastrointestinal tract of animals [6] and as an endolinchenic fungus [7][8][9].
The study has been reported in at least two main areas: (1) chemical and bioactivities studies of the isolated secondary metabolites from different species of fungi and various host origins. The species produce secondary metabolites with multiple biosynthesis pathways. (2) Molecular and genomic studies for species identification and revised genus annotation. A comprehensive review of the Periconia fungal genus for chemical content and its pharmacological aspects between these studies has not been conducted.
as an antimycobacterial agent. These piperidine derivates (2) were treated for multidrugresistant Mycobacterium tuberculosis and an atypical mycobacterium M. smegmetis with a Minimum Inhibitory Concentration (MIC) 1.74 and 2.62 µg/mL (strong activity), respectively, (control positive or negative are not included). In this context, the scientific community increased interest in natural product exploration from endophytic fungi and other fungal sources, especially for the Periconia genus.

Terpenoids
Some species of Periconia appear to produce terpenoids and have engaging pharmacological activities. According to Bach and Rohmer [21], the starting unit of terpenoid is from the five-carbon precursor unit, isopentenyl diphosphate (IPP), and dimethylallyl diphosphate (DMAPP). This is continued with a head-to-tail condensation repetitive reaction of IPP and DMAPP with prenyltransferases. These produce prenyl diphosphates of increasing length: geranyl-, farnesyl-, geranylgeranyl-diphosphate that lead to synthesizing the different isoprenoids and products. There are thirty-nine terpenoid compounds isolated from this genus. This includes six monoterpenoids (carene and menthene-types), two diterpenoids (fusicoccane-type), twenty-five sesquiterpenoids (cadinane, and eremophilane-types), one norsesquiterpenoid, one meroterpene (diterpenoid alkaloid), and one steroid.
Furthermore, Periconia from this plant was demonstrated unequivocally for taxol production by a semi-synthetic medium. The fungi were fermented with a special medium through an activator of metabolism. Several compounds studied include serinol, phydroxybenzoic acid, and a mixture of phenolic acids. Benzoic acid, known as not a taxol precursor, activates taxol production metabolism in Periconia. This was conducted at 0.01 mM with the best yield concentration 831 ± 27 ng L −1 through spectroscopic and immunological methods.
According to Verma et al. [12], Periconia can also produce compounds similar to its host. For example, Piperine (2), an alkaloid ( Figure 1) with many pharmacological activities obtained from the ethanol extract of fruits Piper longum (only consist 3-5% dry weight basis), also being produced by Periconia. The 2 were obtained from ethyl acetate extract after four weeks of fermentation on a potato dextrose broth. The isolated 2 then crystallized, elucidated by single-crystal X-ray crystallography, and studied extensively as an antimycobacterial agent. These piperidine derivates (2) were treated for multidrug-resistant Mycobacterium tuberculosis and an atypical mycobacterium M. smegmetis with a Minimum Inhibitory Concentration (MIC) 1.74 and 2.62 µg/mL (strong activity), respectively, (control positive or negative are not included). In this context, the scientific community increased interest in natural product exploration from endophytic fungi and other fungal sources, especially for the Periconia genus.

Terpenoids
Some species of Periconia appear to produce terpenoids and have engaging pharmacological activities. According to Bach and Rohmer [21], the starting unit of terpenoid is from the five-carbon precursor unit, isopentenyl diphosphate (IPP), and dimethylallyl diphosphate (DMAPP). This is continued with a head-to-tail condensation repetitive reaction of IPP and DMAPP with prenyltransferases. These produce prenyl diphosphates of increasing length: geranyl-, farnesyl-, geranylgeranyl-diphosphate that lead to synthesizing the different isoprenoids and products. There are thirty-nine terpenoid compounds isolated from this genus. This includes six monoterpenoids (carene and menthene-types), two diterpenoids (fusicoccane-type), twenty-five sesquiterpenoids (cadinane, and eremophilane-types), one norsesquiterpenoid, one meroterpene (diterpenoid alkaloid), and one steroid.
Further isolation of peribysins from Periconia was conducted by Inose et al., [37], where it was shown that peribysins O-Q (21-23) were obtained from the P. macropinosa terrestrial herbaceous plant Kanagawa in 2018. The relative structures elucidate with a quantitative NOE experiment. The absolutes structures of 21 and 22 were obtained using the modified Mosher's method and 23 with the ECD exciton coupling theory. Additionally, theoretical ECD calculations were conducted for 21-23 [37]. Reconfirmation of peribysin Q absolute structures were performed by Athawale et al., [34] through enantiospesific total synthesis from (+)-nootkatone.
Several compounds from Periconia have hybrid structural molecules as meroterpenes. This chemical investigation showed a class of diterpenoid alkaloids, where pericolactines A-C (36)(37)(38), the first nitrogen-containing fusicocccane diterpenoids are isolated from Periconia sp. (No. 19-4-2-1) endolichenic fungus Parmelia sp. Furthermore, the structures of 39-41 and their absolute configurations were determined by spectroscopic analyses and quantum chemical ECD calculation. These compounds represent an unusual 5-5-8-5 tetracyclic ring system. The systems were derived from geranylgeranyl diphosphate (GGDP) and serine conjugated biosynthesis. They belong to the atypical diterpenoid alkaloids [7]. Meanwhile, another hybrid molecule meroterpenes namely periconones B-E (42)(43)(44)(45) were isolated from EtOAc extract Periconia sp. F-31 through semi-preparative HPLC. Their structures and absolute configurations were established by extensive spectroscopic data analysis and electronic circular dichroism (ECD). It was suggested that these hybrids are derived from typical polyketide-terpenoid pathways formed from one acetyl-CoA starter and five malonyl-CoA extenders coupled with one C5 unit [43]. A summary of the number and types of terpenoids obtained is demonstrated in Table 1. Meanwhile, Figures 2 and 3 showed the structure of the terpenoids compounds.
represent an unusual 5-5-8-5 tetracyclic ring system. The systems were derived from geranylgeranyl diphosphate (GGDP) and serine conjugated biosynthesis. They belong to the atypical diterpenoid alkaloids [7]. Meanwhile, another hybrid molecule meroterpenes namely periconones B-E (42)(43)(44)(45) were isolated from EtOAc extract Periconia sp. F-31 through semi-preparative HPLC. Their structures and absolute configurations were established by extensive spectroscopic data analysis and electronic circular dichroism (ECD). It was suggested that these hybrids are derived from typical polyketide-terpenoid pathways formed from one acetyl-CoA starter and five malonyl-CoA extenders coupled with one C5 unit [43]. A summary of the number and types of terpenoids obtained is demonstrated in Table 1. Meanwhile, Figures 2 and 3 showed the structure of the terpenoids compounds.

Polyketides
Polyketides are a secondary metabolites group with a large diverse structure derived from the poly-β-keto chain [44,45]. They are biosynthesized from acyl-CoA thioesters and undergo repetitive Claisen condensation reactions catalyzed by polyketide synthases (PKSs), which are homologous to fatty acid synthases (FASs) [46]. These compounds are usually used as pharmaceutical agents due to their antibacterial, antifungal, immunosuppressive and antitumor properties [44]. Moreover, polyketides can be produced from diverse microorganisms such as Periconia. Twenty twenty-one polyketide compounds were isolated from Periconia, including ten cytochalasans and eleven other polyketide derivatives.
Polyketides from Periconia genus are isolated from the same natural source known as A. muricata. The first were periconiasin compounds, which as a cytochalasan group play a role in fungi and plants to compete and act as an inhibitor of spore germination, hyphal growth, and sporulation of B. cinerea [47]. These compounds were also known as a group of polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolites. Periconiasins A-C (46-48) ( Figure 4) were first isolated with the 9/6/5 tricyclic ring system [48], and their structures were determined using 1 H-NMR, 13 C-NMR, DEPT, HMBC, 1 H-1 H COSY, HSQC, and IR spectroscopic data. Furthermore, the absolute configuration of 46 was determined using single-crystal X-ray diffraction data, which yielded 3S, 4R, 5S, 8S, 9S, and 17S configurations. In addition, the circular dichroism (CD) spectrum confirmed the negative Cotton effect at 301.5 nm for 39, 296 nm for 47, and 294 nm for 48, where the n → π* transition indicates the 9S configuration for 46-48. A comprehensible explanation for the unprecedented ring system was supported by the proposed biosynthesis, which occurs from the attachment of an unusual seven acetate/malonate polyketide backbone to one leucine moiety. This was conducted by PKS-NRPS, followed by Diels-Alder and other reactions [48].
Meanwhile, pericoannosin B (57) was isolated in 2016 from the same source and it is known to be the stereoisomer of pericoannosin A (56) [52]. According to Zhang et al., [52], the non-stereoselective Claisen reaction and hemiacetal reaction led to the yield of stereoisomer pairs. The structure of 57 was determined with extensive spectroscopic analysis of hexahydro-1H-isochromen-5-isobutylpyrrolidin-2-one structure skeleton. Meanwhile, the absolute configuration was determined using CD spectra analysis to yield 2R,3S,5S,10R,11R,16S [52].
Subsequently, the investigation for the pericoannosins that was guided by a biosynthetic hypothesis led to the isolation of pericoannosins C-F (58-61) [51]. In this case, Fan et al. [51] proposed the possibility of another Diels-Alder reaction which was conducted by different pairs of conjugated diene and double bond from the same precursor of pericosins and pericoannosins. Their structures were elucidated using 1 H-NMR, 13 C-NMR, DEPT, HSQC, HMBC, 1 H-1 H COSY, and NOESY spectroscopic data. The absolute configurations of 58 were determined as 2R,4R,5S,10S,13R,16S using ECD spectra and TD-DFT comparison method at the B3LYP/6-31G(d) level. By analogy, the absolute configurations of 59-61 were also determined by calculating the ECD [51].
Some polyketide-peptide hybrid compounds pathways were obtained from P. circinata (Mangin) Sacc with the part origin and crown root of the grain sorghum, Sorghum bicolor (L.). The first compound was circinatin (66), which has a biogenetic relationship with PCtoxins. It is the important pathogenicity factor from endophytic fungi P. circinata causing disease symptoms on its host plant, which is the cultivars of sorghum [55]. After two years, Macko et al., isolated the suspected toxins such as peritoxin A-B (67-68), along with periconin A-B (69-70) [56]. From the structural comparison studied, circinatin (66) was reported to be the precursor for the formation of peritoxin A-B (67-68) [56].
Furthermore, macrosphelides, macrolide, and cyclopentenone compounds were also isolated from the Periconia genus. These compounds were synthesized through the polyketide pathway [57][58][59]. Modiolide A (71) is a macrolide compound isolated from P. siamensis and obtained from the leaves of T. lafifolia [60,61]. The relative structures were determined by IR, NMR, and Mass Spectra [60]. Meanwhile, crystal structures were examined by Fun et al., [61], and the absolute configurations at C4, C7, and C9 were assigned and determined by the exciton chirality method using the p-methoxycinnamoyl chloride treatment. For the first time, 71 was obtained as a colorless oil from fungus Paraphaeosphaeria sp. (strain N-119) derived from a marine horse mussel Modiolus auriculatus [62].
Macrosphelides is another macrolide member isolated from P. byssoides symbionts of sea hare A. kurodai and during the chemical investigation, a total of ten were isolated. Numataetal. [6] reported the macrosphelides E, F-H (74, 76-78) along with C (73), and their structures were established based on 1 H-NMR, 13 C-NMR, DEPT, 1 H-1 H COSY, 1 H-13 C COSY, and HMBC spectral analysis. Furthermore, these compounds were re-isolated along with macrosphelide A (72) and I (79) by Yamada et al. [63]. In this report, the determination of the absolute stereochemistry of 74, 76, 77, and 79 were conducted using 1D and 2D NMR spectral analysis and some chemical transformations. Furthermore, the absolute configuration of macrosphelide C (73) was determined using X-ray analysis and application of the modified Mosher method [63]. The next macrosphelide is seco-macrosphelide E (75), which has a similar configuration as macrosphelide E, followed by H (78) and L (79) along with their absolute stereochemistry based on spectroscopic analysis [64,65]. The recent investigation of macrosphelide compounds from Periconia was conducted in 2007, where macrosphelide M (81) was isolated along with the determination of its absolute stereochemistry. This was conducted using 1D and 2D NMR techniques and some chemical transformations including the modified Mosher's method [33].
The carbohydrate carbasugar derivates pericosine A (100) and B (101) were isolated from P. byssoides in the sea hare A. kurodai through reverse-phase HPLC [6]. In addition, these compounds were re-isolated in 2007 from the same natural source along with pericosine C-E (102-104), which was separated as enantiomeric mixtures [66]. Spectroscopic analyses including NMR, MS, and IR led to the elucidation of their structures. Additionally, the structure of pericosine D (103) was revised by (-)-quinic acid precursor synthesis to methyl (3R,4R,5S,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate [67]. Table 1 shows the summary of the number and types of aromatic compounds as well as carbohydrate derivates obtained from the genus Periconia, while Figure 6 shows the structure of compounds.
Sci. Pharm. 2021, 89, x FOR PEER REVIEW 12 of 28 pericochlorosin B (99) [10]. The structures of all the aromatic compounds were determined by extensive 1D and 2D NMR for relative configurations. The carbohydrate carbasugar derivates pericosine A (100) and B (101) were isolated from P. byssoides in the sea hare A. kurodai through reverse-phase HPLC [6]. In addition, these compounds were re-isolated in 2007 from the same natural source along with pericosine C-E (102-104), which was separated as enantiomeric mixtures [66]. Spectroscopic analyses including NMR, MS, and IR led to the elucidation of their structures. Additionally, the structure of pericosine D (103) was revised by (-)-quinic acid precursor synthesis to methyl (3R,4R,5S,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohexene-1carboxylate [67]. Table 1 shows the summary of the number and types of aromatic compounds as well as carbohydrate derivates obtained from the genus Periconia, while Figure  6 shows the structure of compounds.

Pharmacological Activities
Some metabolites of the genus Periconia have shown pharmacological activities for a long time. This genus has tremendous activities such as acting as antimicrobial (antibacterial, antifungal and anti-HIV), potent cytotoxicity, and anti-inflammatory agents [6-9,11-13,43,53,62].

Antimicrobial Activity
The compounds from the Periconia genus have shown antimicrobial activities for numerous bacterial, fungi, and also human immunodeficiency virus. Bhilabutra et al. [60] accessed antibacterial properties from P. siamensis CMUGE015 associated with T. latifolia

Pharmacological Activities
Some metabolites of the genus Periconia have shown pharmacological activities for a long time. This genus has tremendous activities such as acting as antimicrobial (antibacterial, antifungal and anti-HIV), potent cytotoxicity, and anti-inflammatory agents [6-9,11-13,43,53,62].

Antimicrobial Activity
The compounds from the Periconia genus have shown antimicrobial activities for numerous bacterial, fungi, and also human immunodeficiency virus. Bhilabutra et al. [60] accessed antibacterial properties from P. siamensis CMUGE015 associated with T. latifolia in modiolide A (71) and 4-chromanone as well as 6-hydroxy-2-methyl-(5CI) (88). The metabolites 71 inhibit more Gram-positive bacteria rather than Gram-negative. The results showed that the third compound could inhibit Bacillus cereus, Listeria monocytogenes, Methicillinresistant Staphylococcus aureus (MRSA), Pseudomonas aeroginosa, and Escherichia coli with Minimum Inhibitory Concentration (MIC) value of 3.12, 6.25, 25, 12.5 and 50 µg/mL, respectively. As a comparison, penicillin G can be used for standard control with MIC values 6.25, 6,25, 25, 12,5, and 50 µg/mL, respectively. These bacteria are common human pathogen agents, which can cause foodborne disease, listeriosis, skin infection, and lung disease [60]. Furthermore, the second compound from this fungi, 88 has antibacterial activity with MIC values of 6.25, 12.5, 50, 12.5 and 100 µg/mL, respectively [62]. The similar structure of this lactone compound, tuckolide, synthesized by Andrus and Shih, acts as an inhibitor for cholesterol in liver cells [68].
HIV is a virus that attacks the human immune system, and if it is not treated, can lead to AIDS (Acquired Immunodeficiency Syndrome). Liu et al. [10] accessed the isolated compound Pericochlorosin B (99) for anti-HIV activity. The IC 50 value of 99 is 2.2 µM compared to positive control efavirenz with an IC 50 value of 1.4 nM by Firefly Luciferase Assay System. The other compounds, pericochlorosin A (98) and pericoannosin G (62), were also tested for the same assay, but they have weak activity with an IC 50 value of >100 µM [10]. A meroterpene, periconone B (42) has weak anti-HIV activity with an IC 50 value of 18 mM [43]. Additionally, cytochalasans from Periconia, periconiasin F (51) [49], G (52) and J (55) [51] have weak activity with an IC 50 value of 29.2, 67.0, 25.0 µM, respectively. Other polyketides, Pericoannosin B (57) [52], C (58), D (59) and F (61), also have weak activity with IC 50 with a value > 100, 15.5, 13.5 and 81.5 µM, respectively. From this genus, periconicin A (9) has antimicrobial potential, and pericochlorosin B (99) can be used as an anti-HIV agent in future developments.

Conclusions and Future Perspectives
In summary, after being researched for almost 50 years, Periconia fungal genus was found to live in a different ecological niche such as plants, lichens, and animals. Moreover, this fungus can produce plenty of secondary metabolites with various natural products such as terpenes, polyketides, aromatic compounds, and carbohydrate derivates. Owing to these exciting finds, eventually, the fungus has excellent potential to be a rich source for natural product exploration and can be studied for pharmacological agents.
All these compounds have a diverse pharmacological activity that makes research of this genus more interesting. One exciting fact is that Periconia was studied for taxol and piperine production. This fungus can produce these host compounds (high-level plants) and if it lives as endophytes. In addition, it turns out that this Periconia fungus can produce new secondary metabolites that differ from the characteristics of the metabolites of the host plant. This tremendous discovery makes fungus a gold mine for natural product exploration, and it is fascinating to study their pharmacological activity.
Several potential compounds from the Periconia which have pharmacological activity are periconicin A (9), which acts as an antimicrobial, pericochlorosin B (99) possesses anti-HIV properties, peribysin D (14), and pericosine A (100), has vigorous cytotoxic activity, periconianone A (23) can be used as an anti-inflammatory. However, further studies are needed for the action mechanism of apoptosis study. For example, the cytotoxic mechanism of the carbasugar derivate (100). There are intrinsic mechanism studies of mitochondria-dependent cytochrome C, caspase activation, and extrinsic mechanisms of apoptosis (activation of tumor necrotic factor). The mechanism of how this compound can induce apoptosis may lead to new perspectives. On the other hand, the study of the mechanism of anti-inflammatory sesquiterpenoid compounds (25,26,37) in BV2 G13 microglia cells needs to be continued for further testing, such as the production of nitrite, iNOS (inducible nitric oxide synthase) mRNA, and protein expression.
Further intensive investigations are recommended concerning how the Periconia fungus may produce other new compounds by genetic manipulation. There are mutasynthesis, heterologous expression, and metabolic engineering at genomic level, transcriptome, and proteome (enzyme inhibition, direct precursor biosynthesis, substrate feeding) level treatments. Furthermore, the modification of fungal media can also be carried out using the principle of OSMAC (one strain many compounds), epigenetic modification, semi-synthetic media, and even by Co-Culture with other microorganisms. This treatment may induce the silent gene of the Periconia fungus to produce another interesting new compound. Furthermore, omics level studies (metabolomics) using LC-MS or GC-MS tools can identify the new compounds and compare all the treatments. Lastly, the discoveries of new compounds from fungi such as Periconia are always interesting for pharmacological studies and future lead compounds. Notes: * Several compounds with MS predictio.