Prospective Leads from Endophytic Fungi for Anti-Inflammatory Drug Discovery

Abstract

A wide array of therapeutic effects has been exhibited by compounds isolated from natural sources. “Bio-actives of endophytic origin” is a recently explored area that came into recognition over the last 2 decades. Literature search on the secondary metabolites of endophytes have shown several pharmacologically active compounds especially anti-inflammatory compounds, which have been reviewed in the present paper. The article is structured based on the chemical classification of secondary metabolites. The compounds were identified to possess activity against a total of 16 anti-inflammatory targets. The most common targets involved were NO, TNF-α, and inhibition of total ROS. Further, the article gives a detailed insight into the compounds, their endophytic source, and anti-inflammatory target as well as potency. The contents of the article cover all the scientific reports published until Feb. 2019. Thus 118 compounds and 6 extracts have been reported to be obtained from endophytic sources showing anti-inflammatory activities. Amongst these, herbarin, periconianone A, and periconianone B were identified as the most potent compounds in terms of their IC₅₀ values against NO inhibition.

Key words

endophytes - fungi - anti-inflammation - cytokines - herbarin - periconianone - phytochemicals

Abbreviations

AI: anti-inflammatory

COX: cyclooxygenase

IFN-γ: interferon gamma

IL: interleukin

LOX: lipoxygenase

LPS: lipo polysaccharide

PG: prostaglandin.

ROS: reactive oxygen species

TNF-α: tumor necrosis factor alpha
 

Introduction

Endophytes are the nonpathogenic fungi or bacteria that reside and colonize the inner tissues of plants by maintaining a symbiotic relationship with their host plants. They provide immunity to the plants during biotic and abiotic stresses by providing better adaptability to them. Microbial natural products of endophytic origin is a less explored field, yet it has immense possibilities to provide a huge library of novel bioactive lead molecules for drug discovery [1]. Also, endophytes are found to contribute largely to the production of bioactive plant secondary metabolites. Thus endophytic bacteria and fungi can serve as an alternative natural source for the production of bioactive metabolites [2].

Recently, research interest toward endophytic fungi has increased due to the novelty of molecules that are secreted by them. Such molecules have been reported to possess a wide variety of pharmacological activities including anti-bacterial, anti-fungal, cytotoxic, AI, proliferative, antioxidant, antiviral, anti-tubercular, etc. [1].

Inflammation, a local response to chemical/physical irritants, infection, or injury to tissues, can lead to a series of processes involving tissue repair, proliferation, collagen and elastin production, and cytokines release [3]. Cytokines such as IL-1, IL-6, IL-12, IL-18, INF-γ, TNF-α and the granulocyte macrophage colony-stimulating factor promote inflammation and are termed as pro-inflammatory cytokines. On the other hand, those that suppress the pro-inflammatory cytokines expressions such as IL-4, IL-10, IL-13, IFN-α, and transforming growth factor are termed as AI cytokines. A balance between these 2 is essential, and any disruption in the balance can lead to the promotion of inflammation, tissue destruction, or loss of essential functionality of tissues [4]. Pro-inflammatory cytokines including IL and TNF mediate a variety of hyperalgesic states. They are also related to various illness responses such as endocrinal, behavioral, neural, and physiological changes. These responses are a direct or indirect consequence of the production of IL such as IL-1 and IL-6 and TNF released during inflammation, injury, and infection [3].

PG, and cyclooxygenases 1 and 2 (COX-1 and COX-2) have been synonymously linked to inflammation and cause major inflammation-related disorders. COX-2 is a well-known target for AI and analgesic drug discovery. The well-established NSAIDs work through the pathway of inhibition of COX enzyme. COX-2 is an enzyme that gets activated by cytokines and endotoxins. Thus compounds displaying inhibition of COX can serve as promising AI agents [5]. The enzyme COX-2 is believed to trigger inflammatory responses in the CNS by a series of complex reactions in the neurons of the spinal cord and other associated parts of the CNS. This, in turn, results in the elevation of PGE-2 levels in cerebrospinal fluid [6].

ROS like superoxides, hydroxyl, and hydrogen peroxide anions have been responsible for several degenerative diseases like rheumatoid arthritis, inflammation, the progression of cancers, etc. Thus, inhibitors of the total ROS concentration could be probable leads for the design of AI drugs [7].

Further, reports had revealed that inflammation can directly lead to the progression of a tumor. Cancers have been reported to arise from the sites of chronic irritation, infections, and inflammation. The tumor microenvironment is controlled considerably by inflammatory cells and can be correlated to the neoplastic process, encouraging the development of proliferation. Further, tumor cells have signaling mediators similar to that of the innate immune system (chemokines and their receptors) for migration and metastasis. These facts lead to the path of new AI therapy as another possible way of treating cancer [8].

Given the interest in AI therapy, and the structural and pharmacological diversity of endophytic secretions, an attempt was made to present comprehensive data on the AI compounds isolated from endophytic fungi. The review has covered all the scientific reports published on the identified topic until Feb. 2019. The literature search was done through Sci-Finder Scholar search engine using different combination of key words, and 72 and 124 hits were obtained using “inflammation+endophytic fungi” and “anti-inflammatory+endophytes”, respectively. Also, reports on the crude extracts obtained from endophytic fungi showing AI activity have been included. The literature search revealed the evaluation of AI properties of endophytic extracts and compounds using various parameters based on in vitro and in vivo studies, which included LOX, COX, ROS, albumin denaturation, membrane stabilization, proteinase inhibition, etc.

Endophytic Fungi as a Source for AI Leads

Secondary metabolites from diverse genera of endophytic fungi had been researched for AI properties. No study reporting the AI activity of compounds of endophytic bacterial origin was found in the literature. The information on various AI compounds, their endophytic fungal sources along with the host plants are listed in [Table 1]. Research on 29 endophytic fungi had yielded 118 compounds belonging to different phytochemical classifications such as alkaloids, benzophenones, cytochalasans, sesquiterpenes, coumarins, steroids, xanthones, butenolides, lactones, glycosides, azaphilones, quinones, etc. The more explored genera included Aspergillus, Streptomyces, Penicillium, Phomopsis, Trichoderma, and Ascomycota ([Table 1]).

Table 1 Anti-inflammatory metabolites, and their source endophytes.

S. No.	Compound name	Source endophyte	Host plant of endophyte	Reference
1.	(3R,4S)-3,8-dihydroxy-3-hydroxy methyl-6-methoxy-4,5-dimethyl isochroman-1-one (117)	Phoma sp. PF2	Artemisia princeps Pamp.	[9]
2.	(3S,4S)-3,8-dihydroxy-6-methoxy-3,4,5-trimethylisochroman-1-one (118)	Phoma sp. PF2	Artemisia princeps Pamp.	[9]
3.	1,2 seco-trypacidin (70)	Aspergillus fumigatus	Rumex patientia	[10]
4.	1,8-dimethoxynaphthalene (102)	Hypoxylon investiens	Litsea akoensis var. chitouchiaoensis	[11]
5.	11-epichaetomugilin I (57)	Wikstroemia uva-ursi	Chaetomium globosum	[12]
6.	1-methoxy-3-methylcarbazole (3)	Streptomyces sp. LJK109	Alpinia galanga Swartz	[13]
7.	1-O-methyl emodin (64)	Aspergillus fumigatus, Gaeumannomyces sp.	Rumex patientia, Phragmites communis	[10], [14]
8.	1-O-methyl-6-O-(α-D-ribofuranosyl)-emodin (63)	Gaeumannomyces sp.	Phragmites communis	[14]
9.	1α-isopropyl-4α,8-dimethylspiro dec-8-ene-3β,7α-diol (26)	Trichoderma sp. Xy24	Xylocarpus granatum	[15]
10.	3-methylcarbazole (2)	Streptomyces sp. LJK109	Alpinia galanga Swartz	[13]
11.	3β,5α-dihydroxy-6β-methoxyergosta-7,22-diene (39)	Trichoderma sp. Xy24	X. granatum	[16]
12.	4′,5,7-trihydroxyisoflavone-7-O-(4″-O-methyl)-β-D-glucopyranoside (84)	Cordyceps ninchukispora	Beilschmiedia erythrophloia (Seeds)	[17]
13.	4′,7-dihydroxy-6-methoxyisoflavone-7-O-(4″-O-methyl)-β-D-glucopyranoside (83)	Cordyceps ninchukispora	Beilschmiedia erythrophloia (Seeds)	[17]
14.	4′,7-dihydroxyisoflavone-7-O(4″-O-methyl)-β-D-glucopyranoside (85)	Cordyceps ninchukispora	Beilschmiedia erythrophloia (Seeds)	[17]
15.	5,7-dimethoxy-4-phenylcoumarin (28)	Streptomyces aureofaciens CMUAc130	Zingiber officinale Rosc. (Root Tissues)	[18]
16.	5,7-dimethoxy-4-p-methoxylphenylcoumarin (29)	Streptomyces aureofaciens CMUAc130	Zingiber officinale Rosc. (Root Tissues)	[18]
17.	5α,8α-epidioxy-(22E,24 R)-23-methylergosta-6,22-dien-3β-ol (44)	Gaeumannomyces sp.	Phragmites communis	[14]
18.	5α,8α-epidioxyergosta-6,22-dien-3β-ol (38)	Colletotrichum sp. GDMU-1	Santalum album	[19]
19.	5α,8α-epidioxyergosta-6,9(11),22-trien-3-ol (43)	Gaeumannomyces sp.	Phragmites communis	[14]
20.	8-methoxy naphthalene-1,7-diol (100)	Hypoxylon investiens	Litsea akoensis var. chitouchiaoensis	[11]
21.	8-methoxynaphthalen-1-ol (101)	Hypoxylon investiens	Litsea akoensis var. chitouchiaoensis	[11]
22.	Aloe emodin (68)	Aspergillus fumigatus	Rumex patientia	[10]
23.	Alternariol (99)	Phomopsis sp.	Senna spectabilis (Leaves)	[20]
24.	Amestolkolide A (112)	Talaromyces amestolkiae YX1	Kandelia obovata (Leaves)	[21]
25.	Amestolkolide B (111)	Talaromyces amestolkiae YX1	Kandelia obovata (Leaves)	[21]
26.	Andasperfumin (72)	Aspergillus fumigatus	Rumex patientia	[10]
27.	Asperimide C (97)	Aspergillus terreus	Suriana maritima L.	[22]
28.	Asperimide D (98)	Aspergillus terreus	Suriana maritima L.	[22]
29.	Aspernolide A (92)	Aspergillus terreus	Camellia sinensis var. assamica	[23]
30.	Asperteretal A (87)	Aspergillus terreus	Camellia sinensis var. assamica	[23]
31.	Asperteretal C (88)	Aspergillus terreus	Camellia sinensis var. assamica	[23]
32.	Botryoisocoumarin A (36)	Botryosphaeria sp. KcF6	Kandelia candel	[5]
33.	Botryosphaerin B (115)	Botryosphaeria sp. SCSIO KcF6	Kandelia candel	[24]
34.	Butyrolactone I (89)	Aspergillus terreus	Suriana maritima L., Camellia sinensis var. assamica	[22], [23]
35.	Butyrolactone II (90)	Aspergillus terreus	Camellia sinensis var. assamica	[23]
36.	Butyrolactone III (91)	Aspergillus terreus	Camellia sinensis var. assamica	[23]
37.	Chaetoglobosin Fex (Cha Fex) (7)	Chaetomium globosum QEN-14	Ulva pertusa	[25]
38.	Chaetomugulin E (60)	Wikstroemia uva-ursi	Chaetomium globosum	[12]
39.	Chaetomugulin F (61)	Wikstroemia uva-ursi	Chaetomium globosum	[12]
40.	Chaetomugulin I (58)	Wikstroemia uva-ursi	Chaetomium globosum	[12]
41.	Chaetomugulin J (59)	Wikstroemia uva-ursi	Chaetomium globosum	[12]
42.	Chrysophanol (65)	Aspergillus fumigatus	Rumex patientia	[10]
43.	Chrysophanol-8-O-β-D- glucopyranoside (73)	Aspergillus fumigatus	Rumex patientia	[10]
44.	Conioxanthone A (48)	Penicillium sp. ZJ-SY2	Sonneratia apetala	[26]
45.	Cordycepiamide B (82)	Cordyceps ninchukispora	Beilschmiedia erythrophloia (Seeds)	[17]
46.	Cordycepiamides D (86)	Cordyceps ninchukispora	Beilschmiedia erythrophloia (Seeds)	[17]
47.	Corynesidone A (103)	Corynespora cassicola	Gongronema latifolium	[27]
48.	Corynesidone C (104)	Corynespora cassicola	Gongronema latifolium	[27]
49.	Corynesidone D (105)	Corynespora cassicola	Gongronema latifolium	[27]
50.	Corynether A (106)	Corynespora cassicola	Gongronema latifolium	[27]
51.	Cyclonerodiol B (25)	Trichoderma sp. Xy24	X. granatum	[15]
52.	Cytochalasin H (13)	Phomopsis sp	Senna spectabilis (Leaves)	[20]
53.	Cytochalasin J (12)	Phomopsis sp	Senna spectabilis (Leaves)	[20]
54.	Desmethyldichloro diaportin (32)	Ascomycota sp.	Pluchea indica	[28]
55.	Desmethyldichlorodiaportintone (31)	Ascomycota sp.	Pluchea indica	[28]
56.	Diaporindenes A (8)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
57.	Diaporindenes B (9)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
58.	Diaporindenes C (10)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
59.	Diaporindenes D (11)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
60.	Diaporisoindoles A (5)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
61.	Diaporisoindoles B (6)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
62.	Dichlorodiaportin (33)	Ascomycota sp.	Pluchea indica	[28]
63.	Dichlorodiaportintone (30)	Ascomycota sp.	Pluchea indica	[28]
64.	Emodin (66)	Aspergillus fumigatus	Rumex patientia	[10]
65.	Emodin-8-O-β-D- glucopyranoside (75)	Aspergillus fumigatus	Rumex patientia	[10]
66.	Emodin-8-O-β-D-O-acetyl glucopyranoside (74)	Aspergillus fumigatus	Rumex patientia	[10]
67.	Ergoflavin (47)	Ascomycetes sp.	Mimosops elengi (Leaves)	[30]
68.	Ergosterol-3-O-β-D-glucopyranoside (37)	Colletotrichum sp. GDMU-1	Santalum album	[19]
69.	Fusaristerol A (45)	Fusarium sp.	Mentha longifolia L. roots	[31]
70.	Fusaristerol B (46)	Fusarium sp.	Mentha longifolia L. roots	[31]
71.	Glomeremophilanes A (22)	Glomerella cingulata	Gelsemium elegans	[32]
72.	Glomeremophilanes C (23)	Glomerella cingulata	Gelsemium elegans	[32]
73.	Glomeremophilanes D (24)	Glomerella cingulata	Gelsemium elegans	[32]
74.	Herbarin (62)	Dendryphion nanum (Nees) S. Hughes	Ficus religiosa	[33]
75.	Isoprenylisobenzofuran A (109)	Diaporthe sp.	Excoecaria agallocha (branches)	[29]
76.	Koninginin E (107)	Trichoderma koningii	Strychnos cogens plant	[34]
77.	Koninginin F (108)	Trichoderma koningii	Strychnos cogens plant	[34]
78.	Lansai C (4)	Streptomyces sp. SUC1	Ficus benjamina (roots)	[35]
79.	Lasiodiplactone A (52)	Lasiodiplodia theobromae ZJ-HQ1	Acanthus ilicifolius	[36]
80.	Montagnuphilone B (53)	Montagnulaceae sp. DM0194	Persicaria amphibia	[37]
81.	Montagnuphilones E (54)	Montagnulaceae sp. DM0194	Persicaria amphibia	[37]
82.	Nepalenside A (76)	Aspergillus fumigatus	Rumex patientia	[10]
83.	Palmaerones A (34)	Lachnum palmae	Przewalskia tangutica	[38]
84.	Palmaerones E (35)	Lachnum palmae	Przewalskia tangutica	[38]
85.	Patientoside A (77)	Aspergillus fumigatus	Rumex patientia	[10]
86.	Patientoside B (78)	Aspergillus fumigatus	Rumex patientia	[10]
87.	Peniphenone (110)	Penicillium sp. ZJ-SY2	Sonneratia apetala	[26]
88.	Periconianone A (20)	Periconia sp.	Annonsa muricata	[39]
89.	Periconianone B (21)	Periconia sp.	Annonsa muricata	[39]
90.	Pestaloporinate B (27)	Pestalotiopsis sp.	Melia azedarach	[40]
91.	Phomol (51)	Phomopsis sp.	Erythrina crista-galli	[41]
92.	Phomopchalasin C (15)	Phomopsis sp.	Isodon eriocalyx var. laxiflora	[42]
93.	Phomopsterones B (40)	Phomopsis sp. TJ507A	Phyllanthus glaucus	[43]
94.	Physcion (67)	Aspergillus fumigatus	Rumex patientia	[10]
95.	Piniphenol A (116)	Pinus sp.	Porodaedalea pini	[44]
96.	Pinselin (50)	Penicillium sp. ZJ-SY2	Sonneratia apetala	[26]
97.	Pseurotin A (1)	Aspergillus fumigatus	Erythrophloeum fordii Oliv. (Stem)	[45]
98.	Questin (69)	Aspergillus fumigatus	Rumex patientia	[10]
99.	Rubiginosins B (55)	Montagnulaceae sp. DM0194	Persicaria amphibia	[37]
100.	Sorrentanone (113)	Trichoderma sp. Xy24	Xylocarpus granatum	[16]
101.	Stemphol C (80)	Gaeumannomyces sp.	Phragmites communis	[14]
102.	Stemphol D (81)	Gaeumannomyces sp.	Phragmites communis	[14]
103.	Sydowinin A (49)	Penicillium sp. ZJ-SY2	Sonneratia apetala	[26]
104.	Terrusnolides A (93)	Aspergillus sp.	Tripterygium wilfordii (Roots)	[46]
105.	Terrusnolides B (94)	Aspergillus sp.	Tripterygium wilfordii (Roots)	[46]
106.	Terrusnolides C (95)	Aspergillus sp.	Tripterygium wilfordii (Roots)	[46]
107.	Terrusnolides D (96)	Aspergillus sp.	Tripterygium wilfordii (Roots)	[46]
108.	Trichodimerol (114)	Trichoderma sp. Xy24	Xylocarpus granatum	[16]
109.	Trypacidin (71)	Aspergillus fumigatus	Rumex patientia	[10]
110.	Xylapapuside A (79)	Xylaria papulis	Lepidagathis stenophylla	[47]
111.	Xylarenones C (16)	Camarops sp.	Alibertia macrophylla	[48]
112.	Xylarenones D (17)	Camarops sp.	Alibertia macrophylla	[48]
113.	Xylarenones F (18)	Camarops sp.	Alibertia macrophylla	[48]
114.	Xylarenones G (19)	Camarops sp.	Alibertia macrophylla	[48]
115.	Xylariphilone (56)	Annulohypoxylon truncatum	Zizania caduciflora	[49]
116.	Yamchaetoglobosin A (14)	Chaetomium globosum	Hydrocharis dubia	[50]
117.	β-sitosterol (41)	Gaeumannomyces sp.	Phragmites communis	[14]
118.	β-sitosterone (42)	Cordyceps ninchukispora	Beilschmiedia erythrophloia (Seeds)	[17]

General Procedures for the Isolation and Characterization of Endophytic Fungi

Fresh parts of the plant material are thoroughly washed using water and soap solution if required, then surface sterilized by immersing in 70% ethanol, 5% sodium hypochlorite, and 96% ethanol, followed by rinses in sterile distilled water. The sample tissues are then cut into small dimensions of 2 × 2 cm pieces and placed onto separate petri dishes containing the media suitable for the growth of the endophytes. The grown microorganisms are then transferred to fresh plates, and several subculturing are carried out to obtain a pure culture [51]. After incubating the culture for 14 – 21 days (in case of fungi) at room temperature (around 25 °C), the culture broth of the selected strain is added with a suitable solvent like ethyl acetate or methanol. The fungal matter is separated by a process of filtration or macerated along with the broth, and the liquid broth is extracted several times using a suitable organic solvent. The organic layer is then evaporated under reduced pressure to obtain the crude extract, which can be purified by column chromatography to obtain pure compounds [50]

The molecular identification involves the extraction of the fungal genomic DNA. The internal transcribed spacer (ITS) region of the fungus is amplified by PCR using the universal ITS primers ITS1 and ITS4 [52]. PCR is performed and the product can be visualized by agarose gel electrophoresis for confirmation of amplification. The isolated DNA is further purified and used as template for sequencing PCR using Big Dye Terminator Sequence Reaction Ready Mix. The sequence is then subjected to a basic local alignment search tool (BLAST) analysis [37]. For the phylogenetic analysis, related sequences are retrieved from NCBI and aligned with ClustalW. The aligned data could be used for further phylogenetic analysis with the neighbor-joining method using MEGA 5 with 1000 bootstrap replicates.

AI Compounds Produced by Endophytic Fungi

The first AI metabolite of endophytic origin was phomol (51), reported by Weber et al., in 2004 [41]. Phomol, a polyketide lactone, was isolated from Phomopsis sp., an endophyte of the medicinal plant Erythrina crista-galli. It exhibited interesting AI activity in the mouse ear assay [41]. [Table 2] presents a list of reported AI compounds from endophytic fungi arranged alphabetically together with their structure numbers, AI target, and references.

Table 2 Anti-inflammatory efficacy of compounds isolated from endophytic fungi.

S. No.	Compound name	Anti-inflammatory activity	Reference
1.	(3R,4S)-3,8-dihydroxy-3-hydroxy methyl-6-methoxy-4,5-dimethyl isochroman-1-one (117)	NO (Nitric oxide) inhibition	[9]
2.	(3S,4S)-3,8-dihydroxy-6-methoxy-3,4,5-trimethylisochroman-1-one (118)	NO inhibition	[9]
3.	1,2 seco-trypacidin (70)	IL-6 inhibition (diabetic nephropathy)	[10]
4.	1,8-dimethoxynaphthalene (102)	NO and IL-6 inhibition [IC50 2.0 µM and 13.3 µM for IL-6 and NO respectively]	[11]
5.	11-epichaetomugilin I (57)	NO inhibition [IC50 0.8 µM]	[12]
6.	1-methoxy-3-methylcarbazole (3)	NO, PGE-2, TNF-α, IL-1β, IL-6, and IL-10 inhibition	[13]
7.	1-O-methyl emodin (64)	IL-6 inhibition (diabetic nephropathy), NO inhibition [31%]	[10], [14]
8.	1-O-methyl-6-O-(α-D-ribofuranosyl)-emodin (63)	NO inhibition [43%]	[14]
9.	1α-isopropyl-4α,8-dimethylspiro dec-8-ene-3β,7α-diol (26)	NO inhibitor (neural anti-inflammatory) [39.2%]	[15]
10.	3-methylcarbazole (2)	NO, PGE-2, TNF-α, IL-1β, IL-6, and IL-10 inhibition	[13]
11.	3β,5α-dihydroxy-6β-methoxyergosta-7,22-diene (39)	NO inhibition (neural anti-inflammatory) [108.2%]	[16]
12.	4′,5,7-trihydroxyisoflavone-7-O-(4″-O-methyl)-β-D-glucopyranoside (84)	NO inhibition [10.8%]	[17]
13.	4′,7-dihydroxy-6-methoxyisoflavone-7-O-(4″-O-methyl)-β-D-glucopyranoside (83)	NO inhibition [14.8%]	[17]
14.	4′,7-dihydroxyisoflavone-7-O (4″-O-methyl)-β-D-glucopyranoside (85)	NO inhibition [14.0%]	[17]
15.	5,7-dimethoxy-4-phenylcoumarin (28)	NO, PGE2, TNF-α, IL-6, IL-1, and COX-2 inhibition	[18]
16.	5,7-dimethoxy-4-p-methoxylphenylcoumarin (29)	NO, PGE2, TNF-α, IL-6, IL-1, and COX-2 inhibition	[18]
17.	5α,8α-epidioxy-(22E,24 R)-23-methylergosta-6,22-dien-3β-ol (44)	NO inhibition	[14]
18.	5α,8α-epidioxyergosta-6,22-dien-3β-ol (38)	NO inhibition [IC50 8.9 µM]	[19]
19.	5α,8α-epidioxyergosta-6,9(11),22-trien-3-ol (43)	NO inhibition [IC50 8.94 µM]	[14]
20.	8-methoxy naphthalene-1,7-diol (100)	NO and IL-6 inhibition [IC50 9.2 µM and 11.8 µM for IL-6 and NO respectively]	[11]
21.	8-methoxynaphthalen-1-ol (101)	NO and IL-6 inhibition [IC50 18.0 µM and 17.8 µM for IL-6 and NO respectively]	[11]
22.	Aloe emodin (68)	IL-6 inhibition (diabetic nephropathy)	[10]
23.	Alternariol (99)	Total ROS inhibition	[20]
24.	Amestolkolide A (112)	NO inhibition [IC50 30 mM]	[21]
25.	Amestolkolide B (111)	NO inhibition [IC501.6 µM]	[21]
26.	Andasperfumin (72)	IL-6 inhibition (diabetic nephropathy)	[10]
27.	Asperimide C (97)	NO inhibition [IC50 0.78 µM]	[22]
28.	Asperimide D (98)	NO inhibition [IC50 1.26 µM]	[22]
29.	Aspernolide A (92)	NO inhibition [IC50 45.37 µM]	[23]
30.	Asperteretal A (87)	NO inhibition [IC50 26.64 µM]	[23]
31.	Asperteretal C (88)	NO inhibition [IC5016.80 µM]	[23]
32.	Botryoisocoumarin A (36)	COX-2 inhibition [IC50 6.51 µM]	[5]
33.	Botryosphaerin B (115)	COX-2 inhibition [IC50 1.12 µM]	[24]
34.	Butyrolactone I (89)	NO inhibition [IC50 24.2 µM and 17.21 µM as per Ref [22] and [23], respectively]	[22], [23]
35.	Butyrolactone II (90)	NO inhibition [IC50 44.37 µM]	[23]
36.	Butyrolactone III (91)	NO inhibition [IC50 20.60 µM]	[23]
37.	Chaetoglobosin Fex (Cha Fex) (7)	TNF-α, IL-6, MCP-1, and MAPKs [TNF-α inhibition 15.2% 0.5 µg/ml, 21.3% 1 µg/ml, 56.7% 2 µg/ml; IL-6 inhibition 30.9% 0.5 µg/ml, 37.1% 1 µg/ml, and 50.1% 2 µg/ml]	[25]
38.	Chaetomugulin E (60)	NO inhibition [IC50 5.8 µM]	[12]
39.	Chaetomugulin F (61)	NO inhibition [IC50 1.9 µM]	[12]
40.	Chaetomugulin I (58)	NO inhibition [IC50 0.3 µM]	[12]
41.	Chaetomugulin J (59)	NO inhibition [IC50 4.2 µM]	[12]
42.	Chrysophanol (65)	IL-6 inhibition (diabetic nephropathy)	[10]
43.	Chrysophanol-8-O-β-D- glucopyranoside (73)	IL-6 inhibition (diabetic nephropathy)	[10]
44.	Conioxanthone A (48)	Splenic lymphocytes inhibition [IC50 8.1 (Con-A) and 9.3 µg/mL (LPS)]	[26]
45.	Cordycepiamide B (82)	NO inhibition [11.2%]	[17]
46.	Cordycepiamides D (86)	NO inhibition [17.4%]	[17]
47.	Corynesidone A (103)	NO and TNF-α inhibition [IC50 1.88 µM (NO) and 8.16 µM (TNF-α)]	[27]
48.	Corynesidone C (104)	NO and TNF-α inhibition [IC50 3.99 µM (NO) and 9.49 µM (TNF-α)]	[27]
49.	Corynesidone D (105)	NO and TNF-α inhibition [IC50 7.48 µM (NO) and 15.29 µM (TNF-α)]	[27]
50.	Corynether A (106)	NO [IC50 37.22 µM] and TNF-α [IC50 26.52 µM] inhibition	[27]
51.	Cyclonerodiol B (25)	NO inhibition (neural anti-inflammatory) [75.0%]	[15]
52.	Cytochalasin H (13)	Total ROS inhibition	[20]
53.	Cytochalasin J (12)	Total ROS inhibition	[20]
54.	Desmethyldichloro diaportin (32)	NO inhibition [IC50 33.6 µM]	[28]
55.	Desmethyldichlorodiaportintone (31)	NO inhibition [IC50 15.8 µM]	[28]
56.	Diaporindenes A (8)	NO inhibition [IC50 8.5 µM]	[29]
57.	Diaporindenes B (9)	NO inhibition [IC50 5.9 µM]	[29]
58.	Diaporindenes C (10)	NO inhibition [IC50 4.2 µM]	[29]
59.	Diaporindenes D (11)	NO inhibition [IC50 4.2 µM]	[29]
60.	Diaporisoindoles A (5)	NO inhibition [IC50 22.7 µM]	[29]
61.	Diaporisoindoles B (6)	NO inhibition [IC50 18.2 µM]	[29]
62.	Dichlorodiaportin (33)	NO inhibition [IC50 67.2 µM]	[28]
63.	Dichlorodiaportintone (30)	NO inhibition [IC50 41.5 µM]	[28]
64.	Emodin (66)	IL-6 inhibition (diabetic nephropathy)	[10]
65.	Emodin-8-O-β-D-glucopyranoside (75)	IL-6 inhibition (diabetic nephropathy)	[10]
66.	Emodin-8-O-β-D-O-acetyl glucopyranoside (74)	IL-6 inhibition (diabetic nephropathy)	[10]
67.	Ergoflavin (47)	TNF-α and IL-6 inhibition [IC50 1.9 µm (TNF-α) and 1.2 µm (IL-6)]	[30]
68.	Ergosterol-3-O-β-D-glucopyranoside (37)	NO inhibition [IC50 30.4 µM]	[19]
69.	Fusaristerol A (45)	5-LOX inhibition [IC50 2.4 µM]	[31]
70.	Fusaristerol B (46)	5-LOX inhibition [IC50 3.6 µM]	[31]
71.	Glomeremophilanes A (22)	NO inhibition (neural anti-inflammatory) [50.6%]	[32]
72.	Glomeremophilanes C (23)	NO inhibition (neural anti-inflammatory) [36.1%]	[32]
73.	Glomeremophilanes D (24)	NO inhibition (neural anti-inflammatory) [29.4%]	[32]
74.	Herbarin (62)	TNF-α and IL-6 inhibition [IC50 0.06 µM (TNF-α) and 0.01 µM (IL-6)]	[33]
75.	Isoprenylisobenzofuran A (109)	NO inhibition [IC50 9.0 µM]	[29]
76.	Koninginin E (107)	Phospholipase A2 inhibition [90.2%]	[34]
77.	Koninginin F (108)	Phospholipase A2 inhibition [91.8%]	[34]
78.	Lansai C (4)	NO, PGE2, TNF-α, IL-1α, IL-6, and IL-10 inhibition	[35]
79.	Lasiodiplactone A (52)	NO inhibition [IC50 23.5 µM]	[36]
80.	Montagnuphilone B (53)	NO inhibition [IC50 39.6 µM]	[37]
81.	Montagnuphilones E (54)	NO inhibition [IC50 25.5 µM]	[37]
82.	Nepalenside A (76)	IL-6 inhibition (diabetic nephropathy)	[10]
83.	Palmaerones A (34)	NO inhibition [IC50 26.3 µM]	[38]
84.	Palmaerones E (35)	NO inhibition [IC50 38.7 µM]	[38]
85.	Patientoside A (77)	IL-6 inhibition (diabetic nephropathy)	[10]
86.	Patientoside B (78)	IL-6 inhibition (diabetic nephropathy)	[10]
87.	Peniphenone (110)	Splenic lymphocytes inhibition [IC50 6.5 (Con-A) 7.1 µg/mL (LPS)]	[26]
88.	Periconianone A (20)	NO inhibition (neural anti-inflammatory) [IC50 0.15 µM]	[39]
89.	Periconianone B (21)	NO inhibition (neural anti-inflammatory) [IC50 0.38 µM]	[39]
90.	Pestaloporinate B (27)	NO inhibition [IC50 19.0 µM]	[40]
91.	Phomol (51)	In vivo anti-inflammatory activity in mouse ear edema model [53.20%]	[41]
92.	Phomopchalasin C (15)	NO inhibition [IC50 11.2 µM]	[42]
93.	Phomopsterones B (40)	NO inhibition [IC50 4.65 µM]	[43]
94.	Physcion (67)	IL-6 inhibition (diabetic nephropathy)	[10]
95.	Piniphenol A (116)	NO inhibition [IC50 60.0 µM]	[44]
96.	Pinselin (50)	Splenic lymphocytes inhibition [IC50 8.2 (Con-A) and 7.5 µg/mL (LPS)]	[26]
97.	Pseurotin A(1)	NO inhibition [IC50 5.20 µM]	[45]
98.	Questin (69)	IL-6 inhibition (diabetic nephropathy)	[10]
99.	Rubiginosins B (55)	NO inhibition [IC50 9.2 µM]	[37]
100.	Sorrentanone (113)	NO inhibition (neural anti-inflammatory) [100%]	[16]
101.	Stemphol C (80)	NO inhibition	[14]
102.	Stemphol D (81)	NO inhibition	[14]
103.	Sydowinin A (49)	Splenic lymphocytes inhibition[IC50 5.9 (Con-A) and 7.5 µg/mL (LPS)]	[26]
104.	Terrusnolides A (93)	IL-1β, TNF-α, and NO inhibition [IC50 35.23 (IL-1β, 42.57 (TNF-α), and 38.15 µM (NO)]	[46]
105.	Terrusnolides B (94)	IL-1β, TNF-α, and NO inhibition [IC50 17.89 (IL-1β, 23.53 (TNF-α), and 21.45 µM (NO)]	[46]
106.	Terrusnolides C (95)	IL-1β, TNF-α, and NO inhibition [IC50 16.21 (IL-1β), 20.45 (TNF-α), and 19.34 µM (NO)]	[46]
107.	Terrusnolides D (96)	IL-1β, TNF-α, and NO inhibition [IC50 21.16 (IL-1β), 19.83 (TNF-α), and 16.78 µM (NO)]	[46]
108.	Trichodimerol (114)	NO inhibition (neural anti-inflammatory) [75.1%]	[16]
109.	Trypacidin (71)	IL-6 inhibition (diabetic nephropathy)	[10]
110.	Xylapapuside A (79)	NO inhibition [Emax 34.3 µM]	[47]
111.	Xylarenones C (16)	Total ROS inhibition [IC50 6.13 µM]	[48]
112.	Xylarenones D (17)	Total ROS inhibition [IC50 5.73 µM]	[48]
113.	Xylarenones F (18)	Total ROS inhibition [IC50 5.90 µM]	[48]
114.	Xylarenones G (19)	Total ROS inhibition [IC50 4.17 µM]	[48]
115.	Xylariphilone (56)	TNF-α, IL-6, and IL-12 p40 inhibition [IC50 IL-65.3, IL-12 p4019.4, and TNF-α 37.6 µM]	[49]
116.	Yamchaetoglobosin A (14)	NO inhibition [92.5%]	[50]
117.	β-Sitosterol (41)	NO inhibition [35.0%]	[14]
118.	β-Sitosterone (42)	NO inhibition [10.3%]	[17]

AI Alkaloids and Benzophenones

Alkaloids are widely distributed among various families in the plant kingdom and generally found to possess diverse biological activities [53]. Isolation of 11 AI alkaloids from different endophytes had been reported with the genus Streptomyces as a major source. Interestingly, the alkaloids were found to be effective on diverse AI targets ranging from NO, PGE-2, IL-1β, IL-6, IL-10, TNF-α, IL-1α, etc. The structure of the reported compounds pseurotin A (1), 3-methylcarbazole (2), 1-methoxy-3-methylcarbazole (3), lansai C (4), diaporisoindoles A – B (5–6), chaetoglobosin Fex (7), and diaporindene A – D (8 – 11) are presented in [Fig. 1]. These compounds were found to possess excellent AI activities on diverse targets. Among the 11 reported compounds, diaporindene C (10) (IC₅₀ 4.2 µM) and D (11) (IC₅₀ 4.2 µM) were the most potent inhibitors of LPS-induced NO production in raw 264.7 cell lines. Pseurotin A (1) was also found to be highly inhibitory (IC₅₀ 5.20 µM) exhibiting indirect AI activity by suppressing the LPS-induced pro-inflammatory factors in BV2 microglial cells [13], [25], [29], [35], [45].

Fig. 1 Structures of anti-inflammatory alkaloids and benzophenones obtained from endophytic fungi.

AI Cytochalasans

Cytochalasans represent a group of polyketide amino acid hybrid metabolites having diverse biological and pharmacological activities. They are characterized by a highly substituted per hydro-isoindolone moiety to which a macrocyclic ring like a carbocycle, a lactone, or a cyclic carbonate is fused [54]. Four AI cytochalasan derivatives [cytochalasin J (12) and H (13), yamchaetoglobosin A (14), and phomopchalasin C (15)] from endophytic fungal sources were reported ([Fig. 2]). Phomopsis fungi were found to yield 3 out of the 4 reported cytochalasans. The compounds exhibited activities through inhibition of NO and total ROS. Phomopchalasin C (15) was identified as the most active inhibitor of NO production in LPS-induced raw cells with an IC₅₀ value of 11.2 µM ([Table 2]) [20], [42], [50].

Fig. 2 Structures of anti-inflammatory cytochalasans obtained from endophytic fungi.

AI Sesquiterpenes and Sesquiterpenoids

Sesquiterpenes and sesquiterpenoids were found to be the prominent class of compounds possessing AI properties, with a total of 12 compounds isolated from endophytic fungal sources. The compounds were isolated from a variety of fungi and were found to exhibit ROS and NO inhibition effect. The compounds included xylarenones C, D, F and G (16 – 19), periconianone A and B (20 – 21), glomeremophilane A, C and D (22 – 24), cyclonerodiol B (25), 1α-isopropyl-4α,8-dimethylspiro[4.5]dec-8-ene-2β,7α-diol (26), and pestaloporinate B (27) ([Fig. 3]). Periconianone A (20) and periconianone B (21) were found to inhibit LPS-induced NO production in mouse microglia BV2 cells with IC₅₀ values of 0.15 and 0.38 µM, respectively. Nevertheless, all the sesquiterpenes were proven to possess good AI activity ([Table 2]) [15], [31], [38], [39], [47].

Fig. 3 Structures of anti-inflammatory sesquiterpenes obtained from endophytic fungi.

AI Coumarin Derivatives

Nine secondary metabolites having the basic coumarin nucleus (i.e., benzo-α-pyrone structure [55]) had been reported from different endophytic fungi. Such compounds possessing AI activity included 5,7-dimethoxy-4-phenyl coumarin (28), 5,7-dimethoxy-4-p-methoxyl phenyl coumarin (29), dichlorodiaportintone(30), desmethyldichlorodiaportintone (31), desmethyldichlorodiaportin (32), dichlorodiaportin (33), palmaerones A (34) and E (35), and botryoisocoumarin A (36) ([Fig. 4]). These compounds were effective against targets ranging from IL-6, IL-1β, TNF-α, NO, PGE-2, COX-2, and iNOS enzyme in raw 264.7 cells stimulated with LPS. The most potent compound reported among the coumarins was botryoisocoumarin A (36), displaying inhibition of COX-2 enzyme with IC₅₀ value of 6.51 µM ([Table 2]) [5], [18], [28], [38].

Fig. 4 Structures of anti-inflammatory coumarins obtained from endophytic fungi.

AI Steroids and Related Compounds

Ten compounds containing cyclopentanoperhydrophenanthrene as the basic nucleus (i.e., steroids [56]) had been reported from endophytic fungi, which belong to different genus. They were ergosterol-3-O-β-D-glucopyranoside (37), 5α,8α-epidioxyergosta-6,22-dien-3β-ol (38), 3β,5α-dihydroxy-6β-methoxy ergosta-7,22-diene (39), phomopsterone B (40), β-sitosterol (41), β-sitosterone (42), 5α,8α-epidioxyergosta-6,9(11),22-trien-3-ol (43), 5α,8α-epidioxy-(22E,24 R)-23-methylergosta-6,22-dien-3β-ol (44), and fusaristerol A and B (45 – 46) ([Fig. 5]). These compounds had been reported as NO and IL-6 inhibitors. Compound phomopsterone B (40) was found to be potentially active exhibiting IC₅₀ value of 4.65 µM ([Table 2]) [14], [15], [16], [17], [43].

Fig. 5 Structures of anti-inflammatory steroids and related derivatives obtained from endophytic fungi.

AI Xanthone and Xanthenes

These are a group of important compounds that are oxygenated heterocycles. Most xanthones are mono- or polymethyl esters found as glycosides [57]. The biological activities of this class of compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the different substituents [57]. From endophytic fungi, so far 4 compounds [ergoflavin (47), conioxanthone A (48), sydowinin A (49), and pinselin (50)] having xanthene or xanthone nucleus were reported for AI properties ([Fig. 6]). They were isolated from the Ascomycetes and Penicillium genus. They were active against TNF-α and IL-6 in the LPS-induced human monocytic cell line (THP-1) ([Table 2]). Ergoflavin (47) was found to be highly active showing IC₅₀ values of 1.9 µM and 1.2 µM against TNF-α and IL-6, respectively [26], [30].

Fig. 6 Structures of anti-inflammatory xanthenes and lactones obtained from endophytic fungi.

AI Lactones

Two lactones viz., phomol (51) and lasiodiplactone A (52) isolated from endophytic fungi, Phomopsis sp., and Lasiodiplodia theobromae ZJ-HQ1 respectively, were reported as AI compounds. Phomol (51) was effective under in vivo mice ear edema model having inhibition of 53.20%, whereas Lasiodiplactone A(52) was found to inhibit NO production in LPS-stimulated RAW 264.7 cell lines showing IC₅₀ value of 23.5 µM ([Fig. 6] and [Table 2]) [36], [41].

AI Azaphilones

Azaphilones are generally pigments that are polyketides in nature, having pyrone-quinone structures with a highly oxygenated bicyclic core and a chiral quaternary center [59]. Nine azaphilones isolated from endophytic fungi had been reported as AI compounds by acting on a variety of targets such as IL-6, IL-12p40, NO, and TNF-α. Pure characterized compounds include montagnuphilone B (53), montagnuphilones E (54), rubiginosins B (55), xylariphilone (56), 11-epichaetomugilin I (57), chaetomugulin I (58), chaetomugulin J (59), chaetomugulin E, (60) and chaetomugulin F (61) ([Fig. 7]). The most potent compound was chaetomugulin I (58) reported with an IC₅₀ value of 0.3 µM against NO inhibitory assay ([Table 2]) [12], [37], [49].

Fig. 7 Structures of anti-inflammatory azaphilones obtained from endophytic fungi.

AI Anthaquinones, Quinones, and Related Glycosides

Search resulted in 17 AI quinone derivatives from endophytes. Generally, quinones are derived from aromatic compounds such as benzene or naphthalene by conversion of an even number of −CH= groups into −C(=O)− groups with any required rearrangement of double bonds, resulting in a fully conjugated cyclic dione structure [60]. Effective compounds include herbarin (62), 1-O-methyl-6-O-(α-D-ribofuranosyl)-emodin (63), 1-O-methylemodin (64), chrysophanol (65), emodin (66), physcion (67), aloe emodin (68), questin (69), 1,2-seco-trypacidin (70), trypacidin (71) andandasperfumin (72) chrysophanol-8-O-β-D-glucopyranoside(73), emodin-8-O-β-D-(6)-O-acetyl) glucopyranoside (74), emodin-8-O-β-D-glucopyranoside (75), nepalenside A(76), patientoside A (77), patientoside B (78) ([Fig. 8]). These quinone derivatives were found to be effective inhibitors of TNF-α and IL-6 in THP-1 cells, NO in LPS-stimulated BV-2 microglia cells, and IL-6 in diabetic nephropathy. Compound 1-O-methylemodin (64) had been isolated from 2 plant sources, one being Rumex patientia and the other Phragmites communis, which were obtained from Aspergillus fumigatus and Gaeumannomyces sp., respectively. Herbarin (62) was found to be most active among the quinines showing an IC₅₀ value of 0.06 µM and 0.01 µM, respectively in inhibiting TNF-α and IL-6 ([Table 2]) [10], [14], [33].

Fig. 8 Structures of anti-inflammatory anthraquinones, quinones and related glycosides obtained from endophytic fungi.

AI Glycosides

Around 10 compounds containing sugar moieties attached through glycosidic linkage were found to be reported as inhibitors of NO and IL-6 expressions. Endophyte-derived glycosides include xylapapuside A (79), stemphol C (80), stemphol D (81), cordycepiamideB (82), 4′,7-dihydroxy-6-methoxyisoflavone-7-O-(4″-O-methyl)-β-D-glucopyranoside (83), 4′,5,7-trihydroxyisoflavone-7-O-(4″-O-methyl)-β-D-glucopyranoside (84), 4′,7-dihydroxyisoflavone-7-O-(4″-O-methyl)- β-D-glucopyranoside (85), and Cordycepiamides D (86) ([Fig. 9]) [10], [14], [17], [47].

Fig. 9 Structures of anti-inflammatory glycosides obtained from endophytic fungi.

AI Butenolides

Butenolides are unsaturated γ-lactone also known as furan derivatives. Alkyl-substituted butenolides having no exocyclic double bond are usually liquids. α-Arylidene-γ-aryl- (or alky1) butenolides are usually solids with the color varying from yellow to brown [58]. During the study, butenolides emerged as a major class of compounds possessing AI effects. Around 12 compounds were reported from various endophytic fungi, which included asperteretal A (87), asperteretal C (88), butyrolactone I (89), butyrolactone II (90), butyrolactone III (91), aspernolide A (92), terrusnolides A – D (93 – 96), asperimide C (97), and asperimide D (98) ([Fig. 10]). The compounds possessed in vitro AI activity against IL-1, TNF-α, and NO secretions. The most active compound in terms of LPS-induced NO production was asperimide C (97) with IC₅₀ value of 0.78 µM ([Table 2]). Another compound, butyrolactone II (90), was isolated from multiple plant sources. Aspergillus terreus isolated from Suriana maritima L. and Camellia sinensis var. assamica had yielded butyrolactone II (88) [22], [23], [46].

Fig. 10 Structures of anti-inflammatory butenolides obtained from endophytic fungi.

Miscellaneous Compounds

Apart from the above discussed 98 compounds, 20 other compounds belonging to different categories of secondary metabolites had been reported. These include alternariol (99), 8-methoxynaphthalene-1,7-diol (100), 8-methoxynaphthalen-1-ol (101), 1,8-dimethoxynaphthalene (102), corynesidone A, C and D (103–105), corynether A (106), koninginin E and F (107 – 108), isoprenylisobenzofuran A (109), peniphenone (110), amestolkolide A and B (112 – 111), sorrentanone (113), botryosphaerin B (115), piniphenol A (116), (3R,4S)-3,8-dihydroxy-3-hydroxy methyl-6-methoxy-4,5-dimethyl isochroman-1-one (117), and (3S,4S)-3,8-dihydroxy-6-methoxy-3,4,5-trimethylisochroman-1-one (118). Chemical structures of these compounds are presented in [Fig. 11]. These compounds were found to be effective inhibitors of NO, COX-2, IL-6, 5- LOX, proliferation of mouse splenic lymphocytes, and TNF-α. Corynesidone A (103) was found to be significantly active against NO production, exhibiting an IC₅₀ value of 1.88 µM. Compound 1,8-dimethoxynaphthalene (102) showed an IC₅₀ value of 2.0 µM against the secretion of IL-6 ([Table 2]) [9], [11], [16], [18], [20], [21], [24], [26], [27], [29], [31], [34], [44].

Fig. 11 Structures of miscellaneous anti-inflammatory compounds obtained from endophytic fungi.

AI Crude Extracts

Apart from the AI effect by pure compounds isolated from the various endophytic fungi, efficacy by crude extracts was also recorded ([Table 3]). Around 6 reports on extracts obtained from a variety of endophytic fungal sources were reported in the literature. Interestingly, an extract of Penicillium species incorporated in the form of silver nanoparticles was found to enhance the AI activity [66]. The efficacy had been tested against IL-8, COX-2, LOX, in vivo mice paw edema, albumin denaturation, membrane stabilization, and proteinase inhibitor [61], [62], [63], [64], [65], [66]. The EtOAc extract of Geotrichum sp. exhibited AI effect displaying an IC₅₀ value of 0.47 mg/mL under protein denaturation method [65].

Table 3 Anti-inflammatory efficacy of culture broth extracts of endophytic fungi.

S. No.	Endophyte [type of extract]	Host plant	Anti-inflammatory activity	Ref.
1.	Rhizoctonia sp. [Methanolic extract]	Schinu sterebinthifolius (seeds)	In vivo mice paw edema [Inhibition at dose of 10 mg/kg i.p.]	[61]
2.	Talaromyces wortmannii [Crude extract and isolated fractions]	Aloe vera	IL-8 inhibition	[62]
3.	Myrothecium sp. [Crude extract and fraction]	Calophyllum apetalum	Extract: COX-2 (8 µg/mL) and LOX (IC50: 58 µg/mL) inhibition Fraction: COX-2 (50 µg/mL) and LOX (IC50: 25 µg/mL) inhibition	[63]
4.	Aspergillus niger, Penicillium sp., Alternaria alternate Aspergillus flavus [Methanolic and aqueous extracts]	Loranthus sp.	Albumin denaturation, membrane stabilisation, proteinase inhibition [85 – 32%]	[64]
5.	Penicillium citrinum Geotrichum candidum [Ethanol, hexane, methanol, and ethyl acetate extract]	Phoenix dactylifera L.	Protein denaturation method [EtOAc extract (Geotrichum sp.) [IC50 = 0.47 mg/ml] EtOH extract (Geotrichum sp.) [IC50 = 1.37 mg/ml] EtOH extract (Penicillium sp.) [IC50 = 1.88 mg/ml] EtOAc extract (Penicillium sp.) [IC50 = 3.67 mg/ml]	[65]
6.	Penicillium species [Silver nanoparticles of extract]	Glycosmis mauritiana	Albumin denaturation. membrane stabilization, proteinase inhibition [83.63%, 89.41%, and 87.49%, respectively]	[66]

Conclusion

Endophytic fungi can serve as an alternative source for the production of AI metabolites. In all, 118 metabolites, which are chemically and pharmacologically characterized for AI activity, had been reported since the first report in 2004. Both in vitro and in vivo studies had been performed to evaluate the AI effects. Several classes of endophytic fungi had been investigated from a wide variety of plant sources with the most explored genus being Aspergillus, Streptomyces, Penicillium, Phomopsis, Trichoderma, and Ascomycota which produced several AI compounds. The compounds obtained from these endophytes further displayed a wide diversity in their chemical structures incorporating themselves under alkaloids, cytochalasans, sesquiterpenes, steroids, coumarins, glycosides, lactones, butenolides, xanthenes, quinones, azaphilones, etc. Thus, endophytic fungi-derived AI secondary metabolites reviewed under this article could further serve as lead molecules in the production of AI drugs.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The authors would like to thank DST-SERB [EMR/2016/002460] (Department of Science and Technology, Science and Engineering Research Board) for providing the financial support.

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Publication History

Received: 02 December 2019

Accepted after revision: 17 March 2020

Article published online:
25 April 2020