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.
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.
