Secondary Metabolites and Biological Activity of Endophytic Microorganisms

Secondary Metabolites and Biological Activity of Endophytic Microorganisms

Amirbek Toshtemirov 1, Dildora Alimova1, Dilmurod Murodullayev1, Kahramon Davranov1 & Nigora Rustamova1*

1 Institute of Microbiology, Department of Enzymology, Academy of Sciences of the Republic of Uzbekistan, 7 Abdulla Qodiry Street, Shaykhontohur District, 100128, Tashkent, Uzbekistan. amirbektoshtemirov20@gmail.com (A.T); dildoraalimova2000@gmail.com (D.A); dilmurodmurodullayev@gmail.com (D.M); k-davranov@mail.ru (K.D); n.rustamova@yahoo.com(N.R);

*Correspounding author: n.rustamova@yahoo.com (Nigora Rustamova)

Annotatsiya

Secondary natural bioactive compounds produced by endophytic microorganisms play a crucial role in the ecological relationships between plants and microorganisms. Their chemical diversity and biological activity significantly influence plant protection, growth, and development. Many novel compounds synthesized by endophytic microorganisms exhibit potent biological activities, including antibacterial, antifungal, cytotoxic, and antioxidant properties. Overall, these chemical compounds are regarded as a promising resource for the pharmaceutical industry, and ongoing research in this field is revealing their extensive pharmacological potential. This manuscript establishes a foundation for future scientific investigations and paves the way for the development of new natural drugs.

Keywords:

Endophytic microorganisms, secondary metabolites, antimicrobial activity, pathogenic microorganisms

Introduction.

Endophytic microorganisms produce a diverse array of biologically active compounds through their symbiotic relationships with plants. The secondary metabolites generated by these microorganisms not only provide protection to plants but also exhibit properties of significant pharmacological and biotechnological interest. In recent years, natural products derived from endophytic fungi and bacteria isolated from plants have garnered attention for their antimicrobial, cytotoxic, antifungal, antioxidant, and anti-inflammatory properties [1, 2]. The metabolites produced by these microorganisms can also be utilized as pesticides, antimalarial drugs, and agents that promote plant growth [3, 4]. Endophytic microorganisms interact with plants and play a crucial role in helping them adapt to environmental conditions. They are also regarded as an important source for the development of high-value pharmaceutical compounds. The relationship between plants and endophytes provides protection against pathogens and enhances stress tolerance, which, in turn, either eliminates pathogenic microorganisms or inhibits the production of toxins [3, 5-7]. As demonstrated in the examples above, endophytic microorganisms possess significant potential for the development of biological products. Secondary metabolites derived from fungi, such as Stereum gausapatum, have generated interest in pesticide development, while Cladosporium oxysporum has exhibited strong antibacterial activity. The biological diversity of endophytes and their metabolites remains largely unexplored. Researchers are increasingly focusing on studying endophytic microorganisms isolated from various plants to identify compounds that are pharmacologically and biotechnologically significant. This research could play a crucial role in the future development of new drugs and the creation of eco-friendly agricultural products [8, 9].

This manuscript presents information on 160 natural compounds derived from 31 species of endophytic microorganisms, which belong to 21 different taxonomic groups. Details regarding their taxonomy (Figures 1 and 2) and biological properties (Table 1) are included.

Figure 1: Distribution and proportion of endophytic microorganism collection sites

Figure 2: Number of species in different taxonomic groups of endophytic microorganisms

Table 1: Bioactive natural compounds isolated from endophytic microorganisms

Discussion

Nigrospora genus

The chemical compounds released during the co-cultivation of phytopathogens and endophytic microorganisms can vary significantly due to their interactions. Studies indicate that such co-cultivation processes may lead to the production of new and unique metabolites. Phytotoxins, which are compounds synthesized by phytopathogens, can harm plants and have detrimental effects. For example, the co-incubation of the phytopathogen Nigrospora oryzae and the endophyte Irpex lacteus results in the release of phytotoxic azaphilone compounds, which are identified by the numbers (1-5) and (12-17 Figure 3). Antifungal Compounds: Endophytic microorganisms frequently produce antifungal compounds to safeguard plants. For instance, tremulane sesquiterpenes isolated from I. lacteus

demonstrate antifungal activity, aiding in the protection of plants against pathogenic fungi. The interactions between phytopathogenic and endophytic microorganisms during co-cultivation present new opportunities for the development of biological products and environmentally friendly agricultural solutions. Ongoing research in this field continues to explore and reveal the potential of these interactions, necessitating further investigation for a comprehensive understanding. When the phytopathogenic fungi Neonectria oryzae and Colletotrichum gloeosporioides are co-cultivated, the production of new or enhanced phytotoxins is observed compared to when each pathogen is cultivated separately. In studying these interactions, an increase in azaphilone phytotoxins, including the formation of compounds such as nigbeauvin C and nigbeauvin D, has been identified ( 6-10, 20-23). Additionally, other classes of compounds, such as sesquiterpenes, polyketides, and phenolic compounds, can also be produced as a result of the interactions between these phytopathogens. The metabolites produced through the co- cultivation of the host plant, endophyte, and phytopathogen play a significant role in plant defense. These substances include phytotoxic compounds, sesquiterpenes such as syringaresinol and tremulane (11, 12, 18, 19). For example, the co-cultivation of the host plant Dendrobium officinale, the endophyte Irpex lacteus, and the phytopathogen N. oryzae has been shown to enhance the production of antifungal and pathogen-resistant metabolites [2].

Figure 3. The structures of natural compounds (1-23) isolated from Nigrospora genus.

Antrodia genus

Twenty-one bioactive compounds were isolated from the fungus Antrodia camphorata, including 11 new triterpenoids, designated as antcamphorol AK (2434), and 10 known triterpenoids (3544). These compounds include antcamphorol A (24), antcamphorol B (25), antcamphorol C (26), antcamphorol D (27), antcamphorol E (28), antcamphorol F (29), antcamphorol G (30), antcamphorol H (31), antcamphorol I (32), antcamphorol J (33), and antcamphorol K (34, Figure 4), among others, which have been studied for their biological activity. Compounds 30, 32, 33, 39, and 42 exhibited significant reactive oxygen species (ROS) scavenging activity in high-glucose- induced human umbilical vein endothelial cells (HUVECs), with percentages ranging from 63.9% to 70.5% at a concentration of 20 M. Additionally, compounds 26 and 31 demonstrated moderate cytotoxic activity against the U251 (IC50 = 9.2 M) and MCF-7 (IC50 = 8.1 M) human cancer cell lines, respectively [3].

Figure 4. Triterpenoids isolated from the fungus Antrodia camphorata. Eleven of these are new triterpenoids (2434), while ten are previously known triterpenoids (3544).

Strasseria genus

From the endophytic fungus Strasseria geniculata, which belongs to the Ascomycetes class, four compounds named strasseriolides AD (4548, Figure 5) have been isolated. The IC50 values of these compounds against the Plasmodium falciparum 3D7 parasites were 9.810 M, 0.013 M, 0.123 M, and 0.128 M, respectively, indicating strong antimalarial activity. Furthermore, these compounds exhibited no significant cytotoxicity against HepG2 cells (a human liver cancer cell line), suggesting their relative safety and therapeutic potential [4].

Figure 5. Structures of strasseriolides (4548) isolated from the endophytic fungus Strasseria geniculata.

Periconia genus

Peribysins are biologically significant compounds recognized for their unique properties in inhibiting cell adhesion. These compounds include peribysin A (49), peribysin B (50), peribysin C (51), peribysin D (52), peribysin E (53), peribysin F (54), peribysin G (55), peribysin H (56), peribysin I (57), peribysin J (58), peribysin O (59), peribysin P (60), and peribysin Q (61) (see Figure 6). Cell adhesion processes are crucial for cell-to-cell communication and the metastasis of tumor cells, making peribysins effective agents against tumor growth and metastasis. Furthermore, peribysins have been investigated in the context of diseases such as Sickle Cell Anemia, where the abnormal shape of red blood cells hinders their movement through blood vessels; this impairment could potentially be alleviated by inhibiting cell adhesion. The endophytic fungus Periconia byssoides, isolated from marine mollusks (Aplysia

kurodai), produces peribysins 4959, while Periconia macrospinosa, isolated from terrestrial plants, syntheizes peribysins 6061 [6].

Figure 6. Structures of peribysins 4959 isolated from the endophytic fungus Periconia byssoides and peribysins 6061 isolated from the fungus

Periconia macrospinosa.

Penicillium genus

The production of perylenequinones, such as stemphyperylenol and its derivatives, by Setophoma sp. strain was observed to increase significantly when co-cultivated with the endophytic fungus Penicillium brasilianum. The induced stemphyperylenol was isolated based on its combined chromatographic and physicochemical properties and identified using spectroscopic methods. The compounds identified include stemphyperylenol (62), altertoxin I (63), alterlosin II (64), stemphytriol (65), alterlosin I (66), stemphyltoxin I (67), altertoxin II (68), alterperylenol, and alteichin (69) (see Figure 7). Stemphyperylenol exhibited not only antifungal activity against P. brasilianum but also demonstrated strong efficacy against Penicillium digitatum, a major postharvest pathogen of citrus fruits, and Aspergillus fumigatus, a ubiquitous soil fungus and significant human pathogen. Therefore, stemphyperylenol shows potential for agricultural applications as well as for use as a promising antifungal compound for human health [7].

Figure 7. Chemical structures of perylenequinones produced by the endophytic fungus Setophoma sp.

Endophytic Penicillium sp. KMU18029 has produced sesquiterpene coumarins, specifically Penisarins A (70) and B

(71). Penisarins B (71, Figure 8) has demonstrated significant cytotoxicity against human cancer cell lines HL-60 and SMMC-7721, with IC50 values of 3.6 ± 0.2 M and 3.7 ± 0.2 M, respectively [10]. From the bark of Abies beshanzuensis, a new N-methoxy-1-pyridone alkaloid (72) was isolated from the endophytic fungus Penicillium nothofagi P-6. This compound demonstrated significant cytotoxic activity against human cancer cell lines A549 and HeLa, with IC values of 14.7 and 11.3 M, respectively. Furthermore, the compound exhibited strong antibacterial activity against Staphylococcus aureus, with a minimum inhibitory concentration (MIC) value of 62.5 g/ml [11].

Figure 8. Structures of Penisarins A (70) and B (71), isolated from Penicillium sp. KMU18029, and chromenopyridin 72, isolated from

Penicillium nothofagi P-6.

Currently, many individuals are affected by diabetes, with the majority being diagnosed with type 2 diabetes (T2D). The enzyme -glucosidase, which is responsible for converting starch into monosaccharides, is a crucial therapeutic target in the management of T2D. A novel xanthone (73) and two known xanthones (74 and 75, as shown in Figure 9), isolated from the endophytic fungus Penicillium canescens found in the plant Juniperus polycarpos, have demonstrated inhibitory activity as -glucosidase inhibitors. The three xanthones (73, 74, and 75) inhibited – glucosidase activity with IC50 values of 38.80 ± 1.01 M, 32.32 ± 1.01 M, and 75.20 ± 1.02 M, respectively [12]. Three new compounds10-formyl andrastin A (76), 10-demethyl andrastin A (77), and andrastin G (78)were isolated from the endophytic fungus Penicillium vulpinum, and their bioactivities were investigated. Compound 77 demonstrated inhibitory activity against Bacillus megaterium, with a minimum inhibitory concentration (MIC) value of 6.25 mg/mL [13].

Figure 9. Xanthones 73, 74, and 75 were isolated from Penicillium canescens, and 10-formyl andrastin A (76), 10-demethyl andrastin A (77), and andrastin G (78) were isolated from Penicillium vulpinum.

Diaporthe genus

The endophytic fungus Diaporthe sp. SC-J0138 was isolated from the leaves of Cyclosorus parasiticus. From this endophyte, five new cytochalasin compoundsdiaporthichalasins D-H (7983)were identified, along with five known cytochalasins (8488, see Figure 10). Compounds 79 and 83 exhibited significant cytotoxicity against human cancer cell lines A549, HeLa, and HepG2. Specifically, compound 83 demonstrated activity against these cancer cell lines with IC50 values ranging from 9.9 to 32.1 M, while compounds 79, 86, and 88 showed activity against A549 cells with IC50 values between 10.9 and 19.1 M. All compounds (79-88), with the exception of compound 80, displayed activity against HepG2 and HeLa cells, with IC50 values ranging from 8.8 to 38.1 M [5].

Figure 10: Structures of cytochalasin compounds (79-88) isolated from the endophytic fungus Diaporthe sp. SC-J0138. These include new compounds, diaporthichalasins D-H (7983), and known cytochalasins (8488).

Phomopsis genus

Three new azaphilones, phomopsones A-C (89-91), along with two known azaphilones (9293), were isolated from Phomopsis sp. CGMCC No. 5416, an endophytic fungus associated with the medicinal plant Achyranthes bidentata. Compounds 90 and 91 demonstrated significant activity against human immunodeficiency virus type 1 (HIV-1), with IC values of 7.6 and 0.5 mol/L, respectively. Additionally, these compounds exhibited moderate cytotoxicity against A549 (human lung adenocarcinoma), MDA-MB-231 (human breast cancer), and PANC-1 (human pancreatic adenocarcinoma) cell lines, with IC values ranging from 3.2 to 303 mol/L. Furthermore, compound 91 induced apoptosis in PANC-1 cancer cells, resulting in an apoptosis rate of 28.54% [14].

Figure 11: Chemical structures of new azaphilones phomopsones A-C (89-91) and known azaphilones (9293) isolated from Phomopsis sp.

CGMCC No.5416.

From the endophytic fungus Phomopsis prunorum, isolated from the leaves of Hypericum ascyron, phomoterpene (94), two known analogs (95 and 96), and two new isocoumarins, phomoisocoumarins (97-98, Figure 12), were produced. Among these metabolites, phomoterpene 94 and phomoisocoumarin 98 exhibited moderate antibacterial activity against the plant pathogenic bacteria Pseudomonas syringae pv. and Lachrymans, with minimum inhibitory concentration (MIC) values of 15.6 g/mL [15]. The fungus Phomopsis stipata, isolated from the plant Styrax camporum Pohl, produced two new polyketides: koninginin T (99) and koninginin U (100). These metabolites exhibited moderate antifungal activity against Cladosporium cladosporioides (Fresen.) de Vries SPC 140 and Cladosporium sphaerospermum, with nystatin serving as a positive control. Additionally, compound 99 demonstrated activity by inhibiting the enzyme acetylcholinesterase [16].

Figure 12: Structures of compounds 94-98 isolated from the endophytic fungus Phomopsis prunorum and compounds 99-100 isolated from the fungus Phomopsis stipata.

A new azaphilone, chaephilone C, was isolated from the ethyl acetate extract of Chaetomium globosum. The metabolite 101 was evaluated for cytotoxic activity against the human hepatoma cell line HepG-2 in vitro and demonstrated moderate cytotoxic activity, with an IC50 value of 38.6 µM [17]. Two new cytochalasins (102103, see Figure 13) were isolated from the endophytic fungus Chaetomium globosum P2-2-2, and their biological activities were investigated. Among these compounds, only compound 103 exhibited significant cytotoxic activity against the tested cancer cell lines, with IC50 values ranging from 1.04 to 9.90 M, while compound 102 demonstrated no cytotoxicity [18].

Figure 13. Structures of chaephilone C (101) isolated from the endophyte Chaetomium globosum and cytocalasins 102103 isolated from the endophyte Chaetomium globosum P2-2-2.

Trichoderma genus

Three polyketides, including trichodermaketone E (104), 4-epi-7-O-methylkoninginin D (105), and trichopyranone A (106), along with two new terpenoids (107 and 108, Figure 14), were isolated as secondary metabolites from the endophytic fungus Trichoderma koningiopsis QA-3, which was obtained from the plant Artemisia argyi. Metabolites 104-106 exhibited moderate antibacterial activity against Escherichia coli, Micrococcus luteus, Pseudomonas aeruginosa, and Vibrio anguillarum, with minimum inhibitory concentration (MIC) values of 8 µg/mL. The compound 3-hydroxyharzianone (107) demonstrated strong activity against the human pathogen E. coli, with a MIC vlue of 0.5 µg/mL, while metabolite 108 exhibited activity against E. coli, M. luteus, and Vibrio parahaemolyticus, with MIC values of 2, 4, and 4 µg/mL, respectively [1].

Figure 14. Structures of compounds (104-108) isolated from the endophytic fungus Trichoderma koningiopsis QA-3.

The endophytic fungus Trichoderma atroviride was isolated from the healthy flowers of Colquhounia coccinea var. mollis (Schlecht.). From this endophytic fungus, secondary metabolites, specifically diterpenesharzianol (109- 113, Figure 15)were extracted. Among these metabolites, compound 112 demonstrated significant antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus, with IC values of 7.7 ± 0.8, 7.7

± 1.0, and 9.9 ± 1.5 g/mL, respectively [19].

Figure 15. Harzianol structures (109-113) isolated from the endophytic fungus Trichoderma atroviride.

Cladosporium genus

The endophytic fungus Cladosporium oxysporum, isolated from the roots of the mangrove plant Avicennia marina, produced thiocladospolides (structures 114-115, see Figure 16) when cultured in a liquid nutrient medium consisting of soluble starch (4.0%), yeast extract (0.1%), sodium glutamate (0.2%), sucrose (4.0%), maltose (3.0%), soybean

meal (0.05%), peptone (0.2%), MgSO4·7H2O (0.03%), and KH2PO4 (0.05%). Compound 115 demonstrated the highest antimicrobial activity against the aquatic pathogen Edwardsiella tarda, with a minimum inhibitory concentration (MIC) value of 4 g/ml [9].

Figure 16. Structures of thiocladospolides (114-115) isolated from the endophytic fungus Cladosporium oxysporum.

Peniophora genus

The endophytic fungus Peniophora incarnata Z4, isolated from the plant Bruguiera gymnorrhiza, produced novel natural metabolites known as tetrahydroxanthones (structures 116-119, see Figure 17). Among these, compound 117 exhibited significant activity against three human cancer cell lines: A375, MCF-7, and HL-60. The cytotoxic activity of this metabolite was characterized by IC values of 8.6 ± 0.2 M, 6.5 ± 0.4 M, and 4.9 ± 0.2 M, respectively [20].

Figure 17. Structures of tetrahydroxanthones (116-119) isolated from the endophytic fungus Peniophora incarnata Z4.

Phellinus genus

Phellinus igniarius was cultured in a fermentation medium consisting of 5% glucose, 0.15% pork peptone, 0.5% yeast powder, 0.05% KHPO, and 0.05% MgSO, resulting in the production of phellinignins A-D (structures 120- 123, see Figure 18). Phellinignin A (120) was evaluated for its cytotoxic activity against three human cancer cell linesHL-60, SMMC-7721, and SW480using the MTT assay. The metabolite phellinignin A (120) exhibited significant cytotoxic activity, with IC values of 3.8, 12.1, and 0.7 M, respectively [21].

Figure 18. Structures of phellinignins A-D (120-123) isolated from the endophytic fungus Phellinus igniarius.

Trichothecium genus

New meroterpenoids D-G (structures 124-127, Figure 19) were isolated from the endophytic fungus Trichothecium crotocinigenum, which is associated with potatoes. Compounds 124-127 are rare meroterpenoids that contain a seco- phenyl group, and compounds 124 and 125 feature a distinctive 6-6/5 fused ring system. Compounds 124-127 demonstrated antifungal activity against four plant pathogens, with minimum inhibitory concentration (MIC) values ranging from 8 to 128 g/mL [22].

Figure 19. Structures of meroterpenoids D-G (124-127) isolated from the endophytic fungus Trichothecium crotocinigenum.

Streptomyces genus

Four new tetrahydroanthracene derivatives (structures 128, 129, 130, and 131, as shown in Figure 20) were identified from Streptomyces fumigatiscleroticus HDN10255. These compounds include 4-epi-Julichrome Q10 (128), 4-epi-Julichrome Q10.10 A (129), 4-epi-Julichrome Q10.10 B (130), and 4-epi-Julichrome Q10.10 C (131). Compound 130 demonstrated significant cytotoxicity, exhibiting the highest activity against HeLa (cervical cancer) cells, with an IC value of 1.8 M [23].

Figure 20. Structures of tetrahydroanthracene derivatives (128-131) isolated from the endophytic fungus Streptomyces fumigatiscleroticus

HDN10255.

Stereum genus

Three new compounds have been isolated from the fungus Stereum gausapatum ATCC60954. These compounds are designated as strobilol N (132), strobilol O (133), and strobilol P (134). Compound 132 demonstrated activity against the nematode Caenorhabditis elegans, exhibiting 75.8% mortality at a concentration of 200 g/ml within 36 hours [8].

Figure 21. Structures of strobilols (132-134) isolated from the fungus Stereum gausapatum ATCC60954.

Aspergillus genus

A new tetracyclic depsidone derivative, guanxidone (structure 135, Figure 22), was isolated from the endophytic fungus Aspergillus sp. GXNU-A9. This compound significantly reduced nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated cells, with an IC value of 8.22 mM [24]. Two new butenolide derivatives, (±)-aspertereton (136a/136b), were isolated from the endophytic fungus Aspergillus terreus found in the plant Hypericum perforatum. The isolated compounds 136a and 136b demonstrated cytotoxic activity against human pancreatic cancer cell lines, including AsPC-1, SW1990, and PANC-1, with IC values ranging from 1.2 to 15.6 M [25].

Figure 22. Structures of guanxidone A (135) isolated from the endophytic fungus Aspergillus sp. GXNU-A9, and aspertereton F (136a/136b) isolated from the endophytic fungus Aspergillus terreus.

(±)-Versicolin A ((±)-137) was isolated from the endophytic fungus Aspergillus versicolor F210, found in the bulbs of Lycoris radiata. (±)-137 exists as two pairs of keto-enol tautomers ((+)-137a/(+)-137b and ()-137a/()-137b, Figure 23). Compound 137 exhibited moderate cytotoxicity against HL-60 cells, with an IC value of 5.6 M [26].

Figure 23. Structures of (±)-versicolin A ((±)-137) isolated from the endophytic fungus Aspergillus versicolor F210.

Aplosporella genus

A sesterterpene (138) was isolated from the endophytic fungus Aplosporella javeedii. This compound, along with its acetyl derivatives (138a, 138b, 138c; see Figure 24), exhibited moderate cytotoxicity against the mouse lymphoma cell line L5178Y, with IC values ranging from 6.2 to 12.8 M. Furthermore, compounds 138a and 138c demonstrated cytotoxic effects against human leukemia (Jurkat J16) and lymphoma (Ramos) cells [27].

Figure 24. Structures of the sesterterpene (138) and its derivatives (138a, 138b, 138c) isolated from the endophytic fungus Aplosporella javeedii.

Boeremia genus

Five new compounds were isolated from the endophytic fungus Boeremia exigua found in potatoes, and their bioactivity was investigated. Among these compounds, boremexin B (139) and boremexin E (140, Figure 25) demonstrated cytotoxic activity against human breast cancer cells (MCF-7), with IC values of 33.1 M and 4.0 M, respectively [28].

Figure 25. Structures of boremexin B (139) and boremexin E (140) isolated from the endophytic fungus Boeremia exigua.

Fusarium genus

New ergosterol derivatives, chlamydosterol A (141) and chlamydosterol B (143) (see Figure 26), along with the previously known ergosterol (ergosta-5,7,22-trien-3-ol) (142), were isolated from the endophytic fungus Fusarium chlamydosporum, which was obtained from the leaves of Anvillea garcinii (Asteraceae) growing in Saudi Arabia. Compounds 141 and 142 demonstrated activity as 5-LOX (5-lipoxygenase) inhibitors, with IC values of 3.06 mM and 3.57 mM, respectively. This enzyme plays a crucial role in the production of biologically active substances known as leukotrienes from arachidonic acid. Leukotrienes are essential in the inflammatory process and are generated during conditions such as asthma, allergies, arthritis, and other inflammatory diseases [29].

Figure 26. Structures of ergosterol derivatives (141, 142, 143) isolated from the endophytic fungus Fusarium chlamydosporum.

Epicoccum genus

The compounds epipyrone (144) andepicoccamide (145, Figure 27) were isolated from the endophytic fungus Epicoccum nigrum MK214079, and their bioactivity was investigated. Compounds 144 and 145 demonstrated activity against the fungus Ustilago maydis AB33, with minimum inhibitory concentration (MIC) values of 1.6 mM and 1.8 mM, respectively [30].

Figure 27. Structures of epipyrone (144) and epicoccamide (145) isolated from the endophytic fungus Epicoccum nigrum MK214079.

Actinomadura species

Fifteen bioactive compounds were synthesized by the termite-associated bacterium Actinomadura sp. RB99. These compounds, designated as maduractermol A (146), maduractermol B (147), maduractermol C (148), maduractermol D (149), maduractermol E (150), maduractermol F (151), maduractermol G (152), maduractermol I (155),

maduractermol J (156), maduractermol K (157), maduractermol L (158), maduractermol M (159), and maduractermol N (160) (see Figure 28), were isolated in pure form, and their chemical and biological properties were investigated. The compounds' activity against pathogenic microorganisms was assessed, revealing that

compounds 152 and 156 exhibited activity against the pathogenic bacterium H. pylori, with MIC50 values of 6.9 g/mL (9) and 14.5 g/mL (13), respectively [31].

Figure 28. Structures of maduractermol compounds (146-160) synthesized by Actinomadura sp. RB99 bacterium.

Conclusion

In summary, a total of 160 natural compounds have been isolated from 31 endophytic microorganisms, and their biological activities have been thoroughly investigated. Among these microorganisms, species from the genera Penicillium, Phomopsis, Aspergillus, and Chaetomium exhibit the highest levels of bioactivity. The substances produced by these microorganisms demonstrate significant antimicrobial, antifungal, cytotoxic, and antioxidant effects, underscoring their potential as novel sources for drug discovery. These chemical compounds serve as promising leads for the pharmaceutical industry and reveal a wide range of pharmacological potential. The findings of this study establish a foundation for future research and may pave the way for the development of new natural drug candidates.

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