Next Article in Journal
Inhibition of Soluble Epoxide Hydrolase by Cembranoid Diterpenes from Soft Coral Sinularia maxima: Enzyme Kinetics, Molecular Docking, and Molecular Dynamics
Previous Article in Journal
Comparative Transcriptomic Analysis on the Effect of Sesamol on the Two-Stages Fermentation of Aurantiochytrium sp. for Enhancing DHA Accumulation
Previous Article in Special Issue
Macrolactin X, a Macrolactin Antibiotic from Marine Bacillus subtilis sp.18
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Marine Drugs
Volume 22
Issue 8
10.3390/md22080372
marinedrugs-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

New Secondary Metabolites of Mangrove-Associated Strains

by
Yunxia Yu
1,2,
Zimin Wang
2,
Dingmi Xiong
2,
Liman Zhou
2,
Fandong Kong
2,* and
Qi Wang
1,*
1
Department of Pediatric Intensive Care Medicine, Hainan Women and Children’s Medical Center, Haikou 570206, China
2
Key Laboratory of Chemistry and Engineering of Forest Products, State Ethnic Affairs Commission, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, Guangxi Minzu University, Nanning 530006, China
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2024, 22(8), 372; https://doi.org/10.3390/md22080372
Submission received: 20 July 2024 / Revised: 15 August 2024 / Accepted: 15 August 2024 / Published: 16 August 2024
(This article belongs to the Special Issue Bio-Active Products from Mangrove Ecosystems 2.0)
Browse Figures
Versions Notes

Abstract

:
Positioned at the dynamic interface between terrestrial and marine realms, mangroves embody a vibrant tapestry of biodiversity, encompassing an array of plants, animals, and microorganisms. These microbial inhabitants of mangrove habitats have emerged as a pivotal resource for antimicrobials and a plethora of pharmaceutically valuable compounds, spanning enzymes, antineoplastic agents, pesticides, immunosuppressants, and immunomodulators. This review delves into the recent landscape (January 2021 to May 2024, according to the time of publication) of novel secondary metabolites isolated from mangrove-associated microorganisms, analyzing 41 microbial strains that collectively yielded 165 distinct compounds. Our objective is to assess the productivity and potential of natural products derived from microbial populations within mangrove ecosystems in recent times. Notably, fungi stand out as the preeminent contributors to the emergence of these novel natural products, underscoring their pivotal role in the bioprospecting endeavors within these unique environments.

1. Introduction

Despite their fragility and sporadic distribution, mangrove ecosystems worldwide exhibit remarkable productivity [1]. These unique environments are marked by periodic tidal inundation, leading to significant fluctuations in environmental factors such as salinity and nutrient availability, thereby imparting specific and distinguishing traits [2]. The abundance of carbon and other essential nutrients within these ecosystems fosters the proliferation of diverse microbial communities, which have evolved remarkable resilience to moderate salinity levels and the unpredictable nature of their surroundings [3]. This microbial diversity encompasses a broad spectrum of organisms, including bacteria, fungi, cyanobacteria, microalgae, macroalgae, and fungus-like protists, all of which have been documented within mangrove habitats [4].
Natural products (NPs), encompassing the secondary metabolites extracted from animals, plants, marine organisms, and microorganisms, have garnered immense attention since the discovery of their unique physiological activities. This groundbreaking revelation has paved the way for the development of numerous therapeutic and healthcare drugs [5]. Notably, some of these natural products serve as lead compounds, undergoing strategic structural modifications to emerge as novel generations of drugs [6]. Furthermore, they boast significant economic value, finding applications in pesticides, food additives, daily chemicals, and other fine chemical products.
The exploration of bioactive lead compounds from mangrove microorganisms has emerged as a vibrant frontier within natural product chemistry research [7]. Mangrove-derived microbes represent a promising reservoir of bioactive natural products, yielding structurally unparalleled compounds with therapeutic potential [8,9]. However, the challenge remains for drug developers to effectively harness this abundant source of natural products. In recent years, particularly after 2013, Blunt and his colleagues have underscored the distinction between mangrove-associated fungi and marine fungi, driven by the proliferation of reported compounds originating from fungi inhabiting mangrove plants and soils [10,11,12,13]. This distinction underscores the uniqueness and potential of mangrove-derived microorganisms.
Recently, many researchers have reviewed mangrove-associated natural products from different aspects. Chen et al. summarized the discovery relating to the source and characteristics of metabolic products isolated from mangrove-associated fungi from 1989 to 2020, focusing on bioactivity and the unique chemical diversity of these natural products [3]. Braga et al. reviewed antibacterial, antifungal, and antiviral chemicals produced by soil/sediment-derived mangrove fungi from 1990 to 2022 [14]. Wu et al. collected 134 secondary metabolites and classified them into two major families in terms of the biological sources and 15 subfamilies according to the chemical structures, highlighting the structural diversity and bioactivities of the mangrove ecosystem-associated secondary metabolites [15]. Law et al. highlighted research on mangrove-derived streptomycetes and the production of anticancer-related compounds from these microorganisms (2008–2019) [16]. Collectively, these reviews underscore the immense untapped potential of mangrove microbial secondary metabolites as a rich source for the development of novel therapeutic agents in the medical realm. In this comprehensive review, we delve into the diverse strains sourced from mangroves, the myriad of compounds they produce, and the biological activities associated with these compounds. By examining the latest advancements and trends in this field, we aim to provide insights that may inspire future research endeavors and facilitate the discovery of novel bioactive natural products with significant therapeutic and economic implications.

2. Strains

Herein, 41 strains were reviewed, including 39 strains of fungi and 2 strains of actinomycetes, of which 27 strains of endophytic fungi accounted for 69.2% of the total fungi (Figure 1).

2.1. Fungi

Mangrove forests are biodiversity ‘hotspots’ for marine fungi [17]. Fungi are essential to the survival of this ecosystem. They participate in the synthesis of enzymes required for the decomposition of organic matter in this environment, converting it into nutrients available for its metabolism or that of other organisms, as well as allowing subsequent colonization by bacteria and yeasts to supplement the decomposition process, thereby contributing to the cycling and flow of nutrients to higher trophic levels [14,18,19,20]. The mangrove environment is an important target for bioprospection of secondary metabolite-producing fungi because it contributes to the development of several fungal species with potential biotechnological applications. After all, fungal secondary metabolites are typically produced in response to biotic or abiotic environmental influences. The organisms present in these areas are expected to be sources of unusual compounds due to the mangrove’s unique characteristics [21,22]. Currently, research on the secondary metabolites of fungi associated with mangroves has grown significantly. In this paper, the secondary metabolites of 39 strains of fungi were reviewed. Among these fungi, there were 11 strains of Penicillium, 9 strains of Aspergillus, and 3 strains of Phomopsis. There are 17 genera in total (Figure 2).

2.2. Actinomycetes

Actinomycetes are a potential source of bioactive substances and the most abundant source of secondary metabolites. Several reports from different geographical locations around the world have described the occurrences of actinomycetes in different mangrove habitats [23,24]. This relatively large distribution of actinomycete species in mangrove ecosystems worldwide seems to indicate that mangroves are a treasure trove of actinomycetes.

2.3. Endophytic Fungi

Endophytic fungi refer to fungi that live within plant tissues and spend part of their life cycle in plant systems without causing any obvious pathogenic symptoms [25]. Most endophytic fungi belong to the genus Ascomycetes and are a multi-class group [3]. Endophytic fungi are an important class of mangrove fungi, and mangrove endophytic fungi are the second largest group of marine fungi, and the study of secondary metabolites is a promising new field [26,27]. Mangrove endophytic fungi have evolved in symbiosis with host plants, forming a unique bioactive substance synthesis pathway or metabolic pathway, from which a wealth of novel structures and/or bioactive substances with special functions can be metabolized, such as antitumor, antibiotic, neuroprotective, antioxidant, anti-inflammatory, antiviral and immunomodulator compounds [3,25]. Herein, 112 secondary metabolites isolated from 27 strains of endophytic fungi and their biological activities were reviewed (Table 1) (Figure 3 and Figure 4).

3. Compounds

Among the 165 new natural products, there are mainly polyketides, nitrogen-containing compounds, halogenated compounds, and terpenoids, including a pair of tetralone enantiomers, a pair of mutually converting epimers and a pair of new enantiomers (+) and (−) didymetone (among these compounds, some nitrogen-containing and halogenated compounds are also polyketides) (Figure 5).

3.1. Polyketides

Polyketides represent a highly diverse group of natural products with structurally intriguing carbon skeletons, which comprise polyphenols, macrolides, polyenes, ene-diynes, and polyethers [58].
Three new isocoumarins (1–3) and one new pyrone derivative (4) were isolated from the ethyl acetate extract of the fermentation broth of the mangrove endophytic fungus Phomopsis sp. DHS-11 [28]. And a novel benzofuranone compound (5) was discovered for the first time from its fermented extract [29]. Seven new polyketides, including four indenone derivatives, cytoindenones A–C (6, 8–9), 3′-methoxycytoindenone A (7), a benzophenone derivative, cytorhizophin J (10), and a pair of tetralone enantiomers, (±)-4,6-dihydroxy-5-methoxy-α-tetralone (11 and 12) were obtained from the endophytic fungus Cytospora heveae NSHSJ-2 isolated from the fresh stem of the mangrove plant Sonneratia caseolaris [30]. A mangrove endophytic fungus Phomopsis asparagi DHS-48 was found to be particularly productive, and one new compound named phaseolorin J (17) was isolated from the culture treated with sodium butyrate [32,33]. Two new polyketides, pestalotiopin B (19) and pestalotiopyrone N (10) were obtained from the ethyl acetate extracts of the rice solid cultures of the mangrove endophytic fungus Pestalotiopsis sp. HQD-6 [34]. Six new isocoumarin derivatives talaromarins A–F (21–26) were isolated from the mangrove-derived fungus Talaromyces flavus TGGP35 [35]. Six new polyketides, which included three new lactones (talarotones A–C) (27–29), one new polyketide (talarotide A) (30), and two new polyenes (talaroyenes A and B) (31, 32), were isolated from the mangrove-derived fungus Talaromyces flavus TGGP35 [36]. One new chromone fusarimone A (36), two new benzofurans fusarifurans A (37) and B (38), and three new isocoumarins fusarimarins A–C (39–41) were isolated from the mangrove endophytic fungus Fusarium sp. 2ST2 [37]. Two new octaketides, cytosporones W (46) and X (47), were isolated from the mangrove endophytic fungus Diaporthe sp. ZJHJYZ-1. Compounds 46 and 47 were a pair of epimers, whose configuration of C-1 could mutually convert, causing racemization of the lactone ring [41]. One undescribed azaphilone derivative (54) was obtained and identified from the fermented rice cultures of a mangrove endophytic fungus Penicillium sclerotiorum ZJHJJ-18 [42]. One new long-chain polyene pinophol G (59) was obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4 [43]. Five new polyketide derivatives, eschscholin B (72), dalditone A and B (73 and 74), (1R,4R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1,4-dio (75), and daldilene A (76), were isolated from the mangrove endophytic fungus Daldinia eschscholtzii KBJYZ-1 [45]. Two new pyrone derivatives, 2-(12S-hydroxypropyl)-3-hydroxy-methyl-6-hydroxy-7-methoxychromone (77) and (±)-pyrenocine S (78), were obtained from the mangrove endophytic fungus Aspergillus sydowii #2B [46]. A new lactone, asperlactone A (81), was isolated from the mangrove endophytic fungus Aspergillus sp. GXNU-A9 [48]. The mangrove endophytic fungus Aspergillus sp. GXIMD00016 was fermented by using rice medium. The metabolites were isolated by chromatography technology and 2,7-didechlorovicanic (91) were obtained [50]. A new diisoprenyl-cyclohexene-type meroterpenoid, biscognienyne M (93), was isolated from the mangrove endophytic fungus Aspergillus QG1a [51]. A pair of new enantiomers (+) and (−) didymetone (98 and 99) were purified from the mangrove endophytic fungus Didymella sp. CYSK-4 [53]. Five undescribed polyketides, including two talaketide derivatives (100 and 101), two asperpentenone derivatives (102 and 103), and one phomaligol derivative (104), were obtained from the mangrove endophytic fungus Fusarium proliferatum NSD-1 [54]. A new compound, named penicillquei C (105), was isolated from the fermentation broth of the mangrove-derived fungus Penicillium verruculosum TGM14 [55]. Two new isocoumarins named peniciisocoumarins I and J (106 and 107) were obtained from Penicillium sp. GXIMD 03001, an endophytic fungus derived from the rhizophoraceous mangrove Kandelia candel [56].
To discover bioactive natural products from mangrove sediment-derived microbes, a chemical investigation of the two Beibu Gulf-derived fungal strains, Talaromyces sp. SCSIO 41050 and Penicillium sp. SCSIO 41411, led to the isolation of 23 natural products. Five of them were identified as new ones, including two polyketide derivatives with unusual acid anhydride moieties named cordyanhydride A ethyl ester (113) and maleicanhydridane (114), and three hydroxyphenylacetic acid derivatives named stachylines H–J (115–117) [59]. Through the thorough investigation into the chemical constituents of M. purpureus wmd2424, five previously undescribed compounds, monascuspurins A–E (119–123), were isolated from the EtOAc extract of the mangrove-derived fungus Monascus purpureus wmd2424 cultured in RGY medium [60]. Two previously undescribed linear polyketides 131–132 were identified by spectroscopic methods from the culture broth of the mangrove-derived actinomycete Streptomyces sp. WHUA03072 [61]. Three new polyketides penicinones A–C (137–139) were isolated and identified from the culture extract of the mangrove-derived fungus Penicillium sp [62]. Five new alkane derivatives (141–145) were isolated from the mangrove sediment-derived fungus Penicillium ludwigii SCSIO 41408 [63]. Ochlephilone 150 was isolated from the culture broth of the mangrove-derived fungus Penicillium sclerotiorum HY5 [64]. Chemical investigation of the fungus Xylariaceae sp. SCSIO41212 has led to the isolation of two new compounds, xylaolide B (154) and xylaolide C (155) [65]. A novel tetrasubstituted benzene derivative peniprenylphenol A (156) was isolated from a scaled-up culture of the Indonesian mangrove sediment-derived fungus Penicillium chrysogenum ZZ1151 in rice medium [66]. An active compound 157 was isolated from the fermentation broth of Streptomyces sp. MCCG218 [67].

3.2. Nitrogen-Containing Compounds

Nitrogen-containing compounds are core parts not only of natural and synthetic medicines but also of biologically active compounds including natural products [68].
Three new cytochalasins, phomoparagins A–C (14–16), were isolated from Phomopsis asparagi DHS-48, a mangrove-derived endophytic fungus [32,33]. Compound phomoparagin D (18) was isolated from the culture treated with sodium butyrate of the fungus [32,33]. Two new 3-decalinoyltetramic acid derivatives with peroxide bridge fusarisetins E (34) and F (35) were isolated from the mangrove endophytic fungus Fusarium sp. 2ST2 [37]. Chemical investigation of endophytic fungus Aspergillus fumigatus HQD24, isolated from the flower of Rhizophora mucronata, led to the isolation of eight alkaloids, in which compound 42 was known as a synthetic product and isolated as a natural product for the first time [38]. Two new 2,5-diketopiperazines derivatives (43–44) were isolated from a culture broth of an endophytic fungus Nigrospora camelliae-sinensis S30, derived from mangrove Lumnitzera littorea [39]. One previously undescribed alkaloid, named penifuranone A (45), was isolated from the mangrove endophytic fungus Penicillium crustosum SCNU-F0006 [40]. Four undescribed azaphilone derivatives, sclerazaphilones A–D (48–51) were obtained and identified from the fermented rice cultures of a mangrove endophytic fungus Penicillium sclerotiorum ZJHJJ-18 [42]. One new epimer pair of long-chain polyenes penicilqueis E (57) and F (58) was obtained from EtOAc extract of the mangrove-derived fungus Penicillium herquei JX4 [43]. Nine new cytochalasins (60, 63, 65–71) were isolated from the mangrove-derived fungus Phomopsis sp. QYM-13 [44]. Two new glucosidated indole-containing quinazoline alkaloids designated fumigatosides G (79) and H (80) were isolated from the mangrove-derived fungus Aspergillus fumigatus SAl12 [47]. An investigation on bioactive metabolites from the mangrove endophytic fungus Aspergillus sp. GXNU-4QQY1a led to the isolation of two undescribed cyclic peptides, guaspertide A (94) and guaspertide B (95) [52]. Two new 12- or 13-membered-ring macrocyclic alkaloids ascomylactam D and E (96, 97) were purified from the mangrove endophytic fungus Didymella sp. CYSK-4 [53].
An unprecedented di-seco-indole diterpenoid, peniditerpenoid A (118), was obtained from the mangrove-sediment-derived fungus Penicillium sp. SCSIO 41411 [69]. Chemical examination of the fermented broth of the mangrove-derived fungus Phaeosphaeriopsis sp. S296 resulted in the isolation of two new cyclodecadepsipeptides, namely phaeosphamides A (133) and B (134) [70]. Two new prenylated indole diketopiperazine alkaloids (PIDAs) penicamides A and B (135 and 136) were isolated and identified from the culture extract of the mangrove-derived fungus Penicillium sp. [62]. Four new alkaloid compounds asperkaloids A–D (158–161) and four new indole-benzodiazepine-2,5-dione derivatives asperdinones E–H (162–165) were isolated from the culture extracts of the mangrove-derived fungus Aspergillus spinosus WHUF0344 [71].

3.3. Terpenoids

Terpenoids are the most abundant class of compounds in natural substances. There are many terpenoids with strong physiological or biological activity that have been used in clinical practice, and the well-known anti-malarial drug artemisinin and the antitumor drug paclitaxel belong to this family. At the same time, they are also an important class of natural flavors, which are indispensable raw materials for the cosmetics and food industries.
A new polychiral bisabolane sesquiterpene, bisabolanoic acid A (13), was isolated from the mangrove-derived fungus Colletotrichum sp. SCSIO KcB3–2 [31]. One new meroterpenoid (talaropenoid A) (33) was isolated from the mangrove-derived fungus Talaromyces flavus TGGP35 [36]. Nine previously undescribed diisoprenyl-cyclohexene-type meroterpenoids, aspergienynes A–I (82–90), were obtained from the mangrove endophytic fungal strain Aspergillus sp. GXNU-Y65 [49].
Five new sesquiterpenoids, citreobenzofuran D–F (126–128) and phomenone A–B (129–130), were isolated from the culture of the mangrove-derived fungus Penicillium sp. HDN13-494 [72].

3.4. Halogenated Compounds

Marine halogenated compounds comprise a varied assembly of compounds, ranging from peptides, polyketides, indoles, terpenes, acetogenins, and phenols to volatile halogenated hydrocarbons [73]. Halogenation often provides these compounds with interesting key features [74].
Three new chlorinated compounds, including two propenylphenol derivatives, chlorophenol A and B (108 and 109), and one benzofuran derivative, chlorophenol C (110), were isolated from the mangrove endophytic fungus Amorosia sp. SCSIO 41026. 7-Chloro-3,4-dihydro-6,8-dihydroxy-3-methylisocoumarine (111) and 2,4-dichloro-3-hydroxy-5-methoxy-toluene (112) were obtained as new natural products [57]. Compounds 52, 53, 55, and 56 were obtained and identified from the fermented rice cultures of a mangrove endophytic fungus Penicillium sclerotiorum ZJHJJ-18 [42]. One brominated (61) and two iodinated cytochalasins (62 and 64) were isolated from the mangrove-derived fungus Phomopsis sp. QYM-13 treated with 3% NaBr or 3% KI in potato liquid medium [45]. A new benzoquinone, guxiumasperone A (92), was isolated from the mangrove endophytic fungus Aspergillus QG1a [51].
Two new chlorinated metabolites, 8-chlorine-5-hydroxy-2,3-dimethyl-7-methoxychromone (124) and 3,4-dichloro-1H-pyrrole-2,5-dione (125), were isolated from the mangrove sediment-derived fungus Mollisia sp. SCSIO41409 [75]. A new trithiodiketopiperazine derivative, adametizine C (140), was isolated from the mangrove sediment-derived fungus Penicillium ludwigii SCSIO 41408 [63]. Chlorinated compounds 146–149 and 151–153 were isolated from the culture broth of the mangrove-derived fungus, Penicillium sclerotiorum HY5, by various chromatographic methods [64].

4. Bioactivity

Natural products have been relevant sources for drug discovery and the development of medicines since ancient times. Newman and Cragg showed that from January 1981 to September 2019, at least 1881 new drugs were approved worldwide for the treatment of all types of diseases, and among them, 75.38% (1418) were derived from natural products [76,77]. Among the 165 compounds mentioned in this paper, 75 compounds (45.5%) had biological activity, including cytotoxicity, antibacterial activity, anti-inflammatory activity, antioxidant activity, and other activities (active compounds here refer to compounds that are specifically active in the articles reviewed, and some of the weakly active compounds are not counted). Cytotoxic compounds accounted for 37.3% of the active compounds and 17% of the total compounds (Figure 6). It is worth mentioning that compounds 45, 108, 109, 120, 135, and 138 have multiple activities at the same time [40,59,63,75].
The activity of endophytic fungal-derived compounds 1–112 is shown in Table 1. Then, the activity of other compounds (113–165) will be discussed next.
A variety of bioactive screens revealed polyketide derivative (113) to have obvious antifungal activity at 10 μmol L−1, exhibiting obvious inhibition against phosphodiesterase 4 (PDE4) with an inhibitory rate of 49.7%, and 114 displayed moderate cytotoxicity against cell lines A549 and WPMY-1. Compounds 115 and 116 showed potential to inhibit acetylcholinesterase (AChE) by an enzyme activity test, as well as in silico docking analysis [59]. Peniditerpenoid A (118) inhibited lipopolysaccharide-induced NF-κB with an IC50 value of 11 μmol L−1 and further effectively prevented RANKL-induced osteoclast differentiation in bone marrow macrophages [69]. Compounds (121–123) possessed mild antifungal activity against Aspergillus niger, Penicillium italicum, Candida albicans, and Saccharomyces cerevisiae [60]. Compound 125 showed antimicrobial activities against several pathogenic fungi and bacteria, and antiproliferative activities against two human prostate cancer cell lines (IC50 values 2.77 to 9.60 μmol L−1) [63]. Compound phomenone B (130) showed moderate activity against Bacillus subtilis, with an MIC value of 6.25 μmol L−1 [72]. Compound 133 showed inhibitory activities against tumor cell lines of AGS, BEL-7402, HepG2, B16, and BIU87 with IC50 values ranging from 5.14 to 66.38 μmol L−1 [70]. Compound 137 displayed potent cytotoxicity against murine melanoma (B16) cells, human breast adenocarcinoma (MCF-7) cells, and human hepatocellular carcinoma (HepG2) cells at 50.0 μmol L−1 with inhibitory ratios of 82.7%, 75.1%, and 95.9%, respectively [62]. In a variety of bioactivity screenings, compound 140 showed cytotoxicity against prostate cancer cell line 22Rv1. Adametizine C (140), with the strongest inhibitory activity against RANKL-induced osteoclast differentiation in bone marrow macrophage cells at 10 μmol L−1, was suggested to be the promising lead compound for the treatment of osteoclast-related diseases [63]. Compounds 149 and 150 exhibited potent phytotoxicity against the growth of radicle and plumule on Amaranthus retroflexus L., with EC50 values ranging from 234.87 to 320.84 μmol L−1 [64]. New peniprenylphenol A (156) was found to have antimicrobial activity against human pathogenic methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Candida albicans with MIC values of 6, 13, and 13µg mL−1, respectively [66]. Compound 157 showed strong cell proliferation inhibitory activity against nasopharyngeal carcinoma cell lines TW03 and 5-8F, and the semi-inhibitory concentration (half-inhibitory concentration, IC50) was 2.7 μmol L−1 and 9.2 μmol L−1, respectively [67]. Compounds 162, 163, and 165 exhibited moderate inhibitory effects against α-glucosidase with IC50 values in the range of 24.65–312.25 μmol L−1 [71].
Among these compounds, compounds 50–52 exhibited stronger inhibitory effects on LPS-induced NO production in RAW264.7 macrophage cells than that of the positive control indomethacin and had no toxicity towards macrophage RAW 264.7 at 50 μmol L−1 [42]. This means azaphilone derivatives from mangrove fungi have a good chance of contributing to the discovery of potential anti-inflammatory agents. Compound 113 showed obvious antifungal activities, especially against F. graminearum, F. oxysporum, and R. solani, with MIC values of 6.25–12.5 µg mL−1, having the potential to be further developed into antifungal drugs [59]. Compounds 3, 18, 34, 35, 61, 92, 93, 97, 125, and 137 have significant cytotoxic activity against selected tumor cells and have potential to be further developed into anticancer drugs [28,33,37,44,51,53,62,75], which deserve further attention. Compound 133 demonstrated highly selective inhibitory action towards AGS cells, specifically by arresting their cell cycle progression at the G2 phase and triggering apoptosis in a precise, dose-responsive manner [70]. This finding underscores the potential of Compound 133 as a promising lead candidate for the development of therapeutic strategies aimed at treating gastric adenocarcinoma.

4.1. Cytotoxicity

Cancer is the leading cause of death and an important barrier to increasing life expectancy around the world [78]. Currently, there is a great demand for new oncological therapies that reduce or do not cause severe adverse effects to patients, providing an improvement in quality of life. In this context, several studies seek new antitumor molecules from natural sources, attempting to reduce treatment costs, increase specificity, and decrease the side effects [79]. Various tumor cell lines from human and animal sources have been useful and applied for in vitro cytotoxicity and in vivo studies of the anticancer potential of natural products, whether by the academy or by pharmaceutical companies [76]. In this paper, 28 compounds showed cytotoxicity, accounting for 17% of the total compounds.

4.2. Antimicrobial Activity

Antimicrobial activity refers to the ability of a drug to inhibit or kill pathogenic microorganisms to treat infectious diseases. Antimicrobials include antibiotics, antifungals, and antivirals that kill microorganisms or inhibit their growth and reproduction by blocking key physiological functions of bacteria, fungi, or viruses. Compounds 45, 114–118, and 125 showed moderate antimicrobial activity [40,60].

4.3. Anti-Inflammatory Activity

Inflammation is an innate immunity that is the biological response of human tissues to various harmful stimuli. It is known to be a normal bodily defense mechanism that is activated in the event of injury, exposure to pollutants, radioactive materials, poisons, and allergens, as well as infection by various substances such as microorganisms, viruses, etc. Natural products play an important role in human health in the prevention and treatment of inflammation. Compounds 45, 57–59, 72, 76, and 81 showed anti-inflammatory activity [40,43,45,48].

4.4. Antioxidant Activity

Because of restriction on synthetic antioxidants due to their carcinogenicity, interest has increased considerably in finding naturally occurring antioxidants for use in foods, cosmetics, or medicine materials to replace the synthetic ones [80]. Among them, compounds 6–10, 26, and 31 had significant antioxidant activity [30,35,36].

5. Discussion

The microbial diversity within mangrove ecosystems is exceptionally rich and varied, harboring significant biotechnological potential. In a comprehensive review spanning 2021 to the present, we have examined the discovery of 165 novel secondary metabolites derived from 41 distinct microbial strains. Over the past four years, this research has unveiled 82 polyketides, 44 nitrogen-containing compounds, 16 terpenoids, and 23 halogenated compounds. Notably, some of the halogenated and nitrogen-containing compounds are also polyketides. Thus, polyketides dominate the metabolic landscape of mangrove-derived strains, while halogenated compounds also constitute a notable proportion. In terms of functional activity, nearly half of these secondary metabolites exhibit one or more biological activities, underscoring their potential as a foundation and roadmap for the discovery of novel drug leads.
However, our observation reveals that in recent years, there has been a notable surge in research endeavors focusing on the secondary metabolites of fungi, whereas a comparative scarcity of studies has emerged concerning the secondary metabolites of actinomycetes and bacteria. Given this disparity, it is prudent to redirect our attention and invest more efforts towards the exploration of actinomycetes and bacteria, as their secondary metabolites hold immense potential for scientific discovery and practical applications.
Over the past four years, we have witnessed a notable trend in the discovery of new natural products. In 2021, six related articles reported a total of nine novel natural products. This number significantly increased in 2022, with 22 articles yielding an impressive 90 new natural products. In 2023, while still substantial, the number of articles declined to 11, documenting 46 new natural products. From January to May 2024, we observed five articles contributing 20 new natural products (exclusively counting articles dedicated to the discovery of novel natural products). This analysis highlights that 2022 witnessed the highest number of new natural products discovered, closely followed by 2023 (as depicted in Figure 7). One plausible explanation for this surge in 2022 could be attributed to the outbreak of the pandemic, which restricted human mobility and activities, potentially allowing researchers to dedicate more time and energy to their research endeavors, ultimately leading to a proliferation of publications.
With the swift advancements in synthetic biology technologies, including genome mining and enzyme catalysis, researchers are empowered with an arsenal of tools. These tools facilitate computational excavation of genetic data, enabling seamless correlations with known secondary metabolites, and a wealth of reviews document their utility and applications [81]. Furthermore, the incorporation of enzymes in natural product synthesis holds immense potential to revolutionize and streamline overall synthetic processes [82]. These innovative techniques can be seamlessly integrated into the exploration of mangrove microorganism-derived natural products, thereby accelerating the discovery of marine drugs originating from mangroves.
Natural products have long been instrumental in advancing human health and wellbeing, particularly in the realm of cancer prevention and treatment strategies. With advancements in laboratory technology and enhanced capabilities for strain isolation, researchers are increasingly empowered to extract and purify bioactive compounds. However, to fully harness the therapeutic potential of these compounds, it is imperative to deepen our understanding of their mechanisms of action within living organisms and cells. Furthermore, rigorous research is needed to validate the efficacy of these active compounds as potential novel drugs and lead structures for disease management, thereby fostering the development of innovative therapeutic interventions.

Author Contributions

Y.Y. wrote the manuscript, Z.W. and D.X. collected data, L.Z. revised the manuscript, F.K. and Q.W. supervised and revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

Our project was supported by the Specific Research Project of Guangxi for Research Bases and Talents (AD22035018), Guangxi Natural Science Foundation under Grant (2021GXNSFBA075036), the National Natural Science Foundation of China (No. 82204276), 2021 University-Level Scientific Research Projects of Guangxi Minzu University (2021 MDKJ003), the Talent Scientific Research Initiation Project of Guangxi Minzu University (2021KJQD09), the Xiangsi Lake Youth Innovation Team Project of Guangxi Minzu University (2021RSCXSHQN01), the Natural Science Foundation of Hainan Province (822QN488), and the Hainan Province Clinical Medical Center (QWYH202175).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Thatoi, H.; Behera, B.C.; Mishra, R.R.; Dutta, S.K. Biodiversity and biotechnological potential of microorganisms from mangrove ecosystems: A review. Ann. Microbiol. 2013, 63, 1–19. [Google Scholar] [CrossRef]
  2. Kathiresan, K.; Bingham, B.L. Biology of mangroves and mangrove ecosystems. Adv. Mar. Biol. 2001, 40, 81–251. [Google Scholar]
  3. Chen, S.; Cai, R.; Liu, Z.; Cui, H.; She, Z. Secondary metabolites from mangrove-associated fungi: Source, chemistry and bioactivities. Nat. Prod. Rep. 2022, 39, 560–595. [Google Scholar] [CrossRef]
  4. Hastilestari, B.R.; Syahidah, D.; Riyanti, E.I.; Alfiansah, Y.R. Below tropical coastal land ecosystems: Composition and functional diversity of microbial community across mangroves and paddy field. In Microbiome Drivers of Ecosystem Function; Academic Press: Cambridge, MA, USA, 2024; pp. 281–309. [Google Scholar]
  5. Pietra, F. Secondary metabolites from marine microorganisms: Bacteria, protozoa, algae and fungi. Achievements and prospects. Nat. Prod. Rep. 1997, 14, 453–464. [Google Scholar] [CrossRef]
  6. Newman, D.J. Natural products as leads to potential drugs: An old process or the new hope for drug discovery? J. Med. Chem. 2008, 51, 2589–2599. [Google Scholar] [CrossRef] [PubMed]
  7. Zhao, J.X.; Yue, J.M. Frontier studies on natural products: Moving toward paradigm shifts. Sci. China Chem. 2023, 66, 928–942. [Google Scholar] [CrossRef]
  8. Hong, K.; Gao, A.-H.; Xie, Q.-Y.; Gao, H.G.; Zhuang, L.; Lin, H.-P.; Yu, H.-P.; Li, J.; Yao, X.-S.; Goodfellow, M.; et al. Actinomycetes for marine drug discovery isolated from mangrove soils and plants in China. Mar. Drugs 2009, 7, 24–44. [Google Scholar] [CrossRef]
  9. Dias, A.C.F.; Andreote, F.D.; Dini-Andreote, F.; Lacava, P.T.; Sá, A.L.B.; Melo, I.S.; Azevedo, J.L.; Araújo, W.L. Diversity and biotechnological potential of culturable bacteria from Brazilian mangrove sediment. World J. Microbiol. Biotechnol. 2009, 25, 1305–1311. [Google Scholar] [CrossRef]
  10. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2014, 31, 160–258. [Google Scholar] [CrossRef]
  11. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2015, 32, 116–211. [Google Scholar] [CrossRef] [PubMed]
  12. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munroa, M.H.; Prinsepd, M.R. Natural product reports. Nat. Prod. Rep. 2016, 33, 382–431. [Google Scholar] [CrossRef]
  13. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2017, 34, 235–294. [Google Scholar] [CrossRef]
  14. Braga, A.F.V.; Rosário, M.S.D.; Gomes, J.B.N.; Monteiro, C.D.A.; Farias, F.A.; Rodrigues Filho, E.; Cantanhede Filho, A.J. Antimicrobial Potential of Soil/Sediment Mangrove Associated Fungi: A Review. J. Braz. Chem. Soc. 2024, 35, e-20240032. [Google Scholar] [CrossRef]
  15. Wu, M.J.; Xu, B.; Guo, Y.W. Unusual secondary metabolites from the mangrove ecosystems: Structures, bioactivities, chemical, and bio-syntheses. Mar. Drugs 2022, 20, 535. [Google Scholar] [CrossRef] [PubMed]
  16. Law, J.W.-F.; Law, L.N.-S.; Letchumanan, V.; Tan, L.T.-H.; Wong, S.H.; Chan, K.-G.; Ab Mutalib, N.-S.; Lee, L.-H. Anticancer drug discovery from microbial sources: The unique mangrove streptomycetes. Molecules 2020, 25, 5365. [Google Scholar] [CrossRef] [PubMed]
  17. Shearer, C.A.; Descals, E.; Kohlmeyer, B.; Kohlmeyer, J.; Marvanová, L.; Padgett, D.; Porter, D.; Raja, H.A.; Schmit, J.P.; Thorton, H.A.; et al. Fungal biodiversity in aquatic habitats. Biodivers. Conserv. 2007, 16, 49–67. [Google Scholar] [CrossRef]
  18. Assami Doi, S.; Bartelochi Pinto, A.; Carolina Canali, M.; Raquel Polezel, D.; Merguizo Chinellato, R.A.; de Oliveira, A.J.F.C. Density and diversity of filamentous fungi in the water and sediment of Araçá bay in São Sebastião, São Paulo, Brazil. Biota Neotrop. (Ed. Em Iingles) 2018, 18, e20170416. [Google Scholar]
  19. Thatoi, H.; Behera, B.C.; Mishra, R.R. Ecological role and biotechnological potential of mangrove fungi: A review. Mycology 2013, 4, 54–71. [Google Scholar] [CrossRef]
  20. Holguin, G.; Vazquez, P.; Bashan, Y. The role of sediment microorganisms in the productivity, conservation, and rehabilitation of mangrove ecosystems: An overview. Biol. Fertil. Soils 2001, 33, 265–278. [Google Scholar] [CrossRef]
  21. Ali, S.; Khan, A.L.; Ali, L.; Rizvi, T.S.; Khan, S.A.; Hussain, J.; Hamayun, M.; Al-Harrasi, A. Enzyme inhibitory metabolites from endophytic Penicillium citrinum isolated from Boswellia sacra. Arch. Microbiol. 2017, 199, 691–700. [Google Scholar] [CrossRef]
  22. Chávez, R.; Fierro, F.; García-Rico, R.O.; Vaca, I. Filamentous fungi from extreme environments as a promising source of novel bioactive secondary metabolites. Front. Microbiol. 2015, 6, 903. [Google Scholar] [CrossRef] [PubMed]
  23. Eccleston, G.P.; Brooks, P.R.; Kurtböke, D.I. The occurrence of bioactive micromonosporae in aquatic habitats of the Sunshine Coast in Australia. Mar. Drugs 2008, 6, 243–261. [Google Scholar] [CrossRef]
  24. Huang, H.; Lv, J.; Hu, Y.; Fang, Z.; Zhang, K.; Bao, S. Micromonospora rifamycinica sp. nov., a novel actinomycete from mangrove sediment. Int. J. Syst. Evol. Microbiol. 2008, 58, 17–20. [Google Scholar] [CrossRef] [PubMed]
  25. Chen, B.T.; Liang, Z.Y.; Wen, Z.C.; Guo, Z.K.; Xu, J. Research Progress on Bioactive Products from Mangrove-Derived Endophytic Fungi. J. Hainan Norm. Univ. (Nat. Sci. Ed.) 2022, 39, 373–385. (In Chinese) [Google Scholar] [CrossRef]
  26. Heinig, U.; Scholz, S.; Jennewein, S. Getting to the bottom of Taxol biosynthesis by fungi. Fungal Divers. 2013, 60, 161–170. [Google Scholar] [CrossRef]
  27. Nguyen, H.T.; Kim, S.; Yu, N.H.; Park, A.R.; Yoon, H.; Bae, C.; Yeo, J.H.; Kim, I.S.; Kim, J. Antimicrobial activities of an oxygenated cyclohexanone derivative isolated from Amphirosellinia nigrospora JS-1675 against various plant pathogenic bacteria and fungi. J. Appl. Microbiol. 2019, 126, 894–904. [Google Scholar] [CrossRef] [PubMed]
  28. Guo, Z.; Chen, B.; Chen, D.; Deng, X.; Yuan, J.; Zhang, S.; Xiong, Z.; Xu, J. New Isocoumarin and Pyrone Derivatives from the Chinese Mangrove Plant Rhizophora mangle-Associated Fungus Phomopsis sp. DHS-11. Molecules 2023, 28, 3756. [Google Scholar] [CrossRef]
  29. Chen, B.T.; Wu, W.C.; Zhou, D.D.; Deng, X.L.; Zhang, S.Q.; Yuan, J.Z.; Xu, J.; Guo, Z. Bioactive components of endophytic fungi from two Hainan mangrove plants. J. Shenzhen Univ. Sci. Eng. 2022, 39, 245–252. (In Chinese) [Google Scholar] [CrossRef]
  30. Zou, G.; Li, T.; Yang, W.; Sun, B.; Chen, Y.; Wang, B.; Ou, Y.; Yu, H.; She, Z. Antioxidative indenone and benzophenone derivatives from the mangrove-derived fungus Cytospora heveae NSHSJ-2. Mar. Drugs 2023, 21, 181. [Google Scholar] [CrossRef]
  31. Li, K.L.; Dai, Y.; She, J.L.; Zeng, Y.B.; Dai, H.F.; Ou, S.L.; Zhou, X.F.; Liu, Y.H. Bisabolanoic acid A, a new polychiral sesquiterpene with AChE inhibitory activity from a mangrove-derived fungus Colletotrichum sp. J. Asian Nat. Prod. Res. 2022, 24, 88–95. [Google Scholar] [CrossRef]
  32. Feng, Z.; Zhang, X.; Wu, J.; Wei, C.; Feng, T.; Zhou, D.; Wen, Z.; Xu, J. Immunosuppressive cytochalasins from the mangrove endophytic fungus Phomopsis asparagi DHS-48. Mar. Drugs 2022, 20, 526. [Google Scholar] [CrossRef]
  33. Feng, T.; Wei, C.; Deng, X.; Chen, D.; Wen, Z.; Xu, J. Epigenetic manipulation induced production of immunosuppressive chromones and cytochalasins from the mangrove endophytic fungus Phomopsis asparagi DHS-48. Mar. Drugs 2022, 20, 616. [Google Scholar] [CrossRef]
  34. Zhou, J.; Zheng, D.Y.; Xu, J. Two new polyketides from endophytic fungus Pestalotiopsis sp. HQD-6 isolated from the Chinese mangrove plant Rhizophora mucronata. J. Asian Nat. Prod. Res. 2022, 24, 52–58. [Google Scholar] [CrossRef] [PubMed]
  35. Cai, J.; Zhu, X.C.; Zeng, W.N.; Wang, B.; Luo, Y.P.; Liu, J.; Chen, M.-J.; Li, G.-Y.; Huang, G.-L.; Chen, G.-Y.; et al. Talaromarins A–F: Six new isocoumarins from mangrove-derived fungus Talaromyces flavus TGGP35. Mar. Drugs 2022, 20, 361. [Google Scholar] [CrossRef]
  36. Cai, J.; Zhou, X.; Wang, B.; Zhang, X.; Luo, M.; Huang, L.; Wang, R.; Chen, Y.; Li, X.; Luo, Y.; et al. Bioactive polyketides and meroterpenoids from the mangrove-derived fungus Talaromyces flavus TGGP35. Front. Microbiol. 2024, 15, 1342843. [Google Scholar] [CrossRef]
  37. Chen, Y.; Wang, G.; Yuan, Y.; Zou, G.; Yang, W.; Tan, Q.; Kang, W.; She, Z. Metabolites with cytotoxic activities from the mangrove endophytic fungus Fusarium sp. 2ST2. Front. Chem. 2022, 10, 842405. [Google Scholar] [CrossRef] [PubMed]
  38. Zou, R.; Wei, C.; Zhang, X.; Zhou, D.; Xu, J. Alkaloids from endophytic fungus Aspergillus fumigatus HQD24 isolated from the Chinese mangrove plant Rhizophora mucronata. Nat. Prod. Res. 2022, 36, 5069–5073. [Google Scholar] [CrossRef]
  39. Huang, D.Y.; Nong, X.H.; Zhang, Y.Q.; Xu, W.; Sun, L.Y.; Zhang, T.; Chen, G.-Y.; Han, C.-R. Two new 2, 5-diketopiperazine derivatives from mangrove-derived endophytic fungus Nigrospora camelliae-sinensis S30. Nat. Prod. Res. 2022, 36, 3651–3656. [Google Scholar] [CrossRef] [PubMed]
  40. Jia, H.; Wu, L.; Liu, R.; Li, J.; Liu, L.; Chen, C.; Li, J.; Zhang, K.; Liao, J.; Long, Y. Penifuranone A: A Novel Alkaloid from the Mangrove Endophytic Fungus Penicillium crustosum SCNU-F0006. Int. J. Mol. Sci. 2024, 25, 5032. [Google Scholar] [CrossRef]
  41. Yin, Y.; Yang, W.; Chen, T.; Tan, Q.; Zou, G.; Zang, Z.; Li, J.; Wang, B.; She, Z. Cytosporones W and X: Two mutually converting epimers from a mangrove endophytic fungus Diaporthe sp. ZJHJYZ-1. ACS Omega 2023, 8, 26628–26634. [Google Scholar] [CrossRef]
  42. Jiang, H.; Cai, R.; Zang, Z.; Yang, W.; Wang, B.; Zhu, G.; Yuan, J.; She, Z. Azaphilone derivatives with anti-inflammatory activity from the mangrove endophytic fungus Penicillium sclerotiorum ZJHJJ-18. Bioorg. Chem. 2022, 122, 105721. [Google Scholar] [CrossRef]
  43. Long, K.Y.; Dai, D.C.; Zheng, C.J.; Wang, Y.T.; Song, X.M.; Chen, X.; Zhou, X.-M.; Chen, G.-Y. Three new long-chain polyenes from the mangrove-derived fungus Penicillium herquei JX4. J. Asian Nat. Prod. Res. 2023, 25, 422–428. [Google Scholar] [CrossRef]
  44. Chen, Y.; Yang, W.; Zou, G.; Wang, G.; Kang, W.; Yuan, J.; She, Z. Cytotoxic bromine-and iodine-containing cytochalasins produced by the mangrove endophytic fungus Phomopsis sp. QYM-13 using the OSMAC approach. J. Nat. Prod. 2022, 85, 1229–1238. [Google Scholar] [CrossRef]
  45. Wang, G.; Yin, Z.; Wang, S.; Yuan, Y.; Chen, Y.; Kang, W. Diversified polyketides with anti-inflammatory activities from mangrove endophytic fungus Daldinia eschscholtzii KBJYZ-1. Front. Microbiol. 2022, 13, 900227. [Google Scholar] [CrossRef] [PubMed]
  46. Wang, Y.; Zhong, Z.; Zhao, F.; Zheng, J.; Zheng, X.; Zhang, K.; Huang, H. Two new pyrone derivatives from the mangrove-derived endophytic fungus Aspergillus sydowii# 2B. Nat. Prod. Res. 2022, 36, 3872–3878. [Google Scholar]
  47. Guo, S.; Zhou, H.; Huang, X.; Peng, S.; Li, J.; Ding, B.; Tao, Y.; Huang, H. New glucosidated indole-quinazoline alkaloids from mangrove endophytic fungus Aspergillus fumigatus SAl12. Nat. Prod. Res. 2023, 1–6. [Google Scholar] [CrossRef] [PubMed]
  48. Zhang, W.; Hao, L.; Qin, X.; Huang, J.; Yang, R.; Li, J.; Huang, X. A new lactone from mangrove endophytic fungus Aspergillus sp. GXNU-A9. Nat. Prod. Res. 2023, 37, 417–423. [Google Scholar] [CrossRef] [PubMed]
  49. Qin, F.; Luo, L.; Liu, Y.C.; Bo, X.L.; Wu, F.R.; Wang, F.F.; Tan, M.J.; Wei, Y.Q.; Dou, X.B.; Wang, C.Y.; et al. Diisoprenyl-cyclohexene-type meroterpenoids from a mangrove endophytic fungus Aspergillus sp. GXNU-Y65 and their anti-nonalcoholic steatohepatitis activity in AML12 cells. Phytochemistry 2024, 218, 113955. [Google Scholar] [CrossRef] [PubMed]
  50. Xiao, Z.E.; Huang, X.S.; Wei, W.X.; Lu, W.L.; Tan, Z.; Liu, Y.H. Anti-inflammatory secondary metabolites from a Beihai mangrove endophytic fungus Aspergillus sp. GXIMD00016. Acta Sci. Nat. Univ. Sunyatseni/Zhongshan Daxue Xuebao 2022, 61, 69–73. (In Chinese) [Google Scholar] [CrossRef]
  51. Bo, X.; Zhao, Y.; Qin, F.; Wu, F.; Tan, M.; Ju, S.; Song, Z.; Li, W.; He, F.; Wei, Y.; et al. Cytotoxic metabolites from the mangrove endophytic fungus Aspergillus sp. GXNU QG1a. Nat. Prod. Res. 2024, 1–8. [Google Scholar] [CrossRef]
  52. Tan, M.; Xu, X.; Zhang, W.; Wu, F.; Bo, X.; Qin, F.; Ju, S.; Song, Z.; Yang, T.; Li, J.; et al. Isolation and insecticidal activities of new cyclic peptides from mangrove endophytic fungus Aspergillus sp. GXNU-4QQY1a. Fitoterapia 2023, 171, 105693. [Google Scholar] [CrossRef]
  53. Yuan, Y.; Wang, G.; She, Z.; Chen, Y.; Kang, W. Metabolites isolated from the mangrove endophytic fungus Didymella sp. CYSK-4 and their cytotoxic activities. Fitoterapia 2023, 171, 105692. [Google Scholar] [CrossRef] [PubMed]
  54. Li, T.; Yang, W.; Chen, T.; Ouyang, H.; Liu, Y.; Wang, B.; Yu, H.; She, Z. Five secondary metabolites from mangrove endophytic fungus Fusarium. proliferatum NSD-1. J. Mol. Struct. 2024, 1302, 137434. [Google Scholar] [CrossRef]
  55. Wang, B.; Nong, X.H.; Zeng, W.N.; Li, S.S.; Li, G.Y.; Liu, J.; Huang, G.L.; Zheng, C.J. Study on bioactive secondary metabolites from the mangrove-derived fungus Penicillium verruculosum TGM14. Chem. Nat. Compd. 2022, 58, 812–815. [Google Scholar] [CrossRef]
  56. Gan, Y.M.; Xia, J.L.; Zhao, L.Y.; Liu, K.; Tang, Z.Z.; Huang, B.Y.; Liu, Y.-H.; Gao, C.-H.; Bai, M. Two new isocoumarins isolated from a mangrove-derived Penicillium sp. Phytochem. Lett. 2022, 50, 21–24. [Google Scholar] [CrossRef]
  57. Ren, X.; Chen, C.; Ye, Y.; Xu, Z.; Zhao, Q.; Luo, X.; Liu, Y.; Guo, P. Anti-inflammatory compounds from the mangrove endophytic fungus Amorosia sp. SCSIO 41026. Front. Microbiol. 2022, 13, 976399. [Google Scholar] [CrossRef]
  58. Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. 2009, 48, 4688–4716. [Google Scholar] [CrossRef]
  59. Peng, B.; Cai, J.; Xiao, Z.; Liu, M.; Li, X.; Yang, B.; Fang, W.; Huang, Y.-Y.; Chen, C.; Zhou, X.; et al. Bioactive Polyketides and Benzene Derivatives from Two Mangrove Sediment-Derived Fungi in the Beibu Gulf. Mar. Drugs 2023, 21, 327. [Google Scholar] [CrossRef]
  60. Wu, M.D.; Chen, J.J.; Cheng, M.J. Secondary metabolites with antifungal activities from mangrove derived fungus Monascus purpureus WMD2424. Mar. Drugs 2023, 21, 200. [Google Scholar] [CrossRef] [PubMed]
  61. Lu, X.; Zhang, M.; Qiu, Y.; Liu, X.; Wang, C.; Chen, J.; Zhang, H.; Wei, B.; Yu, Y.; Ying, Y.; et al. α-Glucosidase inhibitors from two mangrove-derived actinomycetes. Molecules 2023, 28, 3822. [Google Scholar] [CrossRef] [PubMed]
  62. Huo, R.; Zhang, J.; Niu, S.; Liu, L. New prenylated indole diketopiperazine alkaloids and polyketides from the mangrove-derived fungus Penicillium sp. Front. Mar. Sci. 2022, 9, 1097594. [Google Scholar] [CrossRef]
  63. Cai, J.; Wang, X.; Yang, Z.; Tan, Y.; Peng, B.; Liu, Y.; Zhou, X. Thiodiketopiperazines and alkane derivatives produced by the mangrove sediment–derived fungus Penicillium ludwigii SCSIO 41408. Front. Microbiol. 2022, 13, 857041. [Google Scholar] [CrossRef] [PubMed]
  64. Wang, W.; Wang, M.; Wang, X.B.; Li, Y.Q.; Ding, J.L.; Lan, M.X.; Gao, X.; Zhao, D.L.; Zhang, C.S.; Wu, G.X. Phytotoxic azaphilones from the mangrove-derived fungus Penicillium sclerotiorum HY5. Front. Microbiol. 2022, 13, 880874. [Google Scholar] [CrossRef] [PubMed]
  65. Hung, J.; Ying, C.H.E.N.; Yanchun, H.E.; Bin, Y.A.N.G. Secondary metabolites from the mangrove soil derived fungus Xylariaceae sp. SCSIO41212. J. Holist. Integr. Pharm. 2022, 3, 230–235. [Google Scholar] [CrossRef]
  66. Newaz, A.W.; Yong, K.; Yi, W.; Wu, B.; Zhang, Z. Antimicrobial metabolites from the Indonesian mangrove sediment-derived fungus Penicillium chrysogenum sp. ZZ1151. Nat. Prod. Res. 2023, 37, 1702–1708. [Google Scholar] [CrossRef] [PubMed]
  67. Huang, Y.Y.; Li, Z.; Pan, X.L.; Huang, Y.L.; Hu, W.J.; Li, F.; Wang, Q.Z.; Huang, S.S.; Zhou, X.Y.; Wen, W.S. Screening of Mangrove Soil Bacteria Producing in Vitro Anti-na sopharyngeal Carcinoma Substance and Analysis of Its Active Component. Guangxi Sci. 2022, 29, 846–853. (In Chinese) [Google Scholar] [CrossRef]
  68. Naito, T. Development of new synthetic reactions for nitrogen-containing compounds and their application. Chem. Pharm. Bull. 2008, 56, 1367–1383. [Google Scholar] [CrossRef]
  69. Cai, J.; Li, M.; Chen, C.; Yang, B.; Gao, C.; Liu, Y.; Luo, X.; Tan, Y.; Zhou, X. Peniditerpenoids A and B: Oxidized Indole Diterpenoids with Osteoclast Differentiation Inhibitory Activity from a Mangrove-Sediment-Derived Penicillium sp. J. Nat. Prod. 2024, 87, 1401–1406. [Google Scholar] [CrossRef] [PubMed]
  70. Niu, S.; He, J.; Huang, S.; Wu, S.; Zeng, L.; Wang, J.; Hong, B.; Chen, Z. Phaeosphamides A and B, cytotoxic cyclodecadepsipeptides from the mangrove-derived fungus Phaeosphaeriopsis sp. S296. Mar. Drugs 2022, 20, 591. [Google Scholar] [CrossRef]
  71. Lu, P.; Shi, Y.; Zhang, J.; Hong, K.; Xue, Y.; Liu, L. New prenylated indole-benzodiazepine-2, 5-diones with α-glucosidase inhibitory activities from the mangrove-derived Aspergillus spinosus. Int. J. Biol. Macromol. 2024, 257, 128808. [Google Scholar] [CrossRef]
  72. Wu, Q.; Chang, Y.; Che, Q.; Li, D.; Zhang, G.; Zhu, T. Citreobenzofuran D–F and phomenone A–B: Five novel sesquiterpenoids from the mangrove-derived fungus Penicillium sp. HDN13-494. Mar. Drugs 2022, 20, 137. [Google Scholar] [CrossRef]
  73. Butler, A.; Sandy, M. Mechanistic considerations of halogenating enzymes. Nature 2009, 460, 848–854. [Google Scholar] [CrossRef]
  74. Cabrita, M.T.; Vale, C.; Rauter, A.P. Halogenated compounds from marine algae. Mar. Drugs 2010, 8, 2301–2317. [Google Scholar] [CrossRef]
  75. Cai, J.; Wang, X.; Gan, X.; Zhou, Q.; Luo, X.; Yang, B.; Liu, Y.; Ratnasekera, D.; Zhou, X. New chlorinated metabolites and antiproliferative polyketone from the mangrove sediments-derived fungus Mollisia sp. SCSIO41409. Mar. Drugs 2022, 21, 32. [Google Scholar] [CrossRef]
  76. Conrado, R.; Gomes, T.C.; Roque, G.S.C.; De Souza, A.O. Overview of bioactive fungal secondary metabolites: Cytotoxic and antimicrobial compounds. Antibiotics 2022, 11, 1604. [Google Scholar] [CrossRef]
  77. Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 2020, 83, 770–803. [Google Scholar] [CrossRef]
  78. Bray, F.; Laversanne, M.; Weiderpass, E.; Soerjomataram, I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer 2021, 127, 3029–3030. [Google Scholar] [CrossRef]
  79. Somarelli, J.A.; Boddy, A.M.; Gardner, H.L.; DeWitt, S.B.; Tuohy, J.; Megquier, K.; Sheth, M.U.; Hsu, S.D.; Thorne, J.L.; London, C.A.; et al. Improving cancer drug discovery by studying cancer across the tree of life. Mol. Biol. Evol. 2020, 37, 11–17. [Google Scholar] [CrossRef]
  80. Jain, C.; Khatana, S.; Vijayvergia, R. Bioactivity of secondary metabolites of various plants: A review. Int. J. Pharm. Sci. Res. 2019, 10, 494–504. [Google Scholar]
  81. Ziemert, N.; Alanjary, M.; Weber, T. The evolution of genome mining in microbes—A review. Nat. Prod. Rep. 2016, 33, 988–1005. [Google Scholar] [CrossRef] [PubMed]
  82. Friedrich, S.; Hahn, F. Opportunities for enzyme catalysis in natural product chemistry. Tetrahedron 2015, 71, 1473–1508. [Google Scholar] [CrossRef]
Marinedrugs 22 00372 g001
Figure 1. The types of strains.
Figure 1. The types of strains.
Marinedrugs 22 00372 g001
Marinedrugs 22 00372 g002
Figure 2. Genus of 39 strains of fungi.
Figure 2. Genus of 39 strains of fungi.
Marinedrugs 22 00372 g002
Marinedrugs 22 00372 g003aMarinedrugs 22 00372 g003bMarinedrugs 22 00372 g003cMarinedrugs 22 00372 g003dMarinedrugs 22 00372 g003e
Figure 3. Compounds isolated from endophytic fungi. Note: new compounds are marked in black; the blue ones are new natural products.
Figure 3. Compounds isolated from endophytic fungi. Note: new compounds are marked in black; the blue ones are new natural products.
Marinedrugs 22 00372 g003aMarinedrugs 22 00372 g003bMarinedrugs 22 00372 g003cMarinedrugs 22 00372 g003dMarinedrugs 22 00372 g003e
Marinedrugs 22 00372 g004aMarinedrugs 22 00372 g004bMarinedrugs 22 00372 g004c
Figure 4. Compounds from other sources. Note: new compounds are marked in black; the blue ones are new natural products.
Figure 4. Compounds from other sources. Note: new compounds are marked in black; the blue ones are new natural products.
Marinedrugs 22 00372 g004aMarinedrugs 22 00372 g004bMarinedrugs 22 00372 g004c
Marinedrugs 22 00372 g005
Figure 5. Types of all compounds.
Figure 5. Types of all compounds.
Marinedrugs 22 00372 g005
Marinedrugs 22 00372 g006
Figure 6. The activity of compounds.
Figure 6. The activity of compounds.
Marinedrugs 22 00372 g006
Marinedrugs 22 00372 g007
Figure 7. The number of relevant articles and new natural products in recent years.
Figure 7. The number of relevant articles and new natural products in recent years.
Marinedrugs 22 00372 g007
Table 1. Secondary metabolites isolated from endophytic fungi and their activities.
Table 1. Secondary metabolites isolated from endophytic fungi and their activities.
Sr.
No.		Endophytic
Fungus		Host Plant(s)SourcesCompound IsolatedBioactivity and IC50/EC50/InhibitionReference
1Phomopsis sp. DHS-11the living root
of the mangrove plant Rhizophora mangle		Dong Zhai Gang mangrove garden
on Hainan Island, China		1HeLa cells (11.49 ± 1.64 μmol L−1)[28]
2
3HeLa cells (8.70 ± 0.94 μmol L−1)
4HepG 2 (34.10 ± 2.92 μmol L−1)
5 [29]
2Cytospora heveae NSHSJ-2the fresh stem of
mangrove plant Sonneratia caseolaris		the Nansha
Mangrove National Nature Reserve in Guangdong Province, China		6DPPH radical scavenging activity (11.5 ± 0.1 μmol L−1)[30]
7DPPH radical scavenging activity (21.5 ± 1.0 μmol L−1)
8DPPH radical scavenging activity (19.7 ± 1.8 μmol L−1)
9DPPH radical scavenging activity (16.6 ± 0.4 μmol L−1)
10DPPH radical scavenging activity (9.5 ± 0.1 μmol L−1)
11
12
3Colletotrichum sp. SCSIO KcB3-2a mangrove plant, Kandelia candelDayawan, Shenzhen, Guangdong Province, China13AChE inhibitory activity (2.2 ± 0.18 μmol L−1)[31]
4Phomopsis asparagi DHS-48a healthy tree root of the mangrove plant Rhizophora mangleDong Zhai Gang-Mangrove
Garden in Hainan Province		14 [32]
15normal splenocytes (111.7 ± 1.1 μmol L−1)
ConA-Induced T-Cell Proliferation (21.6 ± 1.7 μmol L−1)
LPS-Induced B-Cell Proliferation (78.5 ± 1.3 μmol L−1)
16
17ConA-Induced T-Cell Proliferation (42.35 ± 2.49 μmol L−1)
LPS-Induced B-Cell Proliferation (88.19 ± 2.59 μmol L−1)		[33]
18HepG2 (59.14 ± 15.79 μmol L−1)
Hela (5.82 ± 0.82 μmol L−1)
5Pestalotiopsis sp. HQD-6fresh, healthy leaf of Chinese mangrove plant Rhizophora mucronataDong Zhai Gang-Mangrove
Garden on Hainan Island, China		19 [34]
20Hela (50.42 ± 0.07 μmol L−1)
6Talaromyces flavus TGGP35the stem of the mangrove plant Acanthus
ilicifolius		Dongzhai Port, Haikou, Hainan Province21 [35]
22
23
24
25
26antioxidant activity (0.14 mmol L−1)
27 [36]
28
29Hela (62.23 ± 0.23 μmol L−1)
30
31antioxidant activity (0.40 mmol L−1)
32Hela (57.14 ± 0.15 μmol L−1)
33anti-insect activity against newly hatched larvae of Helicoverpa armigera Hubner (50–200 µgmL−1)
7Fusarium sp. 2ST2healthy leaves of
Kandelia candel		the South
China Sea, Dong Zhai Harbor Mangrove Nature Reserve Area,
Hainan Province, China		34A549 (8.7 μmol L−1)[37]
35A550 (4.38 μmol L−1)
36
37
38
39
40
41
8Aspergillus
fumigatus HQD24		the flower of the Chinese
mangrove plant Rhizophora mucronata		 42decreased ACAT2 inhibitory activity (12.0 mmol L−1)[38]
9Nigrospora
camelliae-sinensis S30		mangrove Lumnitzera littorea 43 [39]
44
10Penicillium crustosum SCNU-F0006Acanthus ilicifolius L. mangrove plantthe Yangjiang Mangrove Nature Reserve in Guangdong Province45RAW 264.7 cells (above 50 μmol L−1)
anti-inflammatory activity (42.22 ± 2.26 μmol L−1)
DPPH radical scavenging activity (180.2 μmol L−1)
antimicrobial activities against Bacillus subtilis, Penicillium italicum, and Pseudomonas aeruginosa		[40]
11Diaporthe sp. ZJHJYZ-1a fresh leaf of the semi-mangrove plant
Hibiscus tiliaceus L.		Zhanjiang Mangrove National Nature Reserve in Guangdong
Province, China		46 [41]
47
12Penicillium sclerotiorum ZJHJJ-18the stems of the
mangrove plant Hibiscus tiliaceus		the shore of
the Zhanjiang Mangrove Nature Reserve in Guangdong Province, China		48inhibit LPS-induced NO production in RAW264.7 macrophage cells[42]
49inhibit LPS-induced NO production in RAW264.8 macrophage cells
50inhibit LPS-induced NO production in RAW264.9 macrophage cells
51inhibit LPS-induced NO production in RAW264.10 macrophage cells
52inhibit LPS-induced NO production in RAW264.11 macrophage cells
53inhibit LPS-induced NO production in RAW264.12 macrophage cells
54
55
56
13Penicillium herquei JX4the mangrove Ceriops
tagal		the South China Sea57anti-inflammatory activities[43]
58anti-inflammatory activities
59anti-inflammatory activities
14Phomopsis sp. QYM-13healthy leaves of Kandelia candelthe South China Sea, Dongzhai Harbor Mangrove Nature
Reserve Area, Hainan Province, China		60 [44]
61MDA-MB-435 (4.9–8.2 μmol L−1)
62
63
64
65
66
67
68
69
70
71
15Daldinia eschscholtzii KBJYZ-1the root of Pluchea indica
Less		Zhanjiang Mangrove
National Nature Reserve in Guangdong Province, China		72anti-inflammatory activities (19.3 μmol L−1)[45]
73
74
75
76anti-inflammatory activities (12.9 μmol L−1)
16Aspergillus sydowii #2Bthe leaves of the mangrove plant Aricennia marina 77inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 246.7 cells (40.15 μmol L−1)[46]
78VCaP (20.06 ± 2.01 μmol L−1)
17Aspergillus
fumigatus SAI12		leaves of mangrove plant Sonneratia apetala Buch.-Ham.Dongzhaigang National Nature Reserve in south China’s Hainan Province79 [47]
80
18Aspergillus sp. GXNU-A9a leaf of mangrove Acanthus ilicifolius L.Qinzhou City, China81moderate inhibitory activity against nitric oxide (NO) production anti-inflammatory activity[48]
19Aspergillus sp. GXNU-Y65fresh fruit of the
mangrove plant Kandelia candel		Beihai, China82 [49]
83
84anti-nonalcoholic steatohepatitis activity
85
86
87
88
89
90
20Aspergillus sp.
GXIMD00016		Fresh leaves of Kandelia candelBeihai Golden Bay Mangrove Reserve91 [50]
21Aspergillus QG1athe mangrove Kandelia candelthe seaside of Qinzhou, Guangxi Province, China92A549 (59.283 μmol L−1)
A2780 (46.197 μmol L−1)
MIA PACA-2 (42.664 μmol L−1)		[51]
93A2780 (6.808 μmol L−1)
MIA PACA-2 (15.400 μmol L−1)
22Aspergillus sp. GXNU-4QQY1ahealthy leaves of
Acanthus ilicifolius L.		 94insecticidal activity against citrus psyllids (lethality values of 92.31 ± 6.20%)[52]
95exhibited good insecticidal activity against citrus psyllids (lethality values of 87.80 ± 9.32%)
23Didymella sp. CYSK-4a fresh branch of the mangrove plant Pluchea
indica		Shankou Mangrove Na
ture Reserve in Guangxi Province, China		96A549 (11.0 μmol L−1)[53]
97A549 (2.8 μmol L−1)
KYSE 150 (5.9 μmol L−1)
98
99
24Fusarium. proliferatum NSD-1a fresh twig from mangrove
plant Kandelia candel		a Mangrove of
Nansha District of Guangzhou in Guangdong Province, China		100A549 (75.9 ± 10.4 μmol L−1)
SW480 (37.5 ± 8.0 μmol L−1)		[54]
101
102
103moderate IL-1β inhibitory activity
104A549 (24.9 ± 10.1 μmol L−1)
SW480 (77.7 ± 3.6 μmol L−1)
25Penicillium verruculosum TGM14mangrove
Xylocarpus granatum Koenig		the South China Sea105 [55]
26Penicillium sp. GXIMD 03001the rhizophoraceous
mangrove Kandelia candel		the Beibu Gulf106 [56]
107
27Amorosia sp. SCSIO
41026		the leaf of Avicennia marina (Forsk.) Vierh.the mangrove wetland in Zhanjiang, Guangdong
province, China		108inhibit LPS-induced NO production in RAW264.7 macrophage cells[57]
109
110
111inhibit LPS-induced NO production in RAW264.7 macrophage cells
112
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yu, Y.; Wang, Z.; Xiong, D.; Zhou, L.; Kong, F.; Wang, Q. New Secondary Metabolites of Mangrove-Associated Strains. Mar. Drugs 2024, 22, 372. https://doi.org/10.3390/md22080372

AMA Style

Yu Y, Wang Z, Xiong D, Zhou L, Kong F, Wang Q. New Secondary Metabolites of Mangrove-Associated Strains. Marine Drugs. 2024; 22(8):372. https://doi.org/10.3390/md22080372

Chicago/Turabian Style

Yu, Yunxia, Zimin Wang, Dingmi Xiong, Liman Zhou, Fandong Kong, and Qi Wang. 2024. "New Secondary Metabolites of Mangrove-Associated Strains" Marine Drugs 22, no. 8: 372. https://doi.org/10.3390/md22080372

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop