Marine Natural Products from the Beibu Gulf: Sources, Chemistry, and Bioactivities

Marine natural products (MNPs) play an important role in the discovery and development of new drugs. The Beibu Gulf of South China Sea harbors four representative marine ecosystems, including coral reefs, mangroves, seaweed beds, and coastal wetlands, which are rich in underexplored marine biological resources that produce a plethora of diversified MNPs. In our ongoing efforts to discover novel and biologically active MNPs from the Beibu Gulf, we provide a systematic overview of the sources, chemical structures, and bioactive properties of a total of 477 new MNPs derived from the Beibu Gulf, citing 133 references and covering the literature from the first report in November 2003 up to September 2022. These reviewed MNPs were structurally classified into polyketides (43%), terpenoids (40%), nitrogen-containing compounds (12%), and glucosides (5%), which mainly originated from microorganisms (52%) and macroorganisms (48%). Notably, they were predominantly found with cytotoxic, antibacterial, and anti-inflammatory activities. This review will shed light on these untapped Beibu Gulf-derived MNPs as promising lead compounds for the development of new drugs.


Introduction
Natural products have always been at the core of the development of organic chemistry, and as compound entity resources for the discovery of new drugs [1]. It is worth noting that unique marine environments provide a valuable platform for the discovery of drug compounds with novel structures exhibiting remarkable bioactivities [2]. Marine natural products possess obvious therapeutic effects on various human diseases, and they can resist viruses, tumors, inflammation, improve immune function, and prevent diabetes and Alzheimer's disease. These factors have aroused great interest from chemists, biologists, and pharmacologists [3][4][5]. The first marine natural product with biological activity was officially reported by Bergman in the late 1950s [6]. Additionally, the isolation and investigation of MNPs is a rapidly expanding field of research at the interface of biology and chemistry. Looking back to 2009, when only 20,000 MNPs were known, the number has increased 50% in the past 11 years, which highlights the importance of marine habitats [7].
The Beibu Gulf is a semi-closed gulf located in the northwestern South China Sea, with Vietnam lying on the west of the gulf, and Guangxi Zhuang Autonomous Region and Hainan Island, both in China, lying to the north and east of the gulf, respectively. This Gulf is a global center of biodiversity and is an epicenter of marine biodiversity covering 12.8 million square kilometers of ocean and coastal waters. Additionally, this area harbors Craterellin D (13), a new merosesquiterpenoid, was isolated from a soft coral-derived Lophiostoma sp. fungus, which was collected from the Weizhou Island coral reef [15]. A guaiane-type sesquiterpenoid (14) was obtained from gorgonian Echinogorgia sassapo reticulata collected from the Weizhou Islands in the Beibu Gulf [16]. Three new guaiane sesquiterpene lactones, echinofloranolides A-C (15)(16)(17) were isolated from the gorgonian Echinogorgia flora collected from Weizhou Island [17].
Bioactivity-guided isolation of the rare gorgonian Muricella sibogae yielded two new eunicellin-type diterpenes, sibogins A (24) and B (25). The cytotoxicity of 24 and 25 were evaluated in vitro against P388 and BEL-7402 cell lines. Both of them showed only weak activities against P388 cell lines, with inhibition rates ranging from 10 to 60% at a concentration of 50 mg/mL [20].
Bioactivity-guided isolation of the rare gorgonian Muricella sibogae yielded two new eunicellin-type diterpenes, sibogins A (24) and B (25). The cytotoxicity of 24 and 25 were evaluated in vitro against P388 and BEL-7402 cell lines. Both of them showed only weak activities against P388 cell lines, with inhibition rates ranging from 10 to 60% at a concentration of 50 mg/mL [20].
Bioactivity-guided isolation of the rare gorgonian Muricella sibogae yielded three new 9,10-secosteroids, sibogols A-C (130)(131)(132). The cytotoxicity of 130-132 were evaluated in vitro against the selected tumor cell lines P388 and BEL-7402. All the compounds showed only weak activities against P388 cell lines, with inhibition rates ranging from 10 to 60% at a concentration of 50 mg/mL [20].
Bioactivity-guided isolation of the rare gorgonian Muricella sibogae yielded three new 9,10-secosteroids, sibogols A-C (130)(131)(132). The cytotoxicity of 130-132 were evaluated in vitro against the selected tumor cell lines P388 and BEL-7402. All the compounds showed only weak activities against P388 cell lines, with inhibition rates ranging from 10 to 60% at a concentration of 50 mg/mL [20].

Meroterpenoids
Chromatographic separation of the EtOAc extract of Penicillium brasilianum using a large-scale fermentation resulted in the isolation of twelve new 3,5-dimethylorsellinic acid-related meroterpenoids, namely brasilianoids A-L (136-147) ( Figure 10). Among them, compound 136 significantly stimulated the expression of filaggrin and caspase-14 in HaCaT cells in a dose-dependent manner, while compounds 137 and 138 showed moderate inhibition against NO production in LPS-induced RAW 264.7 macrophages [47]. Moreover, only compound 137 exhibited significant inhibition against bacteria invasion into host cells, against the IEC-6 cells, with an IC50 value of 2.5 µM [48]. Two new meroterpenoids, acetoxydehydroaustin B (148) and 1,2-dihydro-acetoxydehydroaustin B (149) were isolated in the form of a mixed crystal from the mangrove endophytic fungus Aspergillus sp. 085241B [49].

Meroterpenoids
Chromatographic separation of the EtOAc extract of Penicillium brasilianum using a large-scale fermentation resulted in the isolation of twelve new 3,5-dimethylorsellinic acid-related meroterpenoids, namely brasilianoids A-L (136-147) ( Figure 10). Among them, compound 136 significantly stimulated the expression of filaggrin and caspase-14 in HaCaT cells in a dose-dependent manner, while compounds 137 and 138 showed moderate inhibition against NO production in LPS-induced RAW 264.7 macrophages [47]. Moreover, only compound 137 exhibited significant inhibition against bacteria invasion into host cells, against the IEC-6 cells, with an IC 50 value of 2.5 upmuM [48]. Two new meroterpenoids, acetoxydehydroaustin B (148) and 1,2-dihydro-acetoxydehydroaustin B (149) were isolated in the form of a mixed crystal from the mangrove endophytic fungus Aspergillus sp. 085241B [49].
During our on-going studies aimed at discovering new secondary metabolites from the Beibu Gulf-derived marine fungi, 13

Fatty Acids and Linear Molecules
Chemical investigation of the fungal strain Penicillium chrysogenum QEN-24S resulted in the isolation of four new compounds. Their structures were identified as two polyketide derivatives penicitides A (207) and B (208) (Figure 15), and one monoterpene derivative penicimonoterpene (209). In addition, compound 209 displayed potent activity against the pathogen Alternaria brassicae with an inhibition zone of 17 mm in diameter at the concentration of 20 µg/disk, while compound 207 exhibited moderate cytotoxic activity against the human hepatocellular liver carcinoma cell line, with the IC 50 value of 32 µg/mL [55].

Fatty Acids and Linear Molecules
Chemical investigation of the fungal strain Penicillium chrysogenum QEN-24S resu in the isolation of four new compounds. Their structures were identified as two polyke derivatives penicitides A (207) and B (208) (Figure 15), and one monoterpene deriv penicimonoterpene (209). In addition, compound 209 displayed potent activity agains pathogen Alternaria brassicae with an inhibition zone of 17 mm in diameter at the con tration of 20 µg/disk, while compound 207 exhibited moderate cytotoxic activity ag the human hepatocellular liver carcinoma cell line, with the IC50 value of 32 µg/mL [5 A new brominated polyunsaturated lipid, methyl (E,E)-14,14-dibromo-4,6,13tetr catrienoate (210), was isolated from the Et2O-soluble portion of the acetone extract o Chinese marine sponge Xestospongia testudinaria treated with diazomethane [56]. Ch cal examination of the Chinese marine sponge Xestospongia testudinaria led to the isola of 16 new brominated polyunsaturated compounds (211-226), which were design with the trivial names xestospongienes A-Z and Z1-Z13 [57]. A new brominated polyunsaturated lipid, methyl (E,E)-14,14-dibromo-4,6,13tetradecatrienoate (210), was isolated from the Et 2 O-soluble portion of the acetone extract of the Chinese marine sponge Xestospongia testudinaria treated with diazomethane [56]. Chemical examination of the Chinese marine sponge Xestospongia testudinaria led to the isolation of 16 new brominated polyunsaturated compounds (211-226), which were designated with the trivial names xestospongienes A-Z and Z1-Z13 [57].
Two new lysophospholipids (236 and 237) were isolated from the sponge Spirastrella purpurea from Weizhou Island, which displayed various moderate in vitro antifungal activities against the fungi Cryptococcus neoformans, with MIC values of 16 and 32 µg/mL, respectively [59]. Halotolerant fungus Cladosporium cladosporioides OUCMDZ-187 was isolated from the mangrove plant Rhizophora stylosa collected in Shankou, Guangxi Autonomous Region, China. Three new fatty acid esters cladosporesters A-C (238-240) and five new fatty acids cladosporacids A-E (241-245) were isolated from the ethyl acetate extract of the fermentation broth of Cladosporium cladosporioides OUCMDZ-187 in a hypersaline (10% salt) medium [60].
Two new lysophospholipids (236 and 237) were isolated from the sponge Spirastrella purpurea from Weizhou Island, which displayed various moderate in vitro antifungal activities against the fungi Cryptococcus neoformans, with MIC values of 16 and 32 µg/mL, respectively [59]. Halotolerant fungus Cladosporium cladosporioides OUCMDZ-187 was isolated from the mangrove plant Rhizophora stylosa collected in Shankou, Guangxi Autonomous Region, China. Three new fatty acid esters cladosporesters A-C (238-240) and five

Phenols, Diphenyl Ethers, and Benzophenones
An endophytic fungus (Talaromyces stipitatus SK-4) was isolated from the leaves of a mangrove plant Acanthus ilicifolius. Its crude extract exhibited significant antibacterial activity and was purified to afford two new depsidones, talaromyones A (250) and B (251) ( Figure 17). Remarkably, compound 251 showed antibacterial activity against Bacillus subtilis with an MIC value of 12.5 µg/mL. Compound 251 displayed moderate inhibitory activity against α-glucosidase with an IC 50 value of 48.4 µM [63].
Chromatographic separation of the bioactive extract resulted in the isolation of three new polyketide derivatives, eurobenzophenones A-C (262-264). Compound 264 exhibited potent radical scavenging activity against DPPH, with an IC 50 value of 1.7 µM. Moreover, compound 263 (10 µM) exerted inhibitory activity against NO production in the LPSinduced BV2 cells of 17.4% [68].

Benzofuranones
Three new isocoumarins, dichlorodiaportintone (292), desmethyldichlorodiaportintone (293), and desmethyldichlorodiaportinol (294) (Figure 19), were isolated from the culture of the mangrove endophytic fungus Ascomycota sp. CYSK-4 from Pluchea indica. In particular, compound 293 showed significant anti-inflammatory activity through inhibiting the production of NO in LPS-induced RAW 264.7 cells with an IC50 value of 15.8 µM, while compound 292 exhibited weak activity with an IC50 value of 41.5 µM. In addition, compound 292 showed an antibacterial effect against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter calcoaceticus with the MIC values in the range of 25-50 µg/mL [80].
Four new altenusin derivatives (299-302) were isolated from a culture of the endophytic fungus Alternaria sp. SK6YW3L, which was isolated from a fresh fruit of the mangrove plant Sonneratia caseolaris, collected from Weizhou Island. Compounds 300 and 301 exhibited moderate α-glucosidase inhibitory activities, with IC50 values of 78.2 and 78.1 µM, respectively [81].
The chemical investigation of the mangrove fruit Sonneratia apetala, collected from the Beibu Gulf, led to the isolation of three new compounds, sonneradons A-C (289-291). Furthermore, compound 289 showed most significant antiaging effects on Caenorhabditis elegans, increasing the survival time of Caenorhabditis elegans from 30.8 ± 0.7% at the concentration of 100 µM to 34.5 ± 0.9% at the concentration of 300 µM, respectively. Moreover, compound 289 can significantly attenuate the aging-related decrease of pumping and bending in the worms of the healthspan essay, which suggests that compound 289 possesses great potential in antiaging applications [79].

Benzofuranones
Three new isocoumarins, dichlorodiaportintone (292), desmethyldichlorodiaportintone (293), and desmethyldichlorodiaportinol (294) (Figure 19), were isolated from the culture of the mangrove endophytic fungus Ascomycota sp. CYSK-4 from Pluchea indica. In particular, compound 293 showed significant anti-inflammatory activity through inhibiting the production of NO in LPS-induced RAW 264.7 cells with an IC 50   Four new altenusin derivatives (299-302) were isolated from a culture of the endophytic fungus Alternaria sp. SK6YW3L, which was isolated from a fresh fruit of the mangrove plant Sonneratia caseolaris, collected from Weizhou Island. Compounds 300 and 301 exhibited moderate α-glucosidase inhibitory activities, with IC 50 values of 78.2 and 78.1 µM, respectively [81].

Quinones and Xanthones
Two new 1, 4-naphthoquinone derivatives (324 and 325) ( Figure 21) were obtained from the endophytic fungus Talaromyces sp. SK-S009 isolated from the fruit of Kandelia obovata. Compound 324 exhibited significantly inhibitory activities against LPS-induced NO production in the murine macrophage cell line, with an IC50 value of 3.9 µM [86].
Leptospyranonaphthazarin A (342) was isolated from an endophytic fungus Leptosphaerulina sp. SKS032. In the antibiotic assay, compound 342 exhibited antibacterial activity against Staphylococcus aureus with an MIC value of 25.0 µg/mL [74]. The mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) was cultivated in potato dextrose liquid medium, and one new thiophene compound (343) was isolated [91]. DPPH assay of the in-house marine-derived fungi uncovered the EtOAc extract of the cultured fungus

Quinones and Xanthones
Two new 1, 4-naphthoquinone derivatives (324 and 325) ( Figure 21) were obtained from the endophytic fungus Talaromyces sp. SK-S009 isolated from the fruit of Kandelia obovata. Compound 324 exhibited significantly inhibitory activities against LPS-induced NO production in the murine macrophage cell line, with an IC 50 value of 3.9 µM [86].
Chromatographic separation of the bioactive extract resulted in the isolation of two new polyketide derivatives, namely euroxanthones A (347) and B (348). Moreover, compound 347 (10 µM) ( Figure 22) exerted inhibitory activity against NO production in the LPS-induced BV2 cells of 42.2% [68]. A pair of novel 2,3-diaryl indone derivatives (+)-and (−)-ascomindone D (350a and 350b) were obtained from the culture of a mangrove endophytic fungus Ascomycota sp. SK2YWS-L. In the anti-inflammatory assay, compounds 350a and 350b exhibited potential anti-inflammatory effects by inhibiting the production of NO in LPS-induced RAW 246.7 mouse macrophages with IC50 values of 17.0 and 17.1 µM, respectively [70].

Macrolides
Secondary metabolites of marine-derived Bacillus siamensis were isolated and screened for inhibitory activities, which led to the discovery of five new 24-membered macrolactins, bamemacrolactins A-E (356-360) (Figure 23), with compound 358 being the most potent sugarcane smut fungicide. In addition, compound 358 had inhibitory effects on MAT-1 and MAT-2 of Sporisorium scitamineum with EC50 values of 0.5 µg/mL and 10.8 µg/mL, respectively [97].
Three new 14-membered resorcylic acid lactones, named cochliomycins A-C (361-363), were isolated from the culture broth of Cochliobolus lunatus, a fungus obtained from the gorgonian Dichotella gemmacea collected from Weizhou Island. All of these compounds completely inhibited the larval settlement of Balanus amphitrite at a concentration of 20.0 µg/mL. Remarkably, compound 361 showed a significant inhibitory effect on larval settlement even at a concentration of 5.0 µg/mL [98]. A pair of novel enantiomeric polyketide dimers, (+)-and (−)-ascomlactone A (349a and 349b) were obtained from a mangrove endophytic fungus Ascomycota sp. SK2YWS-L. T. Both of them exhibited significant inhibition effects against α-glucosidase with IC 50 values of 63.7 and 27.9 µM, respectively [94].
A pair of novel 2,3-diaryl indone derivatives (+)-and (−)-ascomindone D (350a and 350b) were obtained from the culture of a mangrove endophytic fungus Ascomycota sp. SK2YWS-L. In the anti-inflammatory assay, compounds 350a and 350b exhibited potential anti-inflammatory effects by inhibiting the production of NO in LPS-induced RAW 246.7 mouse macrophages with IC 50 values of 17.0 and 17.1 µM, respectively [70].

Macrolides
Secondary metabolites of marine-derived Bacillus siamensis were isolated and screened for inhibitory activities, which led to the discovery of five new 24-membered macrolactins, bamemacrolactins A-E (356-360) ( Figure 23), with compound 358 being the most potent sugarcane smut fungicide. In addition, compound 358 had inhibitory effects on MAT-1 and MAT-2 of Sporisorium scitamineum with EC 50 values of 0.5 µg/mL and 10.8 µg/mL, respectively [97].
Three new 14-membered resorcylic acid lactones, named cochliomycins A-C (361-363), were isolated from the culture broth of Cochliobolus lunatus, a fungus obtained from the gorgonian Dichotella gemmacea collected from Weizhou Island. All of these compounds completely inhibited the larval settlement of Balanus amphitrite at a concentration of 20.0 µg/mL. Remarkably, compound 361 showed a significant inhibitory effect on larval settlement even at a concentration of 5.0 µg/mL [98].
Two new avermectin derivatives, avermectins B1c (364) and B1e (365), were isolated from a Beibu Gulf gorgonian coral, Anthogorgia caerulea. Compounds 364 and 365 showed moderate antifouling activities against the larval settlement of Balanus amphitrite, with ED 50 values of 15.8 and 6.3 µg/mL, respectively [99]. Further chemical investigation of the mangrove fruit Avicennia marina led to the isolation of a new caffeic acid derivative, maricaffeolylide A (366), which showed antioxidant activity with an EC 50 value of 24.0 µM [100].
Two uncommon marine gorgonian-derived symmetric dimers, weizhouochrones A (374) and B (375), with indenone-derived monomers, were isolated from the coral Anthogorgia ochracea collected from Weizhou Island [103]. The marine-derived fungus Alternaria alternata was isolated from branch samples of Beibu Gulf, Qinzhou City, Guangxi Autonomous Region, China. A chemical study of marine-derived fungus Alternaria alternata, led to the isolation of a new isomer compound named tricycloalternarene 18c (376) [104].
Three new 14-membered resorcylic acid lactones, named cochliomycins A-C (361-363), were isolated from the culture broth of Cochliobolus lunatus, a fungus obtained from the gorgonian Dichotella gemmacea collected from Weizhou Island. All of these compounds completely inhibited the larval settlement of Balanus amphitrite at a concentration of 20.0 µg/mL. Remarkably, compound 361 showed a significant inhibitory effect on larval settlement even at a concentration of 5.0 µg/mL [98].
Two new avermectin derivatives, avermectins B1c (364) and B1e (365), were isolated from a Beibu Gulf gorgonian coral, Anthogorgia caerulea. Compounds 364 and 365 showed moderate antifouling activities against the larval settlement of Balanus amphitrite, with ED50 values of 15.8 and 6.3 µg/mL, respectively [99]. Further chemical investigation of the mangrove fruit Avicennia marina led to the isolation of a new caffeic acid derivative, maricaffeolylide A (366), which showed antioxidant activity with an EC50 value of 24.0 µM [100].
Two new azaphilones, asperterilones A (393) and B (394), were isolated from an hdaA mutant. Both of them displayed moderate anti-candida activities against Candida parapsilosis with MIC values of 18.0 and 23.9 µM, respectively (MIC value of amphotericin, 2.2 µM). Additionally, compound 393 exhibited significant cytotoxic activity against human breast cancer cell line MDA-MB-231 [109]. Streptopentanoic acid (395), was obtained from the culture of the marine-derived Streptomyces sp. MDW-06, which showed DPPH radical scavenging activity with 36.4% at 100 mg/L [110]. One new altenusin derivative (396), was isolated from a culture of the endophytic fungus Alternaria sp. SK6YW3L, which was isolated from a fresh fruit of the mangrove plant Sonneratia caseolaris, collected from Weizhou Island [81].

Nitrogen-Containing Compounds
A total of 58 nitrogen-containing compounds were discovered within the period, consisting of 24 alkaloids, 18 peptides, 16 amides and other miscellaneous ones. In addition, a total of 26 active compounds were found in these nitrogen-containing compounds in the Beibu Gulf, including cytotoxic (15 molecules), anti-microbial (5 molecules), enzyme inhibitory (3 molecules), anti-fouling (2 molecules), and anti-viral activities (1 molecule).
Under the guidance of global natural product social molecular networking, three new indolocarbazoles named streptocarbazoles F-H (402-404), were isolated from the marinederived Streptomyces sp. OUCMDZ5380. All of them showed selective antiproliferation of the acute myeloid leukemia cell line MV4-11 with the IC 50 values of 0.8, 0.6, and 1.9 µM, respectively [114].
A new alkaloid (417) was isolated from the hypocotyl of a mangrove plant, Bruguiera gymnorrhiza, and purified with repeated column chromatography on silica and HPLC. It showed anti-Hepatitis B virus activity against HbsAg and HbeAg with IC50 values of 4.4 and 4.9 µM, and TI values of 2.7 and 2.4, respectively [121]. Echinoflorine (418), a new dimethylamino-substituted guaipyridine alkaloid with a novel γ-lactone-cyclohepta [c]pyridine-fused skeleton, was isolated from the gorgonian Echinogorgia flora, collected in Weizhou Island [17].  A new centrosymmetric cyclohexapeptide, aspersymmetide A (428), was isolated from the fungus Aspergillus versicolor isolated from a gorgonian coral Carijoa sp., collected from Weizhou Island. Remarkably, it displayed weak cytotoxicity against NCI-H292 and A new centrosymmetric cyclohexapeptide, aspersymmetide A (428), was isolated from the fungus Aspergillus versicolor isolated from a gorgonian coral Carijoa sp., collected from Weizhou Island. Remarkably, it displayed weak cytotoxicity against NCI-H292 and A431 cells with an inhibition ratio of 53.8% and 63.6% at a concentration of 10 µM (adriamycin, 1 µM, 93.4% and 91.0%), respectively [124].
Six new 16-residue peptaibols, acremopeptaibols A-F (429-434) (Figure 27), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 was grown in the presence of the autoclaved bacterium Pseudomonas aeruginosa on solid rice medium. Compounds 429 and 433 exhibited significant antimicrobial activities against methicillin-resistant Staphylococcus aureus, Bacillus subtilis, and Candida albicans, with MIC values in the range of 16.0-64.0 µg/mL [9].
Six new 16-residue peptaibols, acremopeptaibols A-F (429-434) (Figure 27), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 was grown in the presence of the autoclaved bacterium Pseudomonas aeruginosa on solid rice medium. Compounds 429 and 433 exhibited significant antimicrobial activities against methicillin-resistant Staphylococcus aureus, Bacillus subtilis, and Candida albicans, with MIC values in the range of 16.0-64.0 µg/mL [9].
Three novel cyclic hexapeptides, sclerotides C-E (435-437), and a new lipodepsipeptide, scopularide I (438), were isolated from fermented rice cultures of a soft coral-derived fungus Aspergillus sclerotiorum SCSIO 41031. Particularly, compound 438 exhibited acetylcholinesterase inhibitory activity with an IC50 value of 15.6 µM and weak cytotoxicity against the human nasopharyngeal carcinoma cell line HONE-EBV with an IC50 value of 10.1 µM [125].
One new triterpenoid, named saponin (461), was isolated from the fruits of Avicennia marina in Guangxi Autonomous Region, China, which showed cytotoxicity against GSC3# and GSC-18# with IC 50 values 12.2 and 5.5 µg/mL, respectively [136]. Further chemical investigation of the plant of Bruguiera gymnorrhiza led to the isolation of a new 8-hydroxyquercetagetin glycoside, rugymnoside A (462). It showed antioxidant activity with an EC 50 value of 11.8 ± 0.8 µM [137].
The chemical investigation of the fruits of a mangrove Sonneratia apetala collected from the Beibu Gulf led to the isolation of one new compound, sonneradon D (463) [79]. Four new jacaranone analogs, marinoids F-I (464-467), were isolated from the fruits of a Beibu Gulf mangrove Avicennia marina. Moreover, the antioxidant activity of the isolates was evaluated using a cellular antioxidant assay, and compound 467 showed moderate antioxidant activity, with an EC 50 value of 26 µM [138].

Discussion and Conclusions
MNPs have contributed significantly to modern drug development. We have summarized the sources, structural diversity, and biological activity of 477 newly reported MNPs from the Beibu Gulf region, according to a survey of the literature published from November 2003 to September 2022. This gives us an opportunity to count the MNPs from the Beibu Gulf from the above-mentioned point of view. These reviewed MNPs from Beibu Gulf were found in marine microorganisms (52%) and macroorganisms (48%). In addition, the distribution of these MNPs from macroorganisms and microorganisms was also analyzed. MNPs from macroorganisms were mainly distributed in corals (55%), sponges (26%), and mangroves (12%). However, the top three hosts of microbial-derived MNPs were mangroves (31%), sponges (25%), and corals (22%) (Figure 31). Notably, these MNPs from microorganisms were isolated from 22 genera of fungi (91%) and 6 strains of bacteria (9%). Meanwhile, Aspergillus (17%), Penicillium (13%), and Stachybotrys (13%) were the top three fungal genera from the Beibu Gulf for producing new MNPs (Figure 32). The chemical structures of the derived MNPs were divided into four categories as shown in Figure 33. Remarkably, terpenoids (43%), polyketides (40%), and nitrogen-containing compounds (12%) ranked as the top three structural types, followed by glucosides (5%). Strikingly, nearly 39% of them (184 of 477 compounds) were discovered with a broad spectrum of bioactivities, including anti-microbial (28%), cytotoxic (28%), anti-inflammatory (15%), enzyme inhibitory (12%), anti-viral (7%), anti-oxidative (5%), and anti-fouling activities (5%) (Figure 34). In addition, a total of 133 articles involving 477 newly reported MNPs have been published in 31 kinds of related international journals in the past twenty years ( Figure 35). Interestingly, among them, 67 new MNPs (14%) in 24 articles (18%) were published in Marine Drugs, which was the most populous journal among these references.  The chemical structures of the derived MNPs were divided into four categories as shown in Figure 33. Remarkably, terpenoids (43%), polyketides (40%), and nitrogencontaining compounds (12%) ranked as the top three structural types, followed by glucosides (5%). Strikingly, nearly 39% of them (184 of 477 compounds) were discovered with a broad spectrum of bioactivities, including anti-microbial (28%), cytotoxic (28%), anti-inflammatory (15%), enzyme inhibitory (12%), anti-viral (7%), anti-oxidative (5%), and anti-fouling activities (5%) (Figure 34). In addition, a total of 133 articles involving 477 newly reported MNPs have been published in 31 kinds of related international journals in the past twenty years ( Figure 35). Interestingly, among them, 67 Figure 37). It is worth noting that marine habitats have become the main source of halogenated compounds because the concentrations of bromine and chloride ions in sea water are higher than those in the terrestrial environment [141]. According to the literature survey from November 2003 to September 2022, 58 (12%) halogenated natural products were found in the 477 MNPs newly reported from the Beibu Gulf, which indicates the Beibu Gulf is one of the important areas for producing halogenated MNPs.
Based on the foregoing discussion, over the past 20 years (from November 2003 to September 2022), 477 new natural products were reported in 133 papers. Although the research on secondary metabolites from Beibu Gulf has only been going for 20 years, more attention has been paid to it in recent years. In this review, it seems that fungi are the focus of biological prospects for bioactive metabolites of microorganisms in the Beibu Gulf. Among bacteria, actinomycetes seem to be studied more deeply in natural product research, and they have shown the potential to become biological resources with novel structures and good biological activities. In terms of structural category, polyketides occupy the largest number and show a wide range of biological activities, such as anti-tumor, antibacterial, and anti-inflammatory activities. So far, many well-known research groups in China, represented by Prof. Wenhan Lin, Prof. Changyun Wang, and Prof. Yonghong Liu, have reported a large number of MNPs with novel structures and promising activity. The significant biological activity of these MNPs from the Beibu Gulf is dominated by cytotoxicity (28%) and anti-microbial activity (28%). By exploring untapped novel species of marine organisms and by proposing newer biological targets, it would enhance the possibility for discovering novel lead compounds with potential therapeutic applications. Moreover, careful and innovative techniques for MNPs isolation are required for the identification of new structures and activities, including unstable intermediates. In addition to exploring potential new natural biological resources, the application of drug discoveryrelated techniques, such as gene mining and combinatorial biosynthesis, will improve the structural and biological diversity of MNPs. A large number of the Beibu Gulf marine macro-and microorganisms are still underexplored, and they may provide inspiration for many chemical entities. Therefore, the natural product resources in the Beibu Gulf are still a virgin land to be urgently developed. Reasonable and green application research will contribute more to drug discovery.    anti-oxidative activity 5% anti-fouling activity 5%     anti-oxidative activity 5% anti-fouling activity 5%

Conflicts of Interest:
The authors declare no conflict of interest.