*2.5. Phenylpropanoids*

Phenylpropanoids are a big and structurally diverse group of secondary metabolites, which bear a C6–C3 phenolic scaffold that play crucial roles in a wide spectrum of biological and pharmacological activities [66]. Twenty-three phenylpropanoids were isolated from co-culture of marine fungi–fungi (12 isolates, 52%) and fungi–bacteria (11 isolates, 48%), while there are no reported phenylpropanoids from the co-culture of different marine bacteria.

#### 2.5.1. Phenylpropanoids Derived from the Co-Cultures of Different Marine Fungi

A xanthone derivative known as 8-hydroxy-3-methyl-9-oxo-9*H*-xanthene-1-carboxylic acid methyl ether (**101**) (Figure 18) was discovered from the mixed culture of two mangrove fungi, *Phomopsis* sp. K38 and *Alternaria* sp. E33 [67] from the South China Sea coast. It showed a broad spectrum of antifungal activities against plant pathogens, *Blumeria graminearum*, *Gloeasporium musae*, *F. oxysporum*, *Colletotrichum glocosporioides* and *Peronophthora cichoralearum*.

**101**

**Figure 18.** Chemical structures of **101**.

Ten citrinin analogues were isolated and identified from the co-culture of two marine algal-derived endophytic fungal strains, *Aspergillus sydowii* EN-534 and *Penicillium citrinum* EN-535 collected from marine red alga *Laurencia okamurai*, including two novel compounds, citrinin dimer *seco*-penicitrinol A (**102**) and citrinin monomer penicitrinol L(**103**), and the known penicitrinone A (**104**), penicitrinone F (**105**), penicitrinol A (**106**), citrinin (**107**), dihydrocitrinone (**108**), decarboxydihydrocitrinone (**109**) phenol A acid (**110**) and phenol A (**111**) (Figure 19) [68]. In addition, one novel coumarin named 7-(γ,<sup>γ</sup>-dimethylallyloxy)-6-hydroxy-4-methylcoumarin (**112**) (Figure 19) was detected and characterized from the co-culture of the two mangrove fungi, *Phomopsis* sp. K38 and *Alternaria* sp. E33 [69].

**Figure 19.** Chemical structures of **102**–**112**.

Compounds **104**, **106** and **107** exhibited inhibitory activities against two human pathogens *Micrococcus luteus* and *E. coli*, and three aquatic bacteria *Vibrio parahaemolyticus*, *Vibrio alginolyticus* and *Edwardsiella ictaluri* with MIC values of 4–64 μg/mL. **102**, **103** and **105** inhibited *V. alginolyticus* and *E. ictaluri* with MIC values of 32–64 μg/mL. **103** and **105** inhibited *V. parahaemolyticus* and *E. coli* with MIC values of 32 and 64 μg/mL, respectively. Moreover, **102**–**107** were further evaluated for anti-influenza neuraminidase (homologous protein of H5N1) activity. **104** and **105** exhibited significant inhibitory activities with IC50 values of 12.9 and 18.5 nM, respectively [68]. Thus, these bioactive substances could be further optimized for the development of antibacterial and anti-influenza agents. In addition to the anti-influenza activity, the activated metabolite penicitrinone A (**104**) also exerted an inhibitory effect on four human cancer cell lines, HL-60, K562, BGC-823 and HeLa cells with IC50 values of 43.2, 50.8, 54.2 and 65.6 μM, respectively [70].

#### 2.5.2. Phenylpropanoids Derived from the Co-Cultures of Marine Fungi and Bacteria

The chemical investigation of the mixed culture of the marine fungus *A. versicolor* and *B. subtilis* resulted in the isolation of one novel aflaquinolone, 22-epi-aflaquinolone B (**113**); and ten known metabolites, aflaquinolone A, F and G (**114**–**116**), 3-*O*-methylviridicatin (**117**), 9-hydroxy-3-methoxyviridicatin (**118**), *O*-demethylsterigmatocystin (**119**), sterigmatocystin (**120**), sterigmatin (**121**), AGI-B4 (**122**) and sydowinin B (**123**) (Figure 20) [38].

The metabolite 3-*O*-methylviridicatin (**117**) was reported to possess inhibitory activity against human immunodeficiency virus (HIV) (Heguy et al., 1998). It could prevent cytokine tumor necrosis factor α (TNF-α), induce the HIV expression with long terminal repeat in HeLa cells (IC50, 5μM) and block the viral replication in the model of chronic infection in OM-10.1 cell lines which directed at the induction of TNF-α [71]. **119** exhibited cytotoxic activities towards mouse lymphoma cell line L5178Y with an IC50 value of 5.8 μM. Three xanthone derivatives (**120**–**122**) showed potent cytotoxic activities towards the mouse lymphoma cell lines with IC50 values of 2.3, 2.2 and 2.0 μM, respectively, compared with a positive control, kahalalide F (IC50 = 4.3 μM). Sterigmatocystin (**120**) also exhibited strong cytotoxicity towards human hepatoma cells (HepG2) at 3 μM [72]. Its mechanism suggested that it could stimulate a biotransformation process, increase the population of reactive oxygen species and promote the imbalance in the antioxidant defense system caused by the process of lipid peroxidation [73]. Recently, Zingales et al. (2020) displayed the significant role of mitochondria in sterigmatocystin-induced toxicity in SH-SY5Y cells [74]. The reduced viability of SH-SY5Y cells displayed time- and dose-dependence with mitochondrial dysfunction when exposed to **120** in response to the forced dependency of the cells on mitochondrial oxidative phosphorylation [74]. Thus, these findings provided us a valuable direction for the application of neuroprotective mitochondria-target functional peptides. Moreover, compound **122** inhibited human umbilical vein endothelial cells (VEGF-induced proliferation of HUVECs) with an IC50 value of 1.4 μM [75]. It is considered as a novel inhibitor of vascular endothelial cell growth factor, which is one of the main stimulants of angiogenesis.

**Figure 20.** Chemical structures of **113**–**123**.
