Fungal Naphthalenones; Promising Metabolites for Drug Discovery: Structures, Biosynthesis, Sources, and Pharmacological Potential

Fungi are well-known for their abundant supply of metabolites with unrivaled structure and promising bioactivities. Naphthalenones are among these fungal metabolites, that are biosynthesized through the 1,8-dihydroxy-naphthalene polyketide pathway. They revealed a wide spectrum of bioactivities, including phytotoxic, neuro-protective, cytotoxic, antiviral, nematocidal, antimycobacterial, antimalarial, antimicrobial, and anti-inflammatory. The current review emphasizes the reported naphthalenone derivatives produced by various fungal species, including their sources, structures, biosynthesis, and bioactivities in the period from 1972 to 2021. Overall, more than 167 references with 159 metabolites are listed.


Introduction
Fungi are the second-biggest group of organisms after insects [1]. Many fungal species have a wide range of biotechnological and industrial potential [2][3][4][5][6][7]. They are acknowledged as one of the wealthiest pools of natural metabolites among living organisms due to their unique metabolic system and their capacities to synthesize diverse kinds of metabolites with quite intriguing chemical skeletons [8,9]. These metabolites possess a wide range of applications as agrochemicals, antibiotics, immune-suppressants, anti-parasitic, and anticancer agents [10][11][12][13][14][15][16][17][18][19][20]. Naphtalenones are among the naphthalene derivatives produced by fungi that are strictly related to napthoquinones and involved in the branched pathway of fungal DHN (1,8-dihydroxynaphthalene)-melanin biosynthesis [21,22]. Also, they belong to a group of renowned phytotoxins produced by various crop and forest plants pathogenic fungi [22][23][24]. Moreover, naphthalenone derivatives possess a great structural diversity not only in the planar structure but also in the absolute configuration. Many reported reviews

Bioactivities of Naphthalenones
The reported naphthalenones have been investigated for various bioactivities. In this regard, these metabolites have been associated with many types of bioactivities, including phytotoxic, antiviral, antimicrobial, nematocidal, antimycobacterial, cytotoxic, antimalarial, anti-inflammatory, insecticidal, and alpha-glucosidase and IDO inhibitory activities. Herein, these activities have been discussed and results of the most active metabolites have been listed in Table S2.

Phytotoxic and Nematocidal Activities
Weeds represent the most common and severe biotic factors affecting agriculture and are responsible for remarkable agricultural losses. They have negative effects on the crop plants because of the competition for water, nutrients, sunlight, and space. Additionally, they can be a reservoir for certain plant pathogenic microorganisms and/or herbivorous insects [30]. Integrated management strategies are generally applied for controlling weeds by using mechanical methods along with synthetic herbicides [22]. However, the extensive use of synthetic herbicides has toxic effects not only on the target organism but also on animals and humans, in addition to the adverse environmental impacts and promotion of the emergence of herbicide-resistant species. Therefore, research interest has been directed toward identifying new bioherbicides of natural origin [31]. Fungi are known to have the capacity to produce diverse arrays of secondary metabolites that could be beneficial as bioherbicidal agents [22]. Fungal phytotoxic metabolites have a crucial role in developing disease symptoms in host plants. Although they can cause significant damage to crops, naphthalenones can also function as starting material for the development of natural herbicides to control the growth and spread of weeds [32]. Interestingly, many of the reported naphthalenones have been found to possess phytotoxic potential. These phytotoxic properties could be utilized for developing simple, rapid, and specific tools to identify plant diseases such as a test kit (e.g., rapid test strip) that can be used directly by farmers in the field. Additionally, they can be used as lead compounds by allowing the synthesis of more phytotoxic compounds on a range of weeds based on their structures for potential application as herbicides. Compound 1 isolated from Pyricularia Oryzae reduced the rice seedlings' growth at high concentrations, however, it slightly stimulated the rice seedlings' growth at a concentration of 100 ppm in 24 h [33]. Masi et al. reported that the culture filtrate of Pyricularia grisea afforded 2 and 9 (Figure 1), which were assessed for their phytotoxicity toward buffelgrass (Cenchrus ciliaris) using radicle elongation and buffelgrass coleoptile bioassay. They significantly delayed the seed germination relative to the control, whereas 2 also apparently reduced the germination percentage [34].
Additionally, 1, 9, and 21 were separated from the liquid culture of Tubakia dryina, the causative agent of Quercus rubra (red oak) leaf spot. In the detached leaf assay, these metabolites caused large lesions on the red oak leaves that developed along the veins within 24 h, very similar to those resulting from T. dryina infection. On the other hand, they had a moderate phytotoxic effect on white oak, prickly sida, and sorghum [38]. Moreover, 2 inhibited Lepidium sativum and Setaria italica germinated seed growth (IC50 50 and 100 µg/disc, respectively) [35]. Further, the cup fungus, Urnula craterium yielded 4 and 9 that had no in-vitro activity toward the aspen pathogens: Ophiostoma piliferum, O. crassivaginatum, and Populus tremulae (conc. up to 100 µg/mL) [36]. Also, it was found that 9 (conc.1-10 ppm) stimulated the rice seedlings' root elongation by ≈30%,  The pathogenic fungus, Ceratocystis fimbriata f. sp. platani that caused canker stain in the plane tree (Platanus acerifolia) produced 4 and 5, which produced large necrotic lesions in the plane tree tissues at a concentration of 1.0 mg/mL, whereas 17 possessed significant necrosis only after 7 days, whereas 19 and 28 exhibited less activity after 48 h [39]. Compound 7 was separated from Mycosphaerella fijiensis IMI 105378, the causative agent of Black Sigatoka disease in plantains and bananas. It induced necrotic lesions (Conc. 5 µg/5 µL) in <12 h on the sensitive cultivars of bananas in the leaf-puncture bioassay [40]. Ceratocvstis fimbriata that is accountable for the canker disease of the coffee tree yielded 14 and 17 that exhibited no remarkable toxic effect on coffee trees (conc. 1 × 10 −3 M) [41]. Furthermore, 12 and 17 were separated from Phaeoacremonium aleophilum associated with the esca of grapevine. Compound 12 (Conc. 0.1 mg/mL) produced large, coalescent necrotic, and chlorotic spots then withering and distortion of the lamina, however, 17 (Conc. 0.05 mg/mL) produced light green to chlorotic, rounded to irregular, inter-veinal, or marginal spots on the grapevine detached leaves. Thus, they caused similar symptoms to those shown by the vines leaves with brown wood-streaking that is associated with wood infection by P. chlamydosporum and P. aleophilum [42]. Moreover, 17 separated from Raffaelea quercivora, which caused the Japanese oak wilt disease, inhibited (Conc. 100 µg/mL) the lettuce seedlings' root growth to 54.8% of the negative control [43]. On the other hand, 22 slightly promoted the second leaves growth (Conc. 500 ppm) and 33 possessed no noticeable activity on the growth of rice seedlings [33,37]. Whilst 48 had a weak phytotoxic activity toward Lepidium sativum (IC 50 100 µg/disk) [44]. The new naphthalenone; botrytone (42), along with the formerly separated 3, 4, and 8 were purified from the culture filtrate of Botrytis fabae associated with Vicia faba (fava bean). Compound 8 displayed the highest phytotoxicity together with 3 and 4 on the Vicia faba leaves, however, 42 had moderate potential (Conc. 1 mg/mL) [44]. Neofusicoccum australe strain BL24 (haplotype H1) produced 31 and 53 ( Figure 2). They were assessed for phytotoxic activity on the leaves of holm oak, cork oak, and grapevine leaves utilizing leaf-puncture assay (Conc. 0.125, 0.25, 0.5, and 1 mg/mL). Compound 53 was much less toxic even at the highest concentration. It caused necrotic lesions on the leaves of cork oak, holm oak, and grapevine (area lesions 4.8, 3.3, and 11.9 mm 2 , respectively). On the other hand, 31 did not possess any phytotoxic effect [45]. Neofusicoccum parvum is one of the most virulent botryosphaeriaceous species that affect the grapevine. Investigation of its extract yielded 9, 40, 53, and 94 that were found to be phytotoxic on grapevine leaves in the leaf puncture assay, with 53 having the greatest potential [46]. Masi et al. purified lentiquinones B (115) and C (116) from the culture filtrate of Ascochyta lentis separated from the diseased lentil (Lens culinaris). Both compounds had the same structure but differed in C-2-OH group configuration, showing αand β-configuration, respectively. They featured three six-membered rings skeleton, involving trihydroxy-cyclohexene and hemi-quinone rings. Their absolute configuration was assigned as 2R,3S,4S,4aS,10R and 2S,3S,4S,4aS,10R, respectively using X-ray, ECD (electronic circular dichroism), and TDDFT (time-dependent DFT) calculations. They showed strong phytotoxicity toward Lupinus albus and Chenopodium album in the leaf puncture assay [47]. Compound 132 biosynthesized by Guignardia laricina inhibited the growth of lettuce seedling roots by 71.5, 16.2, and 7.0% at concentrations of 100, 250, and 50 ppm, respectively in the lettuce seedling bioassay [48].
Plant-parasitic nematodes are plant pathogens that can cause significant reductions in agricultural yields resulting in substantial annual economic losses to growers [49]. Chemical nematocidal agents such as organophosphorus and carbamate are used for controlling these parasitic nematodes, however, their long-term use can result in increased nematode resistance, as well as deleterious effects on human health [50]. Recently, research has emphasized the discovery of nematocidal agents from natural sources including the nematocidal potential of naphthalenone derivatives. Therefore, some studies reported the nematocidal potential of naphthalenone derivatives. ticeable activity on the growth of rice seedlings [33,37]. Whilst 48 had a weak phytotoxic activity toward Lepidium sativum (IC50 100 µg/disk) [44]. The new naphthalenone; botrytone (42), along with the formerly separated 3, 4, and 8 were purified from the culture filtrate of Botrytis fabae associated with Vicia faba (fava bean). Compound 8 displayed the highest phytotoxicity together with 3 and 4 on the Vicia faba leaves, however, 42 had moderate potential (Conc. 1 mg/mL) [44]. Neofusicoccum australe strain BL24 (haplotype H1) produced 31 and 53 ( Figure 2). They were assessed for phytotoxic activity on the leaves of holm oak, cork oak, and grapevine leaves utilizing leaf-puncture assay (Conc. 0.125, 0.25, 0.5, and 1 mg/mL). Compound 53 was much less toxic even at the highest concentration. It caused necrotic lesions on the leaves of cork oak, holm oak, and grapevine (area lesions 4.8, 3.3, and 11.9 mm 2 , respectively). On the other hand, 31 did not possess any phytotoxic effect [45]. Neofusicoccum parvum is one of the most virulent botryosphaeriaceous species that affect the grapevine. Investigation of its extract yielded 9, 40, 53, and 94 that were found to be phytotoxic on grapevine leaves in the leaf puncture assay, with 53 having the greatest potential [46]. Masi et al. purified lentiquinones B (115) and C (116) from the culture filtrate of Ascochyta lentis separated from the diseased lentil (Lens culinaris). Both compounds had the same Compounds 9 and 22 isolated from an unidentified freshwater fungus YMF 1.01029 exhibited weak nematocidal potential toward the nematode Bursaphelenchus xylophilus [51]. The four naphthalenones; 8, 9, 19, and 22 separated from the cultural extract of Caryospora callicarpa were assessed in-vitro for antinematodal activity toward Bursaphelenchus xylophilus (fungal-feeding and plant-parasitic nematode) in the nematotoxin bioassay. They showed noticeable nematocidal potential, which was significantly enhanced with the exposure times length at the same concentration (LC 50 s (lethal concentration 50) 209.7, 229.6, 220.3, and 206.1 mg/L, respectively at 36 h exposure). Their mode of action was suggested to be systemic, instead of contact poisons or antifeedants [52].

Antimicrobial, Antimycobacterial, and Anti-Plasmodial Activities
Infectious diseases are a worldwide health problem. Multidrug-resistant (MDR) pathogens remarkably increase morbidity and mortality rates [53]. The continuous emergence of MDR pathogens drastically reduced the efficacy of antibiotics resulting in a growing rate of therapeutic failure [54]. Accordingly, new and effective antimicrobial agents to address microbial infections are needed.
Inácio et al. purified 3 and 8 from Cryptocarya Mandioccana healthy leaves associated with Colletotrichum gloeosporioides by RP-HPLC (reversed phase-high performance liquid chromatography) and evaluated their antifungal activity by direct bioautography on TLC (thin layer chromatography) plate, which includes spraying the fungal suspensions on the developed TLC plates utilizing solvents of different polarities for detecting the antifungal potential of these compounds [55]. The effectiveness was indicated by white spots against a red-purple background on the TLC plates after spraying with tetrazolium violet [56]. It was found that the required detection limit of these compounds for inhibiting the growth of the phytopathogenic fungi: Cladosporium sphaerospermum and C. cladosporioides was 5.0 mg, compared with nystatin [55]. On the other hand, 2 and 17 obtained from Lachnellula sp. cultures had no antimicrobial potential (Conc. 100 µg/mL) in the serial broth dilution assay toward A. calcoaceticus, M. luteus, M. miehei, and P. variotii [35]. Findlay and Kwan stated that 9 and 17 purified from Scytalidium FY had significant antifungal activity [57]. On the other side, 9 had weak activity against B. subtilis (IC 50 100 µg/mL), compared with chloramphenicol (IC 50 3.13 µg/mL) in the colorimetric assay [58] and no activity toward M. smegmatis, S. aureus, S. cerevisiae, C. neoformans, C. albicans, E. coli, A. niger, and Micrococcus luteus [59]. Lu et al. separated 10 from Cytospora sp. isolated from Ilex canariensis that showed antibacterial activity (IZD (inhibition zone diameter) 15.0 mm) toward Bacillus megaterium in the agar diffusion assay, compared with penicillin (IZD 28.0 mm) [60].
The new derivative, 25, and the formerly reported 1 and 3 were separated from the endolichenic fungus, Xylariaceae sp. CR1546C obtained from Costa Rican lichen Sticta fuliginosa. The C-4 R-configuration of 25 was deduced based on the Mosher method and the opposite optical rotation sign to that of similar structural metabolite-21. These metabolites exhibited weak antifungal potential toward C. albicans with MFCs (minimum fungicidal concentrations) between 100 and 150 µg/mL and IC 50 from 60 to 100 µg/mL, compared to amphotericin B (IC 50 1.3 µg/mL) using broth-dilution technique [63].

Cytotoxic Activity
Cancer is a leading cause of death in the world, accounting for ≈10 million deaths in 2020 [81]. Its treatments include radiation therapy, surgical intervention, chemotherapy, or a combination of these options [82]. There are many available therapeutics for treating various types of cancer, however, none of them are totally safe and effective. Many of the  [84]. Also, El-Amrani et al. separated 1 and 21 from Aureobasidium pullulans that did not have anti-proliferative activity toward L5178Y (mouse lymphoma cell line) in the MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay [85]. Additionally, 9 was purified from a marine-derived Aspergillus fumigatus extract by ODS column chromatography and HPLC. It exhibited notable cytotoxicity (Conc. 60 µM) toward MCF-7 after 24 h incubation. It was found to suppress MMP (mitochondrial membrane potential)-2,-9 expressions via attenuation of the MAPK (mitogen-activated protein kinase) signaling pathway. It also significantly reduced cell mobility and prohibited JNK (c-Jun NH 2 -terminal kinase), ERK (extracellular signal-regulated protein kinase), and P38 (p38 mitogen-activated protein kinase) phosphorylation, involved in cell migration and proliferation. Moreover, it remarkably up-regulated p53 (nuclear transcription factor with a pro-apoptotic function) and down-regulated CDK (cyclin-dependent kinase)4, CDK2, and cyclins (B1 and E). Hence, 9 could be a potential therapeutic for breast cancer [58]. However, it was inactive toward SW-620 and MDA-MB-435 (human melanoma cancer) cell lines in the MTT assay [59]. Compound 17 exhibited moderate cytotoxic potential toward L1210 (mouse lymphocytic leukemia cell line) (IC 50  Compounds 18 and 29 were separated from Phomopsis sp. sh917 harbored Isodon eriocalyx var. laxiflora stems. Their absolute configurations 3R for 18 and 3R,4S of 29 were confirmed based on CD, X-ray, or optical rotation comparison. Compound 29 had no obvious inhibitory effect on the viability of HUVECs (human umbilical vascular endothelial cells) (IC 50 > 100 µM) in the MTT assay [86].
Three new dihydronaphthalenones: 66, 67, and 69 were separated from Botryosphaeria sp. BCC 8200, where 66 and 69 were isolated as two mixtures of inseparable isomers. These metabolites had a weak cytotoxic influence toward MCF-7, NCI-H187, and KB cells and Vero cells in the resazurin and green fluorescent protein micro-plate assays, respectively, compared to ellipticine [68].

Serotonin Antagonistic Activity
Serotonin (5-HT) is a neurotransmitter in the central and peripheral nervous systems. It has been implicated in the etiology of various physio-pathological disorders such as anxiety, depression, schizophrenia, social phobia, IOP (intraocular pressure) modification, migraine, systemic and pulmonary hypertension, irritable bowel syndrome, vomiting, and eating disorders [99,100]. 5-HT 2C antagonists have been considered as a potential target for treating various health disorders [101]. Bös  On the other hand, they could not displace [ 3 H]-DOB from the 5-HT 2A receptor binding site at Conc. up to 10 mM. It was found that the alkyl side chain was essential for binding, however, the phenolic OH was not implicated in binding to the receptor [102].

Melanin Synthesis Inhibitory Activity
Melanins are high molecular weight black or dark brown pigments commonly found in microorganisms, plants, and animals that are produced by oxidative polymerization [24]. They are not required for development and growth, but they enhance the competitiveness and survival of these species under conditions of electromagnetic and UV irradiation, high temperature, and desiccation [103]. Most fungal melanins are derived from DHN (1,8dihydroxynaphthalene) [24]. These pigments are correlated with the enhanced virulence of parasitic fungi and play a remarkable role in fungal pathogenic infections [104]. The newly isolated scytalols A-D (70-73) from the mycelial culture of Scytalidium sp. obtained from Basidiomycete infected body, growing on wood were assessed for their inhibitory effect on DHN (1,8-dihydroxynaphthalene) melanin biosynthesis using Lachnellula sp. A32-89 in the agar cultures. Only 70 and 73 selectively inhibited DHN melanin synthesis, however, 70 and 71 were inactive [105].
IDO (indoleamine 2,3-dioxygenase) controls the rate-limiting steps in tryptophan (Trp) metabolism that is correlated with various disorders such as Parkinson's and Alzheimer's diseases and cataracts. Hence, it is considered a promising target for tumor immunotherapy [107]. Cui  the formerly separated 88 and 98 from Fusarium sp. HP-2 isolated from "Qi-Nan" agarwood. Compound 97 had the same structure as 98, which was previously reported as a new metabolite, except for the existence of an additional methoxy group at C-8 [75]. Its configuration was assigned as 2S,3S,4S based on the negative specific rotation as in 98.

Anti-Inflammatory Activity
Inflammation is a host defense mechanism, which enables the body to survive during injury or infection and maintains the homeostasis of tissues in noxious conditions [109].
Endogenous nitric oxide (NO) plays a critical role in maintaining the homeostasis of varied cellular functions. NO local concentrations are highly dynamic as their synthesis is regulated by independent enzymatic pathways. NO has been shown to have a modulatory effect on inflammation, decreasing the secretion of pro-inflammatory cytokines in human alveolar macrophages challenged with bacterial lipopolysaccharides (LPS), while not altering the basal cytokine levels. Drugs used for managing inflammatory disorders relieve these ailments, but they may have serious life-threatening consequences [110][111][112]. Therefore, there is great enthusiasm for developing novel, safe therapeutics from natural sources for the treatment of inflammation. The reported studies revealed that the antiinflammatory potential of thiophenes could be due to the inhibition of the activation of the NF-κB (nuclear factor-κB) pathway that regulates the expression of pro-inflammatory cytokines and chemokines [111]. A new β-tetralonyl glucoside; 129 was purified from the culture of Colletotrichum sp. GDMU-1 associated with Santalum album leaves. Compound 129 had 4 -methyl β-glucopyranose moiety linked at C-4. Enzymatic hydrolysis followed by ECD spectrum for the hydrolysis product sclerone (8) revealed an R-configuration at C-4. It possessed no inhibitory capacity on NO (nitric oxide) production elicited by LPS (lipopolysaccharide) in RAW264.7 cells [112]. The new metabolites; 57, 58, 101-103, 138, and 139 were purified from the marine-derived fungus Leptosphaerulina chartarum 3608. Both 102/103 and 57/101 were enantiomers as they had opposite optical rotations and Cotton effects in their CD spectra. Their configuration was assigned based on ECD. Compounds 58 and 138 were dimeric naphthalenones, consisting of two monomeric units; leptothalenone A (102/103) and 10-norparvulenone (58). Unfortunately, only 139 possessed moderate inhibitory potential on the LPS-induced NO production (IC 50 44.5 µM) in the RAW264.7 cells using the Griess assay, compared to indomethacin (IC 50 37.5 µM), however, the other metabolites (IC 50 > 100 µM) had no significant anti-inflammatory activity [91]. In the anti-COX-2 assay, 148 and 157 revealed COX-2 inhibition (IC 50 s 60.2 and 49.1 µM, respectively) upon comparison to indomethacin and NS-398 [77].

Conclusions
In recent years, more metabolites have been discovered from fungi derived from diversified sources such as plants, animals, soil, and marine. The current review describes the naphthalenone derivatives reported from fungi, focusing on their biosynthesis and bioactivities. In fact, the available literature analysis revealed that a total of 159 naphthalenones with diverse chemical structures and various bioactivities were reported from 66 identified fungal genera and three unidentified genera. The largest number of derivatives have been obtained from Fusarium, Cladosporium, Daldinia, Biatriospora, Neofusicoccum, Leptosphaerulina, and Xylariaceae ( Figure 9).

Conclusions
In recent years, more metabolites have been discovered from fungi derived from diversified sources such as plants, animals, soil, and marine. The current review describes the naphthalenone derivatives reported from fungi, focusing on their biosynthesis and bioactivities. In fact, the available literature analysis revealed that a total of 159 naphthalenones with diverse chemical structures and various bioactivities were reported from 66 identified fungal genera and three unidentified genera. The largest number of derivatives have been obtained from Fusarium, Cladosporium, Daldinia, Biatriospora, Neofusicoccum, Leptosphaerulina, and Xylariaceae ( Figure 9).   Compounds 1, 3, 8, 9, and 17 are the most commonly reported derivatives from various fungal genera. The majority of naphthalenones have been reported in the period from 2008 to 2020 (Figure 10) .  Compounds 1, 3, 8, 9, and 17 are the most commonly reported derivatives from various fungal genera. The majority of naphthalenones have been reported in the period from 2008 to 2020 ( Figure 10). This was due in part to limited knowledge of the fungal diversity and isolation and cultivation techniques that resulted in many fungal species remaining undiscovered [116]. The observed increase in the number of isolated derivatives can be attributed to the extensive application of new separation, screening, and characterization techniques. Also, the advances in the fungal cultivation strategies, as well as the wide array of genetic tools now available, allow for the fungal genome and metabolome to be readily exploited, leading to enhanced discovery of the value-added metabolites [117].
Many of the reported naphthalenones have remarkable phytotoxic potential. As such, they can be used as bioherbicides or as lead compounds for the synthesis of more efficacious phytotoxic compounds capable of targeting a wide range of weeds.
These metabolites have been assessed for antimicrobial, antimycobacterial, cytotoxic, nematocidal, antioxidant, serotonin antagonistic, antiviral, anti-inflammatory, neuroprotective, and anti-plasmodial, as well as melanin synthesis and enzyme inhibitory potential ( Figure 11). This was due in part to limited knowledge of the fungal diversity and isolation and cultivation techniques that resulted in many fungal species remaining undiscovered [116]. The observed increase in the number of isolated derivatives can be attributed to the extensive application of new separation, screening, and characterization techniques. Also, the advances in the fungal cultivation strategies, as well as the wide array of genetic tools now available, allow for the fungal genome and metabolome to be readily exploited, leading to enhanced discovery of the value-added metabolites [117].
Many of the reported naphthalenones have remarkable phytotoxic potential. As such, they can be used as bioherbicides or as lead compounds for the synthesis of more efficacious phytotoxic compounds capable of targeting a wide range of weeds.
These metabolites have been assessed for antimicrobial, antimycobacterial, cytotoxic, nematocidal, antioxidant, serotonin antagonistic, antiviral, anti-inflammatory, neuroprotective, and anti-plasmodial, as well as melanin synthesis and enzyme inhibitory potential ( Figure 11). Some metabolites have shown promising activities that could be utilized as building blocks for the synthesis of various compounds for treating diverse human disorders. However, these metabolites remain to be further in-vivo tested for their bioactivities. Reports on naphthalenones indicated that differences in structural characteristics of derivatives often correlated with different bioactivities. For example, an increasing number of hydroxyl groups attached to the naphthalenone skeleton enhanced phytotoxic activity. It is noteworthy that compound 90 with a spirally linked γ-lactone ring at C-4 of the naphthalen-1(4H)-one moiety possessed potent antifungal potential than 91, 92, and 93 that have C-13 methyl ester, fused THF ring, and δ-lactone ring, respectively. Also, 131 with an oxaneconnected binaphthyl ring system had a more powerful antimicrobial capacity than 63 and 65, which have C6-C7 fused furan rings. In the dimeric napthalenones, the C-4 αconfigured hydroxyl group was found to be essential for antimicrobial activity as in 147 and 149, however, its replacement with carbonyl (e.g., 153 and 154), methoxy group (150 and 152), or β-configured hydroxyl group reduced the activity (e.g., 155). In the cytotoxicity results, compound 13 with the C-3 methoxy group exhibited higher activity than its nonmethoxylated one (22). Additionally, it was revealed that the dihydro-1,4-naphthoquinone nucleus was substantial for the cytotoxic activity (e. g., 153 vs. 150, 152, and 147, 154, and  155) and the C-4 methoxy group intensified the effect (152 vs. 155).
Many of the reported naphthalenones have remarkable phytotoxic potential. As such, they can be used as bioherbicides or as lead compounds for the synthesis of more efficacious phytotoxic compounds capable of targeting a wide range of weeds.
These metabolites have been assessed for antimicrobial, antimycobacterial, cytotoxic, nematocidal, antioxidant, serotonin antagonistic, antiviral, anti-inflammatory, neuroprotective, and anti-plasmodial, as well as melanin synthesis and enzyme inhibitory potential ( Figure 11). On the other hand, there are limited or no studies that focus on the mechanism of action of these metabolites. In addition, many of the reported metabolites have not been evaluated for their bioactivities, this may be due to either the lack of assays or not enough amount of the isolated compounds to perform these assays. Many of the tested metabolites had no substantial effectiveness in some evaluated bioactivities. Finally, assessment of other potential activities and derivatization of these compounds, as well as in-vivo and mechanistic studies of the active compounds should undoubtedly be the focus of future research.