Chemical diversity, medicinal potentialities, biosynthesis, and pharmacokinetics of anthraquinones and their congeners derived from marine fungi: a comprehensive update

Marine fungi receive excessive attention as prolific producers of structurally unique secondary metabolites, offering promising potential as substitutes or conjugates for current therapeutics, whereas existing research has only scratched the surface in terms of secondary metabolite diversity and potential industrial applications as only a small share of bioactive natural products have been identified from marine-derived fungi thus far. Anthraquinones derived from filamentous fungi are a distinct large group of polyketides containing compounds which feature a common 9,10-dioxoanthracene core, while their derivatives are generated through enzymatic reactions such as methylation, oxidation, or dimerization to produce a large variety of anthraquinone derivatives. A considerable number of reported anthraquinones and their derivatives have shown significant biological activities as well as highly economical, commercial, and biomedical potentialities such as anticancer, antimicrobial, antioxidant, and anti-inflammatory activities. Accordingly, and in this context, this review comprehensively covers the state-of-art over 20 years of about 208 structurally diverse anthraquinones and their derivatives isolated from different species of marine-derived fungal genera along with their reported bioactivity wherever applicable. Also, in this manuscript, we will present in brief recent insights centred on their experimentally proved biosynthetic routes. Moreover, all reported compounds were extensively investigated for their in-silico drug-likeness and pharmacokinetics properties which intriguingly highlighted a list of 20 anthraquinone-containing compounds that could be considered as potential drug lead scaffolds.

Dr. Mohamed Sebak was awarded a bachelor's degree in Pharmaceutical Sciences (Excellent with honor degree) from the Faculty of Pharmacy, Beni-Suef University (Egypt) and he received his M.Sc. degree (December 2013) in Microbiology and Immunology from the Faculty of Pharmacy, Beni-Suef University. Then, he obtained his Joint Supervision PhD degree (March 2020) in Microbial Natural Products Metabolomics according to a channel system between Beni-Suef University and the University of Strathclyde, Glasgow (UK) aer two years of a research study in the UK (2016-2018) under supervision of Dr RuAngelie Edrada-Ebel, before starting his new job as a Lecturer of Microbiology and Immunology at Beni-Suef University, while he started his postdoctoral studies in the same University aerwards. Mohamed's main research interests include microbial natural product discovery, LC-MS-and NMR-based metabolomics, antimicrobial resistance, antimicrobial peptides, and biolm.
Dr. Fatma Molham was awarded a bachelor's degree in Pharmaceutical Sciences (excellent with honors) from the Faculty of Pharmacy, Beni-Suef University (Egypt) and she received her M.Sc. degree (October 2016) in Microbiology and Immunology from the same university. She obtained her PhD degree (April 2021) in Microbiology and Immunology from the Faculty of Pharmacy, Beni-Suef University. Then, she started her new job as a Lecturer of Microbiology and Immunology at Beni-Suef University. Fatma's main research interests include bacteriocins, antimicrobial peptides, antimicrobial resistance, biolm, and microbial natural products.
Dr. Mohamed Tammam obtained his BSc degree in soil and water science in 2008 (Excellent with honor), from Fayoum University, Egypt where he acquired his MSc degree in biochemistry and chemistry of natural products in 2013, and later he received his PhD degree in Pharmacy (Excellent), from the National and Kapodistrian University of Athens (NKUA) focused on isolation and structure elucidation of secondary metabolites from marine organisms of the Red Sea under the joint mentorship of Prof. Vassilios Roussis and Prof. Efstathia Ioannou in 2020. Aer completing his PhD in Greece, he was promoted to lecturer in the Biochemistry Department, Faculty of Agriculture Fayoum University, Egypt. Subsequently, since May 2021 till now he is doing his postdoctoral research focusing on isolation and structure elucidation of secondary metabolites from marine organisms, in the Section of Pharmacognosy and Chemistry of Natural Products, Department of Pharmacy, School of Health Sciences, (NKUA) with Prof. Vassilios Roussis and Prof. Efstathia Ioannou. His research interests are on bioactive natural products from marine macro-and microorganisms.
Dr. Amr El-Demerdash received his BSc degree (excellent with honors, 85.6%, ranked 4 th ) in chemistry at the Faculty of Sciences, Mansoura University (Egypt) in 2004, and his MSc degree in organic chemistry (natural product chemistry) at the same university in 2009, before gaining his PhD in organic chemistry (discovery of pharmacologically active marine natural products and biomimetic total synthesis) from the prestigious French chemical institution CNRS-ICSN (Natural Products Chemistry Institute), University of Paris-Saclay (France), under the supervision of Dr Ali Al-Mourabit, in May 2016. Aer pursuing his PhD in France, Dr El-Demerdash was affiliated to Mansoura University (Egypt) as assistant professor while also conducting his rst postdoctoral training (October 2017 to March 2019) within the fungal natural products' chemistry group, CNRS/MNHN, Sorbonne Universities (France). Since April 2019 till now, Dr El-Demerdash is conducting his second postdoctoral training, working on the biosynthesis of pharmacologically active plant natural products (Professor Anne Osbourn's group) at the John Innes Centre, Norwich Research Park, (United Kingdom). Later, in December 2021, Dr El-Demerdash was promoted to associate professorship in organic and natural products' chemistry, at Mansoura University, Egypt. His work covers natural products chemistry including isolation, structure elucidation, biomimetic synthesis, and biosynthesis.

Introduction
Throughout history, different natural sources have been used for treatment of diseases, and more recently as sources and valuable suppliers of biologically active compounds with diverse bioactivities that can be developed to be used in new drugs. [1][2][3][4][5][6] Intriguingly, marine organisms and microorganisms were among the valuable sources of new natural products. 2 Microbial secondary metabolites have been known for their chemical diversity and a broad range of bioactivities. 6,7 Marine microorganisms are considered highly productive sources of physiologically active compounds including peptides, polyketides, terpenes, and alkaloids. [8][9][10] Some marine-based compounds have been approved as drugs with different pharmacological uses, 11,12 while several others are under different clinical trials before their approval as new drugs. 11 During the last few decades, numerous drug discovery programs focused on marine-derived microbial natural products due to their great potential for the production of structurally diverse biologically active secondary metabolites. 13,14 Among the hot microbes responsible for the production of interesting compounds, fungi, served as the primary source for mining the rst reported antibiotic, penicillin, whereas they are still one of the main sources for discovering novel bioactive compounds from different niches including the marine fungi which have high biological diversications. 15,16 Therefore, the bioactive secondary metabolites recovered from the marinederived fungi have gained great interest as promising sources of therapeutics. Interestingly, more than a thousand compounds have been isolated from marine fungi with a wide range of bioactivities including antiviral, anticancer, and antibacterial activities. 17 Even though only one bioactive compound, cyclosporine A, has been approved for clinical use in the market. This might be attributed to problems in the optimization methods or the screening approaches of natural product discovery. 18 Studying the marine-derived fungi has been started around two centuries ago when the rst fungal species, Sphaeria posidoniae (Halotthia posidoniae) was reported on a rhizome of the marine grass Posidonia oceanica in 1846. 19 Marine fungi have been isolated from different habitats including algae, mobile, and sessile invertebrates, sediments, marine mammals, and driwood from different marine locations. 20 Despite the importance of marine fungi as a promising source for novel bioactive secondary metabolites, marine fungi are still less investigated sources for natural product discovery programmes compared to other niches of fungi. 18,21 Although the estimated number of fungal species on the earth is ranging from 1.5 to 5 million species, only around 1100 species have been exclusively isolated from the marine niche. 18,20 Marine-derived fungi produce various classes of different compounds with both chemical and biological diversities. 22,23 For instance, they produce varieties of bioactive compounds such as terpenes, alkaloids, peptides, and polyketides. 18 Polyketides have been reported in many previous studies as dominant natural products from marine lamentous fungi. 24,25 They are a large group of complex chemical architectures such as anthraquinones, hydroxyanthraquinones, naphthoquinones, macrolides, avonoids, polyenes, and tetracyclines. Around 700 anthraquinones and their derivatives have been reported from different natural sources, while anthraquinones are widely produced by marine lamentous fungi. 16,26 Chemically, anthraquinones are a group of polyketides of the quinone family with a basic cyclic scaffold of three fused benzene rings including two ketone groups on the central 9, 10-carbons with a chemical formula of C 14 H 8 O 2 , while their derivatives are generated by the decoration of the around free protons with different functional groups 16 or by enzymatic reaction of the rings or the keto groups such as reduction, oxidation, dehydration or dimerization to result in a wide range of derivatives. 27 Interestingly, many reported anthraquinones and their derivatives exhibited potent biological activities including antitumor, antibacterial, antifungal, antioxidant, and immunomodulatory bioactivities. 16 Drug-likeness and pharmacokinetics properties using SWISSADME online platform, which intriguingly highlighted a list of 20 anthraquinone containing compounds (ESI †) that could be considered as potential drug leads scaffolds. Such a massive connection between chemical spaces and bioactivities highlights the huge capacity of marine-derived fungi as an attractive biological source that is worth further exploitations with distinguished anticipations for the global pharmaceuticals industries.
Several interesting review articles have focused recently on the marine anthraquinones and their derivatives such as Fouillaud et al. who reported the chemical diversity, specic bioactivities, biosynthetic pathways, biological sources, and the producing fungal genera of tens of marine-derived anthraquinones and their derivatives discovered before 2016. 16 Also, another review by Masi and Evidente presented a comprehensive update of the bioactive fungal anthraquinones and analogues including the marine-derived anthraquinones produced via the acetate route over the period 1966-2020 with their sources, biosynthesis, biological activities, and industrial applications. 28 Whereas Greco et al. in their recent review critically described the marinederived anthraquinones which showed anti-tumor activity as well as their mutagenic and genotoxic potentialities. 29 Herein and as a part of our continuous program on pharmacologically active fungal natural products, 4,30,31 we are presenting an extensive coverage over the period 2000-2020 for 208 anthraquinones and their derivatives, extensively reported from different marinederived fungal genera such as Nigrospora, Aspergillus, Penicillium, Stemphylium, Alternaria, Eurotium, Trichoderma, Halorosellinia, and Fusarium. In addition, we reported here their different biological activities, drug-likeliness and pharmacokinetics properties wherever applicable, in addition to a general overview of their proposed biogenesis pathway. The investigation of in-silico drug-likeness and pharmacokinetics properties of the marinederived anthraquinones and their derivatives in this review could be advantageous in predicting the possibility of anthraquinones as drug candidates.

General biosynthetic pathway of anthraquinones
There have been extensive studies since the 1950s to determine the biosynthetic pathway of anthraquinones and the related natural products called xanthones. 32,33 Feeding experiments using labelled acetates in fungi, rst reported by Birch et al., showed that anthraquinone and xanthones are biosynthesized by polyketides. 32,33 Genome sequencing and genetic transformation experiments have conrmed that the core structure of anthraquinones is synthesized in fungi by non-reducing polyketide synthase (nrPKS). 34,35 This class of PKS share a common domain architecture which consists of an SAT (starter unit-ACP transacylase), KS (ketosynthase), AT (acyl transferase), PT (product template), and ACP (acyl carrier protein) (Fig. 1A). The biosynthesis of anthraquinones can be generalized using emodin (14) and endocrocin as examples (Fig. 1B). 27,36 The nrPKS (MdpG) synthesize the polyketide, which is then cyclized with the loss of two water molecules by the PT domain. The polyketide is released by a metallohydrolase protein (MdpF) to obtain atrochrysone carboxylic acid, which can in most cases, undergo decarboxylation by a decarboxylase (MdpH1). This is followed by spontaneous dehydration and oxidation by an anthroneoxidase (MdpH2) to afford emodin (14). 27,36 Some reports also have described that the nal oxidation step could occur spontaneously. 36 Further modication by tailoring proteins give rise to a huge diversity, these include methylation, dehydration, and dimerization. 27  (14) and endocrocin. The isotope labelling pattern is shown black bold lines and the polyketide starter unit is indicated in red.

Chemistry and medicinal potentialities of anthraquinones and their congeners derived from marinederived fungi
In this manuscript, we provide extensive insights about chemical and biological investigations centered on anthraquinones and their derivatives exclusively derived from marine fungi. For the handling of this documentation, all isolated anthraquinones are classied and tabulated according to the marine fungal genera where they have been recovered along with their recorded biological potentialities whenever applicable.
Notably, compounds 2 and 3 showed potent antibacterial activity against both the Gram-positive bacteria, Staphylococcus aureus and Micrococcus tetragenus and the Gram-negative bacteria, Escherichia coli (E. coli), Vibrio anguillarum (V. anguillarum), and V. parahemolyticus. Compound 3 displayed MIC of equal to or less than 2.5 mM against all tested bacteria, whereas compound 2 exhibited MIC of equal to or less than 2.5 mM against all tested bacteria except V. anguillarum and V. parahemolyticus against which it showed MIC value of 25.0 mM. 38 In addition, compound 3 showed potent cytotoxic activity against the human lung cancer cell line, A-549 with an IC 50 value of 4.56 mM, 38 while austrocortirubin (5) displayed an IC 50 value of 6.3 mM against the human breast adenocarcinoma cells, MCF-7 39 .
Further anthraquinone derivatives 6-10 were previously isolated from the sea anemone-derived fungus Nigrospora sp. 38 Also, some of these anthraquinone derivatives have been isolated from other marine fungal species such as Fusarium sp. PSU-F14 from which compounds 6-8 and 10 were recovered, 39 while compounds 7, 8 and 10 were also isolated from the marine-derived fungus Aspergillus sp. 42 Compounds 6-10 exhibited different interesting biological activities. For instance, nigrosporin B (6) displayed modest antimycobacterial activity, 43 phytotoxic activity, 44 and potent antibacterial and cytotoxic activity. 38 Also, 4-deoxybostrycin (9) showed modest anti-mycobacterial activity, 43 potent antibacterial activity, 38 and moderate antitumor activity. 45 Nigrosporin B (6) and 4-deoxybostrycin (9) displayed potent antibacterial activity against both the Gram-positive bacteria, Bacillus subtilis (B. subtilis), B. cereus, Staphylococcus albus (S. albus), S. aureus, and Micrococcus tetragenus and the Gram-negative bacteria E. coli, V. anguillarum, and V. parahemolyticus with MIC values equal to or less than 2.5 and 3.12 mM, respectively. 38 Moreover, both compounds exhibited modest anti-mycobacterial activity against several mycobacterial species including two multidrugresistant Mycobacterium tuberculosis (M. tuberculosis) with MIC values of less than 30.0 mg mL À1 . 43 An additional example of anthraquinones isolated from Nigrospora sp. with multiple bioactivities is tetrahydrobostrycin (8) which exhibited moderate to high antibacterial activity against the Gram-positive bacteria, B. subtilis and B. cereus (MIC values of 2.5 mM), S. aureus and Micrococcus luteus (MIC values of 2.5 mM), and Micrococcus tetragenus (MIC value of 1.25 mM). 38 Compound 8 also displayed good antibacterial activity against the Gram-negative bacteria E. coli (MIC value of 6.25 mM), V. anguillarum (MIC value of 1.56 mM), and V. parahemolyticus (MIC value of 12.5 mM). 38 Additionally, it exhibited potent activity against M. tuberculosis with a MIC value of 12.50 mg mL À1 and was also active as antimalarial agent against Plasmodium falciparum with an IC 50 value of 7.94 mg mL À146 (Fig. 2).

Anthraquinones isolated from Aspergillus sp.
Aspergillus was the richest source of marine anthraquinones and their derivatives among all marine-derived fungi with 73 reported compounds including the previously mentioned 7, 8, and 10 as well as other seventy anthraquinones 11-80. For instance, thirteen compounds 11-23 were isolated from the marine-derived fungus Aspergillus glaucus (A. glaucus). 47 Aspergiolide A (11), which features a naphtho[1,2,3-de]chromene-2,7-dione skeleton was isolated as a novel anthraquinone derivative from the marinederived fungus A. glaucus. 48 Aspergiolide B (12) was isolated from A. glaucus as a new analogue for aspergiolide A (11). 47 Aspergiolides A and B (11 and 12) exhibited potent cytotoxic activities against both adenocarcinoma human alveolar basal epithelial cell line, A-549 with IC 50 values of 0.13 and 0.24 mM and human leukemia cell line, HL-60 with IC 50 values of 0.28 and 0.51 mM, respectively 47,48 indicating that methylation of one hydroxyl group in aspergiolide A (11) to be a methoxy group in aspergiolide B (12) slightly affected the cytotoxicity of aspergiolide A.
Physcion (13) was also isolated from other species of Aspergillus such as A. glaucus, 47 A. wentii , 49 and the halotolerant A. variecolor 50 besides the marine-derived fungus Microsporum sp. 51 Physcion (13) displayed a wide array of biological activities including cytotoxic activity against human cervical carcinoma HeLa cells, 51 moderate antifungal activity against Trichophyton mentagrophytes with a MIC value of 25.0 mg mL À1 and weak antifungal activity against both C. albicans and Cryptococcus neoformans with MIC value of 50.0 mg mL À1 . 52 It also exhibited weak free radical scavenging activity against 1,1-diphenyl-2picrylhydrazyl (DPPH) with an IC 50 value of 99.4 mg mL À1 . 49 Furthermore, emodin (14) which was reported from the marine-derived fungus A. glaucus, was also recovered from many other marine fungal species such as Penicillium citrinum (P. citrinum), 53 Trichoderma aureoviride (T. aureoviride), 54 Monodictys sp., 55 Gliocladium sp., 56 Paecilomyces sp., 57 Eurotium rubrum (Eu. rubrum) 58 and A. versicolor. 59 Emodin (14) showed moderate antibacterial against Pseudomonas putida with a MIC value of 25.0 mM 60 and signicant anti-mycobacterial activity against M. tuberculosis with a MIC value of 12.5 mg mL À1 and modest antifungal activity against Candida albicans (C. albicans) with an IC 50 value of 11.0 mg mL À1 . 61 Noteworthy, it showed potent cytotoxic activity against both oral human epidermoid carcinoma cell line, KB and human breast cancer cell line, MCF7 with IC 50 values of 0.88 and 2.8 mg mL À1 , respectively. 61 Further anthraquinones 17 and 18, and 20 which were isolated from both A. glaucus 47 and the halotolerant A. variecolor, 50 showed variable bioactivities. Questin (17) and catenarin (18) exhibited DPPH radical scavenging activity 62 50 Notably, the known anthraquinone dimer 21, as well as two new isomers of anthraquinone dimer 22 and 23, were also isolated from A. glaucus. 47 However, compound 21 was not evaluated for any relevant bioactivity, the trans isomer of emodinphyscion bianthrone (22) showed good cytotoxicity against the cell lines; A-549 and HL-60 with IC 50 values of 9.2 and 7.8 mM, respectively. On the other hand, its cis isomer 23 was less active as its IC 50 values were 14.2 and 44.0 mM, respectively, 47 suggesting that isomerization has affected the cytotoxicity of compound 22.
Additional thirty anthraquinones 24-54 have been isolated from the marine-derived fungus A. versicolor. Two new anthraquinone dimers 24 and 25 besides three other known closely related anthraquinone derivatives 26-28 were isolated from the marine-derived fungus A. versicolor. 64 Averantin (26) and its derivative 1 0 -O-methyl-averantin (27) were also isolated earlier from the marine-derived fungus P. purpurogenum G59 ref. 65 and Aspergillus sp. SCSIO F063 , 66 while averythrin (28) was formerly reported from the marine-derived fungus Aspergillus sp. SCSIO F063. 66 Compounds 24 and 25 showed selective antibacterial activity against the Gram-positive bacterium, S. aureus using the disk diffusion method at a concentration of 30.0 mg per well, 64 whereas the same study revealed that compound 24 had a selective cytotoxic activity against human CNS cancer cells, XF-498 with an IC 50 value of 22.39 mg mL À1 . In addition, averantin (26) and its derivative 1 0 -O-methyl-averantin (27) displayed a weak antitumor activity against the bone marrow cancer cell line, K562 at a concentration of 100.0 mg mL À1 . 65 Another study mentioned that compound 27 exhibited modest cytotoxic activity against the human glioblastoma SF-268, human breast adenocarcinoma MCF-7 and human large-cell lung carcinoma NCI-H460 cell lines with IC 50 values ranging from 33.59 to 44.22 mM, whilst compounds 26 and 28 displayed weak to moderate cytotoxic activity against MCF-7 with IC 50 values of 45.47 and 29.69 mM, respectively. 66 Also, compounds 26 and 27 displayed potent antioxidant activity, whereas compound 28 exhibited weak antioxidant activity in terms of antioxidant capacity compared to Trolox 67 suggesting that the presence of oxygen in the side chain of the anthraquinones may play role in their antioxidant activity.
Additionally, compound 26 displayed promising antibacterial activity against different strains of the Gram-positive bacteria, Streptococcus pyogenes (Str. pyogenes) and S. aureus with MIC values of equal to or less than 3.13 mg mL À1 , while its 1 0 -O-methylated derivative, 27 showed weaker antibacterial activity as it was only active against one strain of Str. pyogenes with a MIC value of 6.25 mg mL À1 with no activity against the other strain of Str. pyogenes or any strain of S. aureus up to a concentration of 12.5 mg mL À1 , 68 indicating that O-methylation at position 1 greatly affected the antibacterial activity of averantin (26).
Compound 29 which is another derivative of averantin (26) was isolated from another marine-derived fungus A. versicolor EN-7. 69 Compound 29 showed weak antibacterial activity against only E. coli at a concentration of 20.0 mg per disk with no activity against S. aureus, 69 suggesting that the O,O 0 -dimethylation of averantin (26) decreased its antibacterial activity against the Gram-positive bacteria.
The aatoxin, averun (30) and its O-methylated derivatives 6-O-methyl-averun (31) and 6,8-O,O 0 -dimethyl-averun (32) were also isolated from different strains of the marine-derived fungus A. versicolor, 68,69 whereas averun (30) was also isolated from other species of Aspergillus such as A. niger 70  respectively. Both versicolorin B (33) and its hydroxyl derivative, 1 0 -hydroxyversicolorin B (34) showed potent antioxidant activity as they displayed antioxidant capacity approximately equivalent to Trolox, 67 while an old study revealed that 1 0 -hydroxyversicolorin B (34) (UCT1072M1) had potent cytotoxicity against the human cervical cell adenocarcinoma, HeLa S3 and the human lung giant cell carcinoma, Lu-65 with IC 50 values of 2.1 and 2.2 mM, respectively. 74 Indeed, averufanin (35) displayed a good antioxidant activity in terms of antioxidant capacity to Trolox, 67 and weak activity against both acyl-CoA: cholesterol acyltransferase type 1 and 2 in the cell-based assay with IC 50 values of 28.0 and 12.0 mM, respectively, 75 whereas noraverufanin (36) exhibited a weak HIV latency-reversal activity with reactivation of 43.3% at concentration of 10.0 mM. 73 Nidurun (37) which has been also isolated from the marine fungi A. niger 70 as well as P. purpurogenum G59, 65 showed weak antitumor activity against the bone marrow cancer cell line, K562 with an inhibition rate percentage of 25.5% at a concentration of 100.0 mg mL À165 and moderate antioxidant capacity with 0.62 as Trolox equivalent as antioxidant. 67 Another previous study showed that nidurun (37) had exhibited strong anticancer activity against the A-549 cells, the human ovarian cancer cells, SK-OV-3, the human skin cancer cells, SK-MEL-2, the human CNS cancer cells, XF-498, and the human colon cancer HCT-15 with IC 50 values of 1.83, 3.39, 3.16, 1.78, and 2.2 mg mL À1 beside good antibacterial activity against different strains of the Gram-positive bacteria Str. pyogenes and S. aureus with MIC values of equal to or less than 3.13 mg mL À1 . 68 Compound 38 ( (40) showed selective weak antibacterial activity against S. aureus with inhibition zones of 6.5 mm using disk diffusion method at a concentration of 20.0 mg per disk when tested against both S. aureus and E. coli. 69 Other bioactive compounds isolated from the marine fungus A. versicolor were compounds 41 and 42, 47 and 48, and 50-54. 59,69,76 1-methyl-emodin (41) which is an O-methylated derivative of emodin (14) and both were isolated from A. versicolor, 59 exhibited better cytotoxic activity than emodin (14) itself against human epidermoid carcinoma cell line, KBv200 with an IC 50 value of 190.81 mM, 40 although 41 did not show any cytotoxicity against the human leukemia cell line, CCRF-CEM and some other solid tumors including the human lung H-125, human colon HCT-116, and human liver Hep-G2 cells. 76 On the other hand, compound 41 showed less inhibitory activity against Hepatitis C virus (HCV) protease than its parent 14 with IC 50 values of 40.2 and 22.5 mg mL À1 , respectively. 76 The same study showed that the new metabolite from A. versicolor; isorhodoptilometrin-1-methyl-ether (42) displayed moderate antibacterial activity against B. cereus, B. subtilis, and S. aureus at a concentration of 50.0 mg per disk and mild selective cytotoxicity against the Hep-G2 cell line. 76 Additionally, 1-hydroxy-2-methyl-anthraquinone (47) and its novel dimethoxy derivative; 2-(dimethoxy methyl)-1-hydroxy-9,10-anthraquinone (48) were evaluated for their antibacterial activity against two strains of methicillin-resistant S. aureus (MRSA) (CGMCC 1.12409 and ATCC 43300) and three strains of Vibrio (V. rotiferianus, V. vulnicus, and V. campbellii). Noteworthy, the dimethoxy derivative 48 was highly active against the MRSA strains showing MIC values of 7.8 and 3.9 mg mL À1 , respectively, and was moderately active against the Vibrio strains with MIC values ranging from 15.6 to 62.5 mg mL À1 . 59 The same study mentioned that a molecular docking study was conducted to explain the cause behind this antimicrobial activity revealing the least binding energy of compound 48 with both AmpC b-lactamase and topoisomerase IV (Topo IV). 59 On the other hand, its parent compound 47 displayed potent larvicidal activity against the larvae of Aedes aegypti with an IC 50 value of 1.8 mg mL À1 . 77 Moreover, another anthraquinone derivative, damnacanthal (50) which was reported from A. versicolor 59 exhibited strong larvicidal activity against the larvae of Aedes aegypti with an IC 50 value of 7.4 mg mL À177 and weak antibacterial activity against some strains of MRSA and Vibrio with MIC values ranging from 31.3 to 125.0 mg mL À1 . 59 Similarly, xanthopurpurin (51) showed weak antibacterial properties against some strains of MRSA and Vibrio with the same MIC range of damnacanthal (50). 59 Also, compound 51 previously showed strong antiplatelet aggregation activity via inhibition of collagen-induced aggregation. 78 In addition, a chemically related rubiadin (52) showed a strong inhibitory activity on the formation of advanced glycation end products with an IC 50 value of 179.31 mM. 79 Notably, its hydroxylated derivative; 6-hydroxyrubiadin (53) displayed potent inhibitory activity on phosphatase of regenerating liver-3 with an IC 50 value of 1.3 mg mL À1 causing inhibition of migration of phosphatase of regenerating liver-3 expressed tumor cells with no cytotoxicity. 80 Additional four derivatives 55-58 were isolated from the marine-derived fungus A. wentii. 49,81 Wentiquinone C (55) showed no free radical scavenging activity up to a concentration of 1000.0 mg mL À1 , 49 whereas compounds 56-58 were not tested for any relevant bioactivity. 81 Further derivatives including compounds 59-64 were isolated from the halotolerant fungus A. variecolor, 50 while compounds 65-67 were reported from A. nidulans. 71 Compounds 59 and 60 exhibited potent DPPH radical scavenging activity (antioxidant activity) with IC 50 values of 6.0 and 11.0 mM, respectively 50 suggesting that the O-methylation of eurotinone (59), slightly affected its antioxidant activity. Interestingly, Questinol (62) which was also isolated from the marine-derived fungi Talaromyces stipitatus KUFA 0207 82 and Eu. amstelodami, 83 displayed signicant anti-inammatory activity via different mechanisms including inhibition of both nitric oxide and prostaglandin E2 production and, inhibition of the production of some inammatory cytokines such as interleukin-1b (IL-1b), IL-6, and tumor necrosis factor-a. Compound 62 also showed slight inhibitory activity against cyclooxygenase-2 (COX-2) expression at a concentration of 200.0 mM. 83 In addition, compound 62 exhibited potent anti-obesity activity with a 60% reduction in the stained lipids with an IC 50 value of 0.95 mM, while the chemically related compound, fallacinol (63) showed no signicant antiobesity activity. 82 Interestingly, versicolorin C (65) displayed selective potent antibacterial activity against both E. coli and V. parahaemolyticus with a MIC value of 1.0 mg mL À1 and, against V. anguillarum and Edwardsiella ictaluri with MIC values of 4.0 and 8.0 mg mL À1 , respectively, whilst the closely related congener isoversicolorin C (66) displayed selective potent antibacterial activity against both V. alginolyticus and Edwardsiella ictaluri with MIC values of 1.0 and 4.0 mg mL À1 , respectively. 71 Further, twelve anthraquinones including three non-halogenated ones 68-70, seven new chlorinated anthraquinone derivatives 71-77, and two new brominated anthraquinone derivatives 78 and 79 were isolated from the marine-derived fungus Aspergillus sp. SCSIO F063, 66 in addition to compound 80 which was reported from another marine-derived fungus Aspergillus sp. SF-6796. 72 Compounds 68-70 are chemically related to each other and are derivatives of averantin (26) which was isolated in the same study as a metabolite from Aspergillus sp. SCSIO F063, 66 while it was isolated earlier from the marine-derived fungi A. versicolor. 64 Averantin-1 0 -butyl-ether (70) (80) which showed an anti-neuroinammatory effect via different mechanisms including suppression of the overproduction of many pro-inammatory mediators including COX-2, prostaglandin E2, and nitric oxide in lipopolysaccharide-activated BV2 microglial cells 72 ( Fig. 3 and 4).

Anthraquinones from Penicillium sp.
Furthermore, eighteen compounds 81-98 besides the previously reported compounds 14, 17, 26, 27, and 37 were isolated from different species of the marine-derived fungus Penicillium. Indeed, penicillanthranin A (81) and B (82) which are anthraquinone-citrinin derivatives, as well as chrysophanol (83) and u-hydroxyemodin (84), were isolated from the marine fungus P. citrinum PSU-F51. 53 Penicillanthranin A (81) and chrysophanol (83) exhibited selective antibacterial activity against the Gram-positive S. aureus ATCC25923 with MIC value of 16.0 mg mL À1 for both compounds and MRSA SK1 with MIC values of 16.0 and 64.0 mg mL À1 , respectively, while compounds 82 and 84 were not screened for their antimicrobial activity in the same study. 53 Interestingly, some earlier studies revealed that u-hydroxyemodin (84) showed moderate activity against MRSA SK1 and mild activity against S. aureus ATCC 25923 with MIC values of 32.0 and 200.0 mg mL À1 , respectively, 54 in addition to good anti-mycobacterial activity against M. tuberculosis H37Ra with a MIC value of 12.5 mg mL À1 . 61 It also showed potent cytotoxicity against the human oral epidermoid carcinoma KB cells with an IC 50 value of 4.5 mg mL À1 , and weak cytotoxic activity against both the human breast cancer cells, MCF7 and the human lung carcinoma cells, NCI-H187 with IC 50 values of 22.0 and 39.0 mg mL À1 , respectively. 61 In contrast, penicillanthranin A (81) showed selective cytotoxicity to the KB cell lines with an IC 50 value of 30.0 mg mL À1 . 53 Another bioactive metabolite, 2 0 -acetoxy-7-chlorocitreorosein (85) which was rst recovered from a mangrove-derived fungus P. citrinum HL-5126 ref. 84 demonstrated moderate antibacterial activity against S. aureus and signicant activity against V. parahaemolyticus with MIC values of 22.8 and 10.0 mg mL À1 , respectively, 84 suggesting that such modication in its structure by acetylation, chlorination, and O-methylation of u-hydroxyemodin (84) resulted in signicant improvement in its antibacterial activity. Further anthraquinone derivatives discovered from the marine fungus P. oxalicum, including citreorosein-3-Osulphate (86), emodin-3-O-sulphate (87), and aloe-emodin (88) were not tested for any relevant activity. 85 However, other previous studies revealed that aloe-emodin (88) displayed modest antimalarial activity against Plasmodium falciparum (MRC-2) with an EC 50 value of 22.0 mg mL À186 and weak antimicrobial activity against the Gram-positive bacteria, S. aureus, S. epidermidis, B. cereus, B. subtilis, and Micrococcus kristinae, and the Gram-negative bacteria, E. coli, Enterobacter aerogenes, Proteus vulgaris, and Shigella sonnei with MIC values ranging from 62.5 to 250.0 mg mL À1 . 87 Additional ten bioactive compounds including eight newly isolated anthraquinone-amino acid conjugates, namely emodacidamide A-H (89-96) along with the previously isolated anthraquinone derivatives; emodic acid (97) and 2-chloro-1,3,8trihydroxy-6 (hydroxymethyl)-anthracene-9,10 dione (98), were isolated from the marine fungus Penicillium sp. SCSIO sof101. 88 Emodacidamides A-H (89-96) displayed immunomodulatory activity with inhibitory activity against IL-2 production from Jurkat cells. 88 Intriguingly, emodacidamides A (89), C (91), and E (93) showed potent IL-2 inhibitory activity with IC 50 values of 4.1, 5.1, and 5.4 mM, respectively. 88 Meanwhile, emodic acid (97) showed no remarkable inhibition of IL-2 secretion at a concentration of 20.0 mM, indicating that amino acid conjugation with the anthraquinone derivatives enhanced their inhibitory effect on IL-2 secretion. 88 On the other side, emodic acid (97) which was previously isolated from the marine endophytic fungus Eu. rubrum, 58 evoked potent inhibition of p56 lck tyrosine kinase with an IC 50 value of 1.07 mg mL À1 . 89 In addition, compound 97 demonstrated a potent inhibitory effect on both the tyrosine kinase domain of the epidermal growth factor receptor and protein tyrosine kinase p59 fyn with IC 50 values of 0.078 and 0.080 mg mL À1 , respectively without any noted cytotoxicity on human foreskin broblast 89 (Fig. 5).

Anthraquinones from Stemphylium sp.
The marine-derived fungus Stemphylium is another good source of the bioactive anthraquinones with thirty-two recovered compounds 99-130. A group of twenty-ve anthraquinones derivatives 99-123 were reported from a mangrove-derived fungus Stemphylium sp. 33 90 The same study revealed that altersolanol C (104) had a narrow spectrum of activity against only B. subtilis with a MIC value of 8.8 mM, while altersolanol L (105) had no antibacterial activity against the tested strains. 90 In the contrast, another recent study demonstrated that altersolanol L(105), had a modest antifungal activity against P. italicum and Rhizoctonia solani with MIC values of 35.0 and 50.0 mg mL À1 , respectively. 91 Additionally, a recent study showed that both altersolanol A (99) and B (101) had strong cytotoxicity against MCF-7 and HCT-116 cell lines with IC 50 values of [7.21, 1.3 mM] for altersolanol A (99) and, [9.0, 3.5 mM] for altersolanol B (101), respectively. 92 By contrast, dihydroaltersolanol A (100) did not show any antibacterial activity or cytotoxicity when tested against various microbes and cell lines, 90,93 suggesting that the derivatization of its parent altersolanol A (99) into dihydroaltersolanol A (100) lead to a signicant change in its biological activities. Furthermore, ampelanol (107), macrosporin (108) and its sulphate derivative, macrosporin-7-O-sulphate (109), in addition to its glycosidic derivative, macrosporin 2-O-(6 0 -acetyl)-a-Dglucopyranoside (110), as well as auxarthrol C (111), were also recovered from the marine fungus Stemphylium sp. 33 231. 90 Ampelanol (107) displayed moderate cytotoxicity against the murine lymphoma cell line, L5178Y, 94 whereas macrosporin (108) exhibited signicant antibacterial activity against Micrococcus tetragenus, E. coli, and S. aureus with MIC values of 4.6, 4.6, and 9.2 mM, respectively. 90 On the other hand, both derivatives of macrosporin (108), macrosporin-7-O-sulphate (109) and macrosporin 2-O-(6 0 -acetyl)-a-D-glucopyranoside (110) displayed no antibacterial activity against the same indicator strains up to a concentration of 10.0 mM, 90 indicating that these modications in the chemical structure of macrosporin (108) have greatly affected its antibacterial activity. Additionally, macrosporin (108) was shown to have potent antifungal activity against Fusarium oxysporum (F. oxysporum) with a MIC value of 3.75 mg mL À1 and modest antifungal activity against Colletotrichum musae, F. graminearum, P. italicum, and Colletotrichum gloeosporioides with MIC values ranging from 30.0 to 60.0 mg mL À1 . 91 Noteworthy, compound 110 demonstrated a remarkable brine shrimp lethality using Artemia salina with an LD 50 value of 10.0 mM, 90 while the parent compound 108, and its derivative 109 showed no lethality in the same study 90 suggesting that brine shrimp lethality might be dependent on acetylation and/or glycosylation of this compound. Also, the same study revealed that auxarthrol C (111) displayed selective antibacterial activity against only the Gram-negative organism, E. coli with a MIC value of 9.8 mM with no notable cytotoxicity or brine shrimp lethal effect. 90 Moreover, other bioactive anthraquinone dimers including alterporriols B-E (113)(114)(115)(116), N (117), Q (118), U (121), and V (122) were also isolated from the same fungus Stemphylium sp. 33 231. 90 The anthraquinone dimers, alterporriols B-E (113-116) displayed positive antibacterial activity, whereas alterporriol A (112) did not show either antibacterial or cytotoxic activity. 90 Alterporriol B (113) showed a narrow spectrum of antimicrobial activity against B. cereus with a MIC value of 7.9 mM, whereas alterporriol C (114) showed selective antibacterial activity against S. albus with a MIC value of 8.9 mM. Interestingly, alterporriol D (115) exhibited notable antibacterial activity against both S. aureus and E. coli and with MIC values of 5.0 and 7.5 mM, respectively, while alterporriol E (116) displayed potent antimicrobial activity against both B. cereus and E. coli with MIC values of 2.5 and 5.0 mM, respectively. 90 The same study demonstrated that alterporriol Q (118) and R (119) showed no antimicrobial activity against various tested microbes up to a concentration of 10.0 mM. 90 This nding was conrmed in another study which showed that both compounds did not display any antibacterial activity against different Gram-positive bacteria as well as E. coli from the Gramnegative bacteria up to a concentration of 20.0 mM. 93 However, alterporriol Q (118) exhibited strong antiviral activity against the porcine reproductive and respiratory syndrome virus with a MIC value of 22.0 mM, whereas alterporriol R (119) showed no antiviral activity. 93 Also, the same study revealed that alterporriol C (114) had a modest antiviral activity with a MIC value of 39.0 mM. 93 In addition, the other anthraquinone dimers, alterporriol U (121) and V (122) exhibited a narrow spectrum of antibacterial bioactivity against the Gram-positive bacterium, B. cereus with MIC values of 8.3 and 8.1 mM, respectively. 90 Further anthraquinone dimers including alterporriol N (117), F (124), G (125), Z1 (126), Z2 (127), and Z3 (128) were also isolated recently from another marine fungus Stemphylium sp. FJJ006. 95 They showed neither antimicrobial activity against the Gram-positive and Gram-negative bacterial strains up to a concentration of 128.0 mg mL À1 nor antitumor activity against a panel of cancer cell lines with an IC 50 value higher than 20.0 mM. Also, they did not show bioactivity against the microbial enzymes, isocitrate lyase, and sortase A with an IC 50 value of more than 145.0 mM. However, the same study revealed that alterporriols N (117), F, G, and Z 1 -Z 2 (124-127) had anti-inammatory activity through their capability of suppressing the lipopolysaccharide-induced nitric oxide production in the murine macrophages RAW 264.7 cells with IC 50 values of 8.4, 9.6, 10.7, 11.6, and 16.1 mM, respectively, whereas alterporriol Z 3 (128) did not display any anti-inammatory activity. 95 On the other hand, another previous study demonstrated the potent cytotoxicity of alterporriol F (124) against the HeLa and KB human cell lines with IC 50 values of 6.5 and 7.0 mg mL À1 , respectively. 96 In addition, alterporriol N (117) was presented in another study as a weak antimicrobial agent with a narrow spectrum of activity against only the Gram-positive bacteria, Enterococcus faecalis, MRSA, and Str. pneumoniae with MIC values of 15.63, 62.5, and 125.0 mg mL À1 , respectively, while the same study revealed that alterporriol G (125) had a moderate cytotoxicity against the mouse cancer cell line, L5178Y 97 ( Fig. 6  and 7). Additional anthraquinones, tetrahydroaltersolanols C-F (136-139) were also isolated from the marine-derived Alternaria sp. ZJ-2008003. 93 Only tetrahydroaltersolanol C (136) displayed moderate antiviral activity against the porcine reproductive and respiratory syndrome virus with an IC 50 value of 65.0 mM. 93 More anthraquinone derivatives 140-142 were reported recently from the marine fungus Alternaria tenuissima DFFSCS013. 99 (Fig. 8).

Anthraquinones from Trichoderma sp.
Trichoderma sp. is another prolic anthraquinones producer from which the previously discussed compounds 14, 83, and 84 were isolated as well as the anthraquinone derivatives, 143-155. Harzianumnones A and B (143 and 144) were reported earlier as new hydroxyanthraquinones from the marine fungus T. harzianum XS-20090075. 100 They showed neither DNA Topo I inhibitory activity nor anti-acetylcholinesterase activity. 100 The same study revealed that phomarin (145), u-hydroxydigitoemodin (146), pachybasin (147), and (+)-2 0 S-isorhodoptilometrin (148) isolated also from T. harzianum XS-20090075, displayed a weak anti-acetylcholinesterase activity at a concentration of 100.0 mM. 100 Interestingly, pachybasin (147) also demonstrated potent cytotoxic activity against the human cancer cell lines, KB and KBv200 with IC 50 values of 3.17 and 3.21 mM, respectively. 40 In addition, its derivative, u-hydroxypachybasin (149) as well as (+)-2 0 S-isorhodoptilometrin (148)   were recovered also from the marine fungus T. aureoviride PSU-F95, both were not evaluated for any bioactivity in this study. 54 Additionally, coniothyrinone A (154) and lentisone (155) were previously isolated from another marine fungus, Trichoderma sp., and exhibited potent antibacterial activity against the Gram-negative bacteria, V. parahaemolyticus, V. anguillarum, and Pseudomonas putida with MIC values of [6.25, 1.56, 3.13 mM] for coniothyrinone A (154) and [12.5, 1.56, 6.25 mM] for lentisone (155), respectively 60 (Fig. 9).  rubrum. 58,62 The parent compound, 9-dehydroxyeurotinone (156) exhibited weak antibacterial activity against the Gram-negative bacterium, E. coli showing a 7 mm zone of inhibition using 100.0 mg per disk. Also, it displayed selective cytotoxic activity against the human cholangiocarcinoma cells, SW1990 with an IC 50 value of 25.0 mg mL À1 . 58 Another study revealed that compounds 157-159 had positive antioxidant activity through free radical scavenging activity against DPPH. 62 Furthermore, the same study showed that eurorubrin (160) demonstrated a potent free radical scavenging activity with an IC 50 value of 44.0 mM with better antioxidant activity than the standard antioxidant, butylated hydroxytoluene which had an IC 50 value of 82.6 mM. 62 Interestingly, 3-O-(a-D-ribofuranosyl)-questin (159) and eurorubrin (160) were re-isolated also from the marine endophytic fungus Eu. cristatum EN 220. They displayed modest antibacterial activity against the Gram-negative bacterium, E. coli with MIC values of 32.0 and 64.0 mg mL À1 , respectively. 101 Notably, 3-O-(a-D-ribofuranosyl)questinol (161) which is an alcoholic derivative of the bioactive compound, 3-O-(a-D-ribofuranosyl)questin (159) showed no antibacterial activity against E. coli suggesting that this hydroxylation leads to loss of the antimicrobial activity. 101 Furthermore, asperavin ribofuranoside (162) which was isolated earlier from the marine fungus Eu. cristatum EN 220 ref. 101 and the marine-derived fungus Microsporum sp., 102 was reported as a potent free radical scavenging agent with an IC 50  (Fig. 10).

Anthraquinones from Fusarium sp.
Twelve anthraquinone derivatives were isolated earlier from different species of the marine-derived fungus Fusarium sp. including the previously discussed compounds 5-8 and 10 along with other structurally related compounds 164-170. Although both nigrosporin A (164) and fusaranthraquinone (165) were recovered from the marine-derived fungus Fusarium sp. PSU-F14 , 39 only nigrosporin A (164) displayed promising inhibitory activity against photosynthesis and weak antibacterial activity against B. subtilis showing an inhibition zone of 14 mm at 200 ppm, 44 whereas fusaranthraquinone (165) did not demonstrate any antibacterial activity when it was tested against both S. aureus and MRSA. 39 Interestingly, additional bioactive fusaquinons A-C (166-168) were reported from the marine fungus Fusarium sp. ZH-210 and displayed weak cytotoxic activity against MCF-7, KB, and KBv200 cell lines with IC 50 values of more than 50.0 mM. 104 It is noteworthy that nigrosporin A (164) and fusaquinon A (166) were also evaluated in another study for their antimalarial, anti-mycobacterial, antibacterial, and cytotoxic activity. Both compounds showed no antimalarial, antibacterial, or antimycobacterial activity, whereas they showed selective cytotoxicity. 105 105 Another bioactive anthraquinone derivative isolated from the mangrove-derived fungus Fusarium sp. ZZF60 was 6,8-dimethoxy-1-methyl-2-(3-oxobutyl)anthracene-9,10dione (169). 106 Notably, it demonstrated moderate cytotoxicity against Hep2 and Hep-G2 cells with IC 50 values of 16.00 and 23.00, respectively (Fig. 11).
Oral bioavailability, bioavailability score (BS), is another descriptor that indicates the possibility of a compound to be bioavailable with more than 10% in the absorption assays. Molecules obeying the Lipinski rule with BS of 0.55 are considered orally bioavailable. Interestingly, 166 anthraquinones showed a BS of 0.55. In alignment with other parameters, all Fusarium and Trichoderma derived anthraquinones showed a BS of 0.55 and all Engyodontium album derived compounds had a BS of 0.11. Compounds 3, 6, and 9, are of special interest as they showed a good BS of 0.56. Some other compounds, among them 10, 87, 97, and 109, showed good BS (0.56); however, violated one or more drug-likeness rules ( Fig. 15 and ESI Table S1 †).
Oral bioavailability relies as well on the degree of the molecular exibility of the molecule. Candidates with an extreme degree of exibility do not typically display acceptable bioavailability as they tend to be less planar and with very complex 3D shapes. The sp 3 carbons fraction (Fraction Csp 3 ) and the number of RB are two crucial measures for molecular exibility. Csp 3 is the ratio of the sp 3 carbon atoms to the total carbons present in a given compound. It assigns the degree of carbon saturation, characterizes the space complexity, and correlates to the solubility of the compound. A Csp3 score between 0.25 and 1 is considered optimum for drug-likeness. One hundred anthraquinones, distributed in all marine fungi species, displayed a Csp 3 score ranging between 0.28 and 0.6. The water solubility, expressed as log S, is another essential measure for drug bioavailability. Compounds with poor water solubility have poor absorption and oral bioavailability, as well as low formulation potential. Anthraquinones revealed different solubility orders as Sporendonema casei derived compounds were the most soluble (mean value of À1.46), followed by Nigrospora sp (mean value of À2.34), while Engyodontium album derived anthraquinones, as expected, were the most poorly soluble (mean value of À5.44) (Fig. 15 and ESI Table S1 †).
Gastrointestinal (GI) absorption, blood-brain barrier (BBB) permeation, P-glycoprotein (P-gp) substrate and cytochrome P450 members inhibition potentials were also surveyed to draw insight about the pharmacokinetic behavior of the reviewed anthraquinones. Twenty anthraquinones (47,48,49,51,52,57,83,147,152,153,157,169,184,185,186,188,189,195,203, and 204) showed high GI absorption, passively crossed BBB and did not show any potential for P-gp substrate (ESI Table S2 †). Surprisingly, compound 169 obeyed all the surveyed parameters (5 drug-likeness rules, log P, Csp 3 , RB, TPSA, log S, GI, BBB, Pgp) and the other 19 anthraquinones as well except for fraction Csp 3 . Noteworthy, all but one of the 20 anthraquinones have two benzenoid aromatic rings and two C]O groups. Also, several anthraquinones showed potential inhibition for some CYP 450 isoforms which necessitates awareness when coadministered with possible substrates of these enzymes (ESI Table S2 †).
To sum up, marine fungi are a promising source of biologically active anthraquinones that obeyed all the criteria of several drug-likeness rules with promising pharmacokinetic behavior which promotes their utilization as well as further research to isolate their individual components and determine their pharmacological effects.

Conclusions and future prospective
The marine phoma is representing the most, the greatest and most diverse ecological structure on the planet. Over seven decades, marine natural products (MNPs) have owned credits and been privileged as a robust and sustainable supplier for pharmacologically active compounds that meet a huge interest in pharmaceutical and economical applications. Marinederived fungi are valuable sources of structurally diverse MNPs due to their various habitats that range from the warm to the colder areas, and even at extreme temperatures and pressure like in hydrothermal outlets. One of the fascinating classes of fungal derived natural products is the anthraquinones. Herein, we presented a comprehensive literature review centered on marine-derived anthraquinones as a unique group of fungal polyketides over the period 2000-2020 from twenty marine fungal genera. A list of 208 anthraquinones have been reported from different marine fungi, featuring a myriad of structural and biological diversities. Investigating such extensive chemo-biological data has implied two remarkable points. First, it was clear that the marine fungi of the three genera Aspergillus sp., Stemphylium sp., and Penicillium sp., are the most creative fungal genera in terms of producing of anthraquinones. Secondly, the most common reported bioactivity was cytotoxicity, where a notable number of seventy-two compounds have been evaluated for their cytotoxic activity against planes of carcinoma cell lines, whilst the anthraquinones with antibacterial activity were the second on the list with sixty-nine compounds demonstrated bioactivity against a wide range of microorganisms. Meanwhile, an enormous spectrum of further biomedical potentialities exhibited by these compounds as (antioxidant, antiviral, antifungal, immunomodulatory, anti-  inammatory, ...etc.) have been documented. Such a massive connection between chemical spaces and bioactivities highlights the huge capacity of marine-derived fungi as an attractive biological source that is worth further exploitations with distinguished anticipations for the global pharmaceuticals industries. Additionally, recent advances in the level of sampling techniques, fermentation, synthetic biology, genetic engineering, genome mining, and total chemical synthesis, all are crucial to the success of fungal MNPs as future drug leads. Furthermore, all reported anthraquinones were extensively investigated for their in silico Drug-likeness and pharmacokinetics properties using SWISSADME online platform, which intriguingly highlighted a list of 20 anthraquinone containing compounds (ESI †) that could be considered as potential drug leads scaffolds ( Fig. 17 and 18).