Novel Bioactive Natural Products from Marine-Derived Penicillium Fungi: A Review (2021–2023)

Abstract

Marine-derived Penicillium fungi are productive sources of structurally unique and diverse bioactive secondary metabolites, representing a hot topic in natural product research. This review describes structural diversity, bioactivities and statistical research of 452 new natural products from marine-derived Penicillium fungi covering 2021 to 2023. Sediments are the main sources of marine-derived Penicillium fungi for producing nearly 56% new natural products. Polyketides, alkaloids, and terpenoids displayed diverse biological activities and are the major contributors to antibacterial activity, cytotoxicity, anti-inflammatory and enzyme inhibitory capacities. Polyketides had higher proportions of new bioactive compounds in new compounds than other chemical classes. The characteristics of studies in recent years are presented.

1. Introduction

Marine-derived fungi have a variety of medical applications due to their capability of generating various enzymes and antimicrobial agents [1]. Since the first species Sphaeria posidoniae (Halotthia posidoniae) on the rhizome of the sea grass Posidonia oceanica was studied in 1846 [2], scientists have never stopped studying the natural products (NPs) of marine-derived fungi [3]. The rapid development of marine bio-technology and ever-increasing needs of clinic applications resulted in the emergence of marine natural products as alternative drug sources in the early 1990s [4] and the voluminous output in natural product research from the fungi isolated from different marine animals, seaweeds and sediments, with many new bioactive compounds being described each year [5].

As an essential part of marine micro-organisms, Penicillium fungi have received great attention among all marine-derived fungi, accounting for 22% of NPs of marine fungal origin, and play an important role in the discovery of marine natural products with bioactivities and novel structures [6]. Several reviews on natural products isolated from marine-derived Penicillium species have been published [4,6,7,8]. A total of 390 new secondary metabolites from marine-derived Penicillium fungi were highlighted from 1991 to 2014 [6], and 188 new secondary metabolites were summarized from 2015 to 2020 [7]. More than 200 cytotoxic or antitumor compounds isolated from marine Penicillium fungus were included from 1991 to 2017 [4]. Newly reported alkaloids produced by marine-derived Penicillium species were offered from 2014 to 2018 [8]. Recently, some remarkable achievements have been made in the study of marine-derived Penicillium fungi, including an MS/MS targeted molecular networking approach for the discovery of rare communesins [9], the investigation of the apoptosis mechanism of dicitrinone G from by the analyses of the protein–protein interaction (PPI) network and Western blot [10], and so on. These effective approaches have given rise to the generation of unique chemicals and huge biological diversity, making marine-derived Penicillium fungi a hotspot for utilization in the discovery of new drug leads.

A systematic review of the origins, structures, and bioactivities of 452 new NPs produced by marine-derived Penicillium species from January 2021 to December 2023 is provided in this review, based on 115 studies searching in the SciFinder database with marine-derived Penicillium as the key word, with English as the language. The review also covers fifty-one new marine natural products only described based on the HPLC-MS/MS analyses [9]; two previously reported marine natural products with significant new bioactivities [11,12], three known marine natural products supplied the structural NMR data [13,14,15], and two compounds were presented as new natural products [15,16], but their structures are not shown. In addition, due to the narrow publication timespan, seven pairs of new compounds possessing different structures were given the same trivial name, respectively. In this review, the first reported compounds were given the suffix a [17,18,19], and the other ones were given the suffix b [20,21].

2. New Bioactive Compounds from Marine-Derived Penicillium Fungi

2.1. Polyketides

2.1.1. Azaphilones

Azaphilones are a class of structurally diverse fungal metabolites that are mainly defined as polyketides possessing a highly oxygenated pyranoquinone bicyclic core and a quaternary carbon center [17]. A series of azaphilones with novel structures and remarkable bioactivities were reported from marine-derived Penicillium fungi. Penicil-azaphilones Ia–N (1, 2 and 6–9), epi-geumsanol D (3) and penidioxolanes C (4) and D (5) (Figure 1) were isolated from the sponge-derived P. sclerotiorum E23Y-1A culture [17]. Penicil-azaphilone Ia-N 9 showed moderate anti-inflammatory activity with an IC₅₀ value of 22.63 ± 2.95 μM, whereas 4 exhibited various cytotoxic activities. The same strain produced two chlorinated azaphilones, penicilazaphilones F (10) and G (11) (Figure 1), with a moderate anti-inflammatory effect [22]. Based on a one strain–many compounds (OSMAC) approach, two new brominated analogs, 5-bromoisorotiorin (12) and penicilazaphilone Ha (13) (Figure 1), were obtained from P. sclerotiorum E23Y-1A by the addition of NaBr into the culture medium. Both showed moderate antibacterial activities against Staphylococcus aureus ATCC 25923 with inhibition zone diameters of 8.08 ± 0.01 and 7.50 ± 0.05 mm, respectively [18]. New azaphilones, penicilazaphilones Hb–Ib (14–15), 11-epi-geumsanols B and F (17–16), 8a-epi-hypocrellone A (18), and 8a-epi-eupenicilazaphilone C (19) (Figure 1), were isolated from algae-derived P. sclerotiorum [20,23]. Azaphilone 19 significantly promoted SMAD-mediated transcriptional activities stimulated by TGF-β [23]. Azaphilone E/Z isomers isochromophilone H (20a/b), sclerotiorins A (21) and B (22), ochlephilone (23), isochromophilone IV (24), and isochromophilone J (25a/b) (Figure 1) were isolated from the culture broth of the mangrove-derived fungus P. sclerotiorum HY5. Azaphilones 22 and 23 exhibited potent phytotoxicity against the growth of radicles and plumules on Amaranthus retroflexus L., with EC₅₀ values ranging from 234.87 to 320.84 μM, compared to the positive control glufosinate-ammonium, with EC₅₀ values of 555.11 μM for radicles, and 656.04 μM for plumules [24]. Chermesinones D–G (26–29) (Figure 1) were isolated from marine-derived P. chermesinum FS625 [25]. Daldinins G-H (30–31) (Figure 1) were isolated from the soft-coral-derived P. glabrum glmu 003 [26].

2.1.2. Isocoumarins

Penicillols A (32) and B (33) (Figure 1) featuring spiroketal rings were isolated from the mangrove-derived Penicillium sp. BJR-P2. Pannicillol B (33) exhibited significant inhibitory activity on NO production with an IC₅₀ value of 12 μM [27]. Peniciisocoumarins I (34) and J (35) (Figure 1) were obtained from the mangrove-derived Penicillium sp. GXIMD 03001 [28].

2.1.3. Chromones

The marine-derived P. citrinum BCRC 09F458 yielded a class of rare chromone derivatives, epiremisporines C–H (36–41) (Figure 1). Epiremisporines 37 and 38 could significantly inhibit fMLP-induced superoxide anion generation, with IC₅₀ values ≤ 8.28 μM. Through the mitochondrial- and caspase 3-dependent pathways, 38 and 41 markedly induced the apoptosis of A549 with IC₅₀ values of 43.82 ± 6.33 and 31.43 ± 3.01 μM, respectively. Furthermore, 41 obviously induced apoptosis of HT-29 cells, via Bcl-2, Bax, and caspase 3 signaling cascades [29,30]. Eleven 5,7-dioxygenated chromones penithochromones M–W (42–52) (Figure 1), bearing an aliphatic acid side chain, were isolated from the deep-sea-sediment-derived P. thomii YPGA3 [31,32]. Penithochromones 47–49 exhibited remarkable inhibition against α-glucosidase with IC₅₀ values ranging from 842 to 1017 μM, which are more active than the positive control acarbose [31].

2.1.4. Citrinins

Citrinins, as an important class of polyketide mycotoxins, usually have core structure skeletons like benzopyran, benzofuran, and quinone-pyran, etc. [33]. Three extremely rare nitrogen-containing citrinin derivatives, isoquinocitrinins B–D (53–55), and their corresponding enantiomers (53a/b, 54a/b, 55a/b) (Figure 2) were acquired from the hydrothermal-vent-sediment-derived Penicillium sp. TW131-64. These products exhibited potential anti-H. pylori activities towards the standard strain and multidrug-resistant clinical isolates with MIC values ranging from 0.25 to 8 μg/mL, indicating a comparable or even better killing activity than metronidazole. Citrinin derivatives (3R,4S)-8-hydroxy-6-methoxy-3,4,5-trimethylisochromane-7-carboxylatemethyl (56), (3R,4S)-6-hydroxy-8-methoxy -3,4,5-trimethylisochromane-7-carboxy latemethyl (57), and penicitrinone J (58) (Figure 2) were also obtained from this strain [33]. Rare carbon-bridged citrinin dimers, dicitrinones G–J (59–62) (Figure 2) were isolated from starfish-derived Penicillium sp. GGF 16-1-2 and exhibited strong antifungal activities against Colletotrichum gloeosporioides with LD₅₀ values ranging from 9.58 μg/mL to 16.14 μg/mL. Furthermore, 59 showed significant cytotoxicity against human pancreatic cancer cell lines BXPC-3 and PANC-1, which could induce apoptosis by activating caspase 3 proteins (CASP3) [10]. Neotricitrinols A–C (63–65) (Figure 2), isolated from the marine-sediment-derived P. citrinum W23, feature a unique octacyclic carbon scaffold among the few reported citrinin trimers. Neotricitrinol 64 showed potential anti-osteoporosis activity by promoting osteoblastogenesis and inhibiting adipogenic differentiation on primary bone mesenchymal stem cells [34]. Xerucitrinins B and C (66–67) (Figure 2) bearing a 6,6-spiroketal moiety were isolated from hydrothermal vent-associated P. citrinum Y34 [35]. Penicitrinol P (68) and dicitrinol D (69) (Figure 2) were isolated from the sponge-derived Penicillium sp. SCSIO 41302 [36] and Penicillium sp. SCSIO41303, respectively [37].

2.1.5. β-Resorcylic Acid

Resorcylic acid lactones (RALs) are structurally diverse polyketides, which usually consist of condensed resorcylic and macrolide cycles, sometimes possessing an open macrolide cycle [38]. Five β-resorcylic acid derivatives, 14-hydroxyasperentin B (70), β-resoantarctines A–C (71–73) (Figure 2) and 8-dehydro-β-resoantarctine A (74) (Figure 2), were isolated from the brown-alga-derived P. antarcticum KMM 4685. β-resorcylic acid derivatives 71–72 and 74 (Figure 2) inhibited the activity of p-glycoprotein at their noncytotoxic concentrations and consequently synergized with docetaxel in p-glycoprotein-overexpressing drug-resistant cells [38].

2.1.6. Verrucosidin

Verrucosidins belong to a family of highly reduced polyketides, generally sharing a methylated α-pyrone, a conjugated polyene linker, and an epoxidated tetrahydrofuran ring [39]. A pair of epimers, 9-O-ethylpenicyrones A (75) and B (76) (Figure 2), were isolated and identified from the marine-sediment-derived P. cyclopium SD-413. Epimers 75 and 76 showed antibiotic activity against aquatic pathogen A. hydrophilia, each with an MIC value of 8 μg/mL [40]. Poloncosidins A–K (77–87) (Figure 2) [39,41] were identified from the cold-seep-sediment-derived P. polonicum CS-252. Poloncosidins 77–86 were the first verrucosidins with a 2,5-dihydrofuran ring. Most of these compounds exhibited inhibitory activities against several human and aquatic pathogens with MIC values ranging from 4 to 32 μg/mL. Verrucosidinols A (88) and B (89) (Figure 2) were isolated from the marine-sediment-derived P. griseofulvum MCCC 3A00225 [42].

2.1.7. Citreoviridins

Citreoviridins H (90) and I (91) (Figure 2) were isolated from the mangrove-derived Penicillium sp. BJR-P2 [27]. Citreoviridins J-O (92–97) (Figure 2) belonged to diastereomers of 6,7-epoxycitreoviridin with different chiral centers at C-2–C-7 and were isolated from the deep-sea-sediment-derived P. citreonigrum MCCC 3A00169 [43].

2.1.8. Nitrogen-Containing Polyketides

Fungal polyketide–amino acid hybrids are a large family of secondary metabolites produced by PKS-NRPS assembly lines [44]. The derivatives oxopyrrolidine A (98) and B (99) (Figure 2) were isolated based on bioactivity screening and chemical profiles from the marine-derived P. oxalicum MEFC104 [44]. 7-hydroxy-3,10-dehydrocyclopeptine (100) (Figure 2) was isolated from the mangrove-sediment-derived P. polonicum MCCC3A 00951 [45]. Fusarin derivatives steckfusarins A–E (101–105) (Figure 2) were isolated from the green-algae-derived P. steckii SCSIO41040. Steckfusarin A (101) exhibited antioxidant activity against DPPH, with an IC₅₀ value of 74.5 μg/mL [46].

2.1.9. Sorbicillinoids

Bisorbicillchaetones A-C (106–108) (Figure 3) were the first examples of hybrid sorbicillinoids containing a coniochaetone unit and isolated from the deep-sea-sediment-derived Penicillium sp. SCSIO06868. Bisorbicillchaetones 106 and 107 exhibited moderate inhibitory effects on NO production in lipopolysaccharide (LPS)-activated RAW264.7 cells with IC₅₀ values of 80.3 ± 3.6 μM and 38.4 ± 3.3 μM, respectively [47]. Various sorbicillinoids, including two hybrid sorbicillinoids, 10-methylsorbiterrin A (109) and dihydrotrichodermolidic acid (113); three bisorbicillinoids, epitetrahydrotrichodimer ether (110), demethyldihydro-trichodimerol (111) and bisorbicillpyrone A (112); and three monomeric sorbicillinoids, 5-hydroxy-dihydrodemethlsorbicillin (114), sorbicillpyrone A (115) and 5,6-dihydrovert-inolide (116) (Figure 3); were isolated from the deep-sea-sediment-derived Penicillium sp. SCSIO06871. Monomeric sorbicillinoid 114 displayed more potent inhibitory activity against α-glycosidase than acarbose with an IC₅₀ value of 36.0 μM [48]. Sorbicatechols C (117) and D (118) (Figure 3) were isolated from deep-sea-derived P. allii-sativi MCCC3A00580. Sorbicatechol D (118) inhibited HT-29 cells in a dose-dependent manner [49]. A sorbicillinoid, (4E)-1-(4,6-dihydroxy-5-methylpyridin-3-yl)hex-4-en-1-one (119) (Figure 3), was isolated from the mangrove-derived Penicillium sp. DM815 [50].

2.1.10. Isochromans

Penicisteckins A–F (120–125) (Figure 3) represented novel biaryl scaffolds containing both central and axial chirality elements and isolated from the beach-mud-derived P. steckii HNNU-5B18 [51].

2.1.11. α-Pyrone Polyketides

Six α-pyrone polyketides, penipyrols C–G (126–130) (Figure 3) and methyl-penipyrol A (131), were isolated from the mangrove-derived Penicillium sp. HDN-11-131. Penipyrols 127–129 possess a rare skeleton featuring γ-butyrolactone linked to an α-pyrone ring through a double bond. Penipyrol 127 can induce pancreatic β-cell regeneration in zebrafish at 10 μM, demonstrating promising anti-diabetes potential [52].

2.1.12. Hirsutellones

The natural hirsutellones are made of a decahydrofluorene polyketide core (rings A, B and C) involved in a highly strained 12- or 13-membered para-cyclophane (ring D) and highly functionalized 5-hydroxypyrrolidinone [53]. Perpyrrospirone A (132) (Figure 3) was the first example of hirsutellone peroxide from the marine-derived P. citrinum, and characterized an unprecedented 6/5/6/8/5/13/6 oxahexacyclic scaffold with a unique peroxide-bridged 8,9-dioxa-2-azaspiro[4.7] dodecane core [53].

2.1.13. Xanthones and Benzophenones

Xanthones, known as 9H-xanthen-9-ones, are a class of yellow compounds bearing a dibenzo-γ-pyrone scaffold, which are often regarded as privileged structures for binding with a variety of targets [54]. Tetrahydroxanthone 11-O-acetylaspergillusone B (133) and the fully aromatic xanthone 7-dehydroxyhuperxanthone A (134) (Figure 3) were isolated from the deep-sea-sediment-derived Penicillium sp. MCCC 3A00126 [54]. Penicixanthene E (135) (Figure 3), the first reported xanthene derivative in which a carbon–carbon double bond was reduced, was isolated from the mangrove-derived Penicillium sp. GXIMD 03101 [55]. Benzophenone derivative penibenzophenone C (136) (Figure 3) and a new natural product, penibenzophenone D, were isolated from the mangrove-derived Penicillium sp. Penibenzophenone C (136) showed moderate antibacterial activity against methicillin-resistant S. aureus with an MIC value of 3.12 μg/mL [16].

2.1.14. Hydroxybenzenes

Peniketide A (137) and a methyl ester of penipyrol A (138) (Figure 3) were isolated from the marine-sediment-derived Penicillium sp. SCZ-1. Peniketide A 137 bearing a two-carbon side chain at C-2 is seldom found among natural isocoumarins [56]. The deep-sea-sediment-derived P. citrinum W17 yielded penidihydrocitrinins A–C (139–141) (Figure 3). Three isolates exhibited significant inhibitory effects on LPS-stimulated nitric oxide (NO) production in murine brain microglial BV-2 cells in a dose–response manner [57]. Peniciphenalenin G (142) (Figure 3) was isolated from the marine-derived P. oxalicum [58]. Penicinone C (143) (Figure 3) was identified from the mangrove-derived Penicillium sp. LA032 [59]. Six new polyketide derivatives (144–149) (Figure 3) were isolated from the hydrothermal-vent-sediment-derived Penicillium sp. TW58-16. Polyketide derivatives 144–147 showed strong a-glucosidase inhibitory effects with inhibition rates of 73.2%, 55.6%, 74.4%, and 32.0%, respectively, which were comparable with or even better than that of acarbose, a known α-glucosidase inhibitor [60]. Coniochaetone N (150) (Figure 3) was isolated from the deep-sea-sediment-derived Penicillium sp. SCSIO06868 [61].

2.1.15. Lactones

Penicinones A (151) and B (152) (Figure 3) were identified from the mangrove-derived Penicillium sp. LA032. Penicinone A 151, a rare furo[3,4-b]pyran-5-one skeleton with an n-heptyl moiety, was identified and found to exhibit significantly cytotoxic activity against the HepG2 cells, with an IC₅₀ value of 3.87 ± 0.74 μM [59]. Walterolactone E (153) (Figure 3) was isolated from the hydrothermal-vent-sediment-derived Penicillium sp. TW58-16 [62].

2.1.16. Olefinic Acids and Their Derivatives

Tanzawaic acids are a small class of polyketides, characterized by a trans-decalin (A/B fusion) scaffold, isolated mainly from the genus Penicillium [63]. The coral-derived P. steckii AS-324 yielded a series of tanzawaic acids, including steckwaic acids A–D (154–157), 11-ketotanzawaic acid D (158), 6,15-dihydroxytanzawaic acid M (159), 15R-methoxy-tanzawaic acid M (160), 15S-methoxytanzawaic acid M (161), 8-hydroxytanzawaic acid M (162), and 8-hydroxytanzawaic acid B (163) [64], steckwaic acids Ea-Ia (164–168), 18-O-acetyltanzawaic acid R (169), 10-hydroxytanzawaic acid U (170), and 13R-tanzawaic acid S (171) [19] (Figure 4). Among them, 171 showed potent activity against Escherichia coli with an MIC value of 8 μg/mL. Steckwaic acids Eb-Ib (172–176) and J-K (177–178) (Figure 4) were isolated from the green-algae-derived P. steckii SCSIO 41040. Steckwaic acid 173 inhibited LPS-induced nuclear factor kappa-B (NF-κB) with an IC₅₀ value of 10.4 μM, which is the first report of osteoclastogenesis inhibitory activity for tanzawaic acid derivatives [63]. Penicisteck acids A–D (179–182) (Figure 4) were isolated from the mangrove-derived P. steckii SCSIO 41025. Penicisteck acids 179–181 were highly oxygenated decalin derivatives harboring an unusual propanoic acid unit at C-1 [65]. Penifellutins A (183) and B (184), possessing a 22 carbons linear skeleton, were isolated from the co-culture of the deep-sea-derived fungi P. crustosum PRB-2 and P. fellutanum HDN14-323 along with two esterification products, penifellutins C (185) and D (186) (Figure 4). Penifellutins A (183) and B (184) showed obvious inhibitory activity on the liver hyperplasia of zebrafish larvae at a concentration of 10 μmol/L, while penifellutins C (185) and D (186) showed no activity, indicating that two carboxyls in the structure were important active sites [66].

2.1.17. Other Polyketides

Rubenpolyketone A (187) (Figure 4) featuring cyclohexenone condensed with a methyl octenone chain was identified from the Magellan Seamount-derived P. rubens AS-130 [67]. Oxalichroman A (188) and oxalihexane A (189) (Figure 4) were isolated from the red algae-derived P. oxalicum 2021CDF-3. Oxalihexane A (189), formed by a cyclohexane and cyclohexanone moiety via an ether bond, showed a remarkable inhibitory effect on the human pancreatic cancer PATU8988T cell line through downregulation of the expression level of cyclin D1 [68]. Leptosphaerone D (190) (Figure 4) was isolated from the hydrothermal-vent-sediment-derived Penicillium sp. TW58-16 [62]. 15-O-methyl ML-236A (191) (Figure 4) was isolated from the deep-sea-sediment-derived P. solitum MCCC 3A00215 [69].

2.2. Alkaloids

2.2.1. Indoles

Communesins are a class of complex indole alkaloids isolated from the Penicillium fungi. The marine-sediment-derived P. expansum was studied using a targeted molecular networking approach, allowing the detection of 55 new communesins. Among of them, communesins M-P (192–195) (Figure 5) were isolated and showed moderate cytotoxicity against KB and MCF-7 human cancer cell lines in comparison to the positive control docetaxel [9]. The coral-derived P. dimorphosporum KMM 4689 yielded the very first deoxyisoaustamide alkaloid deoxy-14,15-dehydroisoaustamide (196) [70] and seven deoxyisoaustamide derivatives (197–203) [71] (Figure 5). Deoxyisoaustamide derivatives 199, 201 and 202 (Figure 5) showed a statistical increase in paraquat-treated Neuro-2a cell viability by 30–39% at a concentration of 1 μM. Penilline D (204) (Figure 5) was isolated from the Antarctic fungus Penicillium sp. SCSIO 05705 [72]. Penindolacid A (205) (Figure 5) was isolated from the marine-sediment-derived Penicillium sp. LW92 [73]. Prenylated indole diketopiperazine alkaloids (PIDAs) penicamides A (206) and B (207) (Figure 5) were identified from the mangrove-derived Penicillium sp. LA032. Penicamide A (206) was the first example of PIDAs featuring a 6/5/8/6/5 pentacyclic ring system with an α-hydroxy group at C-11[59]. 11S-(−)-penilloid A (208) and 11R,14E-(+)-penilloid A (209) (Figure 5) were isolated from the marine-mud-derived Penicillium sp. ZZ1750 [74].

2.2.2. Pyridones

Eleven new pyridone alkaloids, penicipyridones A-K (210–220) (Figure 5), were isolated from the marine-derived P. oxalicum QDU1. Penicipyridones 210, 213–214, 217 and 219–220 exhibited moderate inhibitory effects on NO production in the LPS-induced RAW264.7 macrophages, with IC₅₀ values ranging from 9.2 to 19 μM [75].

2.2.3. Quinolinones

Penicinolone (221) (Figure 5) was isolated from the sponge-derived Penicillium sp. SCSIO41033 [76]. AChE-inhibitory-activity-guided studies on the mangrove-derived P. citrinum YX-002 led to the isolation of quinolactone A (222), quinolactacin C1 (223), and 3-epi-quinolactacin C1 (224) (Figure 5). Quinolactone A (222) showed moderate AChE inhibitory activity with an IC₅₀ value of 27.6 μmol/L [77]. N-methyl-4-quinolones quinolactacin E (225a/b), quinolactacins F1–F2 (226–227) and quinolactacin G (228a/b) (Figure 5) were isolated from the sponge-derived Penicillium sp. SCSIO 41303. Quinolactacin 226 exhibited enzyme inhibition activity against PL with an IC₅₀ value of 24.6 μg/mL [37]. Four racemic mixtures, (±)-oxypenicinolines A–D (229–232), along with penicinolines F (233) and G (234) (Figure 5) were isolated from the mangrove-derived P. steckii SCSIO 41025. Racemic mixtures 229–232 shared an unusual 6/6/5/5 tetracyclic system incorporating a rare tetrahydro-pyrrolyl moiety, while 229 displayed α-glucosidase inhibitory activity with an IC₅₀ value of 317.8 μM, which was more potent than that of acarbose (461.0 μM) [78].

2.2.4. Decahydrofluorene-Class Alkaloids

Pyrrospirones K–Q (235–241) (Figure 5) were isolated from the soft-coral-derived Penicillium sp. SCSIO 41512. Pyrrospirones 235 and 237 possessed a novel decahydrofluorene-class alkaloid skeleton with 6/5/6/8/5/6/13 and 6/5/6/5/6/13 polycyclic systems, respectively. Pyrrospirones 235–237 and 239 showed antibacterial activity against all or some of the six pathogens B. amyloliquefaciens, B. subtilis, E. coli, S. aureus, S. aureus MRSA, and S. agalactiae. Pyrrospirones 238 and 240 displayed mild inhibitory activity against several PTPs with IC₅₀ values of 39.4–100 μM [79].

2.2.5. Piperazines

A trithiodiketopiperazine derivative, adametizine C (242) (Figure 5), was isolated from the mangrove-sediment-derived P. ludwigii SCSIO 41408. Adametizine C (242) showed cytotoxicity against prostate cancer cell line 22Rv1 with an IC₅₀ value of 13.9 μM, and the strongest inhibitory activity against RANKL-induced osteoclast differentiation in bone marrow macrophage cells with 10 μM [80]. A diketopiperazine alkaloid, (8S,9R,12R,18S)-12-hydroxyl-fumitremorgin B (243) (Figure 5), was isolated from the hydrothermal-vent-sediment-derived Penicillium sp. TW58-16 [62]. Three epithiodiketopiperazine alkaloids, penigainamides A–C (244–246) (Figure 5), were isolated from the marine-derived P. steckii YE [81].

2.2.6. Tetramic-Acid-Based Alkaloids

Tolypocladenols D-F (247–249) (Figure 6) were isolated from the fresh and healthy leaves of the Apocynum venetum-derived fungus P. oxalicum QDU1. Tolypocladenol 249 exhibited moderate inhibitory effects on NO production in the LPS-induced RAW264.7 macrophages, with an IC₅₀ value of 14 ± 1 μM [75]. Penicillenols G1–G2 (250–251) and H (252) (Figure 6) were isolated from cultures of the deep-sea-sediment-derived Penicillium sp. SCSIO06868. Penicillenol H (252) exhibited potent inhibitory activities against S. aureus and methicillin-resistant S. aureus with MIC values of both 2.5 mg/mL [61].

2.2.7. Amines and Amides

(Z)-4-(5-acetoxy-N-hydroxy-3-methylpent-2-enamido) butanoate (253) (Figure 6) was isolated from the mangrove-derived P. oxalicum HLLG-13 and showed significant growth inhibition activities against newly hatched Helicoverpa armigera Hubner larvae, with an IC₅₀ value of 200 μg/mL [15]. Polonimides E (254) and D (255) (Figure 6) were isolated from the sponge-derived Penicillium sp. SCSIO 41413 [82]. Speradine I (256) (Figure 6) was isolated from the soft-coral-derived Penicillium sp. SCSIO 41038 [83]. (S)-2-acetamido-4-(2-(methylamino)phenyl)-4-oxobutanoic acid (257) (Figure 6) was isolated from the deep-sea-gammarid-shrimp-derived P. citrinum XIA-16 [84]. A pentacyclic alkaloid, citrinadin C (258) (Figure 6), was isolated from the deep-sea-sediment-derived P. citrinum and showed cytotoxic activity against human liver cancer cell line MHCC97H, with an IC₅₀ value of 16.7 μM [85]. (2S,2′R,3R,3′E,4E,8E)-N-2′-hydroxyhexadecanoyl-2-amino -9-methyl-4,8-octadecadiene-1,3-diol (259) (Figure 6), a ceramide, was isolated from the seawater-derived P. chrysogenum Y20-2. (2S,2′R,3R,3′E,4E,8E)-N-2′-hydroxyhexadecanoyl-2-amino -9-methyl-4,8-octadecadiene-1,3-diol (259) showed no pro-angiogenic activity using a zebrafish model [86]. N-acetyl-d-glucosamines penichryfurans A (260) and B (261) (Figure 6) were isolated from the red-alga-derived P. chrysogenum. Penichryfuran A (260) exhibited strong cytotoxicity against the HepG2 cell line with an IC₅₀ value of 9.0 μM [87]. Talaroenamines F1–F19 (262–280) (Figure 6) were isolated from the wetland-derived P. malacosphaerulum HPU-J01 using a one-pot/two-stage precursor-directed biosynthesis approach. Talaroenamine 275 was cytotoxic against the K562 cell line with an IC₅₀ value of 2.2 μM [88]. Peniokaramine (281) and penipyranopyridine (282) (Figure 6) were isolated from the hydrothermal-vent-sediment-derived Penicillium sp. LSH-3-1. Peniokaramine (281) showed moderate cytotoxic activity against A549 cells with an inhibition percentage of 53.43 ± 5.89% [89]. Penicidihydropyridones A (283) and B (284) (Figure 6) were isolated from the sponge-derived Penicillium sp. B9. Both of them intriguingly appeared to perturb PD-L1/PD-1 interactions with a considerable inhibitory rate of 88.40% for 283 and 70.72% for 284 with a concentration of 10 μg/mL [90]. (+)-solitumidine D (285) and (±)-solitumidine E (286) were isolated from the marine-sediment-derived P. solitum MCCC 3A00215 [69]. Penicmariae-crucis C acid (287), N-(6-hydroxy-2-oxoindolin-3-ylidene)-5′-methoxy-5′-oxobutyl-amine oxide (288), and methyl-1′-(N-hydroxyacetamido)-butanoate (289) (Figure 6) were isolated from the mangrove-derived P. steckii SCSIO 41025 [65]. Penigrisamide (290), aurantiomoate C (291), N,N-pyroglutamylleucinmethylester (292), methyl-2S-hydroxy-3-methylbutanoyl-L-leucinate (293), and 6R,7-dihydroxy-3,7-dimethyloctanamide (294) (Figure 6) were isolated from the marine-sediment-derived P. griseofulvum MCCC 3A00225 [42].

2.2.8. Other Alkaloids

Sulfoxanthocillin (295) (Figure 6) was isolated from the deep-sea-sediment-derived Penicillium sp. SCSIO sof101. Sulfoxanthocillin (295) showed significant activity against series pathogens with MIC values ranging from 0.06 to 8.0 μg/mL and relatively low cytotoxicity against human tumor cell lines [91]. Penipyridinone B (296) (Figure 6) was isolated from the marine-mud-derived Penicillium sp. ZZ1750. Penipyridinone B (296) represented the first example of its structural type and showed potent antiglioma activity, with IC₅₀ values of 2.45 μM for U87MG cells and 11.40 μM for U251 cells [74].

2.3. Terpenoids

2.3.1. Sesquiterpenes

A linear sesquiterpenoid, chermesiterpenoid D (297) (Figure 7), was identified from the Magellan Seamount-derived P. rubens AS-130 [67]. A series of eremophilane-type sesquiterpenes, copteremophilanes A–J (298–307) (Figure 7), were isolated from the marine-sponge-derived P. copticola. Analogs 298, 299, and 307 represented a group of uncommon skeletons of eremophilanes with an aromatic ring and a methyl migration from C-5 to C-9. The incorporation of a chlorinated phenylacetic unit in 300–306 has rarely been found in nature; 304 showed a neuroprotective effect through increasing the viability of A25-35-induced PC12 cells, whereas 305 exhibited selective inhibition against A549 with an IC₅₀ value of 3.2 ± 0.1 μM [92]. A drimane sesquiterpenoid, astellolide Q (308) (Figure 7), was isolated from the mangrove-soil-derived Penicillium sp. N-5, combined with compound V [14]. A drimane sesquiterpene ester, chrysoride A (309) (Figure 7), was isolated from the red-alga-derived P. chrysogenum LD-201810 and showed moderate cytotoxicity against HepG2 and HeLa cancer cell lines, with IC₅₀ values of 28.9 and 35.6 μM, respectively [93]. The marine-derived Penicillium sp. ZZ1283 yielded a drimane sesquiterpene, lactone purpuride D (310) (Figure 7), which significantly inhibited the growth of methicillin-resistant S. aureus, E. coli and C. albicans with MIC values of 4, 3 and 8 μg/mL, respectively [94]. Acorane-type sesquiterpenes feature a spiro[4.5]decane core with an isopropyl unit at C-1 and dimethyl substitution at C-4 and C-8, which markedly differs from other types of the sesquiterpene family [95]. Eighteen acorane-type sesquiterpenes, bilaiaeacorenols A–R (311–328) (Figure 7), were identified from the deep-sea-sediment-derived P. bilaiae F-28. Sesquiterpene 328 exhibited efficient reduction against NO production in LPS-induced BV-2 macrophages in a dose-dependent manner, and it abolished LPS-induced NF-κB in the nucleus of BV-2 microglial cells, along with the inhibition of iNOS and COX-2 at a cellular level [95]. Citreobenzofurans D–F (329–331) and phomenones A–B (332–333) (Figure 7) were isolated from the mangrove-derived Penicillium sp. HDN13-494. Citreobenzofurans 330 and 331 are eremophilane-type sesquiterpenoids with rare benzofuran frameworks. Phomenone B (332) contained a rare thiomethyl group, which was the first report of this kind of sesquiterpene with sulfur elements in the skeleton; 333 showed moderate activity against Bacillus subtilis, with an MIC value of 6.25 μM [96]. (2S,3S,5S,6S,7S,8R,11S,12R)-15-deacetyl-7,8-dihydroxycalonectrin (334) and 1-methyl-4-[3,4,5-trihydroxy-1,2,2-trimethylcyclopently] benzene (335) (Figure 7) were isolated from the deep-sea-derived Penicillium sp. LXY140-R. 1-methyl-4-[3,4,5-trihydroxy-1,2,2-trimethylcyclopently] benzene (335) showed potent antiproliferative activity against HCT-116 cell lines with an IC₅₀ value of 124.12 μM [97]. Nor-bisabolane derivative enantiomers (±)-1 (336a/b) (Figure 7) were isolated from the algal-derived P. chrysogenum LD-201810 [98]. Two drimane sesquiterpenes, (4S,5R,9S,10R)-11,13-dihydroxy-drim-7-en-6-one (337) and (4S, 5R,9S,10R)-11-hydroxy-13-carboxy-drim-7-en-6-one (338) (Figure 7), were isolated from the hydrothermal-vent-sediment-derived Penicillium sp. TW58-16. (4S,5R,9S,10R)-11,13-dihydroxy-drim-7-en-6-one (337) showed a strong a-glucosidase inhibitory effect with an inhibition rate of 35.4% [60].

2.3.2. Diterpenes

Resistance has been found in many clinical anti-influenza A virus (IAV) drugs. Therefore, developing a safe and effective agent with a unique structure is urgently needed to combat IAV infection [99]. During the search for anti-IAV marine natural products, a series of new indole-diterpenoids have been isolated. Penijanthine E (339) (Figure 7), obtained from the marine-derived P. citrinum ZSS-9, showed antiviral activity against IAV of A/WSN/33(H1N1) and A/PR/8/34(H1N1) strains with IC₅₀ values of 12.6 and 18.9 μM, respectively [99]. The marine-derived P. janthinellium co-cultured with Paecilomyces formosus led to the isolation of janthinellumines A–I (340–348). Janthinellumines 340, 341 and 346 (Figure 7) displayed significant activities against two strains of A/WSN/33 (H1N1) and A/Hong Kong/1/68 (H3N2) with IC₅₀ values of 3.8 and 13.3 μM, respectively, stronger than those of the positive control T-705. Furthermore, the PTP inhibitory activity of 340–341, 343–344 and 348 had the best inhibitory activity towards PTP1B with IC₅₀ values ranging from 0.6 to 9.2 μM, most of which were stronger than that of the positive control Na₃VO₄ (IC₅₀ = 8.5 μM) [100]. Additionally, oxalierpenes A (349) and B (350) (Figure 7) were obtained from the mantis-shrimp-derived P. oxalicum. Oxalierpene A (349) represents the first indole-diterpenoid derivative with a five-membered ring of 4-hydroxy-5,5-dimethyl-dihydrofuran-3-one as a side chain. Oxalierpene B (350) had a unique 6/5/6/5/5/6/6/5/5 ring system. Oxalierpenes A (349) and B (350) showed antiviral activity against the H1N1 virus and respiratory syncytial virus (RSV), with IC₅₀ values ranging from 2.8 to 9.4 μM [101]. 4-Hydroxyleptosphin C (351) and 13-epi-conidiogenone F (352) (Figure 7) were isolated from the marine-sediment-derived P. antarcticum KMM 4670. 4-Hydroxyleptosphin C (351) and 13-epi-conidiogenone F (352) inhibited C. albicans growth by 30.4% and 27.9% at 12.5 μM, respectively. Moreover, they significantly inhibited sortase A activity by 28.2% and 36.9% at 50 μM, respectively [102]. Shearinines R–T (353–355) and 22-hydroxyshearinine I (356) (Figure 7) were isolated from mangrove-sediment-derived Penicillium sp. UJNMF0740 [103]. Conidiogenones J (357) and K (358) (Figure 7) were isolated from the mangrove-derived P. oxalicum HLLG-13. Both of them showed significant growth inhibition activities against newly hatched Helicoverpa armigera Hubner larvae, with IC₅₀ values of 200 μg/mL [15]. Penerpenes K–N (359–362) (Figure 7) were isolated from the bivalve mollusk-derived Penicillium sp. KFD28 [104]. Epipaxilline (363) and penerpene J (364) (Figure 7) were isolated from the marine-derived Penicillium sp. KFD28. Epipaxilline (363) and penerpene J (364) showed inhibitory activities against PTP1B with IC₅₀ values of 31.5 and 9.5 μM, respectively. Penerpene J (364) also showed inhibitory activities against TCPTP with an IC₅₀ value of 14.7 μM [105].

2.3.3. Meroterpenes

Meroterpenoids are a family of hybrid natural products with high scaffold diversity and significant pharmacological activities [106]. Peniscmeroterpenoids H–N (365–371) (Figure 8) were isolated from the marine-derived P. sclerotiorum GZU-XW032. Among them, 365 featured a unique 2-oxaspiro[5.5] undeca-4,7-dien-3-one motif. Peniscmeroterpenoids 366 and 367 owned rare 6(D)/5(E) fused rings. Peniscmeroterpenoid 368 was the first case where the C-24 was oxidized. Peniscmeroterpenoid 369 exhibited a moderate inhibitory effect in NO production with an IC₅₀ value of 48.04 ± 2.51 μM [106]. Andrastin I (372) (Figure 8) was isolated from the seafloor-sand-derived P. ochrochloron [107]. Chermesins E–H (373–376) (Figure 8) were isolated from the alga-derived P. chermesinum EN-480. Chermesin 373 showed effective activities against the aquatic pathogens E. tarda and V. anguillarum with MIC values of 0.5 μg/mL, respectively. Chermesin 374 showed powerful activities against human pathogenic bacterium E. coli with an MIC value of 1 μg/mL [108]. Seven meroterpenoids, peniscmeroterpenoids A–G (377–383) (Figure 8), were isolated from the marine-derived P. sclerotiorum GZU-XW03-2. Peniscmeroterpenoid 377 possessed an unprecedented and highly oxidized 6/7/6/5/5 pentacyclic system, featuring a unique tetrahydrofuro [2,3-b]furan-2(3H)-one motif. Peniscmeroterpenoids 378–381 with 6(D)/5(E) fused rings were rare in natural products, and 381 was the first example of a berkeleyone analogue stripped of the methyl ester fragment. In bioassays, 377 and 380 inhibited the production of NO in RAW264.7 cells with IC₅₀ values of 26.60 ± 1.15 and 8.79 ± 1.22 μM. Moreover, 380 significantly suppressed the production of pro-inflammatory mediators (COX-2, IL-1β and IL-6) and the protein expression of the enzyme iNOS [109].

Meroterpenthiazole A (384) [110] and nine andrastones, namely citrehybridonol B (385), andrastin G (386), and andrastones B–H (387–393) [111] (Figure 8), were isolated from the deep-sea-derived P. allii-sativi MCCC 3A00580. Meroterpenthiazole A (384) had a rare benzothiazole moiety and significantly inhibited the transcriptional effect of retinoid X receptor (RXR)-α (KD = 12.3 μM). Citrehybridonol B (385) had a novel hemiketal moiety, and 386 was the first example to possess a novel tetrahydrofuran moiety via C-7 and C-15. Andrastones 391–393 were the first three examples of andrastones bearing a doublet methyl (C-18) at C-16; 387 potently decreased degranulation with an IC₅₀ value of 40.4 μM. Three andrastin-type meroterpenoids, hemiacetalmeroterpenoids A–C (394–396) (Figure 8), were isolated from the mangrove-soil-derived Penicillium sp. N-5. Hemiacetalmeroterpenoid A (394) possessed a unique and highly congested 6,6,6,6,5,5-hexa-cyclic skeleton and exhibited significant antimicrobial activities against P. italicum and C. gloeosporioides with an MIC value of 6.25 μg/mL [14]. The other three andrastin-type meroterpenoids, penimeroterpenoids A–C (397–399) (Figure 8), were isolated from the deep-water-sediment-derived Penicillium sp. Penimeroterpenoid A (397) showed moderate cytotoxicity against the A549, HCT116, and SW480 cell lines [112]. The unusual austins-type meroterpenoids penicianstinoids C–E (400–402) (Figure 8) were obtained from the mangrove-derived Penicillium sp. TGM112. Penicianstinoid 400 owns two unusual spirocyclic moieties, 401 contains an octahydro-2H-chromen-2-one unit, and 402 has an uncommon five-membered ether ring. Penicianstinoids 400 and 402 inhibited the growth of newly hatched H. armigera Hubner larvae with IC₅₀ values of 100 and 200 μg/mL, respectively [113].

2.4. Steroids

Rubensteroid A (403) (Figure 9) was isolated from the Magellan Seamount-derived P. rubens AS-130. Rubensteroid A (403) had a rare 6/6/6/6/5 pentacyclic system and exhibited strong antibacterial activity against E. coli and Vibrio parahaemolyticus, both with an MIC value of 0.5 μg/mL [114]. Andrastin H (404) (Figure 9) was isolated from the mangrove-derived P. oxalicum HLLG-13 and showed significant growth inhibition activity against newly hatched H. armigera Hubner larvae, with an IC₅₀ value of 50 μg/mL [15]. A unique 6/6/6/6/5 steroid, solitumergosterol A (405) (Figure 9), was isolated from the deep-sea-sediment-derived P. solitum MCCC 3A00215 [115].

2.5. Peptides

Two linear peptides, penicamides A (406) and B (407) (Figure 9), were isolated from the soft-coral-derived Penicillium sp. SCSIO 41512 [21]. Penicillizine A (408) (Figure 9) was isolated from the from the Red Sea tunicate-derived P. commune DY004 [116].

2.6. Others

Penioxa acids A (409) and B (410) (Figure 10) were isolated from the marine-sediment-derived P. oxalicum BTBU20213011 [117], and (Z)-5-acetoxy-3-methylpent-2-enoic acid (411) (Figure 10) was isolated from the mangrove-derived P. oxalicum HLLG-13 with a new natural product (2-hydroxy-5-methoxyphenyl) methyl acetate [15]. Antaketide A (412) (Figure 10) was isolated from the marine-sediment-derived P. antarcticum KMM 4670 [102]. A butyrolactone congener ochrochloronic acid (413) (Figure 10) was yielded from the seafloor-sand-derived P. ochrochloron co-cultivating with Bacillus subtilis [107]. (Z)-4-((6,7-dihydroxy-3,7-dimethyloct-2-en-1-yl)oxy)benzoic acid (414) (Figure 10) was isolated from a marine-mud-derived P. arabicum ZH3-9 [118]. Three α-pyrone derivatives, annularins L–N (415–417) (Figure 10), were isolated from the rhizospheric soil of the mangrove-derived P. herquei MA-370 [119]. Peniprenylphenol A (418) (Figure 10), a tetrasubstituted benzene derivative, was isolated from the mangrove-sediment-derived P. chrysogenum ZZ1151 and had antimicrobial activities against human pathogenic methicillin-resistant S. aureus, E. coli and C.albicans with MIC values of 6, 13, and 13 μg/mL, respectively [120]. 13-(11-Hydroxy-8-(4-hydroxy-1,6-dimethoxybenzyl)-9 -methoxy-12-methylphenyl) propan-15-one, a benzene derivate (419) (Figure 10), was isolated from the green-algae-derived P. steckii SCSIO 41040 [63]. A phloroglucinol derivative, speradine J (420) (Figure 10), was isolated from soft-coral-derived Penicillium sp. SCSIO 41038 [83]. A butenolide derivative, eutypoid F (421) (Figure 10), was isolated from the sponge-derived Penicillium sp. SCSIO 41413 and exhibited an inhibitory effect against the enzyme PI3K with an IC₅₀ value of 1.7 μM [82]. Penisterines A (422) and C–E (423–425) and penisterine A methyl ether (426) (Figure 10) were isolated from the brown-alga-derived P. sumatraense SC29. Penisterine E (425) was a unique 6/6/6-tricyclic ether with an acetal and two hemiketal functionalities. Among these, 424 inhibited human endothelial progenitor cell (EPC) growth, migration, and tube formation without any cytotoxic effect. Furthermore, in in vivo bioassays, the percentages of angiogenesis of 423 on Tg(fli1:EGFP) transgenic zebrafish were 54% and 37% as the treated concentration increased from 10.2 to 20.4 μg/mL, respectively. The percentages of angiogenesis of 424 were 52% and 41% as the treated concentration increased from 8.6 to 17.2 μg/mL, respectively [121]. Five alkane derivatives (427–431) (Figure 10) were isolated from the mangrove-sediment-derived P. ludwigii SCSIO 41408. Alkane derivatives 429 and 431 exhibited obvious inhibitory activities against LPS-induced NF-kB with IC₅₀ values of 10.7 and 21.5 μM, respectively. Moreover, in a further study of their effects on RANKL-induced osteoclastogenesis, alkane derivative 429 was found to be able to suppress the RANKL-induced osteoclast differentiation in BMMCs, with a concentration of 10 μM [80].

5,6-dihydroxy-3-methoxyhex-2-enoic acid (432) (Figure 10) was isolated from the deep-sea-sediment-derived Penicillium sp. LXY140-3 co-culturing with Penicillium sp. LXY140-R [97]. 6-acetyl-4-methoxy-3,5-dimethyl-2H-pyran-2-one (433) and (2E,4E)-5-((2S, 3S,4R,5R)-3,4-dihydroxy-2,4,5-trimethyltetrahydrofuran-2-yl)-2,4-dimethylpenta-2,4-dienal (434) (Figure 10) were identified from the mangrove-derived P. polonicum H175, and they showed no hypoglycemic effect by the Tg (Ins: htBidTE-ON; LR) zebrafish [122]. 5-glycopenostatins F (435) and I (436) (Figure 10), characterized by an unprecedented PKS scaffold bearing a glucose unit, were isolated from the sponge-derived P. Copticola. Their activities have not been identified [92]. (±)-Tetraketides 437a/b were isolated from the sponge-derived Penicillium sp. SCSIO 41302. (-)-Tetraketide 437b exhibited significant inhibitory activities against pancreatic lipase and acetyl cholinesterase with an IC₅₀ value of 48.5 μM, which indicated that different chiral centers between enantiomers (437a/b) may result in different biological activities (IC₅₀ value of 437 against PL > 100 μg/mL) [36]. 8-hydroxyhelvafuranone (438), methyl-3,7,9-trihydroxydecanate (439), and 9-hydroxy-3,7-epoxydecanoic acid (440) (Figure 10) were isolated from the marine-sediment-derived P. griseofulvum MCCC 3A00225 [42]. Phthalides chrysoalides A (441) and B (442) (Figure 10) were isolated from the red-alga-derived P. chrysogenum LD-201810 [98]. P-terphenyl derivatives peniterphenyls A–C (443–445) (Figure 10) were obtained from the deep-sea-sediment-derived Penicillium sp. SCSIO 41030. Peniterphenyl 444 represents the first reported natural product possessing a 4,5-diphenyl-substituted 2-pyrone derivative. Peniterphenyls 443 and 444 significantly increased the viability of Vero cells infected with HSV-1/2 with the EC₅₀ values of the p-terphenyls ranging from 1.4 ± 0.6 to 9.3 ± 3.7 μM, with 50% cytotoxicity concentration values greater than 100 μM against Vero cells [123].

The names and numbers of all new compounds according to their classes, the sources from which marine-derived Penicillium were isolated, the biological activities of new compounds, and corresponding references are listed in

Table 1. New compounds from marine-derived Penicillium fungi.

No.	Compounds	Fungal Species/Strain No.	Source of Fungi	Bioactivities	Ref.
Azaphilones
1	Penicilazaphilone Ia	P. sclerotiorum E23Y-1A	Sponge	Cytotoxic activity Anti-inflammatory	[17]
2	Penicilazaphilone J
3	epi-geumsanol D
4–5	Penidioxolanes C–D
6–9	Penicilazaphilone K–N
10–11	Penicilazaphilones F–G	P. sclerotiorum E23Y-1A	Sponge	Anti-inflammatory	[22]
12	5-bromoisorotiorin	P. sclerotiorum E23Y-1A	Sponge	Antibacterial activity Enzyme inhibitory	[18]
13	Penicilazaphilone Ha
14	Penicilazaphilone Hb	P. sclerotiorum	Algae	Anti-angiogenesis	[20]
13	Penicilazaphilone Ib
16	11-epi-geumsanol F
17	11-epi-geumsanol B
18	8a-epi-hypocrellone A	P. sclerotiorum	Sediment	Cytotoxic activity Anti-inflammatory	[23]
19	8a-epi-eupenicilazaphilone C
20a/b	Isochromophilone H (a/b) (isomers)	P. sclerotiorum HY5	Mangrove	Phytotoxicity	[24]
21	Sclerotiorin A
22	Sclerotiorin B
23	Ochlephilone
24	Isochromophilone IV
25a/b	Isochromophilone J (a/b) (isomers)
26–29	Chermesinones D–G	P. chermesinum FS625	Seawater	Anti-inflammatory	[25]
30–31	Daldinins G–H	P. glabrum glmu 003	Soft coral	Antibacterial activity Enzyme inhibitory	[26]
Isocoumarins
32–33	Peniciisocoumarins I–J	Penicillium sp. GXIMD 03001	Mangrove	Cytotoxic activity	[27]
34–35	Penicillols A–B	Penicillium sp. BJR-P2	Mangrove	Anti-inflammatory	[28]
Chromones
36–38	Epiremisporines C–E	P. citrinum BCRC 09F458	Waste water	Cytotoxic activity Anti-inflammatory	[29]
39–41	Epiremisporines F–H	P. citrinum BCRC 09F458	Waste water	Cytotoxic activity Anti-inflammatory	[30]
42–49	Penithochromones M–T	P. thomii Maire YPGA3	Sediment	Enzyme inhibitory Antioxidant activity	[31]
50–52	Penithochromones U–W	P. thomii YPGA3	Sediment	Enzyme inhibitory	[32]
Citrinins
53	(5R)-and (5S)-isoquinocitrinin B	Penicillium sp. TW131-64	Sediment	Antibacterial activity	[33]
54	(5R)-and (5S)-isoquinocitrinin C
55	(5R)-and (5S)-isoquinocitrinin D
56	(3R,4S)-8-hydroxy-6-methoxy-3,4,5-trimethylisochromane-7-carboxylatemethyl
57	(3R,4S)-6-hydroxy-8-methoxy-3,4,5-trimethylisochromane-7-carboxylatemethyl
58	Penicitrinone J
59–62	Dicitrinone G–J	Penicillium sp. GGF16-1-2	Starfish	Antifungal and cytotoxic activities	[10]
63–65	Neotricitrinols A–C	P. citrinum W23	Sediment	Anti-osteoporosis activity	[34]
66–67	Xerucitrinins B–C	P. citrinum Y34	Sediment	Enzyme inhibitory	[35]
68	Penicitrinol P	Penicillium sp. SCSIO 41302	Sponge	Antibacterial activity Enzyme inhibitory	[36]
69	Dicitrinol D	Penicillium sp. SCSIO 41303	Sponge	Antibacterial, cytotoxic, antiviral activities, and enzyme inhibitory	[37]
β-resorcylic acids
70	14-hydroxyasperentin B	P. antarcticum KMM 4685	Brown alga	Cytotoxic activity	[38]
71–73	β-resoantarctines A–C
74	8-dehydro-β-resoantarctine A
Verrucosidins
75–76	9-O-ethylpenicyrones A–B	P. cyclopium SD-413	Sediment	Antibacterial activity	[40]
77–82	Poloncosidins A–F	P. polonicum CS-252	Sediment	Antibacterial activity	[39]
83–87	Poloncosidins G–K	P. polonicum CS-252	Sediment	Antibacterial activity	[41]
88–89	Verrucosidinol A–B	P. griseofulvum MCCC 3A00225	Sediment	Anti-food allergy	[42]
Citreoviridins
90–91	Citreoviridins H–I	Penicillium sp. BJR-P2	Mangrove	Anti-inflammatory	[27]
92–97	Citreoviridins J–O	P. citreonigrum MCCC 3A00169	Sediment	Cytotoxic activity Anti-inflammatory	[43]
Nitrogen-containing polyketides
98–99	Oxopyrrolidines A–B	P. oxalicumMEFC104	Sediment	Antibacterial activity	[44]
100	7-hydroxy-3,10-dehydrocyclopeptine	P. polonicum MCCC3A00951	Sediment	Antiviral activity	[45]
101–105	Steckfusarins A–E	P. steckii SCSIO41040	Green algae	Antibacterial, antifungal, cytotoxic and antiviral activities Enzyme inhibitory Antioxidant Anti-inflammatory	[46]
Sorbicillinoids
106–108	Bisorbicillchaetones A–C	Penicillium sp. SCSIO06868	Sediment	Anti-inflammatory	[47]
109	10-Methylsorbiterrin A	Penicillium sp. SCSIO06871	Sediment	Antibacterial and antifungal activities Enzyme inhibitory	[48]
110	Epitetrahydrotrichodimer ether
111	Demethyldihydrotrichodimerol
112	Bisorbicillpyrone A
113	Dihydrotrichodermolidic acid
114	5-hydroxy-dihydrodemethy lsorbicillin
115	Sorbicillpyrone A
116	5,6-dihydrovertinolide
117–118	Sorbicatechols C–D	P. allii-sativi MCCC3A00580	Seawater	Cytotoxic activity	[49]
119	(4E)-1-(4,6-Dihydroxy-5-methylpyridin-3-yl)hex-4-en-1-one	Penicillium sp. DM815	Mangrove	Anti-inflammatory	[50]
Isochromans
120–125	Penicisteckins A–F	P. steckii HNNU-5B18	Beach mud	Antibacterial activity Cytotoxic activity	[51]
α-pyrone polyketides
126–130	Penipyrols C-G	Penicillium sp. HDN-11-131	Mangrove	Cytotoxic activity	[52]
131	Methyl-penipyrol A
Hirsutellones
132	Perpyrrospirone A	P. citrinum	Seawater	Cytotoxic activity	[53]
Xanthones and benzophenones
133 134	11-O-acetylaspergillusone B	Penicillium sp. MCCC 3A00126	Sediment	Cytotoxic activity Ferroptosis inhibitory	[54]
	7-dehydroxyhuperxanthone A
135	Penicixanthene E	Penicillium sp. GXIMD 03101	Mangrove	Cytotoxic activity	[55]
136	Penibenzophenone C	Penicillium sp.	Mangrove	Antibacterial and insecticidal activities	[16]
Hydroxybenzenes
137	Peniketide A	Penicillium sp. SCZ-1	Sediment	Enzyme inhibition	[56]
138	Methyl ester of penipyrol A
139–141	Penidihydrocitrinins A–C	P. citrinum W17	Sediment	Anti-inflammatory Anti-osteoporosis	[57]
142	Peniciphenalenin G	P. oxalicum	Seawater	Cytotoxic activity	[58]
143	Penicinone C	Penicillium sp. LA032	Mangrove	----	[59]
144	5-((R,1Z,3E)-6-hydroxy-1,3-heptadien-1-yl)-1,3-benzenediol	Penicillium sp. TW58-16	Sediment	Anti-inflammatory Enzyme inhibition	[60]
145	4-carboxy-5-((R,1Z,3E)-6-hydroxy-1,3-heptadien-1-yl)-1,3-benzenediol
146	4-carboxy-5-((1Z,3E)-1,3-heptadien-1-yl)-1,3-benzenediol
147	5-((1Z,3E)-4-carboxy-1,3-butadienyl-1-yl)-1,3-benzenediol
148	(2E)-3-[(3R)-3,4-dihydro-6,8-dihydroxy-1-oxo-1H-2-benzopyran-3-yl]-2-propenoic acid
149	3-[(3S)-3,4-dihydro-6,8-dihydroxy-1-oxo-1H-2-benzopyran-3-yl]-propanoic acid
150	Coniochaetone N	Penicillium sp. SCSIO06868	Sediment	Antibacterial activity	[61]
Lactones
151–152	Penicinones A–B	Penicillium sp. LA032	Mangrove	Cytotoxic activity	[59]
153	Walterolactone E	Penicillium sp. TW58-16	Sediment	Antibacterial activity	[62]
Olefinic acids and their derivatives
154–157	Steckwaic acid A-D	P. steckii AS-324	Coral	Antibacterial and antifungal activities	[64]
158	11-ketotanzawaic acid D
159	6,15-dihydroxytanzawaic acid M
160	15R-methoxytanzawaic acid M
161	15S-methoxytanzawaic acid M
162	8-hydroxytanzawaic acid M
163	8-hydroxytanzawaic acid B
164–168	Steckwaic acid Ea–Ia	P. steckii AS-324	Coral	Antibacterial activity	[19]
169	18-O-acetyltanzawaic acid R
170	10-hydroxytanzawaic acid U
171	13R-tanzawaic acid S
172–176	Steckwaic acid Eb–Ib	P. steckii SCSIO 41040	Green algae	Antibacterial, antifungal, cytotoxic, and antiviral activities	[63]
177–178	Steckwaic acid J–K
179–182	Penicisteck acid A–D	P. steckii SCSIO 41025	Mangrove	Antibacterial activity Enzyme inhibition	[65]
183–186	Penifellutins A–D	P. crustosum PRB-2 and P. fellutanum HDN14-323	Seawater	Cytotoxic activity	[66]
Other polyketides
187	Rubenpolyketone A	P. rubens AS-130	Coral	Antibacterial activity	[67]
188	Oxalichroman A	P. oxalicum 2021CDF-3	Red algae	Cytotoxic activity	[68]
189	Oxalihexane A
190	Leptosphaerone D	Penicillium sp. TW58-16	Sediment	Antibacterial activity	[62]
191	15-O-methyl ML-236A	P. solitum MCCC 3A00215	Sediment	Cytotoxic activity Anti-food allergy	[69]
Indole alkaloids
192–195	Communesins M–P	P. expansum MMS42	Sediment	Cytotoxic and neuroprotective activities	[9]
196	Deoxy-14,15-dehydroisoaustamide	P. dimorphosporum KMM 4689	Soft coral	Cytotoxic activity	[70]
197	16α-hydroxy-17β-methoxy-deoxydihydroisoaustamide	P. dimorphosporum KMM 4689	Soft coral	Cytotoxic and neuroprotective activities	[71]
198	16β-hydroxy-17α-methoxy-deoxydihydroisoaustamide
199	16β,17α-dihydroxy-deoxydihydroisoaustamide
200	16α-hydroxy-17α-methoxy-deoxydihydroisoaustamide
201	16α,17α-dihydroxy-deoxydihydroisoaustamide
202	16,17-dihydroxydeoxydihydroisoaustamide
203	3β-hydroxy-deoxyisoaustamide
204	Penilline D	Penicillium sp. SCSIO 05705	Soil	Antibacterial and cytotoxic activities Enzyme inhibition	[72]
205	Penindolacid A	Penicillium sp. LW92	Sediment	Antioxidant activity Enzyme inhibitory	[73]
206–207	Penicamides A–B	Penicillium sp. LA032	Soil	Cytotoxic activity	[59]
208	11S-(−)-penilloid A	Penicillium sp. ZZ1750	Marine mud	Cytotoxic activity	[74]
209	11R,14E-(+)-penilloid A
Pyridones
210–220	Penicipyridones A–K	P. oxalicum QDU1	Leaves of plant	Anti-inflammatory	[75]
Quinolinones
221	Penicinolone	Penicillium sp. SCSIO 41033	Sponge	Antibacterial and antifungal activities Enzyme inhibitory	[76]
222	Quinolactone A	P. citrinum YX-002	Mangrove	Enzyme inhibitory	[77]
223	Quinolactacin C1
224	3-epi-quinolactacin C1
225a/b	Quinolactacin E (a racemic mixture)	Penicillium sp. SCSIO 41303	Sponge	Cytotoxic and antiviral activities Enzyme inhibitory	[37]
226	Quinolactacin F1
227	Quinolactacin F2
228a/b	Quinolactacin G (enantiomers)
229–232	(±)-oxypenicinolines A–D	P. steckii SCSIO 41025	Mangrove	Antibacterial, antifungal, and cytotoxic activities Enzyme inhibitory	[78]
	(racemic mixtures, respectively)
233–234	Penicinoline F–G
Decahydrofluorene-class alkaloids
235–241	Pyrrospirone K–Q	Penicillium sp. SCSIO 41512	Soft coral	Antibacterial and cytotoxic activities Enzyme inhibitory	[79]
Piperazines
242	Adametizine C	P. ludwigii SCSIO 41408	Sediment	Antibacterial, antifungal, and cytotoxic activities Anti-osteoporosis	[80]
243	(8S,9R,12R,18S)-12-hydroxy-fumitremorgin B	Penicillium sp. TW58-16	Sediment	Antibacterial activity	[62]
244–246	Penigainamides A–C	P. steckii YE	Seawater	Cytotoxic activity	[81]
Tetramic-acid-based alkaloids
247–249	Tolypocladenols D–F	P. oxalicum QDU1	Leaves of plant	Antifungal and cytotoxic activities Anti-inflammatory	[75]
250–251	Penicillenols G1–G2	Penicillium sp. SCSIO06868	Sediment	Antibacterial and antiviral activities	[61]
252	Penicillenol H
Amines and amides
253	(Z)-4-(5-acetoxy-N-hydroxy-3-methylpent-2-enamido) butanoate	P. oxalicum HLLG-13	Mangrove	Antibacterial and insecticidal activities	[15]
254–255	Polonimides D–E	Penicillium sp. SCSIO 41413	Sponge	Antibacterial and cytotoxic activities Anti-inflammatory	[82]
256	Speradine I	Penicillium sp. SCSIO 41038	Soft coral	Cytotoxic activity Enzyme inhibitory	[83]
257	(S)-2-acetamido-4-(2-(methylamino)phenyl)-4-oxobutanoic acid	P. citrinum XIA-16	Shrimp	Ferroptosis inhibitory	[84]
258	Citrinadin C	P. citrinum	Sediment	Antibacterial and cytotoxic activities	[85]
259	(2S,2′R,3R,3′E,4E,8E)-N-2′-hydroxyhexadecanoyl-2-amino-9-methyl-4,8-octadecadiene-1,3-diol	P. chrysogenum Y20-2	Seawater	Anti-angiogenesis	[86]
260–261	Penichryfurans A–B	P. chrysogenum	Red alga	Cytotoxic activity	[87]
262–280	Talaroenamines F1−F19	P. malacosphaerulum HPU-J01	Wetland	Cytotoxic activity	[88].
281	Peniokaramine	Penicillium sp. LSH-3-1	Sediment	Cytotoxic activity Anti-inflammatory	[89]
282	Penipyranopyridine
283–284	Penicidihydropyridones A–B	Penicillium sp. B9	Sponge	Cytotoxic activity	[90]
285	(+)-solitumidine D	P. solitum MCCC 3A00215	Sediment	Cytotoxic activity Anti-food allergy	[69]
286	(±)-solitumidine E (a racemic mixture)
287	Penicmariae-crucis C acid	P. steckii SCSIO 41025	Mangrove	Antibacterial and antifungal activities Enzyme inhibitory	[65]
288	N-(6-hydroxy-2-oxoindolin-3-ylidene)-5′-methoxy-5′-oxobutyl-amine oxide
289	Methyl-1′-(N-hydroxyacetamido)-butanoate
290	Penigrisamide	P. griseofulvum MCCC 3A00225	Sediment	Anti-food allergy	[42]
291	Aurantiomoate C
292	N,N-pyroglutamylleucinmethylester
293	Methyl 2S-hydroxy-3-methylbutanoyl-L-leucinate
294	6R,7-dihydroxy-3,7-dimethyloctanamide
Other alkaloids
295	Sulfoxanthocillin	Penicillium sp. SCSIO sof101	Seawater	Antibacterial activity Anti-inflammatory	[91]
296	Penipyridinone B	Penicillium sp. ZZ1750	Sea mud	Cytotoxic activity	[74]
Sesquiterpenes
297	Chermesiterpenoid D	P. rubens AS-130	Coral	Antibacterial activity	[67]
298–307	Copteremophilanes A–J	P. Copticola	Sponge	Cytotoxic activity Neuroprotection	[92]
308	Astellolide Q	Penicillium sp. N-5	Soil	Antibacterial and antifungal activities	[14]
309	Chrysoride A	P. chrysogenum LD-201810	Red alga	Cytotoxic activity	[93]
310	Purpuride D	Penicillium sp. ZZ1283	Sea mud	Antibacterial activity	[94]
311–328	Bilaiaeacorenols A–R	P. bilaiae F-28	Sediment	Anti-inflammatory	[95]
329–331	Citreobenzofurans D–F	Penicillium sp. HDN13-494	Soil	Antibacterial and cytotoxic activities	[96]
332–333	Phomenones A–B
334	(2S,3S,5S,6S,7S,8R,11S,12R)-15-deacetyl-7,8-dihydroxycalonectrin	Penicillium sp. LXY140-R and Penicillium sp. LXY140-3	Sediment	Cytotoxic activity	[97]
335	1-Methyl-4-[3,4,5-trihydroxy-1,2,2-trimethylcyclopently]benzene
336a/b	(±)Methylsulfinyl-1-hydroxyboivinianin A (enantiomers)	P. chrysogenum LD-201810	Red alga	Antifungal and cytotoxic activities	[98]
337	(4S,5R,9S,10R)-11,13-dihydroxy-drim-7-en-6-one	Penicillium sp. TW58-16	Sediment	Anti-inflammatory Enzyme inhibition	[60]
338	(4S,5R,9S,10R)-11-hydroxy-13-carboxy-drim-7-en-6-one
Diterpenes
339	Penijanthine E	P. citrinum ZSS-9	Sediment	Antiviral activity	[99]
340–348	Janthinellumines A–I	P. janthinellum	Seawater	Antibacterial and antiviral activity Enzyme inhibition	[100]
349–350	Oxalierpenes A–B	P. oxalicum	Shrimp	Antiviral activity	[101]
351	4-hydroxyleptosphin C	P. antarcticum KMM 4670	Sediment	Antibacterial activity Enzyme inhibition	[102]
352	13-epi-Conidiogenone F
353–355	Shearinines R–T	Penicillium sp. UJNMF0740	Sediment	Antibacterial activity Neuroprotection	[103]
356	22-hydroxyshearinine I
357–358	Conidiogenones J–K	P. oxalicum HLLG-13	Mangrove	Antibacterial and insecticidal activities	[15]
359–362	Penerpenes K–N	Penicillium sp. KFD28	Mollusk	Antibacterial and cytotoxic activities	[104]
363	Epipaxilline	Penicillium sp. KFD28	Mollusk	Enzyme inhibition	[105]
364	Penerpene J
Meroterpenes
365–371	Peniscmeroterpenoids H–N	P. sclerotiorum GZU-XW03-2	Mollusk	Anti-inflammatory	[106]
372	Andrastin I	P. ochrochloron	Seawater	Antibacterial activity	[107]
373–376	Chermesin E–H	P. chermesinum EN-480	Red alga	Antibacterial activity	[108]
377–383	Peniscmeroterpenoid A–G	P. sclerotiorum GZU-XW03-2	Mollusk	Anti-inflammatory	[109]
384	Meroterpenthiazole A	P. allii-sativi MCCC 3A00580	Seawater	Cytotoxic activity	[110]
385	Citrehybridonol B	P. allii-sativi MCCC 3A00580	Seawater	Anti-allergic bioactivity	[111]
386	Andrastin G
387–393	Andrastones B–H
394–396	Hemiacetalmeroterpenoids A–C	Penicillium sp. N-5	Soil	Antifungal activity	[14]
397–399	Penimeroterpenoids A–C	Penicillium sp.	Sediment	Cytotoxic activity	[112]
400–402	Penicianstinoids C–E	Penicillium sp. TGM112	Mangrove	Antifungal and insecticidal activities	[113]
Steroids
403	Rubensteroid A	P. rubens AS-130	Coral	Antibacterial activity	[114]
404	Andrastin H	P. oxalicum HLLG-13	Mangrove	Insecticidal activity	[15]
405	Solitumergosterol A	P. solitum MCCC 3A00215	Sediment	Cytotoxic activity	[115]
Peptides
406–407	Penicamides A–B	Penicillium sp. SCSIO 41512	Soft coral	Antifungal activity	[21]
408	Penicillizine A	P. commune DY004	Tunicate	Cytotoxic activity	[116]
Others
409–410	Penioxa acids A–B	P. oxalicum BTBU20213011	Sediment	Antibacterial and antifungal activities	[117]
411	(Z)-5-acetoxy-3-methylpent-2-enoic acid	P. oxalicum HLLG-13	Mangrove	Antibacterial and insecticidal activities	[15]
412	Antaketide A	P. antarcticum KMM 4670	Sediment	Antibacterial activity	[102]
413	Ochrochloronic acid	P. ochrochloron	Sea sand	Antibacterial and cytotoxic activities	[107]
414	(Z)-4-((6,7-dihydroxy-3,7-dimethyloct-2-en-1-yl)oxy)benzoic acid	P. arabicum ZH3-9	Sea mud	Antibacterial and antifungal activities	[118]
415–417	Annularin L–N	P. herquei MA-370	Soil	Antibacterial activity	[119]
418	Peniprenylphenol A	P. chrysogenum ZZ1151	Sediment	Antibacterial activity	[120]
419	13-(11-hydroxy-8-(4-hydroxy-1,6-dimethoxybenzyl)-9-methoxy-12-methylphenyl) propan-15-one	P. steckii SCSIO 41040	Green algae	Antibacterial, antifungal, cytotoxic and antiviral activities Anti-inflammatory	[63]
420	Speradine J	Penicillium sp. SCSIO 41038	Soft coral	Cytotoxic activity Enzyme inhibitory	[83]
421	Eutypoid F	Penicillium sp. SCSIO 41413	Sponge	Antibacterial activity	[82]
422	Penisterines A	P. sumatraense SC29	Alga	Anti-angiogenesis	[121]
423–425	Penisterines C–E
426	Penisterine A methyl ether
427	2-methyl-3-(5-oxohexyl) maleic acid	P. ludwigii SCSIO 41408	Sediment	Antibacterial, antifungal, and cytotoxic activities Anti-osteoporosis	[80]
428	2-(4-hydroxyhexyl)-3-methylmaleic acid
429	3-(ethoxycarbonyl)-2-methylenenonanoic acid
430	7-hydroxy-3-(methoxycarbonyl)-2-methylenenonanoic acid
431	2-(4-hydroxypentyl)-4-methyl-5-oxo-2,5-dihydrofuran-3-carboxylic acid
432	5,6-Dihydroxy-3-methoxyhex-2-enoic acid	Penicillium sp. LXY140-R and Penicillium sp. LXY140-3	Sediment	Cytotoxic activity	[97]
433	6-acetyl-4-methoxy-3,5-dimethyl-2H-pyran-2-one	P. polonicum H175	Sediment	Hypoglycemic effect	[122]
434	(2E,4E)-5-((2S,3S,4R,5R)-3,4-dihydroxy-2,4,5-trimethyltetrahydrofuran-2-yl)-2,4-dimethylpenta-2,4-dienal
435	5-glycopenostatin F	P. Copticola	Sponge	___	[92]
436	5-glucopenostatin I
437a/b	(±)-Tetraketide	Penicillium sp. SCSIO 41302	Sponge	Antibacterial and cytotoxic activities Enzyme inhibitory	[36]
438	8-hydroxyhelvafuranone	P. griseofulvum MCCC 3A00225	Sediment	Anti-food allergy	[42]
439	Methyl-3,7,9-trihydroxydecanate
440	9-hydroxy-3,7-epoxydecanoic acid
441–442	Chrysoalides A–B	P. chrysogenum LD-201810	Red alga	Antifungal and cytotoxic activities	[98]
443–445	Peniterphenyls A–C	Penicillium sp. SCSIO41030	Sediment	Antiviral activity Enzyme inhibitory	[123]

.

3. Statistical Analysis of New Natural Products from Marine-Derived Penicillium

Penicillium fungi can establish a good relationship with different marine organisms and marine environments. According to the statistical results, sediments and mangroves were the main sources or hosts of marine-derived Penicillium fungi for producing new natural products, nearly 56% (Figure 11).

The new natural products had diverse chemical structures including polyketides, alkaloids, terpenoids, steroids, peptides, and others. Figure 12 shows the proportion of new bioactive compounds in each chemical class. A total of 194, 107 and 107 new compounds belong to polyketides, alkaloids and terpenoids, respectively, adding up to more than 90% of the total. Similarly, these three classes contribute 94% of all new bioactive compounds. The highest proportion of bioactives belongs to the largest number of polyketides (86) with 44.3%, followed by terpenoids (41) with 39.3% and alkaloids (42) with 38.3%.

The new compounds were counted only once when they were analyzed for bioactivity or inactivity. If the article did not provide a description of strong, moderate or weak activity of bioactive compounds, we gave this description according to bioactivity potency criteria used in the review [124]. The multi-active compounds were counted multiple times when they were classified according to anti-cancer/cytotoxicity, anti-inflammatory, antibacterial, antifungal, antiviral, enzyme inhibitory, antioxidant, and anti-allergy activities, as well as others [125].

Figure 13 shows the percentage distribution of new compounds with different bioactivities for 2021–2023. Among them, 24.3% of the new bioactive compounds showed antibacterial activity with the number of 44. This was followed by cytotoxic activity at 38 (21%), enzyme inhibition activity at 30 (16.6%), and anti-inflammatory activity at 27 (14.9%).

Figure 14A shows the proportion distribution of new compounds with different bioactivities in each chemical class for 2021–2023; peptides are not listed due to the absence of activity results. Polyketides displayed antibacterial activity as the dominant activity with a proportion of 29%, highlighting that they encompass many potential antibacterial drug leads. For alkaloids, cytotoxic compounds accounted for 31.7% of the total active compounds, while terpenoids displayed relatively high enzyme inhibitory with a proportion of 21.4%. Figure 14B shows the proportion distribution of new compounds with different chemical classes in each bioactivity for 2021–2023. The major contributors to antibacterial activity are polyketides. The most promising anti-cancer/cytotoxicity agents from marine-derived Penicillium fungi appear to be alkaloids. The main anti-inflammatory and enzyme inhibitory metabolites are still polyketides.

It should be noted that not all new metabolites isolated from the marine-derived Penicillium fungi were tested for biological activity because of scarcity of quantity [37,52,59,79,92], while many bioactive compounds were only studied for one type of bioassay. In addition, most of the biological activities of the experimental subjects are performed in vitro. Correspondingly, bioactive assays in vivo are only applied in a few studies, for example, zebrafish models used for investigations into anti-cancer/cytotoxicity [66], anti-angiogenesis [86,121], and hypoglycemia [122]. Furthermore, the difficulty of the biological screening model was another factor affecting the screening result. In fact, viruses were not considered as screening targets in general laboratory due to inherent complexity of cell-based assays of viruses [125], while mice models were expensive and time consuming. Therefore, more new natural products from the marine-derived Penicillium fungi should be screened on a wider variety of bioassays, as effective enrichment of trace compounds and enhanced methods in bioactivity screening technologies are important.

4. Conclusions

This article provided a comprehensive overview of the source, chemistry, and bioactivities of 452 secondary metabolites from marine-derived Penicillium fungi described from 2021 to 2023. Although the coronavirus disease 2019 (COVID-19) pandemic limited opportunities for field collections in domestic and international travel, the numbers of new compounds from marine-derived Penicillium fungi increased abundantly, compared to 578 new compounds reported from 1991 to 2020 [6,7]. This trend might be associated with fungal large-scale cultures under laboratory conditions and the significant impact of penicillin, the first broad-spectrum antibiotic in drug development [126]. In addition, fungal culture methods, extraction and separation techniques, structure identification technology, and biological screening methods have reached a relatively mature level [125].

New methods and in-depth research on important compounds have been carried out. Affected by the COVID-19 pandemic, both pathways of TNF-α-induced NFκB activation and TGF-β-induced Smad activation were applied to evaluate azaphilone compounds for the first time [23]. The HPLC-MS/MS analyses [9], one-pot/two-stage precursor-directed biosynthesis approach [88], and molecular networks of MS/MS data generated with Global Natural Products Social Molecular Networking (GNPS) [13] have expanded the scope of research on metabolites, especially trace components of marine-derived Penicillium fungi. Co-culture [66,97,100,107] and OSMAC [17,18,20,111] have been used to explore the structural diversity of secondary metabolites from the fungi. Further research on the known compounds, whether penicopeptide A as a candidate compound for osteoporosis prevention [12] or the anti-pancreatic cancer activity of dicitrinone G evaluated using a mouse model [11], provides an opportunity to diversify the targets, increasing the value of natural products from marine-derived Penicillium fungi.

In summary, marine-derived Penicillium fungi resources are found worldwide and have attracted great attention due to their diverse chemical structures. Penicillium fungi have produced a large number of structurally novel and bioactively potent compounds, such as polyketides, alkaloids and terpenoids. Over a thousand secondary metabolites from marine-derived Penicillium fungi have already been reported in the past thirty-three years (1991–2023). Although none of them have reached the market yet, which could partly be related to non-comprehensive screening approaches and a lack of sustained lead optimization, the mass production of trace amounts of compounds by symbiotic Penicillium fungi and the symbiotic relationship with the marine host make marine-derived Penicillium fungi a very important source of bioactive compounds for drug discovery.