Introduction

The genus Penicillium includes four subgenera: Penicillium, Furcatum, Biverticillium, and Aspergilloides. Penicillium is the subgenus that has been examined the most from the genus of Penicillium fungi (Kumar et al. 2018).

It is an anamorphic ascomycete with over 354 species (Nielsen et al. 2017) and is also known for its diverse spectrum of bioactive secondary metabolites with potential pharmacological actions, including antifungal, antibacterial, immunosuppressant and cholesterol-lowering agents (Rabha and Jha 2018). Studies on Penicillium have shown that the species taxonomical classification idea, based not only on DNA sequences, but also on ecological, morphological, and exo-metabolome profiles, provides a more accurate and true classification (Barreto et al. 2011).

Marine-derived fungi from the Penicillium genus have gained attention as a beneficial source of new characteristic natural products with potential applications in industry, agriculture, and medicine (Kodoli et al. 2021). Marine Penicillium fungi have been found in sediments, mangroves, sponges, and algae, and have been shown to have high novelty for more than 390 new metabolites in the last decade, including alkaloids, polyketides, terpenes, and macrolides (Yang et al. 2021) that possess important biological activities such as anticancer, antimicrobial, anti-inflammatory and larvicidal actions with prospective applications in new drug development (Elkhawas et al. 2020; Singab et al. 2022). The Penicillium chrysogenum species, which belongs to the Penicillium subgenus, is particularly interesting due to its ability to produce penicillin and small antifungal proteins, making it beneficial for controlling fungal infections formed by other filamentous fungi (Martín 2020). This review concentrates on P. chrysogenum bioactive metabolites and their biological properties through the years 2013–2023. Various online databases were utilized, such as Web of Science, Marinlit, and Scifinder. The purpose of this review is to highlight all the progress made during the previous decade concerning the potential application of the isolated biomolecules (277 compounds and miscellaneous as shown in Table 1) from different strains of P. chrysogenum. This review deals with the chemical nature along with the reported pharmacological activities of the stated secondary metabolites, in addition to several miscellaneous compounds (Figs. 1, 2 and 3).

Fig. 1
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Percentage of classes of secondary metabolites identified in P. chrysogenum

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Fig. 2
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A map displaying the source of P. chrysogenum reviewed

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Fig. 3
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Structures of identified metabolites in P. chrysogenum

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K-Miscellaneous

The antimicrobial proteins (AMPs) named PAF and PAFB were secreted from the filamentous fungus P. chrysogenum Q176 (Huber et al. 2020).

The P. chrysogenum Q176 antifungal protein C (PAFC) was also characterized, and was different phylogenetically from the two Penicillium AMPs, PAF and PAFB (Holzknecht et al. 2020).

A new ascomycete fungus X5 was identified as P. chrysogenum which had hyperproducer activity of a serine alkaline protease (SAPTEX) (9000 U/mL) (Benmrad et al. 2018).

An acetyl xylan esterase (PcAxe) was cloned from P. chrysogenum P33 and expressed in Pichia pastoris GS115. rPcAxe comprises a domain of carbohydrate esterase and 62 domains of a glycosyl hydrolase family (Yang et al. 2017).

Two RG I-degrading enzymes, termed endo-RG and exo-RG lyases were reported to be secreted by P. chrysogenum 31B. The enzyme precisely acts on rhamnose (Rha) at the non-reducing end of RG oligosaccharides, but had not shown any action on flavonoid glycosides (Matsumoto et al. 2017).

P. chrysogenum could produce β-glucanase enzyme (El-Shora et al. 2019).

The filamentous ascomycete P. chrysogenum culture supernatant abundantly secreted the cysteine-rich, cationic, antifungal protein PAF (Sonderegger et al. 2017).

Chitosan (277) was extracted from broth culture of P. chrysogenum (Alagesan et al. 2016).

Only asexual reproduction is known to be used by P. chrysogenum. But further proof points to the possibility of sexual reproduction with an unidentified sexual stage. P. chrysogenum has recently been found to contain the mating-type (MAT) and pheromone signaling genes, which are associated with mating in other sexual fungus. In heterothallic ascomycete fungi, complementing MAT1-1 and MAT1-2 isolates are required for sex to occur. In contrast to the original Fleming strain, which has the opposite MAT1-2 locus, NRRL1951 (P. chrysogenum derivatives) has a MAT1-1 locus with a MAT1-1–1 gene encoding a putative alpha-box transcription factor. Sexual crosses can be used to develop new strains with improved industrial characteristics (Böhm et al. 2013).

Table 1 Classes of secondary metabolites identified in different strains of P. chrysogenum
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Pharmacological activities

Anti-fungal

According to Al-Saleem et al. (2022), P. chrysogenum extract exhibited significant antifungal activity towards Candida albicans and Cryptococcus neoformans with MIC 93.75 ± 0.55 and 19.53 ± 0.48 µg/mL, respectively. Moreover, kojic acid (156) revealed the same potency towards Fusarium oxysporum and Cryptococcus neoformans with MIC 39.06 ± 0.85 and 39.06 ± 0.98 µg/mL, respectively.

Holzknecht et al. (2020) reported that the antifungal protein C (PAFC) produced by P. chrysogenum Q176 was produced together with PAF and PAFB into the culture broth. Recombinant PAFC's functional characterization revealed a promising novel molecule for anti-Candida therapy. In pre-established biofilms of two strains of C. albicans, the planktonic cells were killed by the thermotolerant PAFC while the sessile cells’ metabolic activity decreased. One of the strains was a fluconazole-resistant that displayed greater PAFC sensitivity than the fluconazole-sensitive one. The absence of hemolytic activity supports the further use of PAFC in clinical therapy.

Huber et al. (2020) found that PAF and PAFB, the antimicrobial proteins (AMPs) secreted by the filamentous fungus P. chrysogenum Q176, are highly stable due to a compact disulfide-bond, β-fold structure. In micromolar doses, these two AMPs effectively prevented the growth of several fungi including: Aspergillus fumigatus, Trichophyton spp., Aspergillus niger, and Candida spp., along with the Neurospora crassa and Saccharomyces cerevisiae., which were vulnerable to both proteins since their growth diminished at 0.25–4 μM PAF or PAFB doses, respectively.

Xu et al. (2020) reported that penicierythritol A (221) isolated from endophytic P. chrysogenum XNM-12, the marine algal-derived fungus, had a moderate antifungal potential towards the plant pathogenic fungus Alternaria alternata with MIC 8 μg/mL.

As elaborated by Sonderegger et al. (2017), PAF, a cysteine-rich, cationic antifungal protein that is mostly made up of 55 amino acids, was abundantly generated by the filamentous ascomycete P. chrysogenum. Botrytis cinerea and Aspergillus fumigatus, two opportunistic human and plant diseases, were discovered to be particularly inhibited, even though in vitro and in vivo tests had shown that they were inert against mammalian cells.

Zhu et al. (2017) have identified penochalasin K (85) from the mangrove endophytic fungus P. chrysogenum V11 culture. In fact, it exhibited serious inhibitory actions towards Colletotrichum gloeosporioides and Rhizoctonia solani (MICs Values = 6.13, 12.26 μM, respectively), which were notably higher than carbendazim.

Previous study by Huang et al. (2016) showed that chaetoglobosin A (84), chaetoglobosin C (81), chaetoglobosin E (87) and armochaetoglobosin I (89) were isolated from the culture of P. chrysogenum V11. They remarkably inhibited the plant pathogenic Rhizoctonia solani fungus ((MICs) = 11.79–23.66 μM), while chaetoglobosin A (84), chaetoglobosin E (87) and penochalasin J (88), significantly inhibited Colletotrichum gloeosporioides (MICs Values = 23.58–47.35 μM), revealing a higher activity than carbendazim. The findings revealed that the corresponding isolates could be greatly employed as fungicides or as primes of newly fungicidal agents against the mentioned pathogenic fungi.

According to Lopes et al. (2013), P. chrysogenum IFL1 produced bioactive compounds that spread on agro-industrial residues, cheese whey, and grape trash. The cheese whey culture filtrate hindered the development of the fungus Fusarium oxysporum as well as the amoeba Acanthamoeba polyphaga.

Anti-viral

In vitro as well as in vivo studies by Huber et al. (2020) on PAF and PAFB, the two antimicrobial proteins (AMPs) secreted by the filamentous fungus P. chrysogenum Q176, displayed that they had antiviral activity without triggering any cytotoxic effects or hemolytic activity on mammalian cells. Experiments in human cervix cancer cells showed that they both reduced Human Coronavirus cytopathogenic effects. Apparently, it was the very first study on the antiviral ability of small, cysteine-rich and cationic proteins derived from fungi.

Hawas and Abou El-Kassem (2019) used a scale-up fermentation approach that yielded haenamindole (74), an uncommon diketopiperazine (DKP) alkaloid, from the endophytic fungus P. chrysogenum in a biomaltpeptone medium. This step was proceeded by cytotoxicity-guided fractionation. It showed low HCV protease potential with an IC50 value of 76.3 μM.

Study by Peng et al. (2014) isolated sorbicatechol A and sorbicatechol B (146,147), from the deep-sea sediment-derived fungus P. chrysogenum strain PJX-17’s culture. Results revealed that both displayed activities against influenza virus A (H1N1), with IC50 at 85 and 113 μM, respectively.

Anti-inflammatory

Liu et al. (2020) have isolated two novel chroman-4-ones named penicichromanone A (175) and penicichromanone B (176) along with three previously identified metabolites emodin (152), moniliphenone (153), and conioxepinol C (182), were attained from an endophytic fungus P. chrysogenum, separated from Eucommia ulmoides Oliver bark. The anti-inflammatory activity for all the obtained compounds were evaluated using HEK293 cells reporting that compounds (175), (152), (153) and (182) had powerful inhibitory actions on TNF-α-stimulated NF-κB activation.

According to Zhang et al. (2017), HPABA (265) is considered a potent anti-inflammatory compound obtained from the marine P. chrysogenum and was found to be an analogue of aspirin by structure.

In a previous study for Qi et al. (2017b), Compounds (40), (41), (43), (48), and (49) were obtained from the fermented cultures of a Huperzia serrata endophytic fungus, P. chrysogenum MT-12, demonstrated inhibition of the production of nitric oxide in the lipopolysaccharide-activated RAW 264.7 macrophage cytes with IC50 values range 4.3–78.2 μM (the standard, indomethacin, IC50 = 33.6 ± 1.4 μM)..

Wang et al. (2014) isolate, a new benzoic acid derivative, HPABA (265) from the fermented broth of P. chrysogenum., where it presented significant anti-inflammatory with pain killer activities when given at 100 mg/kg, while it showed no ulcerogenic actions.

Cytotoxicity

Huang et al. (2022) work showed that chrysoride A (2) had moderate cytotoxicity towards HepG2 and HeLa cancer cell lines with IC50 values of 28.9 and 35.6 μM, respectively.

Chen et al. (2022) exposed compounds penichryfurans A and B (219–220) to Cell Counting Kit-8 (CCK-8) colorimetric assay towards A549, HepG2 and HeLa cell lines to evaluate their cytotoxic activity. Penichryfuran A (219) exhibited high cytotoxicity towards the HepG2 cell line with IC50 value of 9.0 μM.

According to Al-Saleem et al. (2022), cytotoxic activity towards the cell lines (HCT-1 and HEP-2) were investigated using MTT method. In HCT-116 colon carcinoma cells, the ethyl acetate extract of P. chrysogenum and Kojic acid (156) exhibited strong activity with IC50 22.6 ± 0.8 and 23.4 ± 1.4 µg/mL, respectively, with respect to HEP-2 larynx carcinoma, the total extract and Kojic acid (156) had effective comparable cytotoxic profile against HEP-2 cell lines with same IC50 30.8 ± 1.3 and 30.8 ± 1.2 µg/mL, respectively. These substantial antimicrobial and cytotoxic activities may be due to the presence of penicillin G (212), Kojic acid (156), sohirnone B (217), and camptothecin (56) as major constituents in the ethyl acetate extract of P. chrysogenum.

Regarding the quantitative methodology by TLC and HPLC, El-Sayed et al. (2020) revealed that P. chrysogenum is an effective taxol (3) producer. Antiproliferative behavior of taxol was tested towards several cell lines like liver cancer cells (HEPG2) and breast adenocarcinoma (MCF7) cell viability. A considerable impact was revealed (p value < 0.05), since both MCF7 and HEPG2 cell viability were declined particularly by increasing taxol concentrations. The isolated taxol (3) IC50 value was indicated around 3.3 and 3.7 µM against cell lines MCF7 and HEPG2, individually.

Jiang et al. (2020) investigated the cytotoxicity of the obtained compounds from the marine alga-derived P. chrysogenum strain LD-201810 fungus culture against six human cancer cell lines including A549, HeLa, THP-1, MCF-7, HepG2, and BT-549. (2’R)-westerdijkin A (224) demonstrated anticancer activity against the HepG2 cell line with an IC50 22.0 μM. Furthermore, (S)-( +)-11-dehydrosydonic acid (33) showed significant activity towards THP-1 and A549 with an estimated IC50 values of 18.2 and 21.2 μM, respectively. All results suggested that (2’R)-westerdijkin A (224) and (S)-( +)-11-dehydrosydonic acid (33) had apoptosis-triggering action towards the HepG2, A549, and THP-1 cell lines, respectively.

Using MTT method, Qiao et al. (2020) evaluated the cytotoxic activity of the isolated metabolites from the diethyl sulphate (DES) mutant 3d10-01 of the marine-derived fungus P. chrysogenum S-3–25 on the human cancer cell lines, HeLa K562, BGC-823, HL-60, and A549. All the tested compounds revealed poor inhibitory action on the assayed cell lines, except chrysomutanin (4), 3-acetyl chrodrimanin F (5) and chrodrimanin F (7) which revealed higher inhibitory activities on HL-60 cells with an IC50 values 4.8, 8.1 and 8.7 μM, respectively.

Cao et al. (2020) used the surface plasmon resonance imaging (SPRi) method to reveal that 13-hydroxy-dihydrotrichodermolide (109) and 10,11,27,28-tetrahydrotrisorbicillinone C (110) had great affinity for eEF2K (cancer) with Kd values of 0.118 μM, 0.0746 μM for eEF2K, respectively.

In a previous study by Alshehri et al. (2020) stated that the chemical analysis of the P. chrysogenum S003 ethyl acetate extract yielded metabolites which were evaluated towards five human cancer cell lines by SRB assay. Ergosterol (187) and Epidioxyergosterol (194) showed promising cytotoxic activities against prostate (DU-145), hepatocellular (HepG2) cell lines, lung (A-549), and breast adenocarcinoma (MCF-7), with IC50 values of 1.50, 6.10; 2.89, 3.07 21.26, 19.3; and 16.95, 13.6; µM, respectively. However, LAMA (193) and Kojic acid (156) exhibited poor cytotoxic actions against all the corresponding cell lines.

According to Niu et al. (2019), the cytotoxic effects of all the identified compounds from P. chrysogenum MCCC 3A00292 the deep-sea-derived fungus solid cultures were tested for five human cancer cell lines: BEL-7402, BIU-87, ECA109, Hela-S3 and PANC-1. Peniciversiol A (113) showed a marked inhibitory potentials towards the BIU-87 cells (IC50 value of 10.21 μM), while metabolites Penicilactones A-B (116–117) and Decumbenone A-B (11–119) as well Aspermutarubrol (122), 3-hydroxy-5-(3-hydroxy-5-methylphenoxy)benzoic acid (123), Cyclopenol (124), Violaceol-II (125) had inhibitory effects towards the BEL-7402, BIU-87, and ECA109 cancer cell lines with an estimated IC50 values range from 7.70 to > 20 μM.

Hawas and Abou El-Kassem (2019) used a scale-up fermentation approach that yielded Haenamindole (74), an uncommon diketopiperazine (DKP) alkaloid of the endophytic fungus P. chrysogenum in biomaltpeptone media. This step was proceeded by cytotoxicity-guided fractionation within a group of up to 12 cancer cell lines. Results revealed substantial cytotoxicity of the metabolite, with definite selectivity for colon-38 carcinoma cells compared to human normal cells.

Ory et al. (2019) stated that the marine-derived fungus, P. chrysogenum MMS5 extract, shows strong antiproliferative action on breast cancer cells (MCF-7 cell line) in a real-case investigation. Its antiproliferative activity was validated with an IC50 of 0.10 μM on MCF-7 cells mainly due to the presence of high amounts of ergosterol.

A study by Zhen et al. (2018) showed that chrysoxanthones A–C (161–163) were obtained from the P. chrysogenum strain HLS111. In vitro cytotoxic activity against different human cell lines were estimated for these metabolites against renal carcinoma (A498), multiform glioblastoma (U87 MG), leukemia (HL60), non-small cell lung tumor (NCI-H1650), and colonic carcinoma (HT29), by the MTT method. The anticancer activities of compounds (161–163) diminished significantly compared to secalonic acid D which was previously isolated. The cytotoxic effect was reduced due to the presence of β-methyl-γ-lactone ring, meaning that the tricyclic nucleus was important to achieve bioactivity.

Chromatographic analysis performed by Zhao et al. (2018) on extracts of P. chrysogenum AD-1540, a marine algal-derived endophytic fungus which was separated from the red alga Grateloupia turuturu ‘s inner tissue, afforded chryxanthones A and B (161–162), two novel benzophenone derivatives. Their cytotoxic profile was evaluated towards six human cancer cell lines: MCF-7, A549, HeLa, BT-549, HepG2 and THP-1. Chryxanthone A (161) exhibited moderate activity towards BT-549 and HeLa cancer cell lines, with IC50 values of 20.4 and 23.5 µM, respectively, whereas chryxanthone B (162) inhibited the growth of A549 cell line selectively with an IC50 value of 20.4 µM.

The antimetastatic and antiangiogenic properties of the halotolerant fungus P. chrysogenum-1 hPc-1 isolated from Tuz Lake Turkey, were assessed by Dikmen et al. (2017). Its extract activity on human umbilical vein endothelial cells (HUVEC) and colorectal cancer cells (Caco-2) was assessed using the WST-1 technique and real-time cell analysis system-DP. According to the results, mRNA expression levels of the genes for VEGF A, VEGF B, COX-10, EGFR, ANGPT-1, and IL-8 were lower in HUVEC and Caco-2 cells compared to the standard.

According to Zhu et al. (2017), MTT technique revealed the cytotoxicity profile of the isolated metabolites from the mangrove endophytic fungus P. chrysogenum V11 against three diverse human cancer cell lines, lung adenocarcinoma epithelial cell line (A549), gastric cancer cell line (SGC-7901), and a breast cancer cell line (MDA-MB-435). Penochalasin K (85) showed significant broad-spectrum inhibitory actions towards all the assayed cell lines (IC50 < 10 μM). Also, chaetoglobosin A (84), chaetoglobosin C (81) and penochalasin I (83) exhibited mild to noticeable inhibitory activities on the mentioned cell lines with IC50 values range of 6.56–37.56 μM.

Chen et al. (2017) revealed that bipenicilisorin (186), which was obtained from a marine-derived fungus P. chrysogenum SCSIO 41,001, displayed cytotoxic effects towards Huh-7, K562, and A549 cancer cell lines significantly with IC50 values at 2.59, 6.78, and 6.94 μM, respectively, while penicitrinone F (144) displayed a modest inhibitory effect against EV71 with IC50 14.50 μM.

Huang et al. (2016) tested compounds obtained from the culture of P. chrysogenum V11 for their anticancer activity. Penochalasin I (83) showed significant activity against SGC-7901 and MDA-MB-435 cells (IC50 < 10 μM), while cytoglobosin C (90) had high activity against A549 and SGC-7901 cells (IC50 < 10 μM).

Guo et al. (2016) stated that 5-Hydroxymethyl-2-furancarboxaldehyde (270) recovered from the ethyl acetate extract of P. chrysogenum HGQ6 fermentation broth had activity towards BGC823 cell with the IC50 value of 0.19 mg/mL.

Previous studies by Hou et al. (2016) on P. chrysogenum, grown from a Gorgonian Carijoa sp. found in the South China Sea, yielded a novel flavone penimethavone A (154), with a unique methyl group at ring-B which is rarely found. It was tested in vitro for cytotoxicity against cervical cancer (HeLa), rhabdomyosarcoma, non-small cell lung cancer (A549) and human laryngeal epithelial (Hep-2) cell lines. Results indicated that it had moderate selective cytotoxic activity against (HeLa) and rhabdomyosarcoma cell lines, with IC50 values of 8.41 and 8.18 µΜ, respectively.

Mady et al. (2016) yielded meleagrin (61), by bioguided chromatographic analysis of the dichloromethane extract of P. chrysogenum mycelia which could inhibit the development of human breast cancer cell lines, MDA-468, MDA-MB-231, SK BR-3, BT-474, MCF7, and MCF7-dox, while comparable therapeutic doses revealed no impact on the growth of the non-carcinogenic human mammary epithelial cells MCF10A and viability. Additionally, its therapy inhibited the HGF-induced cell migration and invasion in breast cancer cell lines in a dose-dependent behavior.

Preliminary assay by An et al. (2013) applied for the crude extract of P. chrysogenum EN118, separated from the marine brown alga Sargassum palladium, showed a weak cytotoxic activity, while 2-(4-hydroxybenzyl)quinazolin-4(3H)-one (98), N-[2-(4-hydroxyphenyl)acetyl]formamide (100) and N-[(2E)-(4-hydroxyphenyl)ethenyl]formamide (96) showed moderate activities against Du145, HeLa and A-549 cell lines with the IC50 values of 8, 20, and 20 mg/mL, respectively.

Bladt et al. (2013) stated that chloctanspirone A (150) inhibited human leukemia HL-60 and lung cancer cell line A-549 cell lines with IC50 values of 9.2 and 39.7 µM, respectively, while chloctanspirone B (151), showed no activity against the same cell lines.

Antimicrobial

According to Newaz et al. (2022), several compounds were isolated from the Indonesian mangrove sediment-derived fungus P. chrysogenum ZZ1151. The new peniprenylphenol A (200) was found to possess promising antimicrobial activity towards the human pathogens MRSA, E. coli and C. albicans with MIC values of 6, 13, 13 mg/mL, respectively. In addition, the other known isolated compounds, preparaherquamide (203), uridine (205) and 4-hydroxybenzeneacetic acid methyl ester (207) revealed antimicrobial activity with MIC values in a range from 3 to 25 mg/mL towards the three pathogens. Meanwhile thymine (204) and clavatol (206) demonstrated antibacterial activity against MRSA and E. coli only with MIC values of 13–25 mg/mL and 2-hydroxyphenylacetic acid methyl ester (209) showed activity against both MRSA and C. albicans with MIC values of 13 and 7 mg/mL, respectively. Also, penicimumide (201) showed antibacterial activity against E. coli (13 mg/mL), communol G (102) and 4-hydroxyphenylethanone (210) had activity against MRSA (MIC: 25 mg/mL) and 2,5-dihydroxyphenylacetic acid methyl ester (208) exhibited antifungal activity against C. albicans (MIC = 25 mg/mL).

Orfali et al. (2022) investigated compounds (177–181) obtained from Wadi Lajab sediment-derived fungus P. chrysogenum for their antimicrobial activity with comparison with five types of pathogenic bacteria Staphylococcus aureus, Bacillus licheniformis, Escherichia fergusonii, Enterobacter xiangfangensis, and Ps. aeruginosa. All the samples except 6-hydroxymellein (179) revealed selective activities towards Gram-positive bacteria Staph. aureus and B. licheniformis with MIC values range 0.8 to 21.6 μg/mL. However, 4-chloro-6-hydroxymellein (180) displayed highly potent effect towards Gram-positive bacteria, with MIC 1.00 and 0.8 µg/mL−1 for Staph. aureus and B. licheniformis, respectively.

Qiao et al. (2020) isolated 20β-carboxyl conidiogenone K (29) and 19α-hydroxy conidiogenone C (1) from P. chrysogenum TJ403-CA4 extract obtained from the therapeutically valuable arthropod Cryptotympana atrata. It was found that they were active against MRSA with MIC values of 4.0 and 2.0 μg/ mL, respectively. Additionally, they revealed good activity towards ESBL-producing E. coli and E. faecalis with MIC values of 32 μg/mL.

Xu et al. (2020) evaluated the antimicrobial effects of the compounds obtained from the deep-sea algal-derived endophytic fungus P. chrysogenum strain XNM-12. It was found that oxalicine C (63) and penicierythritol A (221) revealed moderate antibacterial activity towards the plant pathogen Ralstonia solanacearum with MIC values of 8 and 4 μg/mL, respectively.

A study by Chang et al. (2019) on tyrosol (242) isolated from P. chrysogenum DXY-1, obtained from deep-sea sediments nearby the East Sea, found that tryosol had an anti-quorum sensing (anti-QS) activity. All studies implied that tyrosol (242) may act as a possible inhibitor for the QS systems to resolve the frightening crisis of bacterial resistance. It may be used as a QS inhibitor against C. violaceum and Ps. aeruginosa. The docking outcomes showed that it inhibited the QS system of CviR in C. violaceum through binding to the DNA-binding domain and blocking pathogenic gene expression.

Zhen et al. (2018) treated chrysoxanthones A-C (161–163) obtained from the P. chrysogenum HLS111 strain with the histone-deacetylase inhibitor VPA. They were examined against Staph. epidermidis (ATCC 12,228, MSSE), B. subtilis (ATCC 63,501), Staph. aureus (ATCC 29,213, MSSA), Enterococcus faecalis (ATCC 29,212, VSE), and E. coli (ATCC 25,922). They showed the maximum antibacterial effects against B. subtilis with a MIC of 5–10 µg/mL, while they exhibited modest activities towards Staph. epidermidis and Staph. aureus with MICs of 10–80 µg/mL.

Lopes et al. (2013) reported that the culture filtrates of P. chrysogenum IFL1antimicrobial activity showed that the cheese whey culture filtrate inhibited the growth of the Staph. aureus, Ps. aeruginosa and B. cereus.

An et al. (2013) isolated chrysotriazoles A and B (94–95) from P. chrysogenum EN118, an endophytic fungus culture extract isolated from the marine brown alga Sargassum pallidium. Its antibacterial activity towards two bacteria, E. coli and Staph. aureus was assayed, however, none of them showed any inhibitory activity.

Antioxidant

According to a study by Al-Saleem et al. (2022), Kojic acid (156) showed a potent antioxidant activity with IC50 33.7 ± 0.8 µg/mL compared to the P. chrysogenum extract, which was nearly inactive as revealed by the DPPH free-radical-scavenging technique.

Various antioxidant activity techniques were utilized by Jakovljevic et al. (2014), including DPPH free-radical-scavenging activity, Fe2 + -chelating ability, Fe3 + -reducing power and total antioxidant activity. P. chrysogenum ethanolic extract which was isolated from wastewater, was found to contain higher total phenolic content and better total antioxidant capacity along with ferrous ion chelating ability.

An et al. (2013) isolated chrysotriazoles A and B (94–95) from P. chrysogenum EN118, an endophytic fungus culture extract isolated from the marine brown alga Sargassum pallidium. Its radical-scavenging activity was evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay but did not show any activity.

Miscellaneous

Results of Li et al. (2023) demonstrated that compounds (1, 53 and 197) had antithrombotic activity. Compared to the model group, cerebroside A (197) exhibited substantial antithrombotic activity at the concentration of 25, 50 and 100 μg/mL; ethyl formyltyrosinate (53) had antithrombotic activity at 50, 100 μg/mL; conidiogenone C (1) revealed antithrombotic activity at 50 μg/mL and resulted in zebrafish death at 100 μg/mL.

According to Han et al. (2020), the protein tyrosine phosphatase 1B (PTP1B) enzyme was a confirmed biological target for treating Type II diabetes mellitus for its negative regulatory effect towards insulin signaling cascade. All the isolated compounds obtained and identified from the fungus P. chrysogenum SCSIO 07,007, were assessed for their enzyme inhibitory activities against (PTP1B). Also, the new compounds chrysopyrones A and B (158 and 159) showed noticeable inhibitory activities towards PTP1B with IC50 values of 9.32 and 27.8 μg/mL, respectively.

Qi et al. (2020) reported penicichrysogene A and B (16–17), from the substrate culture of P. chrysogenum MT-12, an endophytic fungus separated from the medicinal plant of Huperzia serrata. The antiplatelet activities were evaluated by applying D. S. Kim’s technique. Penicichrysogene A (16) exhibited antiplatelet aggregation activity with IC50 value of 42.7 ± 3.5 μM.

According to Hou et al. (2019) study, the coral-derived P. chrysogenum strain (CHNSCLM-0003) yielded chrysogeamides A and B (232–233) which obviously supported angiogenesis in zebrafish at concentration 1.0 μg/mL with nontoxic effect to embryonic zebrafish at concentration 100 μg/mL.

Wang et al. (2018) isolated the compounds (75–77), (195) and (247–263) (246–262) from a deep-sea-derived fungus P. chrysogenum SCSIO 41,001, which were tested for their α-glucosidase inhibitory activity by PNPG method. Nine compounds (257, 248, 195, 250, 252, 253, 256, 260, and 262) demonstrated inhibitory action against α-glucosidase with IC50 values of 0.35, 0.20, 0.04, 0.16, 0.15, 0.09, 0.14, 0.14, and 0.12 μM, respectively (IC50 0.28 μM for the standard acarbose).

Conclusions

By revising the existing literature, a massive library of secondary metabolites was isolated and identified, and they also possessed a unique structure. Up to 277 compounds with a variety of structures that belong to various chemical classes were reported from the Penicillium chrysogenum endosymbiotic fungus. The chemical structures were classified mainly as terpenoids (majority), alkaloids, polyketides, steroids, flavones (minority), and miscellaneous compounds. Penicillium chrysogenum secondary metabolites possess valuable and interesting pharmacological activities, such as antimicrobial, antifungal, cytotoxic, and miscellaneous. This review may be considered a valuable reference for promising pharmaceutical applications or further needed studies on P. chrysogenum. Reviewing such an endophyte metabolic pathway on P. chrysogenum would help to broaden the future search and discovery of several hundred novel bioactive endosymbiotic compounds with the potential for use as therapeutics. From a global perspective, the endosymbiotic metabolites remain very active and now seem to have the necessary momentum to provide additional antimicrobial, anticancer, and antifungal compounds to the marketplace soon.