The structures of heptacyclic duclauxins are described as two tricyclic moieties joined by a cyclopentane ring to form a unique hinge-like structure. About 15 heptacyclic duclauxin derivatives were isolated from several fungal strains dwelling in different ecological niches, such as soil, mangrove endophyte, and marine environment (Figure 3 and Table 1). Two new duclauxin derivatives bacillisporins A-B (2–3), were isolated from the ether (Et₂O) extract of mycelia of T. bacillisporus NHL 2660 grown on a malt extract medium (Yamazaki and Okuyama, 1980). Afterwards, bacillisporin A (2) was re-isolated from T. stipitatus grown on polished rice medium (Zang et al., 2016b). In another report, bacillisporins A (2) and B (3) were produced by fungus T. macrosporus KKU-1NK8 (Chaiyosang et al., 2019). Interestingly, bacillisporins A (2) and B (3) were isolated from a mangrove-derived endophytic fungus T. aculeatus No. 9EB for the first time. The fungus was obtained from the leaves of mangrove Kandelia candel, collected from Yangjiang, Guangdong province, China (Huang et al., 2017). Further investigations revealed compounds 2 and 3 have also been discovered from the soil fungus T. bacillisporus. The continuing research on duclauxin-like secondary metabolites from T. bacillisporus grown on potato dextrose broth (PDB) media led to the discovery of two new duclauxin derivatives, namely bacillisporins I (4) and J (5), respectively. The skeleton of compounds 2, 3, 4, and 5 is identical except for minor differences at C-9′ and C-1 positions. However, the absolute configuration of compounds 4 and 5 at C-1 could not be determined due to the similar CD patterns of both 1S and 1R configurations. Thus the ¹H chemical shift calculation together with DP4 probability analysis may be required to confirm the absolute configuration at C-1 (Figure 3). Heptacyclic oxyphenalenone dimers, bacillisporins D (6) and E (7) were reported first from a soil fungus T. bacillisporus (Dethoup et al., 2006; Dramae et al., 2020). With time, compounds 6–7 were acquired by the chemical investigation of T. macrosporus KKU-1NK8 grown on malt extract peptone broth. The only difference between the structures of compounds 6 and 7 was the C-9′ position (“OH” group for compound 6 and “OAc” group for compound 7). However, the absolute configuration of compounds 6 and 7 at C-9a has not been determined until now. Further experiments such as ¹H chemical shift calculation and DP4 probability analysis may be required to confirm the absolute configuration at C-9a (Chaiyosang et al., 2019).

Three new polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (8), bacillisporin F (9), and 1-epi-bacillisporin F (10) were isolated from the soil fungus T. stipitatus ATCC 10500. Their absolute configurations were determined using Gauge-Independent Atomic Orbital (GIAO) Nuclear Magnetic Resonance (NMR) shift calculation followed by DP4 analysis. The differences between compounds 9 and 10 were the chemical shifts of the methoxy group in CD₃OD (δ_H 3.66 for 9 vs. δ_H 3.58 for 10) and the methine H-1 (δ_H 6.57 for 9 vs. δ_H 6.55 for 10) (Zang et al., 2016b). Subsequently, bacillisporin F (9) and 1-epi-bacillisporin F (10) have also been found in soil fungus T. macrosporus. In addition, compound 9 was isolated from a marine fungus T. verruculosus in soft coral. The resonance signals of bacillisporin F (9) and 1-epi-bacillisporin F (10) were similar to those of the macrosporusone E (11) and 1-epi-macrosporusone E (12), except for a hydroxyl group at C-9′ being replaced by an acetoxyl group (Chaiyosang et al., 2019; Wang et al., 2019; Table 1). Cryptoclauxin (13), a well-known duclauxin derivative, was isolated from T. duclauxii for the first time using the silicic acid column chromatography technique (Ogihara et al., 1966). This compound was also re-isolated from T. stipitatus in 2018 (Gao et al., 2018).

Forest soil fungus T. macrosporus KKU-1NK8 yielded three new polyketide-derived oxaphenalenone dimers named macrosporusone E (11), 1-epi-macrosporusone E (12), and macrosporusone D (14) along with xenoclauxin (15). Their structures were established by spectroscopic data and electronic circular dichroism (ECD) analyses. The structure of compound 14 was very similar to that of compound 15, except that an acetoxyl group at C-9′ in 15 was replaced by a hydroxyl group in 14. The sole difference between compounds 11 and 12 was the configuration of C-1 (1S for 11 and 1R for 12). However, the numerical misrepresentation of macrosporusone E (12) and macrosporusone D (14) was found in the published article (10.1016/j.fitote.2019.03.015) that caused considerable confusion to the readers (Chaiyosang et al., 2019). Further studies also resulted in the identification of xenoclauxin (15) from T. verruculosus, T. duclauxii and a soil fungus Talaromyces sp. IQ-313 (Ogihara et al., 1966; Wang et al., 2019; Jimenez-Arreolaa et al., 2020).

Chemical investigation of marine fungus Talaromyces sp. LF458, isolated from a sponge Axinella verrucosa collected from the Mediterranean Sea, Italy, afforded talaromycesone A (16) (Wu et al., 2015). The continuous research on marine fungus resulted in the discovery of verrucolosin B (17) from a soft coral-associated fungus T. verruculosus collected from the South China Sea. The structure of compound 17 presents a unique methoxycarbonyl-methyl moiety at the C-1 position (Wang et al., 2019; Figure 3).

This class of compounds comprises tetra- and penta-cyclic moieties on one side of the structure joined via two C-C bonds with the tricyclic benzannulated moieties. Only three compounds have been reported in this class and they were isolated from several sources of genus Talaromyces (Figure 4 and Table 1). Talaroketals A (18) and B (19) were isolated from the soil fungus T. stipitatus ATCC 10500. Their structures and absolute configurations were determined based on X-ray diffraction and ECD experiments. Talaroketals A (18) and B (19) represent the first example of bis (oxaphenalenone) 5,6-spiroketal and 5,6-fused ketal, respectively. Compound 18 is a new member of the rare benzannulated [6,5]-spiroketal class of natural products (Zang et al., 2016a). Chemical investigation of the marine-derived fungus, T. verruculosus, isolated from the soft coral Goniopora sp. collected from the South China Sea, yielded a new oligophenalenone dimer, named verrucolosin A (20). The detailed structure and absolute configuration were solved with the aid of spectroscopic data, X-ray crystallography, optical rotation, ECD analysis, and NMR calculations. Compound 20 possesses a unique/distinctive octacyclic skeleton in the oxaphenelenone dimer family (Wang et al., 2019).

Nitrogen-containing duclauxin derivatives are scarcely found in nature, and thus until now, 9 N-containing duclauxin derivatives have been discovered from nature, as shown in Table 1 and Figure 5. The structures of these compounds consist of a heptacyclic dimer in which a nitrogen atom is present in the upper 6/6/6 tri-ring system. Bacillisporin H (21), a new nitrogenated bis-oxaphenalenone was isolated from EtOAc extract of T. stipitatus obtained from rice-based media (Zang et al., 2016b). Studies carried out by Cao et al. (2015) presented the isolation of new polyketide-derived heptacyclic oligophenalenone dimer duclauxamide A1 (22) bearing an N-2-hydroxyethyl moiety from P. manginii YIM PH30375, which was isolated from the elder root of Panax notoginseng, China. X-ray single-crystal diffraction technique and ¹³C NMR DFT calculation confirmed that compound 22 and other duclauxin analogs possess a unified S-configuration at C-9′, which corrected a long-standing misrepresentation of duclauxin and its analogs as C-9′ R epimers (Cao et al., 2015). A few years later, duclauxamide A1 (22) and two new N-containing oxaphenalenone dimers, duclauxamides B-C (23–24), were discovered from the soil fungus T. bacillisporus BCC17645 (Dramae et al., 2020). Five new oxyphenalenone amino acid hybrids, talauxins E, Q, V, L, and I (25–29), have been identified from the culture of T. stipitatus FP2248C on pearl barley medium. The fungus was recovered as a quiescent contaminant from the Australian fungus Aspergillus banksianus isolated from a soil sample collected in Collaroy, New South Wales, Australia (Chaudhary et al., 2020).

This class of monomer compounds presents an irregular shape in their structures as compared to other duclauxin derivatives. 7 duclauxins have been identified in this class from fungi so far (Figure 6 and Table 1). Bacillisporin C (30) was isolated for the first time from the mycelia of T. bacillisporus NHL 2660 grown on malt extract medium (Yamazaki and Okuyama, 1980). Likewise, isolation of bacillisporin C (30) was reported twice from soil fungus T. bacillisporus. Compound 30 was declared as the first compound in the duclauxin family, in which one C-C bond is connected with oxygen (O) between the two tricyclic moieties of a heptacyclic dimer (Dethoup et al., 2006; Dramae et al., 2020). Chemical evaluation of a soil fungus T. stipitatus ATCC 10500 collected from Thailand afforded bacillisporin G (31) (Zang et al., 2016b). With time, compound 31 was reported from other Talaromyces species such as Talaromyces sp. IQ-313 and T. macrosporus KKU-1NK8, both were isolated from soil (Chaiyosang et al., 2019; Jimenez-Arreolaa et al., 2020). Chromatographic separation of the EtOAc extract of a forest soil fungus T. macrosporus KKU-1NK8 resulted in three new polyketide-derived oxaphenalenone dimers, macrosporusones A-C (32–34). The fungus was isolated from the forest soil collected in the Pha Nok Kao Silvicultural Station, Khon Kaen Province, Thailand. The NMR spectroscopic data of compound 32 were similar to bacillisporin G (31) except for the absence of an aldehyde group at C-9a and that a hydroxyl group replaced an acetyl group at C-9′. The ¹H and ¹³C NMR spectroscopic data of compound 33 were similar to those of compound 32, except that the hydroxyl group at C-9′ was replaced by an acetoxyl group (δ_C carbonyl ester group 170.6 and methyl group δ_H/C 1.99 (s)/20.8). Macrosporusone C (34) is the first oxaphenalenone dimer reported with a chlorine atom in the molecule (Chaiyosang et al., 2019).

Talaromycesone B (35) was isolated as a brown powder from the culture broth and mycelia of a marine fungus Talaromyces sp. LF458 on WSP30 medium. Strain LF458 was isolated from tissues of the sponge Axinella verrucosa collected from the Mediterranean Sea, Italy, and tentatively classified as a T. funiculosum. Compound 35 represents the first case of a 1-nor oxaphenalenone dimer carbon skeleton in nature (Wu et al., 2015; Imhoff, 2016). Additionally, talaromycesone B (35) and the new oxaphenalenone dimer talaromycesone C (36) were isolated from the EtOAc extracts of the mycelia of a soil fungus T. macrosporus KKU-1NK8. Compound 36 was reported as the second compound of oxaphenalenone dimer with a 5-membered lactone ring on one side (Chaiyosang et al., 2019). Recently, compound 35 was re-isolated from Talaromyces sp. IQ-313, an anthill soil-dwelling fungus around the Huasteca Hidalguense, Hidalgo State, Mexico. The cultivation of Talaromyces sp. IQ-313 was carried out in potato dextrose agar (PDA) and PDB (Jimenez-Arreolaa et al., 2020).

The cost of production and yield of duclauxin (1) on different culture media are different. The production cost of duclauxin (1) from P. herquei culture on Gostar media (peanut hulls and potato starch substrates) was less than enriched media. However, the yield of duclauxin (1) from Gostar medium (7.71 mg/flask) was less than enriched media (8.57 mg/flask). The cost comparison greatly favors the Gostar-type medium for this process (Bryant et al., 1993). Fourteen in vitro growth media were used to cultivate the fungi to produce duclauxin analogs in the present report, showing that fungi have different compounds on different artificial growth media under different conditions (Table 1).

According to the World Health Organization (WHO), cancer is a hazardous disease primarily caused by malignant tumors resulting from abnormal cell growth. Cancer is a leading cause of death around the globe; nearly 10 million people have died from cancer in 2020 worldwide (World Health Organization, 2021).¹ Various techniques have been used to control cancer, such as radiotherapy, chemotherapy, and surgery. Among these techniques, chemotherapy is the most helpful approach to treat cancer so far (Farce et al., 2004). Therefore, finding effective antitumor agents from a natural source is necessary due to their lower toxicity.

Duclauxin (1), a metabolite that occurs naturally in fungi, is the most effective against numerous tumor cell lines because it prevents ATP synthesis by inhibiting mitochondrial respiration and therefore exhibits potential as a leading anticancer molecule. The antitumor activity of duclauxin (1) was evaluated in vitro against Ehrlich ascites carcinoma (EAC), lymphadenoma L-5178, and HeLa cells. The inhibitory effect was evaluated according to the decreased number of nucleic acids in tested tumor cells. It suppressed the growth of all tested tumor cell lines with cytotoxic effect ED₅₀ from 20 to 50 μg/mL (Fuska et al., 1974). Duclauxin (1) was evaluated for the effect on murine leukemia L1210 culture cells, and it was strongly active with the ID₅₀ value of ca. 3.5 μg/mL (6.6 μM) (Shiojiri et al., 1983). Similarly, duclauxin (1) was examined using an Agrobacterium tumefaciens potato disc assay for crown gall tumor/antitumor induction at the concentrations of 5 μg/disc, 10 μg/disc, 25 μg/disc, and 50 μg/disc, respectively. The inhibitory potential values at the given concentrations were –67, –74, –95, and –94%, respectively. This observation concurs that duclauxin (1) was an effective antitumor agent at the concentrations of 25 μg/disc (camptothecin, positive control, –100% at 25 μg/disc) (Bryant et al., 1994). Duclauxin (1) isolated from T. bacillisporus was intensely active against three human cancer cell lines (MCF-7, NCI-H460 and SF-286) with the following GI₅₀ values of 15.0 ± 1.3, 40.3 ± 1.7, and 78.3 ± 1.9 μM, respectively. However, all the cancer cell lines were less inhibited by the positive control doxorubin with the GI₅₀ values of 42.8 ± 8.2, 93 ± 7.0, and 94.0 ± 8.7 μM, respectively (Dethoup et al., 2006). The cytotoxicity of duclauxin (1) was recently examined against NS-1 (ATCC TIB-18) mouse myeloma cells and found to be inactive (Chaudhary et al., 2020; Table 3).

Duclauxamide A1 (22) isolated from P. manginii, exhibited moderate cytotoxicity against SW480, MCF-7, A-549, MCF-7 SMML-7721, and HL-60 cancer cell lines with inhibitory concentration (IC₅₀) values in the range of 11–32 μM (Cao et al., 2015). The cytotoxic properties of compounds 8, 9, 21, and 31 were determined against HeLa cell line by the MTT assay, in which cisplatin was used as a positive control. Only bacillisporin H (21) displayed modest cytotoxicity against the HeLa cell line with an IC₅₀ value of 49.5 μM, while the other compounds were inactive (cisplatin, positive control, IC₅₀: 10.6 ± 6.6 μM) (Zang et al., 2016b). Biological evaluation against HeLa cell line showed that talaroketals A and B (18–19) exhibited moderate cytotoxicity with IC₅₀ values 36 ± 2.0 μM and 44 ± 2.0 μM, respectively (cisplatine, positive control, IC₅₀: 5.6 ± 2.0 μM) (Zang et al., 2016a). Kawai et al. (1985) assessed the in vitro cytotoxicity effect of xenoclauxin (15) against murine leukemia (L-1210 culture cells), and it exhibited the strongest inhibitory activity by causing a complete growth inhibition at approximately 20 μM. Compound 15 exhibited the same mode of inhibition as that of duclauxin on the ATP synthesis in mitochondria, displaying uncoupling of oxidative phosphorylation and inhibition of state 3 respiration (Kawai et al., 1985; Table 3).

Oxaphenalenones 2–3, 7, and 30 were screened for in vitro cytotoxicity against three human cancer cell lines MCF-7, NCI-H460, and SF-286. Among them, bacillisporin A (2) showed strong growth inhibitory effects against MCF-7 and NCI-H460 with GI₅₀ values of 10.2 ± 0.9 and 7.9 ± 0.3 μM, respectively. It also exhibited a moderate GI₅₀ on SF-268 with a value of 14.7 ± 0.3 μM. Bacillisporins B (3) and C (30) also showed an average mild growth inhibitory effect against all cancer cell lines (MCF-7, NCI-H460, and SF-286) with GI₅₀ from 15.0 ± 1.3 to 78.3 ± 1.9 μM. However, bacilisporin E (7) exhibited a weak activity compared to the positive control and other tested compounds. GI₅₀ values of these compounds were determined by the National Cancer Institute in vitro anticancer molecule discovery screen using protein-binding dye sulforhodamine B (SRB) (Skehan et al., 1990; Dethoup et al., 2006). In another study, bacillisporins A-B (2–3) and duclauxamide B (23) were evaluated against cancerous (MCF-7 and NCI-H187) and non-cancerous (Vero) cells. Only compound 2 displayed notable activity against the MCF-7 cell line with an IC₅₀ value of 35.56 μM as compared to positive control tamoxifen (IC₅₀, 27.64 μM), while compound 3 demonstrated weak cytotoxicity against both cancerous and non-cancerous cells with IC₅₀ values ranging from 78.06 to 103.12 μM. In contrast, duclauxamide B (23) demonstrated moderate cytotoxicity exclusively against NCI-H187 with IC₅₀ 35.58 μM (ellipticine, positive control, IC₅₀: 9.87 μM, Table 3; Dramae et al., 2020).

Macrosporusone B (33) exhibited significant cytotoxic activity against NCI-H187 (human small cell lung cancer) and primate (Vero) cells with the IC₅₀ values of 16.73 and 13.74 μM, respectively (ellipticine, positive control, IC₅₀: 9.26 and 3.45 μM). At the same time, bacillisporin G (31) showed remarkable cytotoxic activity against NCI-H187, MCF-7 (human breast adenocarcinoma), KB (human epidermoid carcinoma in the mouth) and primate (Vero) cell lines with IC₅₀ values of 7.29, 9.16, 5.86, and 7.50 μM, respectively. In this study, ellipticine was used as a positive control, displayed cytotoxicity againstNCI-H187, KB, and Vero cells with the IC₅₀ values of 9.26, 13.80, and 3.45 μM, respectively. The IC₅₀ value of standard control doxorubicin against the MCF-7 cell line was 17.44 μM. This information concurs that compound 31 might be used as a leading hit against the cancer lines. Furthermore, compounds 2, 3, 14–15, and 32 exhibited weak cytotoxicity against Vero cells with IC₅₀ values in the range of 33.55–93.27 μM. In comparison, the KB cell line was slightly inhibited by compound 9 with the IC₅₀ of 33.55 μM (ellipticine, positive control, IC₅₀: 13.80 μM). Resazurin microplate assay (REMA) was employed to perform the activity against NCI-H187, MCF-7, and KB cell lines. In addition, cytotoxicity against Vero cells was tested using the green fluorescent protein (GFP) detection method (Chaiyosang et al., 2019). Talaromycesones A (16) and B (35) isolated from marine fungus Talaromyces sp. LF458 were evaluated for cytotoxic activity against HepG2 (human hepatocellular liver carcinoma cell line) and NIH 3T3 (mouse fibroblasts cell line). Both compounds were inactive against tested cancer cell lines (Wu et al., 2015; Table 3).

Antimicrobial resistance (AMR) has emerged as one of the most serious human health concerns of the twenty-first century. The Center for Disease Control and Prevention (CDC) reported that 23,000 people die every year in developing countries due to AMR. The emergence of multidrug-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), significantly contributes to AMR incidence. Antimicrobials are the most effective way to protect human beings from infectious diseases (Basak et al., 2016; Cruz et al., 2020; Health Research and Educational Trust, 2020).² Thus, fungi-derived secondary metabolites are a potential pool for antimicrobial agent screening, which holds a great promise for new antibiotics.

Duclauxin (1) was evaluated against pathogenic bacteria and fungi using the 96-well microtiter plate method. However, it was not active against Bacillus subtilis ATCC 6633, Escherichia coli ATCC 25922, Candida albicans ATCC 10231, and Saccharomyces cerevisiae ATCC 9763, respectively (Chaudhary et al., 2020). Bacillisporins A (2) and B (3) were inactive against Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecium at a concentration of 50 μg/mL, but bacillisporin A (2) possessed potent antibacterial activity against Gram-positive bacteria such as S. aureus and B. cereus with the same MIC value of 3.13 μg/mL (vencomycin, positive control, MIC: 2.0 and 1.0 μg/mL). However, bacillisporin B (3) exhibited moderate antibacterial activity against B. cereus and S. aureus with MIC values of 6.25 and 12.50 μg/mL, respectively (vencomycin, positive control, MIC: 2.0 and 1.0 μg/mL), while bacillisporin C (30) displayed weak antibacterial activity against both strains with MIC values of 25.0 and 50.0 μg/mL, respectively. Duclauximide B (23), a N-containing oxaphenalenone dimer, displayed moderate inhibitory activity against Mycobacterium tuberculosis, S. aureus and B. cereus with the same MIC value of 12.5 μg/mL. The standard positive control values against Mycobacterium tuberculosis, S. aureus and B. cereus are listed in Table 4 (Dramae et al., 2020). In another report, bacillisporins A (2) and B (3) were tested for antimicrobial activities against B. cereus, Sarcina lutea, S. albus, E. coli, and Salmonella, using the microplate assay method. Both compounds displayed strong inhibitory activities against B. subtilis with the same MIC values of 0.13 ± 0.02 μM, whereas the MIC value of compound 2 against Salmonella was 2.00 ± 0.02 μM (Huang et al., 2017). Substantial antibacterial activities against clinically relevant pathogenic bacterial strains S. epidermidis DSM 20044 and methicillin-resistant S. aureus (MRSA) DSM 18827 were observed for talaromycesone A (16) with an IC₅₀ 3.70 and 5.4 μM, respectively (chloramphenicol, positive control, IC₅₀, 1.81 and 2.46 μM). At the same time, talaromycesone B (35) showed moderate inhibitory effects against S. epidermidis and S. aureus with IC₅₀ values of 17.36 and 19.50 μM, respectively (Wu et al., 2015; Table 4).

Compounds 2, 3, 7, 9, 15, 31–33, and 35 isolated from T. macrosporus KKU-1NK8, evaluated for antibacterial activity against Gram-positive (B. cereus ATCC 11778, S. aureus ATCC 6538, MRSA) and Gram-negative bacteria (E. coli ATCC 25922, P. aeruginosa ATCC 27853, and Salmonella enterica serovar Typhimurium ATCC 13311). Among them, bacillisporins A (2) and E (7) displayed the most vigorous antibacterial activities against B. cereus with MIC of 1.94 and 3.76 μM, respectively. Therefore, they can be used as anti-B. cereus candidate molecule due to their intense effects compared to standard drugs vancomycin (MIC 1.38 μM) and kanamycin (MIC 4.13 μM), respectively. Moreover, compound (3) was slightly active against Gram-positive bacteria, while the other tested compounds were inactive against Gram-positive and Gram-negative bacteria. The dilution method was used to evaluate the minimum inhibitory concentrations (MICs), as described in the M07-A9 of the Clinical and Laboratory Standards Institute (Balouiri et al., 2016; Chaiyosang et al., 2019; Table 4).

Talaroketals A (18) and B (19) were examined for their antimicrobial activities against four strains such as E. coli ATCC 8739, S. aureus ATCC 6538, S. haemolyticus MNHN26, and Enterococcus faecalis CIP 103014. These compounds exhibited weak antimicrobial activity against S. aureus with an IC₅₀ value of around 50 μg mL^–1 but no action against the other bacterial strains (Zang et al., 2016a). Bacillisporins A (2), F (9), G (31), and H (21) were evaluated against human pathogenic bacteria E. coli ATCC 8739, S. aureus ATCC 6538, S. hemolyticus MNHN26, and E. faecalis CIP 103014. Among them, bacillisporins A (2) and H (21) revealed potent antimicrobial activity against S. hemolyticus with MIC values of 9.5 ± 0.4 and 20.4 ± 6.5 μg/mL, respectively. Tetracycline, the positive control (MIC 29.5 ± 0.3 μM), was less active than the compounds 2 and 21. The MIC value of bacillisporin H (21) against S. aureus was 5.0 μg/mL, and the other compounds displayed weak activity against the panel of human pathogenic bacteria (Zang et al., 2016b; Table 4).

Alzheimer’s disease is a progressive neurodegenerative disease that causes brain cells to waste away and die. It is characterized by progressive cognitive deterioration and continuous decline in thinking, behavioral, and social skills that disrupts a person’s ability to function independently (Khan et al., 2016). Around 50 million people are affected by Alzheimer’s disease across the globe, and it is likely to present an increasing demand for the innovation of small molecules for this type of dementia (World Health Organization, 2020).³ Acetylcholinesterase (AChE) is an enzyme that catalyzes acetylcholine hydrolysis. Inhibition of this enzyme leads to an increased level of the neurotransmitter acetylcholine, which improves cholinergic functions in patients (Li et al., 2019). Talaromycesone A (16), isolated from the broth and mycelia of a marine fungus Talaromyces sp. LF458 was the first oxaphenalenone structure that exhibited AChE inhibitory activity with an IC₅₀ of 7.49 μM (huperzine, positive control, IC₅₀ 11.6 μM). Therefore, compound 16 is a potential AChE inhibitor that could be a candidate molecule against Alzheimer’s disease (Figure 8; Wu et al., 2015).

Bacillisporins A (2) and B (3) produced by T. aculeatus exhibited potent inhibitory activity against α-glucosidase enzyme with IC₅₀ values of 33.55 ± 0.63 and 95.81 ± 1.12 μM, respectively (acarbose, positive control, IC₅₀ 1075.53 ± 11.94 μM). The α-glucosidase inhibition activity of these compounds was determined using the method described by Jeon et al. (2013) with slight modifications (Huang et al., 2017; Table 4). Novel molecules against α-glucosidase are urgently needed because of their essential role in glucose absorption in the gastrointestinal tract, the inhibition of which prevents postprandial hyperglycemia. Compounds 2 and 3 are potential candidates of lead compounds for the treatment of type II diabetes.

Oligophenalenone dimers such as 1, 9, 15, 17, and 20 were assayed for their effects against cell division cycle 25B (CDC25B) tyrosine phosphatase. Among them, verruculosin A (20), bacillisporin F (9), and xenocluaxin (15) showed strong inhibitory activity against CDC25B with IC₅₀ values of 0.38 ± 0.03, 0.40 ± 0.02, and 0.26 ± 0.06 μM, respectively (Na₃VO₄, positive control, IC₅₀ 0.52 ± 0.02 μM). The CDC25B regulates cell cycle progression in various cancer cell lines and has contributed to tumor growth. However, the specific mechanism by which increased CDC25B impacts tumor progression is not clear. The results indicated that oligophenalenone dimers might be used for screening as the new CDC25B inhibitor candidates. In addition, compounds 1, 9, 15, 17, and 20 displayed weak inhibitory activity toward epidermal growth factor receptor (EGFR) tyrosine kinase with IC₅₀ values ranging from 0.92 ± 0.25 to 4.41 ± 2.32 μM (afatinib, positive control, IC₅₀ 0.0005 ± 0.00002 μM) (Wang et al., 2019; Table 5).

A critical biological event that contributes to the appearance and progress of cancer and diabetes is the reversible phosphorylation of proteins, a process controlled by protein tyrosine phosphatase (PTPs). Within the PTPs, PTP1B has gained significant interest from a pharmacological point of view since it is an emerging therapeutic target in treating cancer and diabetes. Until now, more than 300 PTP1B_1–300 inhibitors have been identified from nature, including microorganisms and plants (Verma et al., 2017). Particularly, chemical investigation of a soil fungus Talaromyces sp. IQ-313 has resulted in the isolation of many different types of PTP1B inhibitors, such as duclauxin (1), bacillisporin G (31), and xenoclauxin (15), which showed potent inhibitory activity toward human protein tyrosine phosphatase 1B (hPTP1B_1–400) in a concentration-dependent manner with IC₅₀ values of 12.7, 13.4, and 21.8 μM, respectively (Ursolic acid, positive control, IC₅₀ 26.7 μM). These compounds induce conformational changes in the protein, which directly affect its activity, suggesting these compounds are allosteric modulators of the protein. Thus, compounds 1, 15, and 31 have great potential to treat obesity and chronic diseases such as diabetes and cancer (Jimenez-Arreolaa et al., 2020; Table 5).

Malaria is a parasitic disease caused by Plasmodium spp. resulting from the bites of infected mosquitoes. Approximately 220 million people are infected by malaria, resulting in 435,000 deaths worldwide per annum. The emergence of drug-resistant malaria strains to classical synthetic drugs requires a continuous search for new compounds from alternative niches to introduce new and efficient therapies (Cadamuro et al., 2021). Bacillisporin G (31) and macrosporusone B (33) produced by the fungus T. macrosporus displayed weak antimalarial activity against Plasmodium falciparum (IC₅₀ values were 8.07 and 10.28 μM, respectively) in comparison with positive control dihydroartemisinin (IC₅₀ value was 0.003 μM) (Chaiyosang et al., 2019). It was observed that duclauxin (1) significantly inhibited the growth of etiolated wheat coleoptiles in a concentration-dependent manner. The percentage of inhibition at selected concentrations of duclauxin relative to controls were: 100% at 10^–3 M, 80% at 10^–4 M, 39% at 10^–5 M, and 0% at 10^–6 M (Bryant et al., 1993; Table 6).