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. 2022 Jan 27;8(2):127. doi: 10.3390/jof8020127

Chaetomugilins and Chaetoviridins—Promising Natural Metabolites: Structures, Separation, Characterization, Biosynthesis, Bioactivities, Molecular Docking, and Molecular Dynamics

Abdelsattar M Omar 1,2,*, Gamal A Mohamed 3, Sabrin R M Ibrahim 4,5,*
Editor: Laurent Dufossé
PMCID: PMC8875349  PMID: 35205880

Abstract

Fungi are recognized as luxuriant metabolic artists that generate propitious biometabolites. Historically, fungal metabolites have largely been investigated as leads for various therapeutic agents. Chaetomugilins and the closely related chaetoviridins are fungal metabolites, and each has an oxygenated bicyclic pyranoquinone core. They are mainly produced by various Chaetomaceae species. These metabolites display unique chemical features and diversified bioactivities. The current review gives an overview of research about fungal chaetomugilins and chaetoviridins regarding their structures, separation, characterization, biosynthesis, and bioactivities. Additionally, their antiviral potential towards the SARS-CoV-2 protease was evaluated using docking studies and molecular dynamics (MD) simulations. We report on the docking and predictive binding energy estimations using reported crystal structures of the main protease (PDB ID: 6M2N, 6W81, and 7K0f) at variable resolutions—i.e., 2.20, 1.55, and 1.65 Å, respectively. Chaetovirdin D (43) exhibited highly negative docking scores of −7.944, −8.141, and −6.615 kcal/mol, when complexed with 6M2N, 6W81, and 7K0f, respectively. The reference inhibitors exhibited the following scores: −5.377, −6.995, and −8.159 kcal/mol, when complexed with 6M2N, 6W81, and 7K0f, respectively. By using molecular dynamics simulations, chaetovirdin D’s stability in complexes with the viral protease was analyzed, and it was found to be stable over the course of 100 ns.

Keywords: chaetomugilins, chaetoviridins, fungi, Chaetomaceae, characterization, bioactivities, molecular docking, COVID-19, protease, biosynthesis

1. Introduction

Fungi are a wealthy and substantial pool of many secondary metabolites with many different structures and diversified bioactivities [1,2,3,4,5,6,7,8,9,10,11]. These metabolites attract much attention as lead metabolites for pharmaceutical agents, and for plant protection [1,8,9,10,11,12,13,14,15,16]. Fungal polyketides (FPKs) represent one of the largest and most structurally diverse groups of fungal metabolites. They range from simple and aromatic to highly macrocyclic and complex [10,13,17]. Their backbone is biosynthesized by the condensation of acyl-CoA thioesters [18]. Their structural variations originate from differences in the starting and extending units, methylation pattern, chain length, degree of reduction, and modifications by tailoring enzymes [19]. Mycotoxins and pigments are among the FPKs that have had remarkable contributions in the field of drug discovery [20]. Azaphilones (azaphilonoids or isochromenes) are fungal pigments belonging to FPKs. Structurally, they have an isochromene skeleton that contains an oxygenated bicyclic pyrano-quinone core and a quaternary carbon center [21]. Biosynthetically, the O atom in the pyran chromophore could be exchanged by an N atom in the existence of primary amines, and accordingly, the pigment color will shift to red [22]. They are produced by various basidiomycetous and ascomycetous fungi, including Chaetomium, Penicillium, Aspergillus, Talaromyces, Phomopsis, Monascus, Emericella, Epicoccum, Hypoxylon, and Pestalotiopsis, where they are accountable for the green, red, or yellow color of mycelia and/or fruiting bodies [23]. They possess myriad bioactivities: antitumor, cytotoxic, antimicrobial, anti-inflammatory, antioxidant, enzyme inhibitory, antiviral, insecticidal, and antileishmanial [24]. Chaetomugilins and closely related chaetoviridins are azaphilones featuring a C-7-methyl group and C-5 chlorine—except for chaetomugilins T (29) and U (30)—and a C-3-branched pentenyl chain (Figure 1). However, chaetomugiline P (24) differs from the others in that it has no substituent at C-7 and a methyl group at C-5. 3-Methyl-4-hydroxy-1-pentyl chains at C-3 are found in some chaetomugilins and chaetoviridins. Sometimes, they bear a five-membered lactone and/or a fused tetrahydrofuran/δ-lactone [25]. The 7-OH group can have (S) or (R) configuration, though (7S) isomers are the most common among these metabolites. On the other hand, the 7-hydroxyl can be part of a furanone ring [26]. These fungal metabolites are produced by various Chaetomium species. Chaetoviridins were firstly reported by Takahashi et al. from Chaetomium globosum var. flavoviride [27]. Chaetomugilins are known as cytotoxic metabolites, whereas chaetoviridins have antifungal and antibiotic activities [28]. Recently, these metabolites have been recognized as a unique family of fungal metabolites in view of their interesting structural features and prominent bioactivities, which could provoke enormous attention from natural products chemists and pharmacologists. The current review focuses on chaetomugilins and chaetoviridins from fungal sources, including isolation, structural characterization, biosynthesis, and bioactivities (Table 1 and Table 2). Some of the metabolites have been reported with the same names, despite having different structures and molecular formulae—e.g., chaetomugilin S, chaetoviridin B, and chaetoviridin G. Moreover, the structures of some compounds have been revised and renamed: in such cases, both structures have been drawn in the figures, highlighting the new names and corresponding references. Additionally, the emergence of the COVID-19 pandemic motivated us to investigate the potential of these metabolites as antiviral agents towards SARS-CoV-2 using docking studies and molecular dynamics (MD) simulations. Literature searching was carried out using diverse databases—Web of Science, PubMed (MedLine), GoogleScholar, Scopus, and SciFinder—and different publishers— Springer-Link (Cham, Switzerland), Wiley (New York, NY, USA), Taylor & Francis (London, England), Bentham (Sharjah, United Arab Emirates), and ACS (Washington, DC, United States) Publications.

Figure 1.

Figure 1

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The basic skeleton of chaetomugilins and chaetoviridins.

Table 1.

List of chaetomugilins and chaetoviridins. (Molecular weight and formula, fungal source, host, and place of discovery).

Compound Name Mol. Wt. Mol. Formula Fungal Source Host (Part, Family) Place Refs.
Chaetomugilin 106B-6 XXVIII (1) 328 C16H21ClO5 C. globosum Mugii cephalus (Fish bora stomach content, Mugilidae) Katsuura, Nachi, Wakayama, Japan [37]
Chaetomugilin A (2) 450 C23H27ClO7 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [38]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [40]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [41]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [35]
C. globosum Ginkgo biloba (Leaves, Ginkgoaceae) Linyi, Shandong, China [42]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [43]
C. globosum Z1 Broussonetia papyrifera (Barks, Moraceae) Nanjing, Jiangsu, China [44]
C. globosum TY1 Ginkgo biloba (Barks Ginkgoaceae) Linyi, Shandong, China [45]
C. globosum CBS148.51 Cultured China [46]
C. globosum HDN151398 Sediment sea South China Sea [22]
C. globosum TY-2 Polygonatum sibiricum, (Root, Convallariaceae) Linan, Zhejiang, China [32]
C. globosum TY1 Ginkgo biloba (Barks Ginkgoaceae) Linyi, Shandong, China [47]
Seco-chaetomugilin A (3) 482 C24H31ClO8 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [48]
11-Epi-chaetomugilin A (4) 450 C23H27ClO7 C. globosum Mugii cephalus (Fish bora stomach content, Mugilidae) Katsuura, Nachi, Wakayama, Japan [37]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [35]
C. globosum TW1-1 Armadillidium vulgare (Pillbugs, Armadillidiidae) Tongji Medical College, Hubei, China [33]
C. globosum CBS148.51 Culture China [46]
4′-Epi-chaetomugilin A (5) 450 C23H27ClO7 C. globosum Mugii cephalus (Fish bora stomach content, Mugilidae) Katsuura, Nachi, Wakayama, Japan [37]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [35]
Chaetomugilin B (6) 464 C24H29ClO7 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [38]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [40]
C. globosum Z1 Broussonetia papyrifera (Barks, Moraceae) Nanjing, Jiangsu, China [44]
Chaetomugilin C (7) 432 C23H25ClO6 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [38]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [40]
C. globosum HDN151398 Sediment sea South China Sea [22]
Chaetomugilin D (8) 434 C23H27ClO6 C. globosum Adiantum capillus-veneris (Plant, Pteridaceae) Saint Katherine Protectorate, Sinai, Egypt [49]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [40]
C. globosum Ginkgo bilob (Leaves, Ginkgoaceae) Linyi, Shandong province, China [42]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [41]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [43]
C. globosum DAOM 240359 Indoor air samples or building materials Ontario, Alberta, Saskatchewan, Nova Scotia, Canada [30]
C. globosum DAOM 240359 Indoor air samples or building materials Ontario, Alberta, Saskatchewan, Nova Scotia, Canada [50]
C. globosum Amaranthus viridis (Leaves, Amaranthaceae) Central Province of Sri Lanka [51]
C. globosum TW1-1 Armadillidium vulgare (Pill bugs, Armadillidiidae) Tongji Medical College, Hubei Province, China [33]
C. globosum DAOMC 240359 Damp building materials Ontario, Alberta, Saskatchewan, Nova Scotia, Canada [52]
C. globosum TY1 Ginkgo biloba (Barks Ginkgoaceae) Linyi, Shandong, China [45]
C. globosum CBS148.51 Cultured China [46]
Chaetomium sp. NA-S01-R1 Deep-sea West Pacific Ocean, China [25]
C. cochliodes Indoor buildings Finland [53]
C. globosum Seawater and marine deposits Jeju, Korea [54]
C. globosum DAOM 240359 Damp and moldy buildings Canada [55]
Seco-chaetomugilin D (9) 466 C24H31ClO7 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [48]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
C. cupreum National Fungal Culture Collection India, Agharkar Research
Institute, Pune, India		 [29]
Epi-chaetomugilin D (10) 434 C23H27ClO6 C. globosum Adiantum capillus-veneris (Plant, Pteridaceae) Saint Katherine Protectorate, Sinai, Egypt [49]
Chaetomugilin E (11) 448 C24H29ClO6 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [40]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
Chaetomugilin EA-4 (12) 406 C22H27ClO5 C. globosum Kunze ex. 5157 Soils of wheat field New Delhi, India [57]
Chaetomugilin F (13) 416 C23H25ClO5 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [40]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
Chaetomugilin G (14) 464 C24H29ClO7 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [41]
Chaetomugilin H (15) 448 C24H29ClO6 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [39]
C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [41]
Chaetomugilin I (16) 406 C22H27ClO5 C. globosum Mugii cephalus (Fish bora stomach content, Mugilidae) Katsuura, Nachi, Wakayama, Japan [37]
C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
C. globosum TY1 Ginkgo biloba (Barks Ginkgoaceae) Linyi, Shandong, China [45]
C. globosum TY-2 Polygonatum sibiricum, (Roots, Convallariaceae) Linan, Zhejiang, China [32]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong, China [47]
C. globosum Kunze ex. 5157 Soils of wheat field New Delhi, India [57]
11-Epi-chaetomugilin I (17) 406 C22H27ClO5 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [59]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
Chaetomugilin J (18) 390 C22H27ClO4 C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
C. globosum Adiantum capillus-veneris (Plant, Pteridaceae) Saint Katherine Protectorate, Sinai, Egypt [49]
C. globosum Mugii cephalus (Fish bora stomach content, Mugilidae) Katsuura, Nachi, Wakayama, Japan [37]
C. globosum Amaranthus viridis (Leaves, Amaranthaceae) Central Province of Sri Lanka [51]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong, China [45]
C. globosum TY-2 Polygonatum sibiricum (Root, Convallariaceae) Linan, Zhejiang, China [32]
C. globosum Polygonatum sibiricum, (Root, Convallariaceae) China [34]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong, China [47]
C. globosum Kunze ex. 5157 Soils of wheat field New Delhi, India [57]
Chaetomugilin K (19) 420 C23H29ClO5 C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
Chaetomugilin L (20) 404 C23H29ClO4 C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
Chaetomugilin M (21) 450 C23H27ClO7 C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
Chaetomugilin N (22) 432 C23H25ClO6 C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
Chaetomugilin O (23) 416 C23H25ClO5 C. globosum Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [58]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong, China [45]
C. globosum TY-2 Polygonatum sibiricum, (Root, Convallariaceae) Linan, Zhejiang, China [32]
Chaetomugilin P (24) 406 C22H27ClO5 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [59]
Chaetomugilin Q (25) 424 C22H29ClO6 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [59]
C. globosum TW1-1 Armadillidium vulgare (Pill bugs, Armadillidiidae) Tongji Medical College, Hubei Province, China [33]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong,
China		 [45]
C. globosum TY1 Ginkgo bilob (Leaves, Ginkgoaceae) Linyi, Shandong province, China [47]
C. globosum TY-2 Polygonatum sibiricum, (Root, Convallariaceae) Linan, Zhejiang, China [32]
Chaetomugilin R (26) C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [59]
Chaetomugilin S (27) 434 C23H27ClO6 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [43]
C. globosum TW1-1 Armadillidium vulgare (Pillbugs, Armadillidiidae) Tongji Medical College, Hubei Province, China [33]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong,
China		 [45]
Chaetomugilin S (28) 420 C23H29ClO5 C. elatum No. 89-1-3-1 Ramalina calicaris (Lichen, Ramalinaceae) Zixishan Mountain, Yunnan, China [31]
Chaetomugilin T (29) 416 C23H28O7 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [43]
Chaetomugilin U (30) 406 C23H28O6 C. globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [43]
Chaetoviridin A (31) 432 C23H25ClO6 C. globosum DAOM 240359 Indoor air samples or building materials Ontario, Alberta, Saskatchewan, Nova Scotia, Canada [30,50]
Chaetomium sp. NA-S01-R1 Deep sea West Pacific Ocean, China [25]
C. cochliodes VTh01
C. cochliodes CTh05 		Soil Ubon Rajathanee province, Bangkok, Thailand
Chiangrai province, Bangkok, Thailand		 [60]
C. globosum Adiantum capillus-veneris (Plant, Pteridaceae) Saint Katherine Protectorate, Sinai, Egypt [49]
C. globosum 5157 Soils of wheat field New Delhi, India [57]
C. globosum var. flavo-viride Culture - [27]
C. globosum F0142 Echinochloa crusgalli (Stems, Poaceae) Korea [61]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
C. siamense Soil Bangkok, Thailand [62]
C. globosum Cucumber soil (Rhizosphere) Egypt [63]
C. globosum CIB-160 - China [64]
C. subafine Culture Japan [65]
C. globosum DAOM 240359 Damp and moldy buildings Canada [55]
C. globosum Sea water and marine deposits Jeju, Korea [54]
C. globosum F211_UMNG Protium heptaphyllum (Leaves, Burseraceae) Foothill of the west Colombian Andes mountains, Aguazul, Casanare, Colombia [66]
C. globosum 22-10 Soil PaLong ZangBu Brook, Tibet, China [67]
C. globosum Artemisia desterorum (Roots, Asteraceae) Tengger Desert, Ningxia Province, China [68]
C. globosum CEF-082 Gossypium arboreum (Plant, Malvaceae) China [69]
C. globosum E-C-2 Apostichopus japonicas (Surface muscle, Stichopodidae) Chengshantou Island, Weihai City, the Yellow Sea, China [70]
C. globosum Indoor buildings Finland [53]
C. cochliodes indoor buildings Finland [53]
C. globosum MP4-S01-7 Sea water West Pacific Ocean, China [71]
4′-Epi-chaetoviridin A (32) 432 C23H25ClO6 C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
C. globosum F211_UMNG Protium heptaphyllum (Leaves, Burseraceae) Foothill of the west Colombian Andes mountains, Aguazul, Casanare, Colombia [66]
5′-Epi-chaetoviridin A (33) 432 C23H25ClO6 C. cochliodes VTh01
C. cochliodes CTh05 		Soil Ubon Rajathanee province, Bangkok, Thailand
Chiangrai province, Bangkok, Thailand		 [60]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong province, China [72]
C. globosum CDW7, Ginkgo biloba (Leaves, Ginkgoaceae) China [73]
C. globosum 22-10 Soil Palong Zangbu Brook, Tibet, China [67]
C. globosum F211_UMNG Protium heptaphyllum (Leaves, Burseraceae) Foothill of the west Colombian Andes mountains, Aguazul, Casanare, Colombia [66]
7,5′-Bis-epi-chaetoviridin A (34) 432 C23H25ClO6 C. elatum No. 89-1-3-1 Ramalina calicaris (Lichen, Ramalinaceae) Zixishan Mountain, Yunnan, China [31]
N-Glutarylchaetoviridin A (35) 603 C31H38ClNO9 C. globosum HDN151398 Sea sediment South China Sea [22]
4′-Epi-N-2-Hydroxyethyl-azachaetoviridin A (36) 475 C25H30ClNO6 C. globosum DAOM 240359 Indoor air samples or building materials Ontario, Alberta, Saskatchewan, Nova Scotia, Canada [50]
Chaetoviridin B (37) 452 C23H29ClO7 C. globosum var. flavo-viride Culture - [27]
C. globosum F0142 Echinochloa crusgalli (Stems, Poaceae) Korea [61]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
C. globosum Cucumber soil (Rhizosphere) Egypt [63]
Chaetoviridin B (38) C. globosum 5157 Soils of wheat field New Delhi, India [57]
C. globosum E-C-2 Apostichopus japonicas (Surface muscle, Stichopodidae) Chengshantou Island, Weihai City, the Yellow Sea, China [70]
C. globosum Z1 Broussonetia papyrifera (Barks, Moraceae) Nanjing, Jiangsu, China [44]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong, China [47]
Chaetomium sp. Dromaius novaehollandiae (Scat, Casuariidae) Australia [74]
C. globosum Adiantum capillus-veneris (Plant, Pteridaceae) Saint Katherine Protectorate, Sinai, Egypt [49]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong province, China [72]
N-Glutarylchaetoviridin B (39) 543 C28H30ClNO8 C. globosum HDN151398 Sea sediment South China Sea [22]
Chaetoviridin C (40) 434 C23H27ClO6 C. globosum var. flavo-viride Culture - [27]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetomium globosum OUPS-T106B-6 Mugil cephalus (Marine fish, Mugilidae) Katsuura Bay, Japan [41]
C. globosum Indoor buildings Finland [53]
12β-Hydroxychaetoviridin C (41) 450 C23H27ClO7 C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
N-Glutarylchaetoviridin C (42) 571 C30H34ClNO8 C. globosum HDN151398 Sea sediment South China Sea [22]
Chaetoviridin D (43) 486 C23H29ClO8 C. globosum var. flavo-viride Culture Spain [27]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetomium sp. Dromaius novaehollandiae (Scat, Casuariidae) Australia [74]
Chaetoviridin E (44) 414 C23H23ClO5 C. globosum 5157 Soils of wheat field New Delhi, India [57]
C. globosum MP4-S01-7 Sea water West Pacific Ocean, China [71]
C. globosum Artemisia desterorum (Roots, Asteraceae) Tengger Desert in Ningxia, China. [68]
C. globosum E-C-2 Apostichopus japonicas (Surface muscle, Stichopodidae) Chengshantou Island, Weihai City, the Yellow Sea, China [70]
Chaetomium sp. NA-S01-R1 Deep sea West Pacific Ocean, China [25]
C. globosum 22-10 Soil PaLong ZangBu Brook, Tibet, China [67]
C. globosum Sea water and marine deposits Jeju, Korea [54]
C. cochliodes CTh05 Soil Ubon Rajathanee province, Bangkok, Thailand [60]
C. globosum Adiantum capillus-veneris (Plant, Pteridaceae) Saint Katherine Protectorate, Sinai, Egypt [49]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetomium siamense Soil Bangkok, Thailand [62]
Chaetomium sp. Dromaius novaehollandiae (Scat, Casuariidae) Australia [74]
C. globosum TY1 Ginkgo biloba (Barks, Ginkgoaceae) Linyi, Shandong province, China [72]
7-Epi-chaetoviridin E (45) 414 C23H23ClO5 C. elatum No. 89-1-3-1 Ramalina calicaris (Lichen, Ramalinaceae) Zixishan Mountain, Yunnan, China [31]
N-2-Butyric-azochaetoviridin E (46) 499 C27H30ClNO6 C. globosum DAOM 240359 Indoor air samples or building materials Ontario, Alberta, Saskatchewan, Nova Scotia, Canada [50]
Chaetoviridin F (47) 416 C23H25ClO5 C. cochliodes VTh01
C. cochliodes CTh05 		Soil Ubon Rajathanee province, Bangkok, Thailand
Chiangrai province, Bangkok, Thailand		 [60]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
4′-Epi-chaetoviridin F (48) 416 C23H25ClO5 C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetoviridin G (49) 416 C23H25ClO5 C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetoviridin G (50) 420 C23H29ClO5 C. siamense Soil Bangkok, Thailand [62]
Chaetoviridin H (51) 398 C23H26ClO6 C. globosum CBS148.51 Cultured China [46]
C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetoviridin I (52) 466 C23H27ClO8 C. globosum Viguiera robusta (Leaves, Asteraceae) Spain [36]
Chaetoviridin J (53) 408 C22H29ClO5 C. globosum TY1 Ginkgo biloba (Barks Ginkgoaceae) Linyi, Shandong, China [47]
C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
C. globosum Seawater and marine deposits Jeju, Korea [54]
Chaetoviridin K (54) 450 C23H27ClO7 C. globosum Wikstroemia uva-ursi (Leaves, Thymelaeaceae) Hawaiian Islands, USA [56]
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Table 2.

Biological activities of chaetomugilins and chaetoviridines.

Compound Name Biological Activity Assay, Organism, or Cell Line Biological Results Positive Control Refs.
Chaetomugilin 106B-6 XXVIII (1) Cytotoxicity MTT/P388 32.0 µM (IC50) 5-FU 1.7 µM (IC50) [37,58]
MTT/HL-60 51.8 µM (IC50) 5-FU 2.7 µM (IC50) [37,58]
MTT/L1210 67.1 µM (IC50) 5-FU 1.1 µM (IC50) [37,58]
MTT/KB 58.8 µM (IC50) 5-FU 7.7 µM (IC50) [37,58]
Chaetomugilin A (2) Cytotoxicity MTT/P388 8.7 µM (IC50) 5-FU 1.7 µM (IC50) [38,40]
MTT/HL-60 7.3 µM (IC50) 5-FU 2.7 µM (IC50) [38,40]
MTT/HL-60 6.4 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
MTT/K562 11.1 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/BEL-7402 17.9 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/HCT-116 6.1 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/HeLa 20.3 µM (IC50) Adriamycin 0.6 µM (IC50) [22]
SRB/L-02 15.2 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/MGC-803 15.3 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/HO8910 12.1 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/SH-SY5Y 23.4 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/NCI-H1975 18.3 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/U87 27.1 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
SRB/MDA-MB-231 22.7 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
11-Epi-chaetomugilin A (4) Cytotoxicity MTT/P388 88.9 µM (IC50) 5-FU 1.7 µM (IC50) [35]
MTT/HL-60 66.7 µM (IC50) 5-FU 2.7 µM (IC50) [35]
MTT/P388 88.9 µM (IC50) 5-FU 1.7 µM (IC50) [37,58]
MTT/HL-60 66.7 µM (IC50) 5-FU 2.7 µM (IC50) [37,58]
MTT/L1210 80.2 µM (IC50) 5-FU 1.1 µM (IC50) [37,58]
Chaetomugilin B (6) Cytotoxicity MTT/P388 18.7 µM (IC50) 5-FU 1.7 µM (IC50) [38,40]
MTT/HL-60 16.5 µM (IC50) 5-FU 2.7 µM (IC50) [38,40]
Chaetomugilin C (7) Cytotoxicity MTT/P388 3.6 µM (IC50) 5-FU 1.7 µM (IC50) [38,40]
MTT/HL-60 2.7 µM (IC50) 5-FU 2.7 µM (IC50) [38,40]
MTT/HL-60 6.6 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
MTT/K562 12.3 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/BEL-7402 16.8 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/HCT-116 5.7 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/HeLa 13.2 µM (IC50) Adriamycin 0.6 µM (IC50) [22]
SRB/L-02 9.1 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/MGC-803 9.6 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/HO8910 8.8 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/SH-SY5Y 19.4 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/NCI-H1975 12.1 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/U87 17.6 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
SRB/MDA-MB-231 26.6 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
Chaetomugilin D (8) Cytotoxicity MTT/P388 7.5 µM (IC50) 5-FU 1.7 µM (IC50) [38,40]
MTT/HL-60 6.8 µM (IC50) 5-FU 2.7 µM (IC50) [38,40]
Phytotoxic activity Lettuce seed germination bioassay/Root growth inhibition 24.2 ppm (IC50) - [51]
Lettuce seed germination bioassay/Shoot growth inhibition 27.8 ppm (IC50) - [51]
Antimicrobial Microplate assay/Vibrio vulnificus 32.4 µg/mL (MIC) Erythromycin 2.0 µg/mL (MIC) [25]
Microplate assay/Vibrio rotiferianus 15.3 µg/mL (MIC) Erythromycin 3.9 µg/mL (MIC) [25]
Microplate assay/MRSA 1 32.2 µg/mL (MIC) Chloramphenicol 7.6 µg/mL (MIC) [25]
Microplate assay/MRSA 2 32.4 µg/mL (MIC) Chloramphenicol 7.5 µg/mL (MIC) [25]
Seco-chaetomugilin D (9) Cytotoxicity MTT/P388 38.6 µM (IC50) 5-FU 1.7 µM (IC50) [48]
MTT/HL-60 47.2 µM (IC50) 5-FU 2.7 µM (IC50) [48]
MTT/L1210 53.6 µM (IC50) 5-FU 3.0 µM (IC50) [48]
MTT/KB 47.2 µM (IC50) 5-FU 6.0 µM (IC50) [48]
Chaetomugilin E (11) Cytotoxicity MTT/P388 15.7 µM (IC50) 5-FU 1.7 µM (IC50) [38,40]
MTT/HL-60 13.2 µM (IC50) 5-FU 2.7 µM (IC50) [38,40]
Inhibition TNF-α TNF-α activated NF-kB assay 11.6 µM (IC50) TPCK 3.8 µM (IC50)
BAY-11 2.0 µM (IC50)		 [56]
Inhibition NO Nitrite assay 5.8 µM (IC50) L-NMMA 25.1 µM (IC50) [56]
Chaetomugilin F (13) Cytotoxicity MTT/P388 3.3 µM (IC50) 5-FU 1.7 µM (IC50) [38,40]
MTT/HL-60 1.3 µM (IC50) 5-FU 2.7 µM (IC50) [38,40]
Inhibition TNF-α TNF-α activated NF-kB assay 5.1 µM (IC50) TPCK 3.8 µM (IC50)
BAY-11, 2.0 µM (IC50)		 [56]
Inhibition NO Nitrite assay 1.9 µM (IC50) L-NMMA 25.1 µM (IC50) [56]
Chaetomugilin G (14) Cytotoxicity MTT/P388 24.1 µM (IC50) 5-FU 1.7 µM (IC50) [38]
MTT/HL-60 19.8 µM (IC50) 5-FU 2.7 µM (IC50) [38]
MTT/P388 24.1 µM (IC50) 5-FU 1.7 µM (IC50) [41]
MTT/HL-60 19.8 µM (IC50) 5-FU 2.7 µM (IC50) [41]
MTT/L1210 123.6 µM (IC50) 5-FU 3.0 µM (IC50) [41]
MTT/KB 137.8 µM (IC50) 5-FU 6.0 µM (IC50) [41]
Chaetomugilin H (15) Cytotoxicity MTT/P388 12.3 µM (IC50) 5-FU 1.7 µM (IC50) [38]
MTT/HL-60 10.3 µM (IC50) 5-FU 2.7 µM (IC50) [38]
MTT/P388 12.3 µM (IC50) 5-FU 1.7 µM (IC50) [41]
MTT/HL-60 10.3 µM (IC50) 5-FU 2.7 µM (IC50) [41]
MTT/L1210 93.3 µM (IC50) 5-FU 3.0 µM (IC50) [41]
MTT/KB 18.8 µM (IC50) 5-FU 6.0 µM (IC50) [41]
Chaetomugilin I (16) Cytotoxicity MTT/P388 1.1 µM (IC50) 5-FU 1.7 µM (IC50) [37,58,59]
MTT/HL-60 1.1 µM (IC50) 5-FU 2.7 µM (IC50) [37,58,59]
MTT/L1210 1.9 µM (IC50) 5-FU 1.1 µM (IC50) [37,58,59]
MTT/KB 2.3 µM (IC50) 5-FU 7.7 µM (IC50) [37,58,59]
Inhibition TNF-α TNF-α activated NF-kB assay 0.9 µM (IC50) TPCK 3.8 µM (IC50)
BAY-11 2.0 µM (IC50)		 [56]
Inhibition NO Nitrite assay 0.3 µM (IC50) L-NMMA 25.1 µM (IC50) [56]
11-Epi-chaetomugilin I (17) Cytotoxicity MTT/P388 0.7 µM (IC50) 5-FU 1.7 µM (IC50) [59]
MTT/HL-60 1.0 µM (IC50) 5-FU 2.7 µM (IC50) [59]
MTT/L1210 1.6 µM (IC50) 5-FU 1.1 µM (IC50) [59]
MTT/KB 1.2 µM (IC50) 5-FU 7.7 µM (IC50) [59]
Inhibition TNF-α TNF-α activated NF-kB assay 0.9 µM (IC50) TPCK 3.8 µM (IC50)
BAY-11 2.0 µM (IC50)		 [56]
Inhibition NO Nitrite assay 0.8 µM (IC50) L-NMMA 25.1 µM (IC50) [56]
Chaetomugilin J (18) Phytotoxic activity Lettuce seed germination bioassay/Root growth inhibition 22.6 ppm (IC50) - [51]
Lettuce seed germination bioassay/Shoot growth inhibition 21.9 ppm (IC50) - [51]
Cytotoxicity MTT/P388 12.6 µM (IC50) 5-FU 1.7 µM (IC50) [37,58]
MTT/HL-60 12.6 µM (IC50) 5-FU 2.7 µM (IC50) [37,58]
MTT/L1210 2.8 µM (IC50) 5-FU 1.1 µM (IC50) [37,58]
MTT/KB 8.5 µM (IC50) 5-FU 7.7 µM (IC50) [37,58]
Inhibition TNF-α TNF-α activated NF-kB assay 7.6 µM (IC50) TPCK 3.8 µM (IC50)
BAY-11 2.0 µM (IC50)		 [56]
Inhibition NO Nitrite assay 4.2 µM (IC50) L-NMMA 25.1 µM (IC50) [56]
Chaetomugilin K (19) Cytotoxicity MTT/P388 8.2 µM (IC50) 5-FU 1.7 µM (IC50) [58]
MTT/HL-60 14.1 µM (IC50) 5-FU 2.7 µM (IC50) [58]
MTT/L1210 11.2 µM (IC50) 5-FU 1.1 µM (IC50) [58]
MTT/KB 18.7 µM (IC50) 5-FU 7.7 µM (IC50) [58]
Chaetomugilin L (20) Cytotoxicity MTT/P388 10.9 µM (IC50) 5-FU 1.7 µM (IC50) [58]
MTT/HL-60 13.1 µM (IC50) 5-FU 2.7 µM (IC50) [58]
MTT/L1210 15.6 µM (IC50) 5-FU 1.1 µM (IC50) [58]
MTT/KB 20.1 µM (IC50) 5-FU 7.7 µM (IC50) [58]
Chaetomugilin N (22) Cytotoxicity MTT/P388 2.3 µM (IC50) 5-FU 1.7 µM (IC50) [58]
MTT/HL-60 2.3 µM (IC50) 5-FU 2.7 µM (IC50) [58]
MTT/L1210 10.6 µM (IC50) 5-FU 1.1 µM (IC50) [58]
MTT/KB 10.6 µM (IC50) 5-FU 7.7 µM (IC50) [58]
Chaetomugilin O (23) Cytotoxicity MTT/P388 11.1 µM (IC50) 5-FU 1.7 µM (IC50) [58]
MTT/HL-60 11.1 µM (IC50) 5-FU 2.7 µM (IC50) [58]
MTT/L1210 10.1 µM (IC50) 5-FU 1.1 µM (IC50) [58]
MTT/KB 7.2 µM (IC50) 5-FU 7.7 µM (IC50) [58]
Chaetomugilin P (24) Cytotoxicity MTT/P388 0.7 µM (IC50) 5-FU 1.7 µM (IC50) [59]
MTT/HL-60 1.2 µM (IC50) 5-FU 2.7 µM (IC50) [59]
MTT/L1210 1.5 µM (IC50) 5-FU 1.1 µM (IC50) [59]
MTT/KB 1.8 µM (IC50) 5-FU 7.7 µM (IC50) [59]
Chaetomugilin Q (25) Cytotoxicity MTT/P388 49.5 µM (IC50) 5-FU 1.7 µM (IC50) [59]
MTT/HL-60 47.2 µM (IC50) 5-FU 2.7 µM (IC50) [59]
MTT/L1210 80.2 µM (IC50) 5-FU 1.1 µM (IC50) [59]
Chaetomugilin R (26) Cytotoxicity MTT/P388 32.0 µM (IC50) 5-FU 1.7 µM (IC50) [59]
MTT/HL-60 51.8 µM (IC50) 5-FU 2.7 µM (IC50) [59]
MTT/L1210 67.1 µM (IC50) 5-FU 1.1 µM (IC50) [59]
MTT/KB 67.1 µM (IC50) 5-FU 7.7 µM (IC50) [59]
Chaetomugilin S (27) Caspase-3 inhibitory Caspase-3 enzymatic assay 20.6 µM (IC50) Ac-DEVD-CHO 13.7 nM (IC50) [31]
Chaetomugilin T (29) Cytotoxicity MTT/P388 62.4 µM (IC50) 5-FU 1.9 µM (IC50) [43]
MTT/HL-60 67.2 µM (IC50) 5-FU 2.3 µM (IC50) [43]
Chaetomugilin U (30) Cytotoxicity MTT/P388 57.4 µM (IC50) 5-FU 1.9 µM (IC50) [43]
MTT/HL-60 57.4 µM (IC50) 5-FU 2.3 µM (IC50) [43]
MTT/L1210 94.8 µM (IC50) 5-FU 2.2 µM (IC50) [43]
Chaetoviridin A (31) Antifungal Alternaria mali 33.3 µg/mL (MIC) - [61]
Botrytis cinerea 33.3 µg/mL (MIC) - [61]
Colletotrichum gloeosporioides 33.3 µg/mL (MIC) - [61]
Fusarium oxysporum 33.3 µg/mL (MIC) - [61]
Phytophthora capsici 33.3 µg/mL (MIC) - [61]
Phytophthora infestans 33.3 µg/mL (MIC) - [61]
Pythium ultimum 1.23 µg/mL (MIC) - [61]
Magnaporthe grisea 1.23 µg/mL (MIC) - [61]
Sclerotinia sclerotiorum 97.5 (% inhibition) - [73]
Botrytis cinerea 69.1 (% inhibition) - [73]
Fusarium graminearum 77.0 (% inhibition) - [73]
Phytophthora capsici 60.7 (% inhibition) - [73]
Fusarium moniliforme 59.2 (% inhibition) - [73]
5′-Epi-chaetoviridin A (33) Cytotoxicity SRB assay/HepG-2 35.3 µM (IC50) Camptothecin 32.3 µM (IC50) [72]
7,5′-
Bis-epi-chaetoviridin A (34)		 Caspase-3 inhibitory Caspase-3 enzymatic assay 10.9 µM (IC50) Ac-DEVD-CHO 13.7 nM (IC50) [31]
N-glutarylchaetoviridin A (35) Cytotoxicity MTT/HL-60 10.3 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
MTT/K562 20.3 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/BEL-7402 23.9 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
Chaetoviridin B (37) Antifungal Pythium ultimum 33.3 µg/mL (MIC) - [61]
Magnaporthe grisea 33.3 µg/mL (MIC) - [61]
Chaetoviridin B (38) α-Glucosidase inhibiory Spectrophotometric assay 6.328 µM (IC50) Acarbose 54.74 µM (IC50) [47]
N-Glutarylchaetoviridin C (42) Cytotoxicity MTT/HL-60 11.1 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
MTT/K562 11.7 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/BEL-7402 10.9 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/HCT-116 11.3 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/HeLa 22.1 µM (IC50) Adriamycin 0.6 µM (IC50) [22]
SRB/L-02 18.2 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/MGC-803 6.6 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
SRB/HO8910 9.7 µM (IC50) Adriamycin 0.4 µM (IC50) [22]
SRB/NCI-H1975 11.2 µM (IC50) Adriamycin 0.3 µM (IC50) [22]
SRB/U87 18.3 µM (IC50) Adriamycin 0.1 µM (IC50) [22]
SRB/MDA-MB-231 13.2 µM (IC50) Adriamycin 0.2 µM (IC50) [22]
Chaetoviridin E (44) Cytotoxicity SRB assay/BC1 5.6 µg/mL (IC50) Ellipticine 0.26 µg/mL (IC50) [60]
Cytotoxicity SRB assay/NCl-H187 3.5 µg/mL (IC50) Ellipticine 0.32 µg/mL (IC50) [60]
Cytotoxicity SRB assay/HepG-2 40.6 µM (IC50) Camptothecin 32.3 µM (IC50) [72]
Antimalarial
 Microculture radioisotope assay/P. falciparum (K1, MDR) 2.9 µg/mL (IC50) - [60]
7-Epi-chaetoviridin E (45) Caspase-3 inhibitory Caspase-3 enzymatic assay 7.9 µM (IC50) Ac-DEVD-CHO 13.7 nM (IC50) [31]
Chaetoviridin F (47) Cytotoxicity SRB assay/NCl-H187 4.5 µg/mL (IC50) Ellipticine 0.32 µg/mL (IC50) [60]
Cytotoxicity MTT/P388 46.0 µM (IC50) 5-FU 1.9 µM (IC50) [43]
MTT/HL-60 39.1 µM (IC50) 5-FU 2.3 µM (IC50) [43]
MTT/L1210 43.7 µM (IC50) 5-FU 2.2 µM (IC50) [43]
MTT/KB 34.5 µM (IC50) 5-FU 20.6 µM (IC50) [43]
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2. Extraction, Isolation, and Structural Characterization

For isolation of these metabolites, the fungal materials were extracted with EtOAc or MeOH. Their presence in the extract can be detected by TLC using the solvent systems: EtOAc:toluene:AcOH:formic acid 2.5:7.5:1:1, CHCl3:MeOH:AcOH 95:5:0.1, or petroleum spirit/EtOAc 40:60. Upon development, the spots on the SiO2 TLC plates can be visualized as dark spots under ultraviolet light (365 nm and 254 nm), or by using ammonia (red color) or ceric ammonium molybdate stain (dark spots; H2O (90 mL), H2SO4 (10 mL), ammonium molybdate (2.5 g), cerium (IV) sulfate (1.0 g)) [27,29,30,31]. Moreover, they gave positive Beilstein reactions [27]. The EtOAc or MeOH extract can be separated by column chromatography using SiO2 CC (PE:acetone 9:1–6.5:3.5 or 40:1–2:1; CH2Cl2:MeOH; cyclohexane:MeOH; EtOAc:CH2Cl2; cyclohexane:EtOAc; CHCl3:MeOH gradient), Sephadex LH-20 (MeOH; CH2Cl2:MeOH 6:4; CH2Cl2:MeOH 1:1; CHCl3:MeOH 1:1), or MPLC (C-18 ODS) (MeOH:H2O gradient) [25,31,32,33]. Finally, the fractions or isolated compounds can be further purified by preparative HPLC (MeOH:H2O 90%, 85%, 75%, 65%, or 50% v/v), CH3CN/H2O (60:40, 65:35, or 75:25, v/v) [31,32,33,34,35], or normal phase HPLC (n-hexane:EtOAc 7:3, 4:1, 1:4, 2:1, 1: 3, or 3:2) [36]. Their isolation can also be achieved by loading the sample onto TLC SiO2 plates in the form of uniform bands.

The plates were developed by using toluene/EtOAc/formic acid (7:3:1), CH2Cl2/MeOH (20:1), benzene/ethyl acetate (8:2), EtOAc/CH2Cl2 (5:95), n-hexane/ethyl acetate (4:1), or EtOAc/CH2Cl2 (2:8) [29,42,60,63]. The isolated metabolites can be purified by recrystallization from MeOH or CHCl3:MeOH until they show constant melting points.

The structures of isolated metabolites were determined through extensive spectroscopic analyses, including UV, IR, MS, and 1D (1H, 13C NMR, and DEPT) and 2D NMR (COSY, NOESY, ROESY, HMQC, HSQC, or HMBC).

The absolute configurations of these metabolites have been established with the aid of optical rotation sign, X-ray crystallography, CD (circular dichroism), the modified Mosher’s method, and chemical transformation studies, including derivatization and degradation [22,27,35,41,48,60,75]. It has been reported that the absolute configuration at C(7) controls signs of the specific rotation [35]. Compounds with (S) C-11 and C-7 had negative optical rotation values; however, when C-7 was (R), the sign switched to positive with the same magnitude [50]. The absolute (S) configuration at C-7 was determined by the negative Cotton effect in the CD spectrum [58]. Mass spectra of these compounds displayed an isotopic peak [M+H]+/[M+H+2]+ in a ratio 3:1, characterizing the presence of a single chlorine atom. Moreover, their IR spectrum exhibited characteristic bands for a hydroxyl group (3405–3450 cm−1), lactone (1718–1780 cm−1), and α,β-unsaturated ketone (1616–1684 cm−1). Characteristic UV bands of a highly extended conjugation system were observed at 283–429 nm.

3. Biological Activities

3.1. Cytotoxic Activity

Yamada et al. reported the isolation of chaetomugilins A (2), B (6), C (7), D (8), E (11), F (13), G (14), and H (15) from the culture broth of C. globosum associated with marine fish Mugil cephalus and assessed for their cytotoxic effects on P388 and HL-60 cell lines in the MTT assay (Figure 2 and Figure 3; Table 2). It is noteworthy that compounds 7 and 13 exhibited remarkable cytotoxicity towards P388 and HL-60 cell lines (IC50 3.6 and 3.3 µM and 2.7 and 1.3 µM, respectively), nearly equal to that of 5-fluorouracil (IC50 1.7 and 2.7 µM, respectively). While other compounds had moderate to weak cytotoxicity (IC50 ranging from 6.8 to 24.1 µM) [38,39]. Further, 2, 7, and 13 displayed selective cytotoxicity towards a panel of 39 disease-related human cell lines, including breast, CNS, colon, lung, melanoma, ovary, kidney, stomach, and prostate cancer cells with range and delta values of 2 (1.24 and 1.13, respectively), 7 (1.19 and 0.71, respectively), and 13 (1.21 and 1.97, respectively) [38,40]. It was suggested that the existence of C-12-hydroxyl and C-3-methoxyl groups had little effect on the activity [40]. Evaluation of the differential cytotoxicity patterns using COMPARE revealed that the modes of action for 2, 7, and 13 might be different from those of other anticancer drugs [40]. On the other hand, chaetomugilins A (2) biosynthesized by C. globosum Z1 isolated from Broussonetia papyrifera bark had no in vitro effectiveness towards SMMC-7721, MG-63 and A-549 cell lines (IC50 ˃ 50 µg/mL) in the MTT assay in comparison to doxorubicin [44].

Figure 2.

Figure 2

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Structures of compounds 1–8.

Figure 3.

Figure 3

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Structures of compounds 9–16.

C. globosum OUPS-T106B-6 isolated from M. cephalus yielded two new metabolites that demonstrated moderate cytotoxicity towards HL-60 and P388 cell lines (IC50 ranged from 10.3 to 24.1 µM, respectively), compared to 5-FU (IC50 2.7 and 1.7 µM) in the MTT assay [41]: chaetomugilins G (14) and H (15).

In another study by Yamada et al. on the same fungus, two new compounds named seco-chaetomugilins A (3) and D (8) were separated. Compound 8 exhibited weak activity (IC50 38.6–53.6 μM) towards HL-60, P388, KB, and L1210, compared with 5-FU (IC50 1.7–6.0 μM); however, 8 was inactive. It was suggested that the C-12-hydroxyl group decreased the activity [48].

Chaetomugilins I (16), J (18), 11-epichaetomugilin A (4), 4′-epichaetomugilin A (5), and 106B-6 XXVIII (1) were separated from C. globosum 106B-6 and assessed for cytotoxic activity towards P388, HL-60, L1210, and KB cell lines. Interestingly, compounds 16 and 18 had significant cytotoxicity (IC50 1.1–2.3 µM for 16 and 2.8–12.8 µM for 18) towards all cell lines equal to that of 5-FU (IC50 1.1–7.7 µM). In addition, 16 showed potent and selective cytotoxic activity towards a panel of 39 human cell lines. The other compounds exhibited moderate to marginal activity toward the tested cell lines [37].

Muroga et al. assessed the cytotoxicity of the new metabolites, chaetomugilins I–O (16 and 18–23), towards P388, HL-60, L1210, and KB cell lines using the MTT assay. Compounds 16, 18–20, 22, and 23 revealed remarkable cytotoxicity (IC50 ranged from 1.1 to 20.1 µM) towards all cell lines, compared to 5-FU (IC50 1.1–7.7 µM), whereas chaetomugilin M (21) was inactive. Particularly, compound 16 was more potent than 5-FU. Further, 16 had selective and potent cytotoxicity towards a panel of 39 human cell lines [58].

Furthermore, the new metabolites, 11- and 4′-epichaetomugilin A (4 and 5) purified from C. globosum isolated from M. cephalus, displayed moderate to weak cytotoxicity toward KB, P388, HL-60, and L1210 cell lines [35].

The new metabolites, chaetomugilins P–R (24–27) and 11-epi-chaetomugilin I (17), along with the formerly separated chaetomugilin I (16), were purified by the marine fish-associated C. globosum (Figure 4 and Figure 5) [59]. Compounds 24, 17, and 16 possessed stronger cytotoxicity towards HL-60, P388, KB, and L1210 (IC50 1.1, 1.1, 2.3, and 1.9 μM, respectively, for 16; 1.0, 0.7, 1.2, and 1.6 μM, respectively, for 17; and 1.2, 0.7, 1.8, and 1.5 μM, respectively, for 24) cell lines than 5-FU (IC50 2.7, 1.7, 7.7, and 1.1 μM, respectively). The results indicated that the C-2′–C-4′ enone moiety is essential for activity. On the other hand, compounds 25–27 were weakly to moderately active towards all tested cancer cell lines (IC50 32.0–80.2 μM) [59].

Figure 4.

Figure 4

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Structures of compounds 17–24.

Figure 5.

Figure 5

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Structures of compounds 25–31 (* Revised by Makrerougras et al).

The new metabolites, chaetomugilin S (28), T (29), and U (30), separated from C. globosum derived from M. cephalus, revealed moderate to high growth inhibition towards HL-60, P388, KB, and L1210 cell lines (IC50 ranging from 34.4 to 94.9 µM), relative to 5-FU (IC50 1.9–20.6 µM) [43].

In 2019, Sun et al. evaluated the cytotoxicity of the new glutamine-containing derivatives, N-glutarylchaetoviridins A–C (35, 39, and 42), in addition to chaetomugilins A (2) and C (7) from the extract of deep-sea sediment-associated C. globosum HDN151398 toward BEL-7402, HeLa, HCT-116, L-02, HO8910, MGC-803, SH-SY5Y, U87, NCI-H1975, and MDA-MB-231 cancer cells using the SRB method and towards HL-60 and K562 using MTT method (Figure 6). Chaetomugilins A (2) and C (7) and N-glutarylchaetoviridin C (42) exhibited powerful cytotoxicity towards all tested cell lines (IC50 5.7–27.1 µM for 2, 6.6–26.6 µM for 7, and 6.6–26.5 µM for 42) compared to adriamycin (IC50 0.1–0.6 µM) [22]. Among them, N-glutarylchaetoviridin C (42) had a remarkable cytotoxicity toward MGC-803 and HO-8910 (IC50 6.6 and 9.7 µM, respectively) [22].

Figure 6.

Figure 6

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Structures of compounds 32–36 (* Revised and renamed by Makrerougras et al.).

Chaetomugilin A (2), 11-epi-chaetomugilin A (4), and chaetomugilin D (8) displayed no noticeable cytotoxic activity (IC50 ˃ 40 μM) toward HepG-2, A549, and HeLa in the MTT assay compared to etoposide (IC50 16.11, 16.46, and 15.00 μM, respectively) [46].

Wani et al. reported that seco-chaetomugilin D (9) isolated from C. cupreum had cytotoxicity towards MCF-7 (inhibition ranging from 25.25% to 75.25% after 24 h and from 41.5% to 99% after 38 h at 3.12–50 µg/mL). Further, it increased mitochondrial membrane depolarization (16.45% and 32.25% at 5 and 15 µg/mL, respectively) and induced ROS production (19.6% and 26.2% at 5 and 15 µg/mL, respectively) in comparison to untreated cells. Therefore, it caused cell death via induction of mitochondrial ROS production and membrane depolarization [29].

C. globosum isolated from Ginkgo biloba leaves yielded chaetomugilin D (8) and chaetomugilin A (2), which demonstrated significant toxicity toward brine shrimp (Artemia salina) larvae after 24 h (mortality rates 75.2 and 78.3%, respectively, at 10 µg/mL) [42].

Hu et al. proved that chaetomugilin J (18) combined with low-dose cisplatin decreased cell viability and boosted cisplatin-produced apoptosis in ovarian A2780 cells independently of the endoplasmic reticulum apoptotic pathway. It significantly induced mitochondrial dysfunction and apoptosis via increasing the intracellular and mitochondrial ROS levels and decreasing mitochondrial membrane potential. It also prohibited parkin/PINK1 induced mitophagy, resulting in weakening the mitophagy protective effect that led to apoptosis and increased sensitivity to cisplatin [34]. Chaetomugilin D (8), chaetoviridin A (31), and chaetoviridin E (44) purified from a deep sea-derived Chaetomium sp. NA-S01-R1 displayed moderate to weak cytotoxicity toward HeLa, A549, and HepG2, in comparison to doxorubicin (IC50 0.1–1.1 µM) using the CCK-8 assay [25] (Figure 7). Additionally, chaetoviridin A (31) and chaetoviridin E (44) were inactive towards AGS and MGC803 [71].

Figure 7.

Figure 7

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Structures of compounds 37–44 (* Revised Kingsland and Barrow).

In addition, chaetoviridins E and F (44 and 47) had cytotoxicity toward NCI-H187, KB, and BC1 (IC50 ranging from 3.5 to 13.4 µg/mL), in comparison to ellipticine (IC50 ranging from 0.26 to 0.36 µg/mL) [60].

Chaetoviridin A (31) (2 µM, ID50 0.6 μM) inhibited the inflammatory activity of TPA (12-O-tetradecanoylphorbol-13-acetate, 1 µg) in mice (ID50 0.6 μM). Furthermore, it markedly suppressed the promoting effect of TPA on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]an-thracene (50 μg). It was proposed that it inhibited TPA-tumor promotion in a two-stage carcinogenesis model in mice due to its anti-inflammatory potential [76].

C. globosum TY1 associated with Ginkgo biloba barks yielded chaetoviridins B (38) and E (44) and 5′-epi-chaetoviridin A (33). Compounds 44 and 33 had moderate cytotoxicity towards HepG-2 (IC50 40.6 and 35.3 µM, respectively) compared to camptothecin (IC50 32.3 µM) in the SRB assay, and 38 was inactive [72].

C. globosum isolated from Artemisia desterorum roots yielded chaetoviridin E (44) and chaetoviridin A (31). They had no cytotoxic activity toward A549, HCT116, and HepG2 cancer cells [68]. The new metabolite, epi-chetomugilin D (10), along with chaetovirdins A (31), B (37), and E (44) and chetomugilins D (8) and J (18) were purified from C. globosum associated with Adiantum capillus-veneris. Chaetovirdin E (5 µg/mL) exhibited cytotoxicity towards CaCO2 and HepG2 cancers cells with 30% and 59% inhibition, respectively [49].

3.2. Antimicrobial Activity

The liquid culture of C. globosum DAOM-240359 isolated from an indoor air sample collected from Ottawa, Ontario, Canada produced new nitrogen-containing chaetoviridins, 4′-epi-N-2-hydroxyethyl-azachaetoviridin A (36) and N-2-butyric-azochaetoviridin E (46), along with chaetoviridin A (31) and chaetomugilin D (8). Compound 36 is a nitrogenous derivative of 31 with an N-2-hydroxy ethyl chain and (R) configuration at C-4′ instead of the (S) configuration of 31. Compound 46 is a nitrogenous derivative of chaetoviridin E (44) with a C-2 γ-aminobutyric acid moiety. This represents the first reported azaphilone with a 3-methyl-1-pentyl group and an N-2 side chain. Compounds 8 and 46 significantly reduced the growth of Pseudomonas putida and B. subtilus (conc. 20 µM) in the quantitative growth inhibition assay. Additionally, they showed the same effectiveness as chloramphenicol at 200 µM. On the other hand, 8 and 46 showed antifungal activity towards Saccharomyces cerevisiae at 2 mM and 200 µM, respectively. However, 31 exerted its antibacterial activity at 200 µM [50]. Chaetovirdin A (31) possessed weak inhibitory potential towards induction of chlamydospore-like cells of the plant pathogen Cochliobolus lunatus (40–50% at 100 µg/disc), and prohibition of the rice-blast fungus Pyricuralia oryzae’s growth (IC50 2.5 µg/mL) [27]. The new metabolites, 5′-epichaetoviridin A (33), 4′-epichaetoviridin F (48), 12β-hydroxychaetoviridin C (41), and chaetoviridins G-I (49, 51, and 52), along with chaetoviridins A–E (31,37, 40, 43, and 44) and 4′-epichaetoviridin A (32) separated from the endophytic fungus C. globosum, were assessed in an in vivo pathogenicity assay that involved the infection of Caenorhabditis elegans with Enterococcus faecalis (Figure 8). None of them possessed a significant ability to promote nematode survival [36]. Park et al. stated that chaetoviridins A (31) and B (37) also possessed growth inhibitory activity against Magnaporthe grisea (rice blast) and Pythium ultimum (wheat leaf rust) mycelia (MICs 1.23 and 33.3 and 1.23 and 33.3 μg/mL, respectively) in vitro [61]. They also exhibited strong in vivo antifungal activity against M. grisea and Puccnicia recondite (wheat leaf rust) [36]. Chaetoviridin A (Conc. 62.5 µg/mL) inhibited rice blast development by >80%, but it had moderate control (50%) of tomato late blight at 125 µg/mL. Therefore, they can control wheat leaf rust rice blast and tomato late blight [36,61]. Chaetoviridin A (31), chaetoviridin E (44), and chaetomugilin D (8) separated from a deep sea-derived Chaetomium sp. NA-S01-R1 had weak to moderate antibacterial effectiveness against Vibrio strains (V. vulnificus, V. rotiferianus, and V. campbellii) (MIC 15.4–32.3 µg/mL) and MRSA (MICs 15.2–32.4 µg/mL), compared to erythromycin (MIC 2.0–7.7 µg/mL) and chloramphenicol (MIC 7.5–7.6 µg/mL) [25].

Figure 8.

Figure 8

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Structures of compounds 45–54.

Chaetoviridins B (38) and E (44) displayed antibacterial activity towards E. faecalis and S. aureus [74]. Chaetoviridins A (31) and B (34) also had antimicrobial activity against B. subtilis, Rhizoctonia solani, and E. coli (IZDs 15 and 14 mm, respectively, towards all strains) [63].

Yan et al. reported that chaetoviridin A (31) exhibited significant antifungal potential (EC50 1.97 µg/mL) towards Sclerotinia sclerotiorum, which causes rape Sclerotinia rot (RSR). Further, 31 displayed in vivo protective efficacy (64.3%, dose 200 µg/mL) towards RSR, comparable to that of carbendazim (69.2%). Additionally, it had antifungal activity towards Botrytis cinerea, Phytophthora capsici, Fusarium graminearum, and F. moniliforme (inhibition rates 69.1, 60.7, 77.0, and 59.2%, respectively) [73].

C. globosum CEF-082, isolated from cotton plants, produced chaetoviridin A (31), which possesses significant antifungal activity towards Verticillium dahlia, which causes cotton Verticillium wilt (CVW). It induced mycelial deformation and cell necrosis, increased NO and ROS production, prohibited the germination of microsclerotia of V. dahliae, and boosted the cotton defensive response [69].

Chaetoviridin A (31), 5′-epichaetoviridin A (33), and chaetoviridin E (44) were separated from the soil-associated C. globosum 22–10. They showed significant inhibitory effectiveness (inhibition 32.31%, 15.38%, and 13.85%, respectively) at 100 µg/mL towards Bipolaris sorokiniana, a soil-borne pathogen that commonly causes wheat root rot. It is noteworthy that chaetoviridin A had the same inhibitory efficiency as the carbendazim (3 mg/mL), suggesting its potential to be a biocontrol agent for B. sorokiniana [67]. Further, chaetoviridin A identified from an EtOAc extract of C. globosum F211_UMNG isolated from P. heptaphyllum was active towards F. oxysporum [66]. Chaetomugilin D (8) and chaetoviridin A (31) (200 µM) significantly reduced the growth of B. subtilis and Psuedomonas putida [55].

3.3. Phytotoxic Activity

The EtOAc extract of C. globosum associated with Amaranthus viridis yielded chaetomugilin D (8) and chaetomugilin J (18), which exhibited phytotoxic potential against lettuce (Lactuca sativa) seed germination with IC50 24.2 and 22.6 ppm, respectively, for root growth inhibition, and IC50 27.8 and 21.9 ppm, respectively, for shoot growth inhibition. The results revealed the potential of these metabolites as herbicides or weedicides that can replace hazardous synthetic compounds [51]. Chaetomugilin A (2), D (8), S (28), I (16), J (18), Q (25), and O (23) isolated from C. globosum TY1 exhibited allelopathic activity towards Brassica campestris, Cucumis sativus, Eruca sativa, Daucus carota, Lactuca sativa, Scrophularia ningpoensis, Brassica rapa, and Spinacia oleracea. Among them, 23 exhibited higher germination and root and shoot elongation inhibitory potential with lower IC50 values and higher response indexes than glyphosate (positive control). Moreover, 2, 8, and 28 exhibited similar or better inhibitory effects than glyphosate. At the same time, 2, 8, and 23 were more powerful growth inhibitors than 16, 18, and 25, which could be attributed to the existence of a tetrahydrofuran moiety. On the other hand, 23 had a higher growth-suppression effect than those of 2, 8, and 28, suggesting that the lactone rings may reduce the inhibitory effects [45].

3.4. Antimalarial and Antimycobacterial Activities

Phonkerd et al. isolated new derivatives, chaetoviridins E and F (44 and 47) and 5′-epi-chaetoviridin A (33), together with chaetoviridin A (31) from C cochliodes VTh01 and C. cochliodes CTh05. Compound 44 showed antimalarial activity against P. falciparum (IC50 2.9 µg/mL)—and was compared to artemisinin (IC50 0.001 µg/mL)—using the microculture radioisotope technique [60]. Additionally, 44 and 47 displayed weak antimycobacterial potential towards M. tuberculosis (MIC 50 and 100 µg/mL, respectively), in comparison to isoniazid and kanamycin sulfate in the microplate Alamar Blue assay (MABA) [60].

3.5. Anti-Inflammatory Activity

Chaetomugilin D (8) from C. globosum isolated from damp building materials notably increased TNF-α production in RAW 264.7 murine macrophages. Therefore, 8 contributes to the non-allergy-linked respiratory disorders such as non-allergic asthma and rhinitis for people working and living in damp buildings [52]. Two new derivatives, chaetoviridins J (53) and K (54), along with 11-epi-chaetomugilin I (17) and chaetomugilins E (11), F (13), I (16), J (18), and N (22) biosynthesized by C. globosum were isolated from Wikstroemia uva-ursi leaves. Their structures were verified by NMR, Mosher’s method, X-ray diffraction, and CD. Chaetoviridin K (54) was separated as a mixture of diastereoisomers that could not be purified by chiral columns. Their potential to inhibit TNF-α-induced NF-κB and NO (nitric oxide) production in the LPS-stimulated RAW 264.7 cells was assessed. Compounds 16 and 17 remarkably suppressed TNF-α-induced NF-κB activity (IC50 0.9 µM, at 50 µM), in comparison to BAY-11 (IC50 2.0 µM) and TPCK (IC50 3.8 µM), whereas 11, 13, and 18 possessed moderate inhibitory activity (IC50 ranging from 5.1 to 11.6 µM, conc. 50 µM). In addition, 11, 13, 16–18, and 53 strongly prohibited NO production (74.2–99.9%). It is noteworthy that 16 and 17 powerfully suppressed NO release (IC50 0.3 and 0.8 µM, respectively) more than N-monomethyl-L-arginine (IC50 25.1 µM). On the other hand, 11, 13, and 18 also considerably inhibited NO production (IC50 values ranging from 1.9 to 5.8 µM); however, 54 exhibited a weak effect [56].

3.6. Antidiabetic, Antioxidant, and Antiviral Activities

Chaetomugilins A (2), I (16), J (18), and Q (25) and chaetoviridins B (38) and J (53) purified from the EtOAc extract of C. globosum TY-1 isolated from Ginkgo biloba bark were tested for α-amylase and α-glucosidase inhibitory activity. Chaetoviridin B (38) had promising α-glucosidase inhibitory potential (IC50 6.328 µM), compared to acarbose (IC50 54.7 µM). The other compounds displayed no α-amylase or α-glucosidase inhibitory activity (IC50 > 50 µM) compared to acarbose (IC50 13.7 and 54.7 µM, respectively) [47]. Chaetoviridin B (38) and chaetomugilin A (2) have the same skeleton except for the 2 having one more hydroxyl group in the side chain, revealing that the group is detrimental for α-glucosidase inhibition [47]. Chaetoviridins A (31) and B (37) purified from an EtOAc extract of C. globosum exhibited noticeable antioxidant potential on TLC using DPPH [63]. Additionally, chetomugilin D (8) and its analog epi-chetomugilin D (10) possessed antiviral activity towards HSV-2 (inhibition 33.3% and 40.7%, respectively, at 25µg/mL [49].

3.7. Caspase-3 and Monoamine Oxidase (MAO) Inhibitory Activities

Caspase-3 (cysteine aspartyl-specific protease-3) is one of the executioners in caspase-linked apoptosis that is activated in nearly every apoptosis model [77]. It is a prominent therapeutic target for excessive apoptosis-associated disorders, such as ischemic damage and neurodegenerative disorders (e.g., Huntington’s and Alzheimer’s diseases) and autoimmune disorders [78]. New azaphilones, chaetomugilin S (27), 7,5′-bis-epi-chaetoviridin A (34), and 7-epi-chaetoviridin E (45), purified from the lichen-associated C. elatum 89-1-3-1, were isolated from Ramalina calicaris. Their absolute configurations were assigned by CD experiments and X-ray crystallography. They exhibited caspase-3 inhibitory potential (IC50 20.6, 10.9, and 7.9 µM, respectively) in the cysteine aspartyl-specific protease-3 enzymatic assay compared with Ac-DEVD-CHO (IC50 13.7 nM) [31]. On the other hand, 31 possessed weak MAO inhibitory potential (IC50 1.2 × 10−2 g/mL) [27].

3.8. Cholesteryl Ester Transfer Protein Inhibitory Activity

CETP allows the transfer and exchange of neutral lipids such as CE (cholesteryl ester) and TG (triacylglycerol) between plasma and lipoproteins. It is proven to play important role in atherosclerosis [79]. Tomoda et al. reported that chaetoviridin B (37) showed CETP (cholesteryl ester transfer protein) inhibitory activity with an IC50 < 6.3 µM, whereas chaetoviridin A (31) had moderate inhibitory activity (IC50 31.6 µM) [80]. It was indicated that the existence of an electrophilic enone(s) and/or ketone(s) at both C-8 and C-6 of isochromane core is substantial for eliciting activity [80].

3.9. Anti-SARS-CoV-2 Activity

The COVID-19 pandemic has affected global health since 2019. COVID-19 can lead to acute respiratory distress syndrome [81]. It is produced by a novel type of coronavirus (CoV) called SARS-CoV-2 that was first found in Wuhan City, China, and then spread worldwide [82,83]. It is considered a highly pathogenic CoV in the human population. The SARS-CoV-2 genome encodes two polyproteins which are processed by a 3C-like protease (3CLpro) and a papain-like protease [84]. 3CLpro (3C-like protease) and PLpro (papain-like protease) are needed for processing the polyproteins into mature nonstructural proteins, such as helicase and RdRp (RNA-dependent RNA polymerase), which are substantial for viral replication and transcription [85]. 3CLpro has high substrate specificity and is also referred to as Mpro (main protease) [86]. 3CLpro’s substrate specificity makes this enzyme an ideal target for developing broad-spectrum antiviral agents [87]. Its inhibitors are expected to have selective toxicity towards the virus [88].

Fungi are a treasure that can provide a remarkable pool of secondary metabolites with antiviral activities [89]. The characterization and discovery of antiviral fungal metabolites is an emerging and promising research field. Recently, many reports have been published on the structure-based virtual screening approach for the repurposing of natural metabolites, hoping to accelerate and assist in the discovery of agents for COVID-19 treatment [82]. We carried out a computational study on the reported fungal chaetomugilins and chaetoviridins was carried out to identify their 3CLpro inhibitory potential, using docking calculations and MD simulations (Table 3, Table 4, Table 5, Table 6 and Table 7). Three crystal structures containing non-covalent inhibitors for the protease (PDB entry: 6W81, 6M2N, and 7K0F) were selected. All the listed metabolites were docked with extra precision for maximum accuracy. The docking method was validated by redocking the inhibitors that co-crystallized with 6W81, 6M2N, and 7K0F; and RMSD values were within an acceptable range and less than 1.50 Å. All the redocked inhibitors revealed the same binding interaction with the active site in the original pose. Further, in silico ADMET (drug absorption, distribution, metabolism, excretion, and toxicity) predictions of the properties of the investigated compounds were carried out. Finally, a molecular dynamics simulation was conducted to evaluate the nature of the ligand–target interaction under simulated physiological conditions for the most compatible drug-like molecule that could be used in pursuit of a truly adequate medication for COVID-19.

Table 3.

In silico screening results of top candidates of the reported chaetomugilins and chaetoviridins against SARS-CoV-2 3CL protease (PDB: 6W81, 6M2N, and 7K0F).

Name & Structure For 6W81 For 6M2N For 7K0F
Docking Score Glide Gscore Glide Emodel XP GScore Docking Score Glide Gscore Glide Emodel XP Gscore Docking Score Glide Gscore Glide Emodel XP Gscore
graphic file with name jof-08-00127-i001.jpg −6.901 −6.918 −45.952 −6.918 −6.862 −6.879 −40.382 −6.879 −6.428 −6.445 −45.402 −6.445
graphic file with name jof-08-00127-i002.jpg −6.634 −6.933 −53.592 −6.933 −6.657 −7.205 −59.649 −7.205 −6.214 −6.762 −57.163 −6.762
graphic file with name jof-08-00127-i003.jpg −7.293 −7.294 −52.497 −7.294 −7.851 −7.851 −46.384 −7.851 −6.886 −6.904 −44.124 −6.904
graphic file with name jof-08-00127-i004.jpg −6.838 −7.269 −59.268 −7.269 −7.4 −7.791 −61.032 −7.791 −6.599 −7.03 −50.901 −7.03
graphic file with name jof-08-00127-i005.jpg −6.94 −6.958 −40.421 −6.958 −6.921 −6.939 −42.35 −6.939 −6.886 −6.904 −44.124 −6.904
graphic file with name jof-08-00127-i006.jpg −6.48 −6.48 −57.388 −6.48 −7.519 −7.519 −67.872 −7.519 −7.311 −7.311 −65.197 −7.311
graphic file with name jof-08-00127-i007.jpg −7.944 −7.944 −51.069 −7.944 −8.141 −8.141 −48.92 −8.141 −6.615 −6.615 −60.199 −6.615
Inline graphic
Ref_6W81		 −5.377 −5.377 −86.001 −5.377
Inline graphic
Ref_6M2N		 −6.995 −6.995 −52.4 −6.995
Inline graphic
Ref_K0F		 −8.159 −8.159 −113.296 −8.159
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Table 4.

In silico screening results of the reported chaetomugilins and chaetoviridins against SARS-CoV-2 3CL protease (PDB: 6W81).

Fungal Chaetomugilins and Chaetoviridins Docking Score Glide Gscore Glide Emodel XP Gscore
Chaetovirdin D (43) −7.944 −7.944 −51.069 −7.944
Chaetomugilin P (24) −7.293 −7.294 −52.497 −7.294
N-Glutrylchaetovirdin A (35) −7.101 −7.101 −66.739 −7.101
Chaetovirdin B (37) −6.959 −6.959 −37.203 −6.959
Chaetomugilin R (26) −6.94 −6.958 −40.421 −6.958
Chaetomugilin 106B-6 XXVIII (1) −6.901 −6.918 −45.952 −6.918
N-Glutarylchaetovirdin C (42) −6.881 −6.881 −60.87 −6.881
Chaetomugilin Q (25) −6.838 −7.269 −59.268 −7.269
Chaetomugilin EA-4 (12) −6.634 −6.933 −53.592 −6.933
7,4′,5′-Tris-Epi-chaetovirdin A (34) −6.519 −6.519 −56.68 −6.519
4′-Epi-N-2-Hydroxyethyl-azachaetovirdin A (36) −6.48 −6.48 −57.388 −6.48
Chaetomugilin T (26) −6.407 −6.407 −45.87 −6.407
Chaetovirdin J (53) −6.295 −6.673 −54.688 −6.673
12β-Hydroxychaetovirdin C (41) −6.074 −6.08 −54.03 −6.08
Chaetomugilin M (21) −5.985 −6.143 −53.589 −6.143
Chaetovirdin G (50) −5.925 −5.925 −50.419 −5.925
Chaetomugilin I (16) −5.919 −6.467 −53.609 −6.467
N-2-Butyric-azochaetovirdin E (46) −5.862 −5.863 −58.955 −5.863
11-Epi-chaetomugilin A (4) −5.771 −5.774 −45.965 −5.774
Chaetovirdin C (40) −5.752 −5.752 −48.221 −5.752
Chaetomugilin H (15) −5.741 −5.741 −40.295 −5.741
N-Glutarylchaetovirdin B (39) −5.733 −5.735 −57.615 −5.735
Chaetomugilin U (30) −5.622 −5.622 −40.195 −5.622
4′-Epi-chaetovirdin A (5) −5.561 −5.561 −47.473 −5.561
Chaetomugilin S (27) −5.539 −5.539 −45.867 −5.539
4′,5′-Bis-chaetovirdin A (33) −5.507 −5.507 −48.38 −5.507
Chaetovirdin A (31) −5.493 −5.493 −51.732 −5.493
Ref_6W81 −5.377 −5.377 −86.001 −5.377
Chaetovirdin I (52) −5.354 −5.419 −42.206 −5.419
Seco-Chaetomugilin D (9) −5.345 −5.347 −45.22 −5.347
Chaetomugilin L (20) −5.25 −5.25 −39.261 −5.25
Chaetomugilin B (6) −5.248 −5.248 −41.211 −5.248
Chaetomugilin A (2) −5.241 −5.243 −44.852 −5.243
11-Epi-chaetomugilin I (17) −5.099 −5.647 −54.765 −5.647
Chaetomugilin D (8) −5.093 −5.095 −41.171 −5.095
7-Epi-chaetovirdin E (45) −5.089 −5.089 −40.702 −5.089
Chaetovirdin K (54) −4.987 −4.989 −45.166 −4.989
Chaetomugilin N (22) −4.977 −4.977 −3454.68 −4.977
Seco-chaetomugilin A (3) −4.926 −4.928 −54.168 −4.928
Chaetomugilin K (19) −4.903 −4.903 −38.494 −4.903
Chaetovirdin H (51) −4.898 −4.898 −51.406 −4.898
4′-Epi-chaetovirdin F (X48) −4.873 −4.873 −47.708 −4.873
Chaetovirdin B (38) −4.792 −4.794 −42.458 −4.794
Chaetovirdin E (44) −4.61 −4.61 −48.663 −4.61
Chaetomugilin G (14) −4.516 −4.516 −50.66 −4.516
Chaetomugilin S (28) −4.391 −4.393 −48.292 −4.393
Chaetomugilin F (13) −4.28 −4.28 −40.132 −4.28
Chaetovirdin F (47) −4.271 −4.271 −50.793 −4.271
Epi-chaetomugilin D (10) −4.137 −4.139 −36.43 −4.139
Chaetomugilin E (11) −3.597 −3.597 −40.424 −3.597
Chaetomugilin C (7) −3.509 −3.509 −44.435 −3.509
Chaetovirdin G (49) −3.492 −3.492 −48.133 −3.492
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Table 5.

In silico screening results of the reported chaetomugilins and chaetoviridins against SARS-CoV-2 3CL protease (PDB: 6M2N).

Fungal Chaetomugilins and Chaetoviridins Docking Score Glide Gscore Glide Emodel XP Gscore
Chaetovirdin D (43) −8.141 −8.141 −48.92 −8.141
Chaetovirdin B (37) −7.851 −7.851 −46.384 −7.851
4′-Epi-N-2-Hydroxyethyl-azachaetovirdin A (36) −7.519 −7.519 −67.872 −7.519
Chaetomugilin Q (25) −7.4 −7.791 −61.032 −7.791
12β-Hydroxychaetovirdin C (41) −7.045 −7.051 −58.607 −7.051
Ref_6M2N −6.995 −6.995 −52.4 −6.995
Chaetomugilin R (26) −6.921 −6.939 −42.35 −6.939
Chaetomugilin P (24) −6.9 −6.901 −48.711 −6.901
Chaetomugilin 106B-6 XXVIII (1) −6.862 −6.879 −40.382 −6.879
Chaetomugilin S (27) −6.785 −6.785 −50.138 −6.785
Chaetomugilin EA-4 (12) −6.657 −7.205 −59.649 −7.205
Chaetomugilin M (21) −6.655 −6.813 −56.59 −6.813
7,4′,5′-Tris-Epi-chaetovirdin A (34) −6.44 −6.44 −55.163 −6.44
Chaetovirdin I (52) −6.439 −6.504 −53.296 −6.504
Chaetovirdin J (53) −6.362 −6.741 −54.219 −6.741
Chaetovirdin G (50) −6.312 −6.312 −48.248 −6.312
Chaetomugilin G (49) −6.272 −6.272 −56.423 −6.272
Chaetovirdin C (40) −6.219 −6.219 −59.734 −6.219
N-Glutarylchaetovirdin B (39) −6.178 −6.179 −53.868 −6.179
11-Epi-chaetomugilin I (17) −6.077 −6.625 −61.469 −6.625
Chaetovirdin H (51) −6.071 −6.071 −45.006 −6.071
Chaetovirdin A (31) −5.93 −5.93 −47.164 −5.93
4′,5′-Bis-chaetovirdin A (33) −5.896 −5.896 −46.971 −5.896
Seco-chaetomugilin A (3) −5.89 −5.892 −44.484 −5.892
Chaetovirdin E (44) −5.871 −5.871 −48.647 −5.871
Chaetomugilin I (16) −5.87 −6.418 −55.891 −6.418
Chaetovirdin F (47) −5.866 −5.866 −54.419 −5.866
4′-Epi-chaetovirdin F (48) −5.859 −5.859 −51.775 −5.859
Chaetomugilin F (13) −5.759 −5.759 −43.54 −5.759
N-2-Butyric-azochaetovirdin E (46) −5.453 −5.454 −54.064 −5.454
N-Glutrylchaetovirdin A (35) −5.405 −5.405 −59.359 −5.405
Seco-Chaetomugilin D (9) −5.376 −5.379 −41.076 −5.379
Chaetomugilin H (15) −5.293 −5.293 −52.628 −5.293
Chaetovirdin B (38) −5.217 −5.219 −38.105 −5.219
11-Epi-chaetomugilin A (4) −5.166 −5.168 −41.465 −5.168
Chaetovirdin K (54) −5.11 −5.113 −38.902 −5.113
Chaetomugilin A (2) −5.09 −5.092 −36.177 −5.092
Chaetomugilin T (29) −5.012 −5.012 −39.774 −5.012
Chaetomugilin C (7) −4.987 −4.987 −44.839 −4.987
4′-Epi-chaetovirdin A (32) −4.905 −4.905 −58.103 −4.905
Chaetomugilin S (28) −4.627 −4.629 −36.966 −4.629
Chaetovirdin G (49) −4.612 −4.612 −42.176 −4.612
7-Epi-chaetovirdin E (45) −4.485 −4.485 −51.758 −4.485
Epi-chaetomugilin D (10) −4.341 −4.343 −31.912 −4.343
Chaetomugilin U (30) −4.248 −4.249 −40.187 −4.249
Chaetomugilin O (23) −4.208 −4.208 −1767.6 −4.208
Chaetomugilin N (22) −4.07 −4.07 −31.442 −4.07
Chaetomugilin B (6) −4.068 −4.068 −41.99 −4.068
Chaetomugilin K (19) −3.867 −3.867 −34.284 −3.867
Chaetomugilin D (8) −3.667 −3.669 −35.613 −3.669
Chaetomugilin L (20) −3.622 −3.622 −38.371 −3.622
Chaetomugilin E (11) −3.506 −3.506 −41.116 −3.506
N-Glutarylchaetovirdin C (42) −1.412 −1.412 −62.951 −1.412
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Table 6.

In silico screening results of the reported chaetomugilins and chaetoviridins against SARS-CoV-2 3CL protease (PDB: 7K0F).

Fungal Chaetomugilins and Chaetoviridins Docking Score Glide Gscore Glide Emodel XP Gscore
Ref_7K0F −8.159 −8.159 −113.296 −8.159
4′-Epi-N-2-Hydroxyethyl-azachaetovirdin A (36) −7.311 −7.311 −65.197 −7.311
Chaetomugilin R (26) −6.886 −6.904 −44.124 −6.904
Chaetovirdin D (43) −6.615 −6.615 −60.199 −6.615
Chaetomugilin Q (25) −6.599 −7.03 −50.901 −7.03
Chaetomugilin 106B-6 XXVIII (1) −6.428 −6.445 −45.402 −6.445
Chaetovirdin I (52) −6.381 −6.446 −60.443 −6.446
Chaetomugilin EA-4 (12) −6.214 −6.762 −57.163 −6.762
Seco-chaetomugilin A (3) −6.164 −6.166 −54.533 −6.166
Chaetomugilin T (29) −6.003 −6.003 −44.936 −6.003
Chaetomugilin A (2) −5.937 −5.939 −49.214 −5.939
4′-Epi-chaetovirdin F (48) −5.781 −5.781 −53.249 −5.781
Chaetovirdin G (50) −5.73 −5.73 −46.915 −5.73
11-Epi-chaetomugilin A (4) −5.634 −5.636 −45.502 −5.636
Chaetomugilin M (21) −5.56 −5.718 −41.62 −5.718
Chaetovirdin K (54) −5.521 −5.523 −43.983 −5.523
Chaetovirdin H (51) −5.487 −5.487 −53.211 −5.487
Chaetovirdin J (53) −5.475 −5.853 −56.559 −5.853
Chaetomugilin D (8) −5.457 −5.459 −40.705 −5.459
Chaetomugilin S (28) −5.409 −5.411 −37.945 −5.411
Chaetovirdin A (31) −5.356 −5.356 −55.812 −5.356
Chaetomugilin J (18) −5.262 −5.758 −44.768 −5.758
Chaetovirdin F (47) −5.214 −5.214 −51.016 −5.214
Chaetovirdin E (44) −5.207 −5.207 −57.958 −5.207
Chaetomugilin U (30) −5.17 −5.17 −39.245 −5.17
Chaetomugilin G (14) −5.154 −5.154 −52.872 −5.154
4′,5′-Bis-chaetovirdin A (33) −5.147 −5.147 −56.898 −5.147
Chaetomugilin H (15) −5.144 −5.144 −51.211 −5.144
Chaetovirdin C (40) −5.119 −5.119 −51.53 −5.119
Epi-chaetomugilin D (10) −5.11 −5.112 −41.394 −5.112
Chaetomugilin P (24) −5.083 −5.085 −47.434 −5.085
Chaetomugilin S (27) −5.005 −5.005 −53.874 −5.005
N-2-Butyric-azochaetovirdin E (46) −4.926 −4.927 −58.939 −4.927
7,4′,5′-Tris-Epi-chaetovirdin A (34) −4.883 −4.883 −50.65 −4.883
11-Epi-chaetomugilin I (17) −4.785 −5.084 −57.348 −5.084
Chaetomugilin B (6) −4.732 −4.732 −44.687 −4.732
Chaetomugilin I (16) −4.534 −4.834 −53.036 −4.834
Chaetomugilin C (7) −4.469 −4.469 −45.833 −4.469
12β-Hydroxychaetovirdin C (41) −4.352 −4.357 −51.515 −4.357
Chaetomugilin E (11) −4.268 −4.268 −39.678 −4.268
N-Glutarylchaetovirdin C (42) −4.247 −4.247 −59.534 −4.247
Chaetomugilin K (19) −4.245 −4.245 −47.953 −4.245
Chaetovirdin G (59) −4.218 −4.218 −46.464 −4.218
Seco-Chaetomugilin D (9) −4.205 −4.207 −48.935 −4.207
N-Glutrylchaetovirdin A (39) −4.171 −4.171 −55.598 −4.171
Chaetomugilin F (13) −3.88 −3.88 −42.311 −3.88
Chaetomugilin R (26) −3.808 −5.942 −41.217 −5.942
7-Epi-chaetovirdin E (45) −3.699 −3.699 −46.38 −3.699
Chaetomugilin L (20) −3.612 −3.612 −43.218 −3.612
4′-Epi-chaetovirdin A (32) −3.552 −3.552 −58.379 −3.552
Chaetomugilin O (23) −2.951 −2.951 31.679 −2.951
Chaetovirdin B (38) −2.642 −2.644 −45.702 −2.644
Chaetomugilin N (22) −0.921 −0.921 −3319.51 −0.921
N-Glutarylchaetovirdin B (39) −0.451 −0.453 −57.257 −0.453
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Table 7.

In silico predicted ADME properties of the selected fungal chaetomugilins and chaetoviridins.

Title Mol MW #Stars Dipole SASA Donor HB accptHB QPlogPo/w QPlogS QPlogKhsa #Metab QPlogBB Percent Human Oral Absorption QPlogHERG CNS #rtvFG
Recommended Range (130–725) (0.0–5.0) (1–12.50) (300–1000) (0–6) (2.0–20.0) (−2–6.5) (−6.5–0.5) (−1.5–1.5) (1–8) (−3–1.2) (<25% Poor; >80% High) Concern Below −5 (−2 Inactive) (+2 Active) (0–2)
Chaetovirdin K (54) 450.915 0 6.534 733.38 2 7.75 3.725 −6.195 0.507 3 −0.978 100 −5.072 −1 2
Chaetovirdin J (53) 408.921 0 9.823 723.174 1 5.95 4.444 −6.019 0.636 6 −1.162 100 −4.971 −2 1
Chaetovirdin I (52) 466.914 0 8.017 729.53 3 9.7 2.323 −5.013 0.029 5 −1.839 77.834 −4.801 −2 1
Chaetovirdin H (51) 398.455 0 10.648 693.648 0 8.2 2.632 −3.929 −0.18 3 −1.388 87.791 −4.859 −2 0
Chaetovirdin G (50) 420.932 0 11.089 718.605 0 6.2 4.554 −5.704 0.494 4 −0.639 100 −4.912 0 1
Chaetovirdin G (49) 416.9 0 9.346 698.669 0 4.5 4.914 −6.381 0.89 5 −0.882 100 −4.698 −1 1
4′-Epi-chaetovirdin F (48) 416.9 0 11.445 723.973 0 7.5 3.722 −5.295 0.155 2 −0.793 100 −5.072 −1 0
Chaetovirdin F (47) 416.9 0 11.992 704.483 0 7.5 3.502 −4.926 0.089 2 −0.858 100 −4.864 −1 0
N-2-Butyric-azochaetovirdin E (46) 499.99 1 13.922 827.776 1 9.5 4.264 −6.466 0.317 6 −2.11 77.59 −3.438 −2 1
7-Epi-chaetovirdin E (45) 414.885 0 11.745 707.051 0 7.5 3.482 −5.136 0.123 3 −0.816 100 −4.941 −1 1
Chaetovirdin E (44) 414.885 0 11.253 703.096 0 7.5 3.481 −5.061 0.115 3 −0.776 100 −4.877 −1 1
Chaetovirdin D (43) 468.93 0 11.587 715.44 3 8.4 3.631 −4.999 0.09 5 −1.572 78.707 −2.816 −2 1
N-Glutarylchaetovirdin C (42) 572.053 0 12.347 840.463 0 11.5 3.737 −4.755 0.074 7 −1.845 73.79 −4.594 −2 3
12β-Hydroxychaetovirdin C (41) 450.915 0 2.581 723.069 1 6.9 3.938 −5.652 0.514 6 −1.528 92.976 −4.818 −2 0
Chaetovirdin C (40) 434.916 1 9.724 758.733 0 5.7 4.847 −6.568 0.718 5 −1.201 100 −5.436 −2 0
Chaetovirdin C (40) 434.916 0 8.19 737.905 0 5.7 4.746 −6.172 0.662 5 −1.084 100 −5.134 −2 0
N-Glutarylchaetovirdin B (39) 544 0 12.329 793.894 2 11.5 3.491 −5.111 −0.161 7 −2.718 36.417 −0.961 −2 1
Chaetovirdin B (38) 434.916 0 5.891 722.451 1 7 4.223 −6.419 0.644 3 −0.608 100 −5.051 0 2
Chaetovirdin B (37) 452.931 0 11.095 702.548 2 6.7 4.584 −5.524 0.416 4 −1.112 90.886 −2.679 −2 1
4′-Epi-N-2-Hydroxyethyl-azachaetovirdin A (36) 475.968 1 14.774 776.474 1 9.9 3.056 −5.251 0.144 6 −2.061 80.997 −4.863 −2 0
N-Glutrylchaetovirdin A (35) 604.095 0 10.792 927.971 0 13.2 3.721 −5.198 −0.147 7 −2.026 76.425 −5.269 −2 2
7,4′,5′-Tris-Epi-chaetovirdin A (34) 432.9 0 12.018 729.829 0 8.2 3.205 −4.877 −0.033 3 −1.26 92.089 −5.078 −2 0
4′,5′-Bis-chaetovirdin A (33) 432.9 0 10.874 710.174 0 8.2 3.028 −4.504 −0.097 3 −1.245 90.472 −4.825 −2 0
4′-Epi-chaetovirdin A (32) 432.9 1 10.365 711.04 0 8.2 3.114 −4.52 −0.071 3 −1.186 91.808 −4.763 −2 0
Chaetovirdin A (31) 432.9 0 11.776 730.571 0 8.2 3.204 −4.891 −0.033 3 −1.263 92.089 −5.091 −2 0
Chaetomugilin U (30) 400.471 0 4.358 680.73 1 7 3.638 −5.427 0.501 3 −0.724 100 −4.736 −1 2
Chaetomugilin T (29) 416.47 0 5.838 708.003 2 8.7 2.784 −5.198 0.232 4 −1.243 89.439 −5.03 −2 2
Chaetomugilin S (28) 434.916 1 3.205 728.386 1 7 4.315 −6.524 0.659 3 −0.522 100 −5.07 0 2
Chaetomugilin S (27) 420.932 0 10.429 713.238 0 6.2 4.401 −5.611 0.469 4 −0.769 100 −4.83 −1 1
Chaetomugilin R (26) 328.792 0 6.746 578.157 3 6.9 1.802 −3.7 −0.18 5 −1.075 83.055 −4.136 −2 0
Chaetomugilin Q (25) 424.92 0 10.445 738.393 2 7.65 3.474 −5.495 0.295 7 −1.67 90.232 −5.126 −2 1
Chaetomugilin P (24) 406.905 0 7.876 701.865 2 6.95 3.532 −5.371 0.361 7 −1.223 95.462 −4.879 −2 1
Chaetomugilin O (23) 416.9 1 15.406 699.173 0 5.25 4.493 −6.001 0.677 4 −0.949 100 −4.786 −1 0
Chaetomugilin N (22) 432.9 1 14.072 676.058 1 6.95 3.558 −5.135 0.461 5 −1.296 90.388 −4.184 −2 0
Chaetomugilin M (21) 450.915 1 12.895 720.323 1 9.9 2.623 −4.609 −0.057 6 −1.517 84.164 −4.712 −2 2
Chaetomugilin L (20) 404.933 1 8.629 737.101 0 4 6.159 −7.539 1.184 4 0.149 100 −5.329 1 1
Chaetomugilin K (19) 420.932 1 6.053 732.931 1 5.7 5.186 −6.78 0.887 5 −0.327 100 −5.087 0 1
Chaetomugilin J (18) 390.906 0 7.403 711.543 1 5.25 4.761 −6.404 0.766 6 −0.712 100 −5.115 −1 1
11-Epi-chaetomugilin I (17) 406.905 0 8.987 705.067 2 6.95 3.831 −5.476 0.389 7 −0.942 100 −4.938 −1 1
Chaetomugilin I (16) 406.905 0 8.14 722.387 2 6.95 3.744 −5.781 0.415 7 −1.23 96.783 −5.14 −2 1
Chaetomugilin H (15) 448.942 1 5.803 788.745 1 6.95 4.895 −7.125 0.798 4 −0.859 100 −5.48 −1 0
Chaetomugilin G (14) 464.942 0 2.574 796.89 2 8.65 3.897 −6.478 0.455 5 −1.373 96.768 −5.491 −2 0
Chaetomugilin F (13) 416.9 0 5.154 721.74 0 6.25 4.481 −6.393 0.6 3 −0.338 100 −5.109 0 0
Chaetomugilin EA-4 (12) 406.905 0 7.867 720.199 2 6.95 3.729 −5.743 0.405 7 −1.214 96.92 −5.132 −2 1
Chaetomugilin E (11) 448.942 0 6.895 737.896 0 7 4.607 −6.146 0.54 3 −0.279 100 −5.022 0 2
Epi-chaetomugilin D (10) 434.916 1 5.857 727.72 1 7 4.222 −6.512 0.645 3 −0.622 100 −5.102 0 2
Seco-Chaetomugilin D (9) 466.958 1 8.323 773.281 1 6.7 4.99 −6.784 0.844 4 −0.967 100 −5.112 −1 2
Chaetomugilin D (8) 434.916 1 5.813 727.059 1 7 4.221 −6.501 0.645 3 −0.621 100 −5.091 0 2
Chaetomugilin C (7) 432.9 0 6.592 728.877 1 7.95 3.666 −6.164 0.441 4 −0.828 100 −5.118 −1 0
Chaetomugilin B (6) 464.942 0 8.241 745.54 1 8.7 3.831 −6.002 0.415 4 −0.756 100 −5.038 −1 2
11-Epi-chaetomugilin A (4) 450.915 0 4.613 735.43 2 8.7 3.255 −5.915 0.322 4 −1.091 93.153 −5.126 −2 2
Seco-chaetomugilin A (3) 482.957 0 7.988 774.455 2 8.4 3.951 −6.021 0.479 5 −1.427 95.73 −5.066 −2 2
Chaetomugilin A (2) 450.915 0 4.464 734.849 2 8.7 3.266 −5.905 0.335 4 −1.106 92.834 −5.084 −2 2
Chaetomugilin 106B-6 XXVIII (1) 328.792 0 6.746 578.786 3 6.9 1.79 −3.71 −0.186 5 −1.081 82.981 −4.167 −2 0
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#Stars: Number of property or descriptor values that fall outside the 95% range of similar values for known drugs. A large number of stars suggests that a molecule is less drug-like than molecules with few stars. Dipole: Computed dipole moment of the molecule. SASA: Total solvent accessible surface area (SASA) in square angstroms using a probe with a 1.4 Å radius. Donor H-bond: Estimated number of hydrogen bonds that the solute would donate to water molecules in an aqueous solution. Acceptor H-bond: Estimated number of hydrogen bonds that the solute would accept from water molecules in an aqueous solution. QPlogPo/w: Predicted octanol/water partition coefficient. QPlogS: Predicted aqueous solubility, log S. QPlogkhsa: Prediction of binding to human serum albumin. No. of Metabolites: Number of likely metabolic reactions. QplogBB: Predicted brain/blood partition coefficient. % Human Oral Absorption: Predicted human oral absorption on 0 to 100% scale. QPlogHERG: Predicted IC50 value for blockage of HERG K+ channels. CNS: Predicted central nervous system activity on a –2 (inactive) to +2 (active) scale. #rtvFG: Number of reactive functional groups; the specific groups are listed in the jobname out file. The presence of these groups can lead to false positives in HTS assays and to decomposition, reactivity, or toxicity problems in vivo.

3.9.1. Preparations of Ligands and Proteins

By using LigPrep, the conversion of 2D structures to 3D, tautomerization, and ionization yielded 254 minimized 3D structures. The minimized 3D structures were used for docking with the crystal structure of the 3CL hydrolase (Mpro). Preparation of the viral protease (6M2N, 6W81, and 7K0f) by the Protein Preparation Wizard tool optimized the H-bonding network and minimized the geometry. Assurance of assigning the proper formal charges and force field treatments was achieved by adding missing hydrogens and correct ionization states (Figure 9).

Figure 9.

Figure 9

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The 3CL pro-hydrolase prepared via Protein Preparation Wizard, Maestro. H-bonding network optimized and geometry minimized structures of 2019-nCOV 3CL hydrolase (Mpro)—PDB ID: (a) 7K0F, (b) 6W81, (c), and 6M2N. Represented as 3D molecular surfaces and ribbon structures.

3.9.2. Molecular Docking Studies

After defining the grid box in the prepared viral protease via the Receptor Grid Generation tool of Glide in Maestro, the prepared 3D molecular structures were docked into the co-crystallized inhibitor binding site of the viral protease. Table 3 shows the results of the top-score docked ligands chosen based on the most negative docking scores. These scores represent the best bound ligand conformations and relative binding affinities. Chaetovirdin D (43) exhibited the highly negative docking scores of −7.944, −8.141, and −6.615 kcal/mol, complexed with 6M2N, 6W81, and 7K0f, respectively. The reference inhibitor exhibited the following scores: −5.377, −6.995, and −8.159 kcal/mol, complexed with 6M2N, 6W81, and 7K0f, respectively.

The docking analysis was updated by re-docking the selected chaetomugilins and chaetoviridins with the three crystal structures of the 3CL pro-hydrolase (PDB ID: 6M2N, 6W81, and 7K0f) at variable resolutions, 2.20, 1.55, and 1.65A, respectively. Analysis of the docking scores of these compounds with the inhibitor binding sites of 2019-nCoV main protease (PDB ID: 6M2N, 6W81, and 7K0f) revealed different docking scores, and hence binding affinities (Table 4, Table 5 and Table 6). These differences can be attributed to the differences in the grid formation due to the presence of different inhibitors in the binding sites of the three crystal structures.

Analysis of the docking of 43 revealed that it interacted through hydrogen bonds (Figure 10) with the binding site residues of SARS-CoV-2 main protease (6W81). The binding site residues Asn141, Gly142, and Thr189 of the viral protease exhibited hydrogen bonding with the various hydroxyl groups of 43. Additionally, 43 interacted through hydrogen bonds (Figure 11) with the binding site residues of SARS-CoV-2 main protease (6M2N). The binding site residues Asn142 and Thr190 of the viral protease showed hydrogen bonding with the various hydroxyl groups of 43. Its interactions through hydrogen bonds with the binding site residues of SARS-CoV-2 main protease (7K0F) are shown in Figure 12. The binding site residues Thr24, His41, Gly143, His 164, and Glu166 of the viral protease displayed H-bonding with the various hydroxyl groups of 43.

Figure 10.

Figure 10

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(A) Putative binding mode of chaetovirdin D in the binding site of 2019-nCOV 3CL hydrolase (Mpro), PDB: 6W81. Chaetovirdin D is displayed as green sticks. The amino acids of the binding site are represented as grey sticks, and H-bonds are represented as yellow dotted lines. (B) 2D depiction of the ligand–protein interactions.

Figure 11.

Figure 11

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(A) Putative binding mode of Chaetovirdin D in the binding site of 2019-nCOV 3CL hydrolase (Mpro), PDB: 6M2N. Chaetovirdin D is displayed as green sticks. The amino acids of the binding site are represented as grey sticks, and H-bonds are represented as yellow dotted lines. (B) 2D depiction of the ligand–protein interactions.

Figure 12.

Figure 12

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(A) Putative binding mode of Chaetovirdin D in the binding site of 2019-nCOV 3CL hydrolase (Mpro), PDB: 7K0F. Chaetovirdin D is displayed as green sticks. The amino acids of the binding site are represented as grey sticks, and H-bonds are represented as yellow dotted lines. (B) 2D depiction of the ligand–protein interactions.

3.9.3. In Silico ADMET Properties of Selected Ligands

Fifty-three compounds from among the reported fungal chaetomugilins and chaetoviridins were selected and processed using LigPrep of the Schrodinger suite (Schrödinger Release 2021-4: LigPrep, Schrödinger, LLC, New York, NY, USA, 2021; making 3D models with ionization states at pH 7.0 ± 0.2 generated by the OPLS3 force field. The QikProp module of the Schrodinger suite (Schrödinger Release 2021-4: QikProp, Schrödinger, LLC, New York, NY, USA, 2021; was used to predict the ADME properties. The predicted ADMET properties are summarized in Table 7. ADMET analysis describes and determines the biological function, drug-likeness, physicochemical characters, and expected toxicity of compounds. This is meant to evaluate the usefulness of the molecules. The examined descriptors, such as drug-likeness, molecular weight, solvent accessible surface area, dipole moment, hydrogen bond acceptors, donor traits, aqueous solubility, octanol/water coefficient, binding to human serum albumin, number of likely metabolic reactions, brain–blood partition coefficient, human oral absorption, IC50 value for blockage of HERG K+ channels, central nervous system activity, and number of reactive functional groups, were predicted for the reported metabolites. The values obtained for all the compounds are in the recommended ranges.

3.9.4. Molecular Dynamics Simulation

The docking studies took a static view for the binding of each molecule in the active site of the protein. A molecular dynamics (MD) simulation computes the atoms movements over time. By using Desmond software, the stability and frequency of the 43 complex with the proteases—PDB ID 6M2N, 6W81, and 7K0f—were studied. Three MD simulations were run for complexes with 43 for 100 ns of simulated time; the complexes’ structures were optimized at pH 7.0 ± 2.0. Complex stability was checked by analysis of the interaction map and the RMSD (root mean square deviation) plot of the ligand and protein.

The RMSD plots in Figure 13a for the chaetovirdin D-SARS-CoV-2 main protease (PDB ID 6W81) complex, Figure 13b for the chaetovirdin D-SARS-CoV-2 main protease (PDB ID 7K0F) complex, and Figure 13c for the chaetovirdin D-SARS-CoV-2 main protease (PDB ID 6M2N) indicate that the complexes tended to stabilize during the simulations (100 ns) with respect to a reference frame at time 0 ns. There were slight fluctuations during the simulations, but within the permissible range of 1–3 Å; hence, they can be considered non-significant. Since the RMSD plots of 43 and protein backbone lie over each other, the formation of a stable complex can be inferred.

Figure 13.

Figure 13

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RMSD analysis of MD simulation trajectory. The RMSD plot obtained for (a) chaetovirdin D-SARS-CoV-2 main protease complex (PDB ID 6W81), (b) chaetovirdin D-SARS-CoV-2 main protease complex (PDB ID 7K0F), and (c) chaetovirdin D-SARS-CoV-2 main protease complex (PDB ID 6M2N). The simulated time of 100 ns shows the formation of a stable complex without any significant conformational changes in protein structure.

Figure 14a shows the residue interactions of chaetovirdin D with SARS-CoV-2 main protease (PDB ID 6W81) (the docked poses were retained during the simulation of 100 ns)—i.e., molecular interactions with His41, Asp141, and Glu165 residues. Moreover, a hydrophobic interaction was also established between the Leu165 and aliphatic hydrocarbons of 43. In Figure 14b, the viral protease (PDB ID 7K0F)-chaetovirdin D contacts over the course of 100 ns are categorized into water bridges, hydrogen bonds, and hydrophobic interactions. The initial docked pose of 43 shows that the important hydrogen bonds (Thr24, His41, Asn142, Gly143, Ser144, Cys145) did not change during the MD simulation. Hydrogen bonding with residue Cys145 was retained for more than 70% of the simulation time. Figure 14c reveals that the viral protease (PDB ID 6M2N)-chaetovirdin D contacts over the course of 100 ns were categorized into water bridges, hydrogen bonds, and hydrophobic interactions. The bar chart shows that hydrogen bonds, hydrophobic contacts, and water bridges prevailed during the course of the simulation. The important hydrogen bonds observed in the initial docked pose of 43 (Thr26, His41, Glu166, Thr190, Gln192) did not change during the MD simulation. Hydrogen bonding with residue Thr26 was retained for more than 5% of the simulation time.

Figure 14.

Figure 14

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Analysis of molecular interactions and types of contacts with 3CL pro-hydrolase during the MD simulations. Detailed schematic interactions of chaetovirdin D atoms with binding site residues of hydrolase crystal structures (a) 6W81, (b) 7K0F, and (c) 6M2N. Interactions happening during more than 30% of the simulation is shown. Normalized stacked bar charts show the viral protease binding site residues interacting with chaetovirdin D via hydrogen bonds, hydrophobic and ionic interactions, and water bridges.

3.9.5. Materials and Methods

Preparation of PDB Structures

The three PDB structures (PDB ID: 6M2N, 6W81, and 7K0f) were downloaded from the Protein Data Bank (Protein Data Bank; available online, prepared, and optimized by using “Protein preparation wizard” tool of Schrödinger suite (Schrödinger Release 2021-4: LigPrep, Schrödinger, LLC, New York, NY, USA, 2021) [90]. For this purpose, the bond orders for untemplated residues and known HET groups were assigned and hydrogens were added. Bonds to metals were broken, zero-order bonds between metals and nearby atoms were added, and formal charges to metals and neighboring atoms were corrected. Disulfide bonds were created. Water molecules beyond 5 Å from HET groups were deleted. For ligands, cofactors and metals het states were generated at pH 7.0 ± 2.0 using LigPrep (Schrödinger Release 2021-4: LigPrep, Schrödinger, LLC, New York, NY, USA, 2021). Finally, H-bonds were optimized by using PROPKA [91] at pH 7.0, water molecules beyond 3 Å from HET groups were removed, and restrained minimization was done using the OPLS4 force field.

Predictions of ADME Properties

The ADME properties and drug-likeness of selected compounds were determined in terms of distribution, absorption, metabolism, excretion, etc., via the QikProp module of Maestro Schrodinger (Schrödinger Release 2021-4: QikProp, Schrödinger, LLC, New York, NY, USA, 2021).

Receptor Grids Generation and Docking

Glide (Schrödinger Release 2021-4: Glide, Schrödinger, LLC, New York, NY, USA, 2021) was utilized for both grid generation and ligands docking. For docking of fifty-three fungal chaetomugilins and chaetoviridins, three grids were generated using the PDB: 6M2N, 6W81, and 7K0f. For the first grid of PDB 6M2N, the binding region was defined by selecting 3WL. For the second grid PDB 6W81, the binding region was defined by selecting X77. For the third grid PDB 7K0f, the binding region was defined by selecting VR4. The non-polar atoms were set for the VdW radii scaling factor to 1.0, and the partial charge cut-off was 0.25. The ligands docking was performed by using the “ligand docking” tool of Schrödinger suite [92]. The selected protocol was standard precision (SP), the ligand sampling method was flexible, and all the other settings were maintained as default.

MD Simulations of Chaetovirdin D in Complexes with 6M2N, 6W81, and 7K0f

MD simulations were run using Schrödinger suite (Schrödinger Release 2021-4: Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY, USA, 2021. Maestro-Desmond Interoperability Tools, Schrödinger, New York, NY, USA, 2021). The systems of 43 in complexes with 6M2N, 6W81, and 7K0f were retrieved from docking results and first tuned through the “System Builder” tool. The solvent model TIP3P and then orthorhombic shape box shape were selected. The side distances box was set to 10 Å, and the system was neutralized by adding Na+ ions. The MD calculations were run for 100 ns per trajectory, with the number of atoms, pressure, and the temperature kept maintained constant (NPT ensemble). Pressure was set to 1.01325 bar and temperature 300.0 K, and the force field was set as OPLS4.

4. Biosynthesis of Chaetomugilins and Chaetoviridins

The biosynthetic studies revealed that these metabolites are generated via a polyketide pathway [93,94,95,96]. Their main polyketide chain was produced from malonate and acetate units in a conventional way [93,95]. Briefly, a reduced triketide chain (I) was the starting unit to give the aromatic intermediate II, which was processed by the halogenase, followed by hydroxylation-stimulated cyclization catalyzed by monooxygenase to yield cazisochromene (III, chloropyranoquinone) [96]. Then, the addition of an oxidized triketide unit (IV) to III by acyltransferase formed the pyranoquinone V. The latter underwent a Knoevenagel reaction, resulting in chaetoviridin A (31). Chaetoviridin A (31) was converted into other chaetomugilins and chaetoviridins through reductions, oxidations, rearrangements, or reactions with amines [93] (Scheme 1).

Scheme 1.

Scheme 1

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Proposed biosynthesis of chaetomugilins and chaetoviridins [93,94,95,96].

5. Conclusions

Fungi are important sources of natural polyketide pharmaceuticals with structural complexities that make them interesting and beneficial biometabolites. Chaetomugilins and chaetoviridins are azaphilone derivatives that are mainly sourced from various Chaetomaceae species. In this work, fifty-six metabolites were isolated from four species, C. globosum, C. cochliodes, C. siamense, C. elatum, and C. subafine, in addition to unidentified Chaetomium species. Most of them were from C. globosum, as shown in Figure 15. The largest quantities of these metabolites were found in 2011 (18 compounds), 2009 (16 compounds), and 2017 (14 compounds) (Figure 16).

Figure 15.

Figure 15

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Chaetomugilins and chaetoviridins from various Chaetomium species.

Figure 16.

Figure 16

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Number of chaetomugilins and chaetoviridins reported per year.

These metabolites have been evaluated for diverse bioactivities, such as cytotoxic, antimicrobial, phytotoxic, antimalarial, anti-mycobacterial, anti-inflammatory, antidiabetic, antioxidant, and antiviral ones; and caspase-3, cholesteryl ester transfer protein, and monoamine oxidase (MAO) inhibitory activities (Figure 17). It was found that some chaetomugilins possessed remarkable cytotoxicity towards certain cancer cell lines, equal to or stronger than the effects of control anticancer drugs, such as chaetomugilins C (7), F (13), I (16), and J (18).

Figure 17.

Figure 17

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Biological activities of chaetomugilins and chaetoviridins.

Some studies revealed that the use of some additional compounds alongside anticancer drugs increased the sensitivity of the cancer cell lines towards these drugs. These metabolites could be further developed into anticancer agents; however, extensive in vivo studies and explorations of their mechanisms of action are needed. Chaetoviridins, particularly chaetoviridin A (31), have substantial activity towards different plant pathogens; thus, they might be used as biocontrol agents. Additionally, some reports revealed that chaetomugilins (e.g., A (2), D (8), O (23), and S (28)) have serious phytotoxicity, more than the positive controls; therefore, they could be utilized for developing natural eco-friendly herbicides or weedicides that can replace hazardous synthetic compounds. However, extensive studies and field trials should be conducted.

In molecular docking studies, chaetovirdin D exhibited the highly negative docking scores of −7.944, −8.141, and −6.615 kcal/mol, in complexes with 6M2N, 6W81, and 7K0f respectively. The reference inhibitor exhibited the following scores: −5.377, −6.995, and −8.159 kcal/mol, in complexes with 6M2N, 6W81, and 7K0f, respectively. By using molecular dynamics simulations, chaetovirdin D’s stability in complexes with the viral protease was analyzed, and it was found to be stable over the course of 100 ns simulation time.

Undoubtedly, chaetomugilins and chaetoviridins are fungi-derived metabolites that have multiple biological activities. They meet all the requirements for becoming drug leads in their respective therapeutic categories. They have varied chemical compositions that might provide the basis for the synthesis and design of novel and effective pharmaceutical agents. The different substituents at various positions in their skeleton play critical roles in the determination of some of their bioactivities. Finally, studies of the possible mechanisms, biosynthetic pathways, structure–activity relationships, and/or derivatization of these metabolites should be the focus of future research.

Author Contributions

Conceptualization, S.R.M.I. and G.A.M.; resources, G.A.M. and S.R.M.I., molecular docking and molecular dynamic, A.M.O.; discussion of the contents, G.A.M., S.R.M.I. and A.M.O., writing—original draft preparation, S.R.M.I., G.A.M. and A.M.O., writing—review and editing, S.R.M.I., G.A.M. and A.M.O. All authors have read and agreed to the published version of the manuscript.

Funding

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number IFPRP: 200-166-1442 and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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