Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

Zhang, Mingyue; Zhang, Qinrong; Zhang, Qunde; Cui, Xinyuan; Zhu, Lifeng

doi:10.3390/md21020084

Open AccessEditor’s ChoiceReview

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

by

Mingyue Zhang

¹,

Qinrong Zhang

¹

,

Qunde Zhang

¹,

Xinyuan Cui

¹ and

Lifeng Zhu

^1,2,*

¹

College of Life Sciences, Nanjing Normal University, Nanjing 210046, China

²

School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China

^*

Author to whom correspondence should be addressed.

Mar. Drugs 2023, 21(2), 84; https://doi.org/10.3390/md21020084

Submission received: 12 January 2023 / Revised: 19 January 2023 / Accepted: 23 January 2023 / Published: 25 January 2023

(This article belongs to the Special Issue Marine Antiparasitic Agents)

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Abstract

:

Parasitic diseases still threaten human health. At present, a number of parasites have developed drug resistance, and it is urgent to find new and effective antiparasitic drugs. As a rich source of biological compounds, marine natural products have been increasingly screened as candidates for developing new antiparasitic drugs. The literature related to the study of the antigenic animal activity of marine natural compounds from invertebrates and microorganisms was selected to summarize the research progress of marine compounds and the structure–activity relationship of these compounds in the past five years and to explore the possible sources of potential antiparasitic drugs for parasite treatment.

Keywords:

bioactive compound; antiparasitic drugs; marine sponges; cnidaria; bryozoa; marine bacteria; marine fungi; cyanophyta

1. Introduction

Parasitic diseases common in the tropics and subtropics, including malaria, leishmaniasis, trypanosomiasis, and others, still threaten the lives and property of indigenous people [1].

Malaria, which occurs mainly in sub-Saharan Africa [2], is caused by Plasmodium. Anopheles gambiae is the principal vector of the disease in the Afrotropical Region [3]. Plasmodium enters human liver cells via infected female Anopheles and proliferates. Then, merozoites invade red blood cells and further cause disease [4], which is characterized by fever, headache, vomiting, diarrhea, chills, and muscle aches [5]. According to the World Health Organization, an estimated 240 million malaria cases were endemic in 84 countries worldwide in 2021 [6].

Leishmaniasis and trypanosomiasis are neglected tropical diseases (NTDs) that are associated with extreme poverty [7], spread in tropical and subtropical areas in 149 countries, and affect more than 2 billion poor people worldwide [8].

Leishmaniasis is affected by poor nutrition, poor sanitation, a weak immune system, and a lack of preventive measures [9]. This parasite occurs in Asia, Africa, the Americas, and the Mediterranean region. The main genera responsible for this disease are Phlebotomus and Lutzomyia [10]. Sand flies bite an infected animal host and acquires Leishmania, which multiplies in the gut. After 8 to 20 days, they become infectious and spread the disease by biting other hosts [11]. Leishmaniasis includes cutaneous leishmaniasis (CL), visceral leishmaniasis (VL), and mucocutaneous leishmaniasis (MCL). CL is the most common form, while VL is the most severe and is characterized by fever, weight loss, enlargement of the spleen and liver, and anemia [12]. Currently, the only effective treatment for leishmania is pentavalent antimony [10].

Trypanosomiasis includes sleeping sickness and Chagas disease (American trypanosomiasis); sleeping sickness is common in 36 sub-Saharan African countries [13] and is transmitted by blood-sucking tsetse flies. This parasite has two main forms: the slower-progressing form caused by Trypanosoma brucei gambiense and the faster-progressing form caused by Trypanosoma brucei rhodesiense [14]. A prominent feature of African trypanosomiasis is lethargy. T. brucei can circulate freely in the host’s blood and tissue fluids until it reaches the central nervous system, where it is usually fatal. Therefore, therapeutics at this stage must cross the blood–brain barrier [4]. American trypanosomiasis occurs in the Americas (including Mexico, Central, and South America) and is caused by Trypanosoma cruzi, which is transmitted through reduviid bugs [15,16].

Because of the widespread use of drugs, many parasites have developed resistance to treatment. For example, artemisinin-based combination therapy (ACT), which combines artemisinin and quinolines [17], is considered a first-line treatment for Plasmodium falciparum malaria globally [18]. Unfortunately, in the Greater Mekong subregion, such as Cambodia, Thailand, and Myanmar, the efficacy of artemisinin derivatives and ACT partner drugs is decreasing [19,20,21,22]. Additionally, the parasite has resistance to inexpensive drugs such as chloroquine and sulfadoxine/pyrimethamine. Similar situations were also observed with praziquantel for the treatment of schistosomiasis infection [23] and ivermectin for worms [24]. In addition to drug resistance, the efficacy and toxicity of drugs also deserve attention. Benznidazole and nifurtimox, which are used to treat Trypanosoma cruzi infection, are highly toxic to adult patients and have low efficacy [25]. Moreover, although a large number of resources have been invested, no effective vaccine against parasitic diseases has been developed thus far [26]. These reasons are forcing researchers to find new safe and effective antiparasite drugs.

The ocean covers more than 70% of the Earth’s surface area. Plants and animals, approximately 500,000 species in approximately 28 phyla, exist in this environment [27]. Compared with the terrestrial environment, the ocean has much richer biodiversity. The marine environment is more complex, and marine organisms have been in a harsh environment of high salinity, high pressure, lack of oxygen, limited food supply, and lack of photosynthesis for a long time [28]. Some organisms have evolved adaptations that allow them to synthesize toxic compounds or acquire toxic compounds from others. These toxic compounds can help protect marine life from predators [29]. Marine natural products are bioactive metabolites extracted from marine organisms, including marine animals, plants, and microorganisms [30]. Therefore, the ocean is an important source of bioactive compounds. Currently, compounds isolated from marine organisms mainly include terpenoids, alkaloids, polyketones, steroids, peptides, lactones, and so on [27,31], which have effective antibacterial, antifungal, anti-inflammatory, antiviral, antiparasitic, and other bioactivities [32,33].

We searched the Web of Science database from January 2017 to November 2022 for references with the keywords “marine-derived natural antiparasite products” and further screened the relevant research literature on invertebrates and microorganisms. We did not include meetings or review articles. In this review, we also used the following criteria to determine the activity of compounds:

When IC₅₀ > 20 μM, the activity of the compounds was low or inactive; when 1 ≤ IC₅₀ ≤ 20 μM, the compounds showed moderate activity. When IC₅₀ < 1 μM, they showed good potent activity [34];
When measured in μg/mL, if IC₅₀ > 20 μM, the activity of the compounds was low or inactive; if 3 ≤ IC₅₀ ≤ 10 μg/mL, the compound showed moderate activity. If IC₅₀ < 3 μg/mL, the compound showed good potent activity [35].

We screened 36 studies on the derivatives from invertebrates and microorganisms (Table 1) and six studies on their crude extracts (Table 2). We reviewed the literature on the purification of the derived compounds. Twelve invertebrate marine sponges came from 11 genera: Aplysinella, Dysidea, Fascaplysinopsis, Hyrtios, Ircinia, Pseudoceratina, Monanchora, Mycale, Tedania, and Xestospongia. Five genera, Bebryce, Macrorhynchia, Plumarella, and Sinulari, were included in the seven studies regarding cnidarians. Two genera, Amathia and Orthoscuticella, were involved in two bryozoan studies. For microorganisms, two genera, including Streptomyces and Pseudomonas, were studied in three bacterial studies. Aspergillus, Cochliobolus, Exserohilum, and Paecilomyces were involved in four fungal studies. Nine cyanobacteria studies involved Caldora, Dapis, Leptolyngbya, Okeania, Salileptolyngbya, and Moorea. Finally, we summarized the chemical structures with good potent activity (Figure 1, Figure 2, Figure 3 and Figure 4) and the possible structure–activity relationships.

2. Marine Invertebrate-Derived Antiparasitic Compounds

Invertebrates make up a large part of the literature collected on antiparasitic compounds of marine origin (58.33%). Most of these compounds are alkaloids (including bromotyrosine alkaloids, tryptophan-derived alkaloids, acyclic guanidine alkaloids, etc.), sesquiterpenoids, diterpenoids, sterols, steroids, etc. (Table 1). Invertebrate-derived compounds against P. falciparum have highly effective bioactivity (Figure 1).

2.1. Alkaloid Compounds

Bromopyrrole alkaloids are a field worth exploring for antiparasitic drugs [46]. The bromotyrosine alkaloid bisaprasin (3) extracted from marine sponges was moderately effective against T. cruzi (IC₅₀ = 0.61 µM) [36]. Pseudoceratidine (1) (29) and its derivatives extracted from Tedania brasiliensis have moderate efficacy against P. falciparum, L. infantum, L. amazonensis, and T. cruzi (Table 1). The antiplasmodium activity of this alkaloid is related to the length of the polyamine chain containing basic nitrogen and the presence of bromine atoms on the terminal portion of pyrrole or furan. Moreover, Parra et al. [46] found that pseudoceratidine (1) (29) had additive effects when used in combination with artesunate. Consequently, pseudoceratidine (1) (29) can be used as a promising source of antiplasmodial drugs.

Campos et al. [44] extracted pentacyclic alkaloids (ptilomycalin E, ptilomycalin F, and ptilomycalins G+H (21–23)) and acyclic guanidine alkaloids (crambescidin 800 (24) and fromiamycalin (25)) from Monanchora unguiculata sponges, which have extremely high activity against the chloroquine-sensitive 3D7 strain of P. falciparum (IC₅₀ were 0.35, 0.23, 0.46, 0.52, and 0.24 µM, respectively) [82]. The antimalarial activity of pentacyclic alkaloids is related to their five-ring structure. Unguiculin A (20), which has no five-ring structure, has lower antimalarial activity (IC₅₀ = 12.89 µM). Ceratinadin E (19), a new bromotyrosine alkaloid, was isolated from the marine sponge Pseudoceratina by Kurimoto et al. [43] and showed good potent activity against the chloroquine-resistant strain FCR3 (IC₅₀ = 0.77 µg/mL) and multidrug-resistant strain K1 (IC₅₀ = 1.03 µg/mL) of P. falciparum. In 2019, Campos et al. [38] isolated 8-oxo-tryptamine (7) and the mixture of (E) with (Z)-6-bromo-2′-demethyl-3′-N-methylaplysinopsin (8), which showed moderate activity against the P. falciparum 3D7 strain ((IC₅₀ were 8.8 and 8.0 µg/mL, respectively). These two aplysinopsins with antimalarial activity have a double bond between C-8 and C-1′, suggesting that antimalarial activity may be connected to the skeleton of the compounds.

Brominated alkaloids extracted from the bryozoan Amathia lamourouxi showed effective antimalarial activity against the P. falciparum 3D7 strain. Moreover, volutamide F (60) showed a higher selectivity index for the human embryonic kidney cell line HEK293. The antimalarial activity of volutamide H (62) (IC₅₀ = 1.6 µM) was lower than that of volutamide F (60) (IC₅₀ = 0.61 μM) and volutamide G (61) (IC₅₀ = 0.57 µM), indicating that the presence of tertiary amides plays an important role against Plasmodium [55]. Alkaloids (orthoscuticellines A, D, E, 1-ethyl-β-carboline (63, 65, 66, 68)) isolated from Orthoscuticella ventricosa, another bryophyte, also had moderate antimalarial activity, ranging from 12–21 μM (Table 1). Ligand efficiency calculations showed that β-carboline was partly related to the antiplasmodium activity [56].

2.2. Terpenoids, Sesquiterpenoids, and Diterpenoids Compounds

Imperatore et al. [37] obtained the natural sesquiterpenoid quinone avarone (4) and avarol (6) from Dysidea avara sponges. They obtained the semisynthetic thiazinoquinone derivative thiazoavarone (5) by condensation reaction of avarone (4) with subtaurine. Compared with the two natural products, thiazoavarone (5) showed better activity against the chloroquine-resistant strain W2 (IC₅₀ = 0.21 μM) and drug-sensitive strain D10 (IC₅₀ = 0.38 μM) of P. falciparum. In addition, this derivative also had bioactivity against Schistosoma mansoni (IC₅₀ = 5.90 μM). These results suggested that the substituent of the 1,1-dioxo-1,4-thiazine ring played a vital part in bioactivity.

Among the five new furan diterpenes keikipukalides (A–E) (46–50) isolated from Plumarella delicatissima, four keikipukalides (B–E) (47–50) showed moderate activity against L. donovani (IC₅₀ were 8.5, 8.8, 12, and 8.8 μM, respectively). In addition, the two known compounds pukalide (51) and norditerpenoid (52) ineleganolide that were isolated, also showed good biological activity (IC₅₀ were 1.9 and 4.4 μM, respectively). In particular, these compounds were not toxic to human lung carcinoma cells when they were below 50 μM. [52]. The sesquiterpenoids alcyopterosin V (41) and alcyopterosin E (42) obtained from another cnidarian Alcyonium sp. also had moderate activity against L. donovani (IC₅₀ were 7.0 and 3.1 μM, respectively) [49].

2.3. Steroids and Sterols Compounds

Chlorinated steroid (3) (53), 24-methylenecholestane-3β-5α,6β-triol-6-monoacetate (55), and dibromoditerpene compounds pinnaterpene C (54) extracted from Sinularia brassica at 50 μM showed positive effects. The inhibitory effects of L. donovaniamastigote on amastigotes were 58.7%, 54.7%, and 74.3%, respectively. In addition, the three compounds showed little toxicity to THP-1 cells at these concentrations [53].

Two sterol compounds, kaimanol (39) and saringosterol (40), were extracted from the sponge Xestospongia sp. The antimalarial activity of kaimanol (39) was lower than that of saringosterol (40), suggesting that benzoyl may reduce the activity in the sterol structure [47]. The terpenoids extracted from the sponge Hyrtios erectus and the cnidarian Bebryce grandis showed moderate or greater activity against chloroquine-resistant Dd2 strains [39,50]. It is worth noting that both compounds extracted from B. grandis act on the life cycle of Plasmodium parasites. They found that the addition of nitenin (44) before the ring transition to the early trophozoite stage inhibited the maturation of the parasites. Bebrycin A (43) prevented the parasite from maturing. Among the clinical antimalarial drugs, only artemisinin is active against the merozoite of Plasmodium [83]. Consequently, Wright et al. [50] noted that it might be possible to develop new artemisinin combination therapy partner drugs based on the properties of these two terpenoids.

2.4. Other Compounds

Sala et al. extracted several nitrile-containing polyacetylene secondary metabolites from the sponge Mycale sp.SS5; however, only albanitrile A (26) showed moderate bioactivity against Giardia duodenalis (IC₅₀ =12 μM). The lower bioactivity of albanitrile B (27) than A 26 also suggested that the activity of antigenic animals depended on the chain length of the alkyl group [45].

Notably, isololiolide (45), which was extracted in the sponge Macrorhynchia philippina, had certain effects on T. cruzi trypomastigotes and amastigotes (IC₅₀ = 31.9 and 40.4 μM, respectively). Lima et al. [51] studied the lethal mechanism of this compound and suggested that isololiolide (45) may cause damage to plasma membrane integrity and depolarization of mitochondrial membrane potential.

3. Marine Microorganisms-Derived Antiparasitic Compounds

3.1. Steroids and Sterols Compounds

Previous studies have shown that polyketones, alkaloids, fatty acids, terpenes, and other compounds isolated from marine bacteria have potential antibacterial, antifungal, and antiparasitic activities [74,84,85]. Salinivibrio and Streptomyces from Actinomycetes are Gram-positive bacteria [74], while Pseudomonas from Proteobacteria is Gram-negative bacteria [86]. The active compounds extracted from these bacteria mainly include alkaloids and quinoline (Table 1) (Figure 2).

Marinopyrrole A (70), an alkaloid compound found in marine Streptomyces sp., has strong antibacterial activity against methicillin-resistant Staphylococcus aureus [87]. Martens et al. [58] explored the activity of this compound against Toxoplasma gondii. In in vitro experiments, marinopyrrole A (70) showed potent inhibitory activity at 0.31 µM against Toxoplasma gondii tachyzoites. However, the anti-toxoplasma effect was inhibited when more than 20% bovine calf serum was added to the liquid medium. Based on compound (70), they obtained three analogs, RL002, RL003, and RL125 (71–73), which showed 3.6- to 6.8-fold increased efficacy against toxoplasmosis (P < 0.001, Student’s paired t-test) and decreased serum sensitivity. RL003 (72), the most inhibitory analog, is highly active against cysts in vitro (IC₅₀ = 0.245 μM). Hence, further in vivo chronic studies are needed to assess the potential antiparasitic activity of RL003 (72) in the host. Another alkaloid, staurosporine (69), isolated from Streptomyces sp. PBLC04 can kill the trophozoites of Acanthamoeba (IC₅₀ = 0.265 µg/mL) [57]. The cysts of Acanthamoeba allow the parasite to cope with harsh environments such as a lack of nutrients, high temperatures, and high osmotic pressure, so Acanthamoeba, in this stage is highly resistant [88,89]. Notably, taurosporine also showed good potent inhibition against cysts (IC₅₀ = 0.771 μg/mL). The protein kinase family is generally considered to be the main target of staurosporine (69) [90]. Acanthamoeba is rich in known kinase genes, which may explain the high activity of this compound against Acanthamoeba.

Martinez-Luis et al. [59] isolated five hydroxyquinoline compounds from Pseudomonas aeruginosa, among which three compounds had good antiparasitic effects: 3-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2.4-dione (2), 2-heptyl-4-hydroxyquinoline (3), and 2-nonyl-4-hydroxyquinoline (4) (74–76). These three compounds showed moderate and greater antimalarial activity against the chloroquine-resistant strain W2 of P. falciparum (IC₅₀ = 3.47, 2.57, and 2.79 µg/mL, respectively). Compounds (3) (75) (IC₅₀ = 3.66 µg/mL) and (4) (76) (IC₅₀ = 3.99 µg/mL) also showed resistance to Trypanosoma cruzi. In addition, this study also found that the corresponding tautomers of compounds (3) (75) and (4) (76) showed strong activity against the chloroquine-sensitive D6 strain and chloroquine-resistant Plasmodium falciparum W2 strain [91], indicating that the hydroxyquinoline compounds maintained antimalarial activity independently of their tautomers [59].

3.2. Marine Fungi

Endophytes are microfungi that reside in the internal tissues of plants without causing any immediate obvious negative effects [92,93]. Marine invertebrates, algae endophytes, or fungi found in marine sediments are also rich sources of bioactive natural products [94,95,96]. In the four studies on marine fungi from 2017 to 2022, the natural products were mostly polyketones and alkaloids (Table 1).

The compound harzialactone A (117) was extracted from Paecilomyces sp.7A22, a marine fungus isolated from sea squirts. This known polyketone compound has been isolated from Trichoderma harzianum, an endophytic fungus of the sponge Halichondria okadai [97]. Braun et al. [72] investigated the antiparasitic activity of this polyketone compound.

Harzialactone A (117) had the ability to overcome the transmembrane barriers to reach the macrophage phagolysosome, where amastigotes grow, and showed moderate activity against L. amazonensis promastigotes (IC₅₀ = 5.25 μg/mL). In addition, another polyketone isolated from Cochliobolus lunatus by Xu et al. [70] (Derivatives 103–111, Acyl derivatives 69–71) showed moderate antiplasmodial activity (Table 1). The structure–activity relationships showed that biphenyl substituents at C-2, acetone at C-5′ and C-6′, and triple or quadruple substitution of acyl groups increased antiplasmodium activity.

Isocoumarins (1) (112) and isocoumarins (3) (113) extracted from Exserohilum sp. (CHNSCLM-0008) fungus isolated from button coral Palythoa haddoni by Coronado et al. [71] showed moderate activity against chloroquine-sensitive HB3 strains of Plasmodium falciparum (IC₅₀ values were 1.13 and 11.7 μM, respectively). Semisynthetic derivatives were obtained by changing the substituents of the aromatic ring and adipose chain to explore the structure–activity relationship of the compounds. The newly synthesized compounds, derivatives 114–116 (Figure 3), showed good potent activity against P. falciparum (IC50 values were 0.77, 0.38, and 2.58 μM, respectively). Among them, derivative 115 was an accidental ring-opening product obtained during the demethylation process, which had a very strong antimalarial effect. Moreover, structure–activity analysis demonstrated that the configuration of methoxy groups and 3R, 4R, and 10S was necessary for antimalarial activity, and the lipid solubility of the side chain could help improve antimalarial activity. On the one hand, derivative 115 can inhibit heme polymerization and reduce mitochondrial membrane potential in the parasite; on the other hand, they can inhibit DNA gyrase enzymes and thus inhibit DNA replication. In conclusion, this study suggested that derivatives 115 may be a potential lead agent for malaria treatment.

Bunbamrung et al. [69] isolated the fungus Aspergillus terreus BCC51799 from decaying wood samples in the ocean and extracted new natural products from this fungus. Among them, the alkaloid astechrome (99) (Figure 3) showed strong antimalarial activity (IC₅₀ = 0.94 μM) (Table 1).

4. Cyanophyta

Cyanobacteria, also known as blue-green algae because of the presence of phycocyanin and chlorophyll, are the only prokaryotes that can produce oxygen through photosynthesis [98]. Some secondary metabolites in marine cyanobacteria have good activity and are considered lead compounds for drugs [99]. Some of these compounds are antimicrobial peptides, and cyanobacterial peptides can be divided into linear peptides, depsipeptides, and cyclic peptides according to their structure [98].

4.1. Linear Peptides

Ozaki et al. [66] isolated the linear peptides mabuniamide (1) (90) and stereoisomer 2 (91), from Okeania sp., which showed moderate activity (IC₅₀ were both 1.4 μM) against the chloroquine-sensitive 3D7 strain of P. falciparum. In 2020, Iwasaki et al. [65] isolated another linear peptide, ikoamide (1) (89) (Figure 4), from Okeania and discovered strong activity against the P. falciparum 3D7 strain. Kurisawa et al. [62] isolated three linear peptides from the cyanobacteria Dapis sp. However, only iheyamides A (86) showed moderate activity against T. b. rhodesiense (IC₅₀ = 1.5 μM) and T. b. brucei (IC₅₀ = 1.5 μM). Structure–activity analysis proved that the C-terminal pyrrolinone moiety was vital for antiparasitic activity. The team then isolated the C-terminal part of iheyamide A (1) to obtain iheyanone (2), which also showed some activity against T. b. rhodesiense. To further clarify the structure–activity relationship of this compound, Iswasaki et al. [61] synthesized a variety of compounds with different peptide chain lengths and found that longer lengths of the peptide chain were more effective in inhibiting the growth of Trypanosoma. Hoshinoamide C (77) (Figure 4), a natural product discovered by Iswasaki et al. [60] in Caldora penicillate, also had some effective activity against P. falciparum (IC₅₀ = 0.96 μM) and T. b. rhodesiense (IC₅₀ = 2.9 μM). Finally, the configuration at C-43 (Figure 4) did not affect antiparasitic activity when used to synthesize two possible isomers of hoshinoamide C (77,78). The linear peptide Kinenzoline (1) (92) isolated from Salileptolyngbya sp. showed moderate activity (IC₅₀ = 5.0 μM) against the IL-1501 strain of T. b. rhodesiense. Kurisawa et al. [67] also identified a synthetic pathway for kinenzoline (1) (92) and showed that neither natural nor synthetic Kinenzoline (1) (92,93) was toxic to WI-38 cells.

4.2. Cyclic Peptides

Cyclic peptides are likely to mimic peptide substrates or ligands of endogenous proteins (such as enzymes or receptors). Therefore, they are often considered “privileged structures” of bioactivity [100,101]. Motobamide (1) (87), a cyclic decapeptide isolated from Leptolyngbya sp., inhibited the growth of T. b. rhodesiense. Almaliti et al. [68] explored the relationship between the structure and activity of several dudawalamides 94–97, which are cyclic depsipeptides isolated from the cyanobacterium Moorea producens. The results indicated that the activity of Dhoya natural products was affected by the structure of the configuration and order of residues. Keller et al. [64] isolated Palstimolide A (88), a polyhydroxy macrolide compound from cyanobacteria, with an IC₅₀ of 0.1725 μM against the Dd2 strain of P. falciparum, showing very high antiplasmodium activity. This compound also showed moderate activity against the promastigotes phase of L. donovani (IC₅₀ = 4.67μM).

5. Conclusions

Our review of the literature published in the last five years found that sponges are still the major source of marine-derived compounds. Marine sponge-derived compounds have shown excellent activity against Plasmodium falciparum in in vitro studies. A total of 40 natural products or synthetic compounds from marine sponges were included in this study, among which 12 compounds had good potent activity. These sponges belong to Xestospongia, Dyside, Hyrtios, Pseudoceratina, and Monanchora. Approximately 17 compounds were derived from cnidarians, and one compound from Bebryce showed good potent activity. In addition, 11 compounds from bryophytes and two high bioactivity compounds were derived from Amathia. A total of 8 compounds from marine bacteria were collected, and seven compounds with effective bioactivity were extracted from Streptomyces, Salinivibrio, and Pseudomonas. Twenty compounds were identified from marine fungi, with three highly active compounds from Exserohilum and Aspergillus. Finally, 21 were derived from Cyanophyta, with 4 highly active compounds from Caldora, Okeania, and Leptolyngbya.

Naturally derived or semisynthetic molecular analogs can be developed by structure–activity relationship (SAR) analysis and tend to have higher bioactivity and less toxicity [102]. In addition, it has been shown that coupling natural products with nanomaterials may enhance the activity of compounds. Walvekar et al. used silver nanoparticles coupled with extracts of Kappaphycus alvarezii, which enhanced anti-acanthamoebic activity [103].

Although the association between the structure of some compounds and their antiparasitic activity has been explored through SAR, the molecular targets and mechanisms of some compound molecules have not been clarified [104]. At present, a large number of promising active antiparasitic compounds have been discovered, but translating them into a drug for clinical use still faces many difficulties: (1) if the purified antiparasitic product is not chemically synthesized, clinical studies and mass production of those compounds often require more biomass than discovering new compounds and (2) if the compounds can be obtained through chemical synthesis, it is also worth considering how to reduce the synthesis steps and reduce the cost of chemical synthesis.

Author Contributions

L.Z. conceived the ideas and methodology. M.Z., Q.Z. (Qunde Zhang), Q.Z. (Qinrong Zhang) and X.C. collected the data. M.Z. and L.Z. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

Financial support was provided by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Data Availability Statement

Not applicable.

Acknowledgments

We thank the team members for the help during data collection.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Figure 1. The structure of compounds with effective antiparasitic activity in invertebrates.

Figure 2. The structure of compounds with effective antiparasitic activity in marine bacteria.

Figure 3. The structure of compounds with effective antiparasitic activity in marine fungi.

Figure 4. The structure of compounds with effective antiparasitic activity in Cyanophyta.

Table 1. Natural products or derivatives from marine invertebrates and microorganisms.

Category		Species	Compounds	Chemistry	Target Parasite	Stage/Strain	IC₅₀	Cytotoxicity		Site	Reference
Category		Species	Compounds	Chemistry	Target Parasite	Stage/Strain	IC₅₀	Type of Cells	IC₅₀	Site	Reference
Invertebrate	sponges	Aplysinella rhax	1 Psammaplin A	Bromotyrosine Alkaloids	T. cruzi	C2C4	30 μM	NT	NT	Fiji Islands	[36]
			1 Psammaplin A		P. falciparum	3D7	60 μM
			2 Psammaplin D		T. cruzi	C2C4	43 μM
			2 Psammaplin D		P. falciparum	3D7	67 μM
			3 Bisaprasin		T. cruzi	C2C4	19 μM
			3 Bisaprasin		P. falciparum	3D7	29 μM
			Benznidazole *	-	T. cruzi	C2C4	2.6 μM	-	-	-
			Chloroquine *	-	P. falciparum	3D7	0.017 μM	-	-	-
		Dysidea avara	4 Avarone	Sesquiterpene Quinone Avarone	P. falciparum	D10	2.74 μM	Human microvascular endothelial cells, HMEC-1	62.19 μM	Bay of Izmir, Turkey	[37]
						W2	2.09 μM
						3D7 elo1-pfs16-CBG99	15.53 μM
					L. infantum	promastigote	28.21 μM	Human acute monocytic leukemia cells, THP-1	>100 μM
					L. tropica	promastigote	20.28 μM
					L. infantum	amastigotes	7.64 μM
					S. mansoni	schistosomula	42.77 μM
			5 Thiazoavarone		P. falciparum	D10	0.38 μM	Human microvascular endothelial cells, HMEC-1	3.31 μM
						W2	0.21 μM
						3D7 elo1-pfs16-CBG99	15.01 μM
					L. infantum	promastigote	8.78 μM	Human acute monocytic leukemia cells, THP-1	7.41 μM
					L. tropica	promastigote	9.52 μM
					L. infantum	amastigotes	4.99 μM
					S. mansoni	schistosomula	5.90 μM
			6 Avarol		P. falciparum	D10	0.96 μM	Human microvascular endothelial cells, HMEC-1	36.85 μM
						W2	1.10 μM
						3D7 elo1-pfs16-CBG99	9.30 μM
					L. infantum	promastigote	7.42 μM	Human acute monocytic leukemia cells, THP-1	31.75 μM
					L. tropica	promastigote	7.08 μM
					L. infantum	amastigotes	3.19 μM
					S. mansoni	schistosomula	33.97 μM
			Chloroquine *	-	P. falciparum	D10	0.04 μM	-	-	-
			Chloroquine *	-		W2	0.54 μM
			Methylene blue *	-		3D7 elo1-pfs16-CBG99	0.155 μM
			Amphotericin B *	-	L. infantum	promastigote	0.2 μM
					L. tropica	promastigote	0.17 μM
					L. infantum	amastigotes	0.189 μM
		Fascaplysinopsis reticulata	7 8-oxo-tryptamine	Tryptophan-Derived Alkaloids	P. falciparum	3D7	8.8 µg/mL	NT	NT	Mayotte	[38]
			8 The mixture of the known (E) and (Z)-6-bromo-2′-demethyl-3′-N-methylaplysinopsin	Tryptophan-Derived Alkaloids			8.0 µg/mL	NT	NT	Mayotte
			Artemisinin *	-			0.006 μg/mL	-	-	-
		Hyrtios erectus	9 Smenotronic acid	Sesquiterpenoids	P. falciparum	Dd2	3.51 μM	NT	NT	Sesquiterpenoids	[39]
			10 Ilimaquinone				2.11 μM
			11 Pelorol				0.80 μM
		Hyrtios sp.	12 Hyrtiodoline A	Alkaloid	T. brucei brucei	-	48 h: 15.26 μM	J774.1 macrophages	>200 μM	Red Sea at Sharm el-Sheikh, Egypt	[40]
		Hyrtios sp.	12 Hyrtiodoline A	Alkaloid	T. brucei brucei	-	72 h: 7.48 μM	J774.1 macrophages	>200 μM	Red Sea at Sharm el-Sheikh, Egypt	[40]
		Ircinia oros	13 Ircinin-1	Linear Furanosesterterpenoids	T. b. rhodesiense	-	97 μM	L6 rat myoblast cells	150 μM	Gökçeada, Northern Aegean Sea, Turkey	[41]
					T. cruzi		120 μM
					L. donovani		31 μM
					P. falciparum		58 μM
			14 Ircinin-2		T. b. rhodesiense		65 μM		140 μM
					T. cruzi		110 μM
					L. donovani		28 μM
					P. falciparum		56 μM
			15 Ircinialactam E		T. b. rhodesiense		130 μM		>200 μM
			15 Ircinialactam E		P. falciparum		95 μM		>200 μM
			16 Ircinialactam F		T. b. rhodesiense		130 μM		>200 μM
			16 Ircinialactam F		L. donovani		95 μM		>200 μM
			Melarsoprol *	-	T. b. rhodesiense	-	0.015 μM	-	-	-
			Benznidazole *		T. cruzi		3.07 μM
			Miltefosine *		L. donovani		0.51 μM
			Chloroquine *		P. falciparum		0.009 μM
			Podophyllotoxin *		-	-	-	L6 rat myoblast cells	0.010 μM
		Ircinia wistarii	17 Ircinianin	Sesterterpenes	P. falciparum	NF54	25.4 μM	HeLa	>64 μg/mL	Wistari Reef, Great Barrier Reef, Australia	[42]
					T. brucei rhodesiense	STIB900	82.8 μM	HeLa	>64 μg/mL
					T. cruzi	C2C4	190.9 μM	L6	59.5 μg/mL
					L. donovani	MHOM/ET/67/L82	16.6 μM	L6	59.5 μg/mL
Chloroquine *	-		P. falciparum	NF54	0.006 μM	-	-	-
Melarsoprol *			T. brucei rhodesiense	STIB900	0.020 μM
Benznidazole *			T. cruzi	C2C4	3.36 μM
Miltefosine *			L. donovani	MHOM/ET/67/L82	0.486 μM
Pseudoceratina sp.	18 Psammaplysin F	Bromotyrosine Alkaloid	P. falciparum	K1	3.77 µg/mL	MRC-5	12.65 µg/mL	Okinawa, Japan	[43]
	18 Psammaplysin F			FCR3	2.45 µg/mL		12.65 µg/mL
	19 Ceratinadin E			K1	1.03 µg/mL		15.99 µg/mL
	19 Ceratinadin E			FCR3	0.77 µg/mL		15.99 µg/mL
	Chloroquine *	-		K1	0.34 µg/mL		>25.80 µg/mL	-
	Chloroquine *			FCR3	0.035 µg/mL		>25.80 µg/mL
	Artemisinin *			K1	0.010 µg/mL		>14.12 µg/mL
	Artemisinin *			FCR3	0.0088 µg/mL		>14.12 µg/mL
Monanchora unguiculata	20 Unguiculin A	Acyclic Guanidine Alkaloid	P. falciparum	3D7	12.89 μM	KB Cells	7.66 μM	Mitsio Islands, Madagascar	[44]
	21 Ptilomycalin E	Pentacyclic Alkaloids			0.35 μM		0.85 μM
	22 Ptilomycalin F				0.23 μM		1.61 μM
	23 Ptilomycalins G+H				0.46 μM		0.92 μM
	24 Crambescidin 800	Acyclic Guanidine Alkaloid			0.52 μM		1.31 μM
	25 Fromiamycalin	Acyclic Guanidine Alkaloid			0.24 μM		1.17 μM
	Artemisinin *	-			0.004 μM	--	-	-
Mycale sp. SS5	26 Albanitrile A	Nitrile-Bearing Polyacetylenes	Giardia duodenalis	713	12 μM	Mammalian myeloma cell line NS-1	50 μM	Near Albany	[45]
	26 Albanitrile A				12 μM	Normal nontumor NFF cells	100 μM
	27 Albanitrile B				25 μM	Mammalian myeloma cell line NS-1	50 μM
	27 Albanitrile B				25 μM	Normal nontumor NFF cells	100 μM
	28 Albanitrile C				90 μM	Mammalian myeloma cell line NS-1	180 μM
	28 Albanitrile C				90 μM	Normal nontumor NFF cells	90 μM
	Metronidazole *				2.9 μM	-	-	-
	Sparsomycin *	-	-	-	-	Mammalian myeloma cell line NS-1	0.55 μM
	Sparsomycin *	-	-	-	-	Normal nontumor NFF cells	1.7 μM
Tedania brasiliensis	29 Pseudoceratidine	Bromopyrrole Alkaloids	P. falciparum	3D7	EC₅₀ = 1 μM	Bone marrow-derived macrophages	NT	Cabo Frio, Rio de Janeiro state, Brazil	[46]
				3D7	1.1 μM
				K1	1.1 μM
	30 Pseudoceratidine derivative		P. falciparum	3D7	EC₅₀ = 6 μM
	31 Pseudoceratidine derivative		P. falciparum	3D7	EC₅₀ = 4 μM
	32 Pseudoceratidine derivative		L. infantum	promastigotes	EC₅₀ = 24 μM		52 μM
			L. amazonensis	promastigotes	EC₅₀ = 19 μM
			T. cruzi	epimastigotes	EC₅₀ = 7 μM
	33 Pseudoceratidine derivative		L. infantum	promastigotes	EC₅₀ = 19 μM		>100 μM
			L. amazonensis	promastigotes	EC₅₀ = 7 μM
			P. falciparum	3D7	EC₅₀ = 19 μM
	34 Pseudoceratidine derivative		P. falciparum	3D7	EC₅₀ = 44 μM		NT
	35 Pseudoceratidine derivative		L. infantum	promastigotes	EC₅₀ = 2 μM		66 μM
			L. amazonensis	promastigotes	EC₅₀ = 3 μM
			T. cruzi	epimastigotes	EC₅₀ = 24 μM
	36 Pseudoceratidine derivative		P. falciparum	3D7	EC₅₀ = 7 μM		NT
	37 Pseudoceratidine derivative		L. infantum	promastigotes	EC₅₀ = 20 μM		>100 μM
	37 Pseudoceratidine derivative		L. amazonensis	promastigotes	EC₅₀ = 76 μM		>100 μM
	38 Pseudoceratidine derivative		L. infantum	promastigotes	EC₅₀ = 23 μM		82 μM
			L. amazonensis	promastigotes	EC₅₀ = 18 μM		82 μM
			P. falciparum	3D7	EC₅₀ = 3 μM		NT
	Chloroquine *	-	P. falciparum	3D7	0.013 μM	-	-	-
	Chloroquine *	-	P. falciparum	K1	0.167 μM	-	-	-
	Pyrimethamine *	-	P. falciparum	3D7	0.03 μM	-	-	-
	Pyrimethamine *	-	P. falciparum	K1	3.9 μM	-	-	-
	Cycloguanil *	-	P. falciparum	3D7	0.010 μM	-	-	-
	Cycloguanil *	-	P. falciparum	K1	0.54 μM	-	-	-
	Artesunate *	-	P. falciparum	3D7	0.004 μM	-	-	-
	Artesunate *	-	P. falciparum	K1	0.003 μM	-	-	-
Xestospongia sp.	39 Kaimanol	Sterol	P. falciparum	3D7	0.359 μM	NT	NT	Indonesia	[47]
	40 Saringosterol	Sterol			0.00025 μM	NT	NT	Indonesia	[47]
	Artemisinin *	-			5.207 × 10⁻³ nM	-	-	-	[48]
Cnidaria	Alcyonium sp.	41 Alcyopterosin V	Illudalane Sesquiterpenes	L. donovani	-	7.0 μM	J774.A1 macrophages	110 μM	Scotia Arc of Antarctica	[49]
							Host cell lines HEK293T	220 μM
							Host cell lines HepG2	288 μM
		42 Alcyopterosin E				3.1 μM	J774.A1 macrophages	62 μM
							Host cell lines HEK293T	570 μM
							Host cell lines HepG2	331 μM
		Miltefosine *	-			6.2 μM	-	-	-
	Bebryce grandis	43 Bebrycin A	Diterpene	P. falciparum	Dd2	EC₅₀ = 1.08 μM	HepG2 human hepatocyte carcinoma cell line	EC₅₀ =21.8 μM	Southeast coast of Curacao, East of Fuikbaai	[50]
	Bebryce grandis	44 Nitenin	C21 Degraded Terpene	P. falciparum	Dd2	EC₅₀ = 0.29 μM	HepG2 human hepatocyte carcinoma cell line	EC₅₀ =18.3 μM	Southeast coast of Curacao, East of Fuikbaai	[50]
	Macrorhynchia philippina	45 Isololiolide	Carotenoid Isololiolide	T. cruzi	trypomastigotes	31.9 μM	BMM cells	>200 μM	São Sebastião Channel, Brazil	[51]
		45 Isololiolide	Carotenoid Isololiolide		amastigotes	40.4 μM		>200 μM	São Sebastião Channel, Brazil
		Benznidazole *	-		trypomastigotes	16.2 μM		>200 μM	-
		Benznidazole *	-		amastigotes	5.3 μM		>200 μM	-
	Plumarella delicatissima	46 Keikipukalide A	Furanocembranoid Diterpenes	L. donovani	amastigotes	> 28 μM	Human lung carcinoma, cells, A549 cytotoxicity	>50 μM	Stanley, Falkland Islands (Islas Malvinas), in the Southern Ocean	[52]
		47 Keikipukalide B				8.5 μM		>50 μM
		48 Keikipukalide C				8.8 μM		>50 μM
		49 Keikipukalide D				12 μM		>50 μM
		50 Keikipukalide E				8.8 μM		>50 μM
		51 Pukalide aldehyde				1.9 μM		>50 μM
		52 Norditerpenoid ineleganolide				4.4 μM		>50 μM
		Miltefosine *	-			6.2 μM	-	-	-
	Sinularia brassica	53 Chlorinated steroid	Steroid	L. donovaniamastigote	amastigote	Inhibition of a growth of L. donovani at 50 μM = 58.7%	THP-1 cells at 50 μM	88.8%	Van Phong bay, Khanh Hoa province, Vietnam and Institute of Oceanography, Nha Trang, Vietnam	[53]
		54 Pinnaterpene C	Dibromoditerpene			Inhibition of a growth of L. donovani at 50 μM = 74.3%		106.2%
		55 24-methylenecholestane-3β-5α,6β-triol-6-monoacetate	Steroid			Inhibition of a growth of L. donovani at 50μM = 54.7%		96.1%
		56 Cholestane-3β-5α,6β-triol-6-monoacetate	Steroid			Inhibition of growth of L. donovani at 50μM = 39.0%		92.7%
	Sinularia sp.	57 Sinuketal	Sesquiterpenoids	P. falciparum	3D7	80 μM	Jurkat	24.9 μM	Yongxing Island (16°50′ N, 112°20′ E) of Xisha Islands in the South China Sea	[54]
							MDA-MB-231	32.3 μM
							U2OS	41.7 μM
		Dihydroartemisinine *	-			10 nM	-	-	-
Bryozoa	Amathia lamourouxi	58 Convolutamines K	Brominated Alkaloids	P. falciparum	3D7	1.7 μM	Human embryonic kidney cell line, HEK293	17.01 μM	Rock pools of Woolgoolga, New South Wales, Australia	[55]
		59 Convolutamines L			3D7	11 μM		IA at 40 μM
		60 Volutamides F			3D7	0.61 μM		IA at 40 μM
		60 Volutamides F			Dd2	0.75 μM		IA at 40 μM
		61 Volutamides G			3D7	0.57 μM		11 μM
		61 Volutamides G			Dd2	0.85 μM		11 μM
		62 Volutamides H			3D7	1.6 μM		IA at 40 μM
		62 Volutamides H			Dd2	1.9 μM		IA at 40 μM
		Chloroquine *	-		3D7	0.025 μM		67% at 4 μM	-
		Chloroquine *	-		Dd2	0.18 μM		67% at 4 μM	-
		Dihydroartemisinin *	-		3D7	0.0020 μM		IA at 0.1 μM	-
		Dihydroartemisinin *	-		Dd2	0.0020 μM		IA at 0.1 μM	-
		Puromycin *	-		3D7	0.11 μM		0.81 μM	-
		Puromycin *	-		Dd2	0.068 μM		0.81 μM	-
	Orthoscuticella ventricosa	63 Orthoscuticellines A	Alkaloids	P. falciparum	3D7	10 μM	Human embryonic kidney cell line, HEK293	10 μM	Northern NSW, Australia	[56]
		64 Orthoscuticellines B				> 40 μM		>40 μM
		65 Orthoscuticellines D				14 μM		>40 μM
		66 Orthoscuticellines E				12 μM		>40 μM
		67 1-ethyl-4-methylsulfone-β-carboline				21 μM		>40 μM
		68 1-ethyl-β-carboline				18 μM		>40 μM
		Chloroquine *	-			0.007 μM		>40 μM
		Artesunate *	-			0.0003 μM	-	-	-
Microorganisms	Actinomy-cetes	Streptomyces sp. PBLC04	69 Staurosporine	Alkaloid	Acanthamoeba castellanii	Trophozoites	0.265 µg/mL	Murine macrophage J774.A1 cell line	4.076 μM	Jambelí mangrove, Ecuador	[57]
		Streptomyces sp. PBLC04	69 Staurosporine	Alkaloid	Acanthamoeba castellanii	Cysts	0.771 µg/mL	Murine macrophage J774.A1 cell line	4.076 μM	Jambelí mangrove, Ecuador	[57]
		Streptomyces sp.	70 Marinopyrrole A	Alkaloids	T. gondii	Tachyzoites/Type I RH	0.31 μM	Human foreskin fibroblast (HFF)	>50 μM	Marinopyrrole A was obtained from Sigma-Aldrich	[58]
			70 Marinopyrrole A				0.31 μM	Human hepatocarcinoma (HepG2)	5.3 μM
			71 RL002				0.17 μM	Human foreskin fibroblast (HFF)	>50 μM
			71 RL002				0.17 μM	Human hepatocarcinoma (HepG2)	29.0 μM
			72 RL003				0.09 μM	Human foreskin fibroblast (HFF)	>50 μM
			72 RL003				0.09 μM	Human hepatocarcinoma (HepG2)	49.7 μM
			73 RL125				0.16 μM	Human foreskin fibroblast (HFF)	>50 μM
			73 RL125				0.16 μM	Human hepatocarcinoma (HepG2)	46.5 μM
			Pyrimethamine *	-			0.61 μM	-	-	-
	Proteobacteria	Pseudomonas aeruginosa	74 3-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2.4-dione	Hydroxyquinoline	P. falciparum	Indochina W2	3.47 µg/mL	NT	NT	Pacific of Panama	[59]
			75 2-heptyl-4-hydroxyquinoline		P. falciparum	Indochina W2	2.57 µg/mL
			75 2-heptyl-4-hydroxyquinoline		T. cruzi	C4	3.66 µg/mL
			76 2-nonyl-4-hydroxyquinoline		P. falciparum	Indochina W2	2.79 µg/mL
			76 2-nonyl-4-hydroxyquinoline		T. cruzi	C4	3.99 µg/mL
			Chloroquine *	-	P. falciparum	Indochina W2	0.03 µg/mL	-	-	-
			Nifurtimox *	-	T. cruzi	C4	1.6 µg/mL	-	-	-
	Cyanophyta	Caldora penicillata	77 Hoshinoamide C (natural)	Lipopeptide	P. falciparum	3D7	0.96 μM	Human cancer cells, HeLa and HL60	No cytotoxicity at 10 μM	Ikei Island, Okinawa, Japan	[60]
			77 Hoshinoamide C (natural)		T. brucei rhodesiense	IL-1501	2.9 μM
			78 Hoshinoamide C(synthetic)		P. falciparum	3D7	3.2 μM
			78 Hoshinoamide C(synthetic)		T. brucei rhodesiense	IL-1501	3.7 μM
			79 43-epi-hoshinoamide C(synthetic)		P. falciparum	3D7	0.87 μM
			79 43-epi-hoshinoamide C(synthetic)		T. brucei rhodesiense	IL-1501	4.4 μM
			Atovaquone *	-	P. falciparum	3D7	0.00096 μM	-	-	-
			Pentamidine *	-	T. brucei rhodesiense	IL-1501	0.001 μM	-	-	-
		Dapis sp.	80 Iheyanone	Linear Peptides	T. brucei rhodesiense	IL-1501	35 μM	WI-38 cells	>50 μM	Noho Island, Okinawa, Japan	[61]
			81 Peptides				33 μM		>50 μM
			82 Peptides				24 μM		>50 μM
			83 Peptides				15 μM		>50 μM
			84 Peptides				17 μM		>50 μM
			85 Peptides				6.2 μM		>50 μM
			Pentamidine *	-	T. brucei rhodesiense	IL-1501	0.05 μM	-	--	-
		Dapis sp.	86 Iheyamides A	Linear Peptides	T. b. rhodesiense	IL-1501	1.5 μM	Normal human fibroblasts, WI-38 cells	18 μM	Noho Island, Okinawa, Japan	[62]
					T. b. brucei	221	1.5 μM		18 μM
					T. b. rhodesiense	IL-1501	> 20 μM		>20 μM
					T. b. brucei	221	> 20 μM		>20 μM
					T. b. rhodesiense	IL-1501	> 20 μM		>20 μM
					T. b. brucei	221	> 20 μM		>20 μM
			Pentamide *	-	T. b. rhodesiense	IL-1501	0.005 μM	-	-	-
			Pentamide *	-	T. b. brucei	221	0.001 μM	-	-	-
		Leptolyngbya sp.	87 Motobamide	Cyclic Peptide	T. b. rhodesiense	IL-1501	2.3 μM	WI-38 cells	55 μM	Bise, Okinawa Island, Okinawa Prefecture, Japan	[63]
		Leptolyngbya sp.	87 Motobamide	Cyclic Peptide	T. b. rhodesiense	IL-1501	2.3 μM	HeLa or HL60 cells	IA at 10 μM	Bise, Okinawa Island, Okinawa Prefecture, Japan	[63]
		Leptolyngbya sp.	88 Palstimolide A	Polyhydroxy Macrolide	P. falciparum	Dd2	0.1725 μM	HepG2 human liver cell line	5.04 μM	Palmyra Atoll	[64]
		Leptolyngbya sp.	88 Palstimolide A	Polyhydroxy Macrolide	L. donovani	promastigotes	4.67 μM	B10R murine macrophages (L. donovani host cell toxicity)	>10 μM	Palmyra Atoll	[64]
		Okeania sp.	89 Ikoamide	Lipopeptide	P. falciparum	3D7	0.14 μM	HeLa cells or HL60 cells	No cytotoxicity at 10 μM	Iko-pier, Kuroshima Island, Okinawa, Japan	[65]
			Chloroquine *	-	P. falciparum	3D7	6.9 nM	-	-	-
			doxorubicin	-	-	-	-	HeLa cells	0.24 μM	-
			doxorubicin	-	-	-	-	HL60 cells	46 nM	-
		Okeania sp.	90 Mabuniamide	Lipopeptide	P. falciparum	3D7	1.4 μM	L6 myotubes	No cytotoxicity at 10–40 μM	The coast of Odo, Okinawa, Japan	[66]
			91 Stereoisomer 2	Lipopeptide			1.4 μM	L6 myotubes	No cytotoxicity at 10–40 μM	The coast of Odo, Okinawa, Japan
			Chloroquine *	-			7.6 nM	-	-	-
		Salileptolyngbya sp.	92 Kinenzoline (natural)	Linear Depsipeptide	T. b. rhodesiense	IL-1501	5.0 μM	WI-38 cells	>20 μM	Kinenhama beach, Kagoshima, Japan	[67]
			93 Kinenzoline (synthetic)	Linear Depsipeptide			4.5 μM	WI-38 cells	>100 μM	Kinenhama beach, Kagoshima, Japan
			Pentamide *	-			0.001 μM	-	-	-
			Adriamycin *	-	-	-	-	WI-38 cells	0.73 μM	-
		Moorea producens	94 Dudawalamide A	Cyclic Depsipeptides	P. falciparum	W2	3.6 μM	H-460 human lung cancer cell line	Little to no cytotoxicity	Papua New Guinea	[68]
					T. cruzi	Transgenic β-galactosidase-expressing strain	12% GI (Percentage growth inhibition) at 10 μg/mL
					L. donovani	WR2810	> 10 μM
			95 Dudawalamide B		P. falciparum	W2	8.0 μM
					T. cruzi	Transgenic β-galactosidase-expressing strain	7% GI at 10 μg/mL
					L. donovani	WR2810	> 10 μM
			96 Dudawalamide C		P. falciparum	W2	10 μM
			97 Dudawalamide D		P. falciparum	W2	3.5 μM
T. cruzi					Transgenic β-galactosidase-expressing strain	60% GI at 10 μg/mL
L. donovani					WR2810	2.6 μM
Ascomycetes	Aspergillus terreus BCC51799	98 Astepyrazinoxide	Alkaloid	P. falciparum	K-1	24.82 μM	MCF-7	34.70 μM	The marine fungus was isolated from a decayed wood sample at Hat Bang Pu, Khao Sam Roi Yot National Park, Prachuap Khiri Khan Province	[69]
							NCI–H187	5.98 μM
							Vero	15.61 μM
		99 Astechrome				0.94 μM	MCF-7	IA
							NCI–H187	IA
							Vero	7.9 μM
		Dihydroartemisinin *	-			2.12 × 10⁻³ μM	-	-	-
		Mefloquine *	-			0.422 μM	-	-	-
		Ellipticine *	-	-	-	-	NCI–H187	9.87 μM	-
		Ellipticine *	-	-	-	-	Vero	5.32 μM	-
		Doxorubicin *	-	-	-	-	MCF-7	10.97 μM	-
		Doxorubicin *	-	-	-	-	NCI–H187	0.16 μM	-
		Tamoxifen *	-	-	-	-	MCF-7	32.95 μM	-
	Cochliobolus lunatus TA26-46	100 Derivatives	14-Membered Resorcylic Acid Lactone Derivatives	P. falciparum	HB3	12.59 μmol/L	HUVEC	NT	Marine-derived	[70]
		101 Derivatives				12.39 μmol/L		NT
		102 Derivatives				11.55 μmol/L		NT
		103 Derivatives				8.06 μmol/L		>100 μmol/L
		104 Derivatives				6.69 μmol/L		>100 μmol/L
		105 Derivatives				7.82 μmol/L		>100 μmol/L
		106 Derivatives				9.72 μmol/L		>100 μmol/L
		107 Derivatives				7.82 μmol/L		>100 μmol/L
		108 Derivatives				7.25 μmol/L		>100 μmol/L
		109 Acyl derivatives				9.18 μmol/L		NT
		110 Acyl derivatives				6.91 μmol/L		>100 μmol/L
		111 Acyl derivatives				3.54 μmol/L		>100 μmol/L
		Chloroquine *	-			32.9 nmol/L	-	-	-
	Exserohilum sp.	112 Isocoumarins	Polyketide	P. falciparum	HB3	1.13 μM	Vero cells	87.5 μM	Zoanthid Palythoa haddoni	[71]
		113 Isocoumarins				11.7 μM		124.2 μM
		114 Derivatives				0.77 μM		258.0 μM
		115 Derivatives				0.38 μM		106.3 μM
		116 Derivatives				2.58 μM		262.5 μM
	Paecilomyces sp. 7A22	117 Harzialactone A	Polyketone	L. amazonensis	promastigotes	5.25 μg/mL	Peritoneal macrophages	35.21 μg/mL	Ascidian Aplidiopsis sp. collected from São Sebastião Channel in Brazil	[72]
		117 Harzialactone A	Polyketone	L. amazonensis	amastigotes	18.18 μg/mL		35.21 μg/mL
		Amphotericin B *	-	L. amazonensis	promastigotes	0.119 μg/mL		22.41 μg/mL	-
		Amphotericin B *	-	L. amazonensis	amastigotes	0.095 μg/mL		22.41 μg/mL	-

* Positive control; NT indicates not text; IA indicates inactive.

Table 2. Crude extracts of marine invertebrates and microorganisms.

Category	Species	Extract Type	Target Parasite	Stage/Strain	IC₅₀	Site	References
Cnidaria	Linuche unguiculata	Distilled water	Giardia duodenalis	Trophozoites, IMSS 0989:1 strain	63 µg/mL	Puerto Morelos Reef Lagoon, Mexico	[73]
Actinomycetes	Nocardia sp. UA 23	ISP2 medium	Trypanosoma brucei	TC 221	MIC, 72 h = 7.2 µg/mL	Coscinoderma mathewsi was collected from Ahia Reefs	[74]
	Micromonospora sp. W305	Resin, MeOH	Antiplasmodial Activities	Dd2	0.42 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Nocardiopsis sp. V671	ASE, MeOH	Antiplasmodial Activities	Dd2	0.88 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Streptomyces tendae V324	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.35 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Streptomyces sp. INV ACT2	Ethyl acetate	T. gondii	GFP-RH tachyzoites	Inhibition ≥ 80% at 120 μg/mL	Caño Aguas Negras	[76]
	Streptomyces sp. RM66	On ISP2, solid media with GlcNAc	Trypanosoma brucei	TC 221	MIC, 72 h = 4.7 µg/mL	Hurghada (Egypt)	[77]
	Streptomyces sp. V881	Resin, CH₂Cl₂	Antiplasmodial Activities	Dd2	0.062 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Streptomyces sp. E677	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.037 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Unidentified actinomycete V663	ASE, heptane	Antiplasmodial Activities	Dd2	0.89 µg/mL	The microbial population associated with deep-water invertebrates	[75]
Bacteroides	Alcanivorax sp. V174 (G-)	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.969 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Alcanivorax sp. V193 (G-)	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	1.079 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Endozoicomonas numazuensis H402 (G-)	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.978 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Marinobacter sp. V184 (G-)	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	1.008 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Marinobacter sp. V201 (G-)	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	1.091 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Marinobacter sp. V208 (G-)	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	1.091 µg/mL	The microbial population associated with deep-water invertebrates	[75]
Firmicutes	Bacillus sp. INV FIR35	Ethyl acetate	T. gondii	GFP-RH tachyzoites	Inhibition ≥ 80% at 48 μg/mL	Punta Betín	[76]
	Bacillus sp. INV FIR48	Ethyl acetate	T. gondii	GFP-RH tachyzoites	Inhibition ≥ 80% at 120 μg/mL	Caño Grande	[76]
	Fictibacillus sp. INV FIR149	Ethyl acetate	T. gondii	GFP-RH tachyzoites	Inhibition ≥ 80% at 1080 μg/mL	Caño Grande	[76]
	Paenibacillus sp. #91_7 (IN-CRY)	Waters™ Oasis^® HLB extraction plates, with the sorbent Oasis^® HLB, was equilibrated using methanol and HPLC grade water	T. cruzi	Tulahuen C4	97%	Isolated from marine sponges of the Erylus genus, collected in Portuguese waters	[78]
	Penicillium citrinum V170	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	1.069 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Penicillium sp. N161	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.266 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Penicillium sp. Z691	Resin, CH₂Cl₂	Antiplasmodial Activities	Dd2	0.049 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Talaromyces rotundus S920	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.677 µg/mL	The microbial population associated with deep-water invertebrates	[75]
	Tritirachium sp. V199	Resin, MeOH/CH₂Cl₂	Antiplasmodial Activities	Dd2	0.339 µg/mL	The microbial population associated with deep-water invertebrates	[75]
ɣ-Proteobacteria	Enterococcus faecalis #118_3 (IN-CRY)	EPA vials: Sepabeads^® SP207ss resin, HPLC-grade water and acetone; medium IN-CRY	T. cruzi	Tulahuen C4	Percentage of growth inhibition = 81%	Isolated from marine sponges of the Erylus genus, collected in Portuguese waters	[78]
	Enterococcus faecalis #118_3 (IN-CRY)	Duetz extraction: Waters™ Oasis^® HLB extraction plates, with the sorbent Oasis^® HLB, was equilibrated using methanol and HPLC grade water; medium IN-CRY	T. cruzi	Tulahuen C4	Percentage of growth inhibition = 102%	Isolated from marine sponges of the Erylus genus, collected in Portuguese waters	[78]
	Enterococcus faecalis #118_4 (IN-CRY)	Duetz extraction: Waters™ Oasis^® HLB extraction plates, with the sorbent Oasis^® HLB, was equilibrated using methanol and HPLC grade water; medium IN-CRY	T. cruzi	Tulahuen C4	Percentage of growth inhibition = 103%	Isolated from marine sponges of the Erylus genus, collected in Portuguese waters	[78]
	Pseudoalteromonas sp. INV PRT33	Ethyl acetate	T. gondii	GFP-RH tachyzoites	Inhibition ≥ 80% at 48 μg/mL	Caño Grande	[76]
Phaeophyta	Cladostephus hirsutus	Ethyl acetate	T. brucei brucei	-	27.2 μg/mL	North-west coast of Algeria	[79]
	Cystoseira sedoides	Hexane	Acanthamoeba castellanii	Trophozoite/Neff	1009 μg/mL	Tunisian coasts, Tabarka	[80]
		Ethyl acetate			860 μg/mL
		Methanol			836 μg/mL
	Dictyota ciliolata	Hexane	Schistosoma mansoni		Death Ratio = 100%	Espírito Santo State, Southeastern Brazil	[81]
		Chloroform			Death Ratio = 100%
		Supercritical fluid			Death Ratio = 100%

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Zhang, M.; Zhang, Q.; Zhang, Q.; Cui, X.; Zhu, L. Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms. Mar. Drugs 2023, 21, 84. https://doi.org/10.3390/md21020084

AMA Style

Zhang M, Zhang Q, Zhang Q, Cui X, Zhu L. Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms. Marine Drugs. 2023; 21(2):84. https://doi.org/10.3390/md21020084

Chicago/Turabian Style

Zhang, Mingyue, Qinrong Zhang, Qunde Zhang, Xinyuan Cui, and Lifeng Zhu. 2023. "Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms" Marine Drugs 21, no. 2: 84. https://doi.org/10.3390/md21020084

APA Style

Zhang, M., Zhang, Q., Zhang, Q., Cui, X., & Zhu, L. (2023). Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms. Marine Drugs, 21(2), 84. https://doi.org/10.3390/md21020084

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Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

Abstract

1. Introduction

2. Marine Invertebrate-Derived Antiparasitic Compounds

2.1. Alkaloid Compounds

2.2. Terpenoids, Sesquiterpenoids, and Diterpenoids Compounds

2.3. Steroids and Sterols Compounds

2.4. Other Compounds

3. Marine Microorganisms-Derived Antiparasitic Compounds

3.1. Steroids and Sterols Compounds

3.2. Marine Fungi

4. Cyanophyta

4.1. Linear Peptides

4.2. Cyclic Peptides

5. Conclusions

Author Contributions

Funding

Data Availability Statement

Acknowledgments

Conflicts of Interest

References

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