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. 2023 Jan 25;21(2):84. doi: 10.3390/md21020084

Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

Mingyue Zhang 1, Qinrong Zhang 1, Qunde Zhang 1, Xinyuan Cui 1, Lifeng Zhu 1,2,*
Editors: Saccoccia Fulvio, Carla Fernandes
PMCID: PMC9965275  PMID: 36827125

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:

  1. 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];

  2. 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.

Table 1.

Natural products or derivatives from marine invertebrates and microorganisms.

Category Species Compounds Chemistry Target Parasite Stage/Strain IC50 Cytotoxicity Site Reference
Type of Cells IC50
Invertebrate sponges Aplysinella rhax 1 Psammaplin A Bromotyrosine Alkaloids T. cruzi C2C4 30 μM NT NT Fiji Islands [36]
P. falciparum 3D7 60 μM
2 Psammaplin D T. cruzi C2C4 43 μM
P. falciparum 3D7 67 μM
3 Bisaprasin T. cruzi C2C4 19 μM
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 - - -
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 8.0 µg/mL
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]
72 h: 7.48 μM
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
P. falciparum 95 μM
16 Ircinialactam F T. b. rhodesiense 130 μM >200 μM
L. donovani 95 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
T. cruzi C2C4 190.9 μM L6 59.5 μg/mL
L. donovani MHOM/ET/67/L82 16.6 μM
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]
FCR3 2.45 µg/mL
19 Ceratinadin E K1 1.03 µg/mL 15.99 µg/mL
FCR3 0.77 µg/mL
Chloroquine * - K1 0.34 µg/mL >25.80 µg/mL -
FCR3 0.035 µg/mL
Artemisinin * K1 0.010 µg/mL >14.12 µg/mL
FCR3 0.0088 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 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]
Normal nontumor NFF cells 100 μM
27 Albanitrile B 25 μM Mammalian myeloma cell line NS-1 50 μM
Normal nontumor NFF cells 100 μM
28 Albanitrile C 90 μM Mammalian myeloma cell line NS-1 180 μM
Normal nontumor NFF cells 90 μM
Metronidazole * 2.9 μM - - -
Sparsomycin * - - - - Mammalian myeloma cell line NS-1 0.55 μM
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]
1.1 μM
K1 1.1 μM
30 Pseudoceratidine derivative P. falciparum 3D7 EC50 = 6 μM
31 Pseudoceratidine derivative 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
L. amazonensis promastigotes EC50 = 76 μM
38 Pseudoceratidine derivative L. infantum promastigotes EC50 = 23 μM 82 μM
L. amazonensis promastigotes EC50 = 18 μM
P. falciparum 3D7 EC50 = 3 μM NT
Chloroquine * - P. falciparum 3D7 0.013 μM - - -
K1 0.167 μM
Pyrimethamine * - P. falciparum 3D7 0.03 μM - - -
K1 3.9 μM
Cycloguanil * - P. falciparum 3D7 0.010 μM - - -
K1 0.54 μM
Artesunate * - P. falciparum 3D7 0.004 μM - - -
K1 0.003 μM
Xestospongia sp. 39 Kaimanol Sterol P. falciparum 3D7 0.359 μM NT NT Indonesia [47]
40 Saringosterol 0.00025 μM
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]
44 Nitenin C21 Degraded Terpene EC50 = 0.29 μM EC50 =18.3 μM
Macrorhynchia philippina 45 Isololiolide Carotenoid Isololiolide T. cruzi trypomastigotes 31.9 μM BMM cells  >200 μM São Sebastião Channel, Brazil [51]
amastigotes 40.4 μM
Benznidazole * - trypomastigotes 16.2 μM  >200 μM -
amastigotes 5.3 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 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
Dd2 0.75 μM
61 Volutamides G 3D7 0.57 μM 11 μM
Dd2 0.85 μM
62 Volutamides H 3D7 1.6 μM IA at 40 μM
Dd2 1.9 μM
Chloroquine * - 3D7 0.025 μM 67% at 4 μM -
Dd2 0.18 μM
Dihydroartemisinin * - 3D7 0.0020 μM IA at 0.1 μM -
Dd2 0.0020 μM
Puromycin * - 3D7 0.11 μM 0.81 μM -
Dd2 0.068 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]
Cysts 0.771 µg/mL
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]
Human hepatocarcinoma (HepG2) 5.3 μM
71 RL002 0.17 μM Human foreskin fibroblast (HFF) >50 μM
Human hepatocarcinoma (HepG2) 29.0 μM
72 RL003 0.09 μM Human foreskin fibroblast (HFF) >50 μM
Human hepatocarcinoma (HepG2) 49.7 μM
73 RL125 0.16 μM Human foreskin fibroblast (HFF) >50 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
T. cruzi C4 3.66 µg/mL
76 2-nonyl-4-hydroxyquinoline P. falciparum Indochina W2 2.79 µg/mL
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]
T. brucei rhodesiense IL-1501 2.9 μM
78 Hoshinoamide C(synthetic) P. falciparum 3D7 3.2 μM
T. brucei rhodesiense IL-1501 3.7 μM
79 43-epi-hoshinoamide C(synthetic) P. falciparum 3D7 0.87 μM
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
T. b. rhodesiense IL-1501 > 20 μM >20 μM
T. b. brucei 221 > 20 μM
T. b. rhodesiense IL-1501 > 20 μM >20 μM
T. b. brucei 221 > 20 μM
Pentamide * - T. b. rhodesiense IL-1501 0.005 μM - - -
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]
HeLa or HL60 cells IA at 10 μM
Leptolyngbya sp. 88 Palstimolide A Polyhydroxy Macrolide P. falciparum Dd2 0.1725 μM HepG2 human liver cell line 5.04 μM Palmyra Atoll [64]
L. donovani promastigotes 4.67 μM B10R murine macrophages
(L. donovani host cell toxicity)		 >10 μM
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 * - 6.9 nM - - -
doxorubicin - - - - HeLa cells 0.24 μM -
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 1.4 μM
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) 4.5 μM >100 μM
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 -
Vero 5.32 μM
Doxorubicin * - - - - MCF-7 10.97 μM -
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]
amastigotes 18.18 μg/mL
Amphotericin B * - L. amazonensis promastigotes 0.119 μg/mL 22.41 μg/mL -
amastigotes 0.095 μg/mL
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* 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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Figure 1.

Figure 1

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The structure of compounds with effective antiparasitic activity in invertebrates.

Figure 2.

Figure 2

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

Figure 3.

Figure 3

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

Figure 4.

Figure 4

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The structure of compounds with effective antiparasitic activity in Cyanophyta.

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.

Acknowledgments

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

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.

Data Availability Statement

Not applicable.

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.

Funding Statement

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

Footnotes

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