Promising Antiparasitic Natural and Synthetic Products from Marine Invertebrates and Microorganisms

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.

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 (Figures 1-4) and the possible structure-activity relationships.

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 (IC 50 = 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.
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.

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 (IC 50 =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 (IC 50 = 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.

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)(72)(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 (IC 50 = 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 (IC 50 = 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 (IC 50 = 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.

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.
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 (IC 50 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 activ-ity, 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.

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].

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 IC 50 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 (IC 50 = 4.67µM).

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 structureactivity 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.