Promising bioactive compounds from the marine environment and their potential effects on various diseases

Background The marine environment hosts a wide variety of species that have evolved to live in harsh and challenging conditions. Marine organisms are the focus of interest due to their capacity to produce biotechnologically useful compounds. They are promising biocatalysts for new and sustainable industrial processes because of their resistance to temperature, pH, salt, and contaminants, representing an opportunity for several biotechnological applications. Encouraged by the extensive and richness of the marine environment, marine organisms’ role in developing new therapeutic benefits is heading as an arable field. Main body of the abstract There is currently much interest in biologically active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Studies are focused on bacteria and fungi, isolated from sediments, seawater, fish, algae, and most marine invertebrates such as sponges, mollusks, tunicates, coelenterates, and crustaceans. In addition to marine macro-organisms, such as sponges, algae, or corals, marine bacteria and fungi have been shown to produce novel secondary metabolites (SMs) with specific and intricate chemical structures that may hold the key to the production of novel drugs or leads. The marine environment is known as a rich source of chemical structures with numerous beneficial health effects. Presently, several lines of studies have provided insight into biological activities and neuroprotective effects of marine algae, including antioxidant, anti-neuroinflammatory, cholinesterase inhibitory activity, and neuronal death inhibition. Conclusion The application of marine-derived bioactive compounds has gained importance because of their therapeutic uses in several diseases. Marine natural products (MNPs) display various pharmaceutically significant bioactivities, including antibiotic, antiviral, neurodegenerative, anticancer, or anti-inflammatory properties. The present review focuses on the importance of critical marine bioactive compounds and their role in different diseases and highlights their possible contribution to humanity.


Introduction
Marine sources have played a significant role as an origin for lead molecules ascertained for various pharmacological utilizations in recent times. Interestingly, marine microorganisms remain as the most undiscovered and essential provenience of umpteen bioactive metabolites. From the shallow water in the seashore to the abysmal seaward areas that canvas 70% of the biosphere, microorganisms engross an endurable stretch [6]. The varying temperature, pressure, and source of light in the marine system compared to the terrestrial environment possibly helps in producing novel secondary metabolites by some marine organisms.
Microbes, especially in the marine environment, can withstand high salt concentrations, high pressure, nutrition depletion, and cold temperatures. Natural sources producing biological materials, screened by high throughput screening methods for their therapeutic activity, lead to developing a commercially viable process or product [7]. Bioprospecting marine habitat is one of the most prolific platforms because of its diverse and under passed microbial population. Microbes can easily detect, adapt, and react to their environment and compete by producing specific secondary metabolites for protection and survival. These compounds developed in reaction to stress have shown value in biotechnological or pharmaceutical applications [7] (Fig. 1).
In reality, marine natural products' ecology shows that many of these compounds are chemical weapons and have grown into highly potent physiological process inhibitors in prey, predators, or marine organism rivals that use them for survival. Bioprospecting will help in unraveling the enigma of the bioactive metabolites from marine microbes [8].
From the beginning of humankind, natural products have been a beneficial source as a remedy for various ailments. In worldwide, the available drugs for clinical purpose represents more than 50% are of their natural origin. The drug discovery process from natural products is still ongoing due to synthetic drugs' side effects [9]. The crude product has a significant impact on producing new medicines that bypass infectious diseases [10].
The marine microbial species tends for conceivable biotechnological and is also an essential source of ecological maintenance. It is evident from the 16S rRNA sequencing that marine microbial species such as Bacteria and Archae have a highly diverse taxonomy [11]. Metagenomic studies have revealed that extremophile prokaryotes from marine habitats are also sources of novel genes and, consequently, new bioproducts, including enzymes and other active metabolites [12] (Fig. 2).
The extreme ecological variations in the marine habitat forced the inhabitant organisms to produce a class of tolerable hydrolase enzymes such as proteases, lipases, glycoside hydrolases, which is used in industrial processes due to their novel specificities and properties of tolerance to extreme industrial conditions. Therefore, studying a severe global issue. There is a need for novel chemical compounds capable of a battle against infections provoked by multidrug-resistant pathogens. The discovery of new products from natural sources is mainly essential for the development of novel antimicrobial agents. Currently, antimicrobial drugs for medical treatment derived from natural origin exhibit Actinobacteria as the most important secondary metabolite source. Carbohydrates, pigments, polyphenols, peptides, proteins, and essential fatty acids are marine bioactive compounds widely studied for various applications. These compounds have rheological effects and are found helpful in the food industry and diverse biological functions such as antioxidant, anti-thrombotic, anti-coagulant, anti-inflammatory, anti-proliferative, anti-hypertensive, anti-diabetic, and cardio-protective activities [14]. Novel bioactive compounds with extensive activities will be discussed here.

Antibacterial potential of bioactive compounds from marine microorganisms
The treatment options for some diseases like Alzheimer's disease, Parkinson's disease, rheumatoid arthritis (RA) and other forms of arthritis, type-1 diabetes, heart diseases, irritable bowel syndrome, allergies, asthma, cancer, and many others are limited, and certain drugs have significant side effects on patients' health on overdose. Therefore, other alternatives that could theoretically help to manage these troublesome bacterial infections need exhaustive investigations. Since ancient times, the utility of natural products for antimicrobial therapy and other diseases has been a promising treatment [14]. The antibacterial potential of specific bioactive compounds from marine bacteria is extensively mentioned below.
The Actinomadura sp. TP-A0878 is capable of producing a spirotetrone compound nomimicin of polyketide origin. Nomimicin showed potent antimicrobial activity against Micrococcus luteus, Candida albicans, and Kluyveromyces fragilis with MIC values of 6.3, 12.5, and 12.5 μg/ml [16].  [17]. The Streptomyces sp. strain MS1 00061 with provenance from the South China Sea is efficient to produce three secondary metabolites of the family lobophorin (lobophorin A, B, and G). The significant anti-BCG effect is identified with these three metabolites [18].
Ansamycin-type polyketide compounds Novel ansamycin-type compounds isolated from Chilean Atacama Desert soil from the Streptomyces sp. strain C34 labeled as chaxamycins A-D showed potent antibacterial activity against Staphylococcus aureus ATCC25923 and Escherichia coli ATCC25922. Chaxamycins (A-C) were found to inhibit ATPase activity (41-46% of inhibition at 100 micromolar) [19]. ml. The number of substituents regulated the increase in antibacterial activity [24].
RSP 01 from the actinomycin group is a bicyclic chromopeptide lactone biosynthesized with RSP02 by the Streptomyces sp. RAB12. RSP01 with higher antimicrobial potential is possessed to have a ketocarbonyl group with MIC values of the range 0.007 to 0.06 μg/ml [25].

Antioxidant potential of bioactive compounds from marine microorganisms
Marine sediments acquired from Chennai, Tamilnadu, India, labeled as VSKB 1 to VSKB 6 were screened out for their antibacterial and antioxidant activities in which VSKB 3 exhibited activity against Salmonella typhi and higher antioxidant activity in DPPH scavenging assay (88.32%), metal chelating assay (80.7%), and reducing power assay (0.80%) VSKB-3. Further, the isolate VSKB-3 is partially characterized by conventional methods, using the Nonomura key. It showed similar characteristics to Streptomyces bluensi and will be helpful in producing drugs against Salmonella typhi [36].

Anti-inflammatory activity of bioactive compounds from marine microorganisms
Inflammation, a crucial component of host responses to multiple stimuli, including injury, microbial invasion, and immune responses, includes different biological pathways guided by external and internal stimuli. Compounds known as non-inflammatory agents may be modulated, diminished, or blocked by these biological pathways. Drugs developed from natural products are in high demand as the synthetic drugs used in treating inflammatory disorders cause adverse side effects. Novel compounds like sesquiterpenoids, diterpenes, steroids, polysaccharides, alkaloids, and fatty acids, isolated from marine organisms, are found to exhibit anti-inflammatory activity.
Polysaccharides Marine polysaccharides including alginate, porphyran, fucoidan, chitin, and chitin derivatives, are used as down regulators of allergic responses [42]. Polysaccharides isolated from algae that are mostly sulfated exhibit anti-inflammatory activity in vitro and in vivo [43][44][45], which attributes to their structure and physicochemical characteristics [46].
Proteins Marine lectins are found to have anti-inflammatory activity due to their carbohydrate-binding site [47]. Green seaweed Caulerpa cupressoides efficiently produce lectin and is administered in the left temporomandibular joint half an hour before zymosan injection. As a result, reduced zymosan-elicited arthritis and mechanical hypernociception are noticed in rats. Also, suppression in the leukocyte accumulation in synovial fluid is observed. But when treated with opioid receptor antagonist naloxone or ZnPP-IX, the activity of lectin declined. However, lectin blocked leukocyte influx and TNF-alpha and IL-1beta expression in the temporomandibular joint, proving that lectin vitiates temporomandibular joint hypernociception and inflammation depends partially on suppression of IL-1beta and TNF-alpha [48].

Enzyme inhibitors
Polymeric 3-alkylpyridinium salts composing of N-butyl (3-butylpyridinium) have been isolated from marine sponge Renierasarai. N-Butyl-3-butylpyridinium iodide, the monomer of the inhibitor, has been synthesized which acts as acetylcholinesterase inhibitors. The TLC bioautography method was carried out to assess the acetylcholinesterase inhibitory activity of the marine extracts. Extracts obtained from soft corals were more active. 14-Acetoxycrassine was determined as the bioactive compound using X-ray diffraction. Adding to this, the acetylcholinesterase inhibitory activity of 14 cembranoids has been isolated from soft corals Euniceaknighti and Pseudoplexauraflagellosa. The quantitative test, 14-acetoxycrassine and asperdiol, exhibited IC 50 values of 1.40-0.113 and 0.358-0.130 μM, respectively [49]. In Alzheimer's disease, acetylcholinesterase inhibition is an important checkpoint. Acetylcholinesterase, alphaglucosidase, and xanthine oxidase inhibitory activity of 55 ethyl acetate extracts were identified in which Vibrio neocaledonicus exhibited 98.95% activity [50]. Table 1 shows the bioactive secondary metabolites isolated from marine sources, their structure, and applications in different fields.

Leading secondary metabolites from marine sources and their role against various diseases Against tuberculosis
Tuberculosis is the greatest threat around the globe. However, there are anti-tuberculosis (anti-TB) medicines, which lowered the fatality drug-resistant forms. Nevertheless, of the clinical drugs, biodiverse marine microorganisms have been identified as a drug source in treating tuberculosis. Nearly 170 compounds isolated from marine sources tended to exhibit anti-TB properties. The current anti-TB agents rifampicin, streptomycin, amikacin, viomycin, capreomycin, kanamycin, and cycloserine possess in vitro activity against Mycobacterium tuberculosis with MICs of 0.2, 0.5, 1.0, 4.0, 5.0, and 6.0 μg/mL, respectively [97]. The initial MIC value should be less than 64 μg/mL to identify potential anti-TB compounds, or the growth inhibition should be more significant than 75% at 12.5 μg/mL [98,99]. Additionally, a selectivity index (SI, IC 50 /MIC) more significant than 10 has been used as a benchmark to screen anti-TB compounds that can further develop [98,99]. With their unique aquatic environment and rich biodiversity, the oceans have proven to be a plentiful source of diverse natural products with significant antimicrobial, antiviral, antimalarial, antitumor anti-inflammatory, and antioxidant activities [100].

Neurodegenerative diseases
Neurodegenerative disorders are characterized by mitochondrial dysfunction and reactive production of oxygen species (ROS), among cellular pathologies, thereby related to oxidative stress. The central nervous system is peculiarly sensitive to free radical damage due to its high oxygen consumption ratio, rich content of phospholipids, and high levels of iron, which can catalyze oxidative reactions and contribute to an increase in the production of free radicals. This is coupled with a low content of antioxidant defenses in the brain that is even more altered in Neurodegenerative disease.
Secondary metabolites preventing oxidative stress Oxidative stress is a frequent checkpoint in neurodegenerative diseases, widely associated with mitochondria. These two compounds, glutathione and catalase, displayed complete protection against oxidative stress with mitochondrial function improvement, ROS production inhibition, and antioxidant enzyme levels. Further studies have reported that anhydroexfoliamycin acts as an inducer of Nrf2 nuclear translocation over the Nrf2-ARE pathway and can significantly inhibit the uncoupler's mitochondrial effect FCCP over cytosolic Ca2+, pointing mitochondria as a cellular target for this molecule. Also, both compounds were able to reduce the caspase-3 activity induced by staurosporine, an apoptotic enhancer. These show that Streptomyces metabolites could help develop new drugs to prevent neurodegenerative disorders such as Parkinson's and Alzheimer's diseases and cerebral ischemia [101].
The Streptomyces sp. UTMC 1334 is considered a potential anti-acetylcholinesterasic sources with an IC 50 value of 0.36 ± 0.02 μg/mL, since extracts with an IC 50 value lower than 1.0 μg/mL were considered strong anti-acetylcholinesterasic [102,103]. The Streptomyces sp. UTMC 1334 is taxonomically identified as Streptomyces lateritius (99.41%). This is the first report of marine-isolated Streptomyces lateritius producing metabolites with AChE inhibitory activity. Six antibiotics of the granaticin group have been isolated from Streptomyces lateritius so far. The Granaticins are a well-documented series of quinone antibiotics and are reported to have antibacterial, antitumor, and anti-protozoal activities [104,105].
Granaticin B is highly active against Staphylococcus aureus with a MIC range from 0.9 to 3.6 μmol/l. Effective inhibition of biofilm formation against Staphylococcus aureus is also reported [95]. Streptocyclinones A and B, isolated from the Streptomyces sp. to improve AD hallmarks, were evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from H 2 O 2 -induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2) [106].
Alzheimer's disease Alzheimer's disease (AD) is a slow and progressive degeneration with synaptic loss and final neuronal death. The impairments are located in specific brain regions engaged in learning and memory processes. The indication of this disorder is the presence of senile plaques and neurofibrillary tangles (NFTs). These senile plaques are extracellular aggregates of amyloid-beta protein produced by the incorrect cleavage of the amyloid precursor protein (APP), and NFTs are intracellular accumulations of abnormal hyperphosphorylated tau proteins. Many hypotheses illustrate these mechanisms, the most accepted of which is the amyloid cascade hypothesis that proposes the abnormal amyloid is processed by beta and gamma secretases and as the main event of AD [107] (Fig. 3).
Although amyloid and tau approaches have been widely adopted and currently are the most studied ones, oxidative stress-based strategies have also been tried, using two different routes: through exogenous antioxidants or by the induction of endogenous antioxidant defenses through the nuclear factor erythroid 2-related factor 2 (Nrf2) [107].
Hymenialdisine belongs to a novel class of CDK inhibitors isolated from Agelasidae, Axinellidae, and Halichondriidae families of marine sponges. The CDK inhibitory efficacy of HD is understood by observing its binding interactions in the CDK2-HD crystal structure. In vivo phosphorylation of particular neuronal proteins by GSK-3 and CDK5 is inhibited by HD. It inhibits the phosphorylation of tau, which is indicative of Alzheimer's disease. HD could be a lead chemical for analyzing the role of tau hyperphosphorylation in neurodegenerative diseases and specific inhibitors of kinases involved in AD and other degenerative disorders. Several models were used to demonstrate the effects of HD on kinases in vivo. These findings motivated researchers to look into HD as a potential treatment for neurodegenerative diseases [96]. Hymenialdisine also suppresses many pro-inflammatory cytokines (IL-1, IL-2, IL-6, and NO) by inhibition of the NF-kB signaling pathway, which could be useful in the treatment of inflammatory diseases [108]. Parkinson's disease Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons, leading to patients' motor dysfunctions. Although PD's etiology is still unclear, the death of dopaminergic neurons during PD progress was revealed to be associated with the abnormal aggregation of synuclein, the elevation of oxidative stress, the dysfunction of mitochondrial functions, and the increase of neuroinflammation. However, current anti-PD therapies could only produce symptom-relieving effects because they could not provide neuroprotective effects and stop or delay dopaminergic neuron degeneration. Marine-derived natural compounds, with their novel chemical structures and unique biological activities, may provide anti-PD neuroprotective effects [109].
Secondary metabolites from marine-derived bacteria represent a rich source for drug development with novel chemical structures and diverse biological activities [110,111]. NP7 is a marine-derived compound from the Streptomyces sp. NP7 is an antioxidant and can pass the bloodbrain barrier. NP7 at 5-10M is capable of preventing apoptosis and necrosis induced by H 2 O 2 in neurons and glial cells [112]. Also, NP7 can inhibit microglial activation and prevent the increased phosphorylation of ERK induced by H 2 O 2 . Therefore, NP7 can act as a neuroprotective agent against oxidative stress in PD [113].
The inhibitory activity of marine-derived compounds piloquinones, isolated from the Streptomyces sp., on MAO-B was reported by Takeuchi et al. [114]. Piloquinone A and piloquinone B were isolated from the Streptomyces sp. CNQ-027 [115]

Autoimmune diseases
The autoimmune disease includes rheumatoid arthritis (RA) and other forms of arthritis, type-1 diabetes, heart diseases, irritable bowel syndrome, allergies, asthma, cancer, and many others. Over the past few decades, it was realized that the process of inflammation is virtually the same in different disorders, and a better understanding of inflammation may lead to better treatments for numerous diseases. Inflammation is the activation of the immune system in response to infection, irritation, or injury, with an influx of white blood cells, redness, heat, swelling, pain, and dysfunction of the organs involved. Although these conditions' pathophysiological basis is not fully understood, reactive oxygen species (ROS) have often been implicated in their pathogenesis. In fact, the antioxidant defense system is compromised in inflammatory diseases, as evidenced by increased oxidative stress markers and decreased protective antioxidant enzymes in patients with rheumatoid arthritis (RA).
Secondary metabolites from the Actinomycetes sp. for inflammatory diseases Cyclomarins are three cyclic heptapeptides (A, B, and C), isolated from the marine bacterium actinomycete, belonging to the Streptomyces sp., along the Californian coast. Marine actinomycetes have been exploited as a source of biologically active secondary metabolites with antibacterial and anti-cancer properties [93]. Some molecules have also been reported to be anti-inflammatory, such as cyclomarins and salinamides [116]. Cyclomarin A, constituted of three common and four unusual amino acids, showed potent antiinflammatory and anti-proliferative activities in in vivo and in vitro assays, managing to inhibit edema pain similar to the drug hydrocortisone [117]. A moderate antiinflammatory effect has also been reported in cyclomarin C, whose total synthesis was recently experimented and reported [118]. That is why both cyclomarin A and C and their derivatives can act as potent anti-inflammatory therapies naturally.
These five peptides (A, B, C, D, and E) were isolated, like cyclomarin, from marine actinomycetes, belonging to the Streptomyces sp., isolated from the surface of the jellyfish Cassiopeaxamachana, found in Florida waters [116]. Salinamides A and B are the two primary bicyclic metabolites, with potent topical anti-inflammatory activity and moderate antibiotic activity against gram-positive bacteria, and could be used to treat tissue inflammation and some infections [119].
Spectral and chemical techniques are useful to construct minor metabolites, Salinamides C, D, and E. In salinamide D, a similar structure is observed with isoleucine replaced by valine. Light anti-inflammatory activity is identified in salinamides C and E, thus potentially able to combat inflammatory disease.

Different types of cancer
Chemotherapy is one of the primary therapies against cancer. A significant number of antitumor compounds are natural products or their derivatives, mainly produced by microorganisms. In particular, actinomycetes are the producers of many natural products with different biological activities, including antitumor properties. Several structural classes of antitumor compounds include anthracyclines, enediynes, indolocarbazoles, isoprenoids, macrolides, non-ribosomal peptides, etc. These compounds' antitumor activity is exerted by inducing apoptosis through DNA cleavage mediated by topoisomerase I or II inhibition, mitochondria permeabilization, and inhibition of key enzymes involved in signal transduction like proteases or cellular metabolism and some cases by inhibiting tumor-induced angiogenesis. Marine organisms have attracted particular attention in the last years for their ability to produce interesting pharmacological lead compounds [120] (Fig. 4). Many of the antitumor compounds from marine drugs result from marine actinobacteria, and these metabolites show a crucial part in the proof of identity of the pharmaceutical compound. Presently, it seems that there have been only a few studies concentrating on finding therapeutic compounds obtained from marine actinobacteria to be used as anti-cancer agents, as well as anti-infective. Some antitumor compounds from marine sources and their role in different types of cancer are discussed below.
Human colon cancer A high number of type I polyketide-derived compounds with antitumor activity have been isolated from marine actinomycetes. Such is the case of arenicolides, 26-membered polyunsaturated macrolactones, produced by the obligate marine actinomycete Salinisporaarenicola strain CNR-005 isolated from a marine sediment sample collected at a depth of 20 m from the coastal water around the island of Guam.
Daryamides also belong to the manumycin family of compounds. They were isolated from Streptomyces strain CNQ-085 obtained from marine sediment collected at a depth of 50 m off the San Diego coast, California. Daryamides A to C and (2E,4E)-7-methylocta-2,4-dienoic acid amide are subjected to cytotoxicity evaluation against the human colon carcinoma cell line HCT-116, showing that daryamide A exhibited significantly more potent cancer cell cytotoxicity, with an IC 50 of 3.15 μg/mL than daryamides B and C [58].
Marineosins, related to the prodigiosin class of polypyrrole bacterial pigments, are spiroaminal compounds containing two pyrrole functionalities produced by Streptomyces strain CNQ-617 isolated from a marine sediment sample collected offshore of La Jolla, California. Marineosins showed significant inhibition of human colon carcinoma HCT-116 cell line with IC 50 values of 0.5 μM for marineosin A and 46 micromolar for marineosin B [121].
Human cervical cancer Chalcomycin, a 16-membered macrolide, is produced by the Streptomyces sp. M491 isolated from the Qingdao coast (China) [122]. Besides, chalcomycin and the related compound chalcomycin B have been isolated from Streptomyces strain B7064 found in mangrove sediments in Hawaii [123]. Chalcomycin is found to inhibit protein synthesis in HeLa human cervix carcinoma cell line [124].
Human skin cancer Human rare macrodiolides composed of dimeric 2-hydroxy-6-alkenyl-benzoic acid lactones with conjugated tetraene-pentahydroxy polyketide chains, produced by the Marinispora sp. CNQ-140 was isolated from a sediment sample collected at a depth of 56 m offshore of La Jolla, California. These compounds inhibit cancer cell proliferation with an average LC50 of 0. Blood cancer Nonactin, a cyclic polyether, also known as macrotetrolide, is isolated from cultures of the Streptomyces sp. KORDI-3238 from a deep-sea sediment sample collected at Ayu Trough in the western Pacific Ocean [125]. The biosynthesis gene cluster of nonactin has previously isolated and characterized from S. griseus DSM40695 [61], revealing that it is synthesized by a noniteratively acting type II PKS that involves five ketosynthases and lacks the acyl carrier protein. Nonactin is an effective inhibitor against the human K-562 erythroleukemia cell line [126].
Chartreusin is an aromatic glycosylated polyketide, currently in phase II clinical trials [62], that possesses an unusual bislactone synthesized through anthracycline intermediates that might undergo a series of oxidative rearrangements to generate the final bislactone structure. This particular biosynthetic process is unraveled by the isolation of the chartreusin biosynthesis gene cluster from S. chartreusis [127]. Chartreusin shows antitumor activity by binding to DNA, radical-mediated singlestrand breaks, and inhibition of topoisomerase II [128].
It possessed significant chemotherapeutic activity against various tumor cell lines such as murine P388 and L1210 leukemia and was identified from Streptomyces sp cultures. FX-58, isolated from marine plant Salicorniaherbacea collected in Qingdao, Shandong province, China, showed an inhibitory effect against human tumor cell lines of pro-myelocytic leukemia HL-60, gastric carcinoma BGC-823, and adenocarcinoma MDA-MB-435 with IC 50 of 6.83, 82.2, and 56.59 μg/mL, respectively.
Altemicidin with a monoterpene-alkaloid skeleton is produced by Streptomyces sioyaensis SA-1758 isolated from sea mud collected at Gamo, Miyagi Prefecture, Japan. This compound inhibited the growth of murine lymphoid leukemia L1210 and carcinoma IMC cell lines with IC 50 values of 0.84 and 0.82 μg/mL, respectively, although it showed high acute toxicity in mice [63].
Streptochlorin is a 3-substituted indole compound with antiangiogenic and anti-cancer activities produced by Streptomyces strain 04DH110 isolated from shallow water sediment taken at 1 m depth of Ayajin Bay, on the East Sea of Korea. Streptochlorin exhibited significant in vitro growth inhibitory activity against human leukemia K-562 cells with an IC 50 of 1.05 μg/mL [64].
Prostate cancer Ammosamides are pyrroloiminoquinone compounds produced by Streptomyces strain CNR-698 isolated from bottom sediments collected at a depth of 1618 m in the Bahamas Islands. Ammosamide A and B exhibited significant in vitro cytotoxicity against human colon adenocarcinoma HCT-116 cells with an IC 50 of 320 nM each [129].
Hepatic cancer Caboxamycin is a benzoxazole compound produced by the Streptomyces sp. NTK 937 was isolated from an Atlantic Ocean deep sea sediment collected in the Canary Basin. It was tested against different tumor cell lines and showed moderate growth inhibitory activity towards human gastric adenocarcimona AGS, hepatocellular carcinoma Hep G2, and breast carcinoma MCF7 cell lines with GI50 7.5, 7.4, and 7.3 μg/mL, respectively [67].
Compounds of the prodigiosin family, isolated from the Saccharopolyspora sp. nov. from sponge Mycale plumose, were collected along the coast of Qingdao, China [130]. The compounds identified as metacycloprodigiosin and undecylprodigiosin [131] exhibited significant cytotoxic activities in vitro, as it is recently described for prodigiosin family of compounds [132], against five cancer cell lines: mouse lymphoma P388, human peripheral blood promyeloblast HL60, lung carcinoma A-549 and SPCA4, and hepatic carcinoma BEL-7402 with IC 50 values between 0.007 and 7.52 μM for metacycloprodigiosin and 0.013 to 0.11 μM for undecylprodigiosin [130].
Dysidiolide is a novel alkyl-hydroxybutenolide diterpene derived from the Bahamas sponge Dysidea etheria capable of inhibiting Cdc25 protein phosphatase, causing the G2/M transition of the cell cycle to be delayed by dephosphorylating the p34cdc2/cyclin B complex at Tyr15 and Thr14 residues [75]. Sulfircin, a sesquiterpene sulfate extracted from a marine sponge Ircinia sp., had an IC 50 of 7.8 μM for inhibiting Cdc25 phosphatase [76]. Coscinosulfate is a sesquiterpene sulfate obtained from the new Caledonian sponge Coscinoderma mathewsi having significant inhibitory activity towards Cdc25A (IC 50 = 3μM) [77]. The Fijian sponge Xestospongia carbonaria produced halenaquinone, a pentacyclic polykeyide molecule that works as an irreversible inhibitor of recombinant human Cdc25B phosphates (activator of cyclin-dependent kinase Cdc2), which prevents the cell cycle from progressing to the mitotic phase. With an IC 50 value of 19 μM, this drug displayed an inhibitory effect against the kinase activity of human EGFR [78]. SAD is a mycotoxin that is isolated from Penicillium oxalicum. DNA topoisomerase I is inhibited by SAD (MIC = 0.4 μM) and also inhibited the G1 phase of the cell cycle in the GSK-3/-catenin/c-MYC pathway, resulting in considerable cytotoxic action against different cancer cells. SAD slowed the course of the cell cycle in human embryonic palatal mesenchymal cells, preventing them from proliferating [79,136].
The triterpene Stellettin B was isolated from the sea sponge Jaspis stellifera. At a dose of 0.01 μM, this chemical inhibits the development of the glioblastoma cell line SF295 by 50%. Stettettin B's mitotic G1 phase arrest resulted in a decrease in Cdk and an increase in p27 expression. The cleavage of Poly ADP Ribose Polymerase (PARP) and an increase in ROS generation may be linked to apoptosis induction [80].
Phidianidine A is an indole alkaloid isolated from the marine opisthobranch mollusk Phidiana military capable of inhibiting CXCL12-induced DNA synthesis, cell migration, and ERK1/2 activation [137,138]. Fucoidan is a sulfated polysaccharide isolated from brown seaweeds that contains fucose. Fucoidan crude extracts bind CXCL12 and inhibit lung metastasis and tumor growth in 4T1 breast cancer cells [139]. JG6 is a new marinederived oligosaccharide that has been demonstrated to reduce angiogenesis and tumor metastasis by inhibiting CXCL12/CXCR4 [140].

Drugs derived from marine sources under clinical trials Phase III
Plitidepsin is a cyclic depsipeptide isolated from a Mediterranean marine tunicate (Aplidium albicans) and is structurally linked to didemnins, some of which exhibit antiviral effects [141,142].
Plitidepsin exhibited high antiviral effectiveness and a favorable therapeutic index in invitro models of SARS-CoV-2 infection, outperforming other medicines, including remdesivir, preclinical trials. Notably, plitidepsin has a similar in vitro antiviral impact against the B.1.1.7 variety of SARS-CoV-2, which is known to have multiple mutations altering the viral spike protein, which aids viral entry by interacting with the human ACE2 receptor [143].
Tetrodotoxin (TTX) is a neurotoxin that is primarily present in puffer fish and other marine and terrestrial species. TTX inhibits voltage-gated sodium channels (VGSCs). Some TTX-sensitive VGSCs are extensively expressed by main sensory neurons, and they play a significant role in pain signaling. TTX is now being tested in clinical trials for neuropathic pain caused by chemotherapy and cancer-related pain. Tetrodotoxin has been studied in both preclinical and clinical settings to treat pain caused by neuropathies or cancer and has shown efficacy and a favorable safety profile [144].

Phase II
GTS-21 is active in a variety of animal models that are commonly used to study memory and learning. In various in vitro and in vivo investigations, GTS-21 was beneficial in boosting cell survival. GTS-21 is being developed for the treatment of both cognitive dysfunction and neurodegeneration exhibited in Alzheimer's patients based on its preclinical characteristics. GTS-21 was well tolerated up to 450 mg/day (150 mg t.i.d.) in normal people and showed improvements in cognitive behavior. GTS-21 could be a novel dementia medication, and it should be studied further for its potential therapeutic effects in several disorders affecting cognitive function, including Alzheimer's disease [145].
Irvalec ® (elisidepsin trifluoroacetate, PM02734) is a new marine-derived cyclic peptide from the Kahaladide family in clinical trials with preliminary anticancer efficacy. Previous research has found a link between elisidepsin sensitivity and ErbB3 receptor expression in a panel of NSCLC cell lines [146].
Elisidepsin, in combination with CDDP, TAX, or gemcitabine, could be an effective and viable therapeutic approach that could be tested in several in vivo investigations and give a basis for further development of these combinational treatments in clinical trials in the future. In several cell lines, elisidepsin combined with any of the chemotherapeutic drugs had a synergistic impact. Elisidepsin treatment could influence cells on the lipidic bilayer membrane, which are more likely to possess high numbers of ErbB3 receptors, enhancing the activity of the various medications examined (CDDP, TAX, or gemcitabine). In this regard, cancers with overexpression of ErbB3, such as metastatic breast or lung tumors, could be suitable candidates for these types of combinational trials [147].

Phase II
Pseudopterosins and seco-pseudopterosins were isolated from the octocoral Pseudopterogorgia elisabethae of the San Andrés and Providencia islands (southwest Caribbean Sea), and the antimicrobial profile against four pathogenic microorganisms (Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, and Candida albicans), as well as a more comprehensive cytotoxic profile against five human cell lines (HeLa, PC-3, HCT116, MCF-7, and BJ) for the compounds PsG,  [148].
Pseudopterosin H was discovered in the Pseudopterogorgia elisabethae marine coral. In vitro screening with the MTT, NBT, and LDH assays, as well as AO/EB fluorescence, was used to examine the therapeutic efficiency of pseudopterosin H on the PC-3 cell line at varying concentrations. Results show that treatment with pseudopterosin H reduces PC-3 cell viability by inducing apoptosis and downregulating the production of intracellular reactive oxygen species. The chemosensitivity of PC-3 cells to pseudopterosin H therapy implies that it could be used as a preventative and therapeutic treatment for metastatic castration-resistant prostate cancer. PsH lowers PC-3 cell viability by causing apoptosis and lowering ROS levels. PsH may directly impact prooxidant enzyme function or indirectly block the pro-inflammatory pathway, NF, resulting in a reduction in ROS. PsH has pharmacological properties that could be beneficial in the treatment of prostate cancer [149].
Bryostatin 1, a marine-derived natural compound, showed procognitive and antidepressant benefits in animals and is currently being tested in human clinical studies for the treatment of Alzheimer's disease (AD). The effects of bryostatin 1 on the structure and function of hippocampus neurons have been related to its potential to improve learning and memory.
Calvin et al. showed that bryostatin 1 promotes cortical synaptogenesis while lowering dendritic spine density in a protein kinase C (PKC)-dependent manner using a combination of chemical probes and pharmacological inhibitors. Compounds that increase synaptic density while also causing the loss of immature dendritic spines could be a novel pharmaceutical technique for boosting memory by raising the signal-to-noise ratio in the brain [150].
Tissue factor (TF) is a possible target in cervical cancer due to its high expression and link to a poor prognosis. In solid tumors, tisotumab vedotin, a first-in-class experimental antibody-drug combination targeting TF, has shown promising action. Patients with recurrent or metastatic cervical cancer were given tisotumab vedotin 2.0 mg/kg every 3 weeks until their disease progressed, toxicity became unacceptable, or they withdrew their consent. In patients with previously treated recurrent or metastatic cervical cancer, tisotumab vedotin showed a controllable safety profile and promising anticancer efficacy [151].
Other drugs derived from marine sources The hunt for novel chemicals, particularly from marine sources, has piqued the scientific community's interest due to the growing number of diabetic patients and the restricted number of anti-diabetic medications. Marine bioresources have been demonstrated to generate a variety of new scaffolds, several of which have unique structures [152,153]. Surprisingly, a terpene (Dysidine) isolated from the sponge Dysidea villosa is now being tested in preclinical studies for the treatment of diabetes [154].
Cytarabine (Cytosar-U ® , Ara-C, DepoCyt ® ), an anticancer medication derived from the Caribbean sponge Tethya crypta, is used to treat acute myelocytic leukemia and non-Hodgkin's lymphoma [155,156]. ET-743 (Yondelis ® ), derived from the tunicate Ecteinascidia turbinata, is approved for the treatment of tissue sarcomas and ovarian cancer, and eribulin (Halaven ® ), derived from the sponge Halichondria okadai [157], is approved for the treatment of metastatic breast cancer and advanced liposarcoma. Marine compounds like ziconotide (Prialt ® ), obtained from the cone snail Conus magus is used to treat severe and chronic pain [158], and vidarabine (Ara-A), isolated from the sponge Tethya crypta is used to treat herpes simplex infections [159].
Callyspongidiol and 14,15-dihydrosiphonodiol are polyacetylenediols isolated from marine sponges and are pharmacologically active substances. Callyspongidiol and 14,15-dihydrosiphonodiol activate human DC by phenotypic and functional maturation and altered cytokine production. The results suggested that some polyacetylenediols modulate human DC function in a fashion that favors Th1/Th2 cell polarization or IL-10-producing T cells, and might have implications in tumors or in autoimmune diseases [161].  [162].
The cone snail Conus pulicarius from the Philippines provides a specific habitat for actinomycetes and other bacteria. A phenotypic screen using primary cultures of mouse dorsal root ganglion neurons revealed that one C. pulicarius associate, Streptomyces sp. CP32, produces a series of natural products that enhance or diminish whole-cell Ca2+ flux. These compounds include thiazoline compounds and a series of new derivatives, pulicatins A-E (6-10) [163].
Arenamides are cyclohexadepsipeptides that are produced via marine bacterial Salinispora arenicola. There are three types of these peptides named arenamides A-C. Arenamides A and B block or inhibit the activation of TNF-induce in a dose-and time-dependent manner with IC 50 values of 3.7 and 1.7 μM, respectively. Furthermore, they are cytotoxic NFkappaB inhibitors and could inhibit the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Also, arenamides A and B show moderate cytotoxic activity against human colon carcinoma cell line HCT-116 [164]. Derivatives of plakortin named gracilioetheres A-C from Agelas gracilis were isolated from a bioassay-guided approach from an active extract using P. falciparum assay in vitro, highlighting gracilioether B with a IC 50 value of 1.41 μM and moderate cytoxicity [165].

Conclusion
In this review, we have identified the derivatives of structurally unique MNPs obtained from marine sources. These MNPs display different potent bioactivities involving not only chemical effects but also pharmaceutical activities, including antibacterial, antiviral, fungicidal, cytotoxic, neurodegenerative, and antimalarial activities because these MNPs derived from marine sources usually contain reactive groups such as -OH, -NH2, and -SH in their chemical structures, and may act as antioxidants. For instance, brown seaweeds contain several bioactive forms, such as omega-3 polyunsaturated fatty acids (PUFAs), polyphenols, fucosterol, and carotenoids at the same time. Marine peptides, marine carotenoids, and marine polyphenols are superior compared to analogous terrestrial resources as they can relieve symptoms and tackle the possible side effects of pharmacological treatment, reducing the risk of complications. The microorganisms associated with the marine environment have great potential as an essential source of structurally exciting molecules. Increasing ocean exploration has brought more marine drugs to the fore. Marine organisms with novel structures and diverse behaviors generate a large number of bioactive compounds. Bioactive compounds that are modified and synthesized from derived leads are directly extracted or isolated from marine species. Commercial medications remain limited in relieving symptoms and cannot reverse or interrupt the onset or prolong certain diseases' progression. High cost and adverse side effects of drugs in older adults under treatment involve scientific research falling on natural treatment practices surrounding marine bioactive compounds. Marine-derived compounds have reached ongoing clinical trials against multiple diseases and have become primary drug production sources.
The consideration of marine samples will be an amazing and potential route for identifying new secondary metabolites. It is evident from the study that secondarymetabolite development patterns are highly complex and that molecular studies may enhance drug discovery. Genetic technologies and bioinformatics methods, including metagenomic approaches, genome mining, and heterologous biosynthesis, accelerate the discovery and accessibility of remaining undiscovered MNPs with novel structures and promising marine microorganism bioactivities. It is prominent that implementing multiple techniques and exploration methods could effectively facilitate the exploitation of novel MNPs with various systems. MNPs are well-known sources of secondary metabolites suggesting the potential for pharmaceutical, food, cosmetic, and medical use. Therefore, it is of great economic value and can be used for its industrial and academic needs to its new horizons.
To create new medicines for the future, knowledge about secondary metabolites from marine sources is crucial. They are an essential source of bioactive molecules and inspire drug development by supplying a mixture of several bioactive molecules that can synergize and treat several diseases with biological outcomes.
The scaffolds of terrestrial natural materials are used in more than half of all pharmaceuticals. Despite this, with the introduction of high-throughput screening technology, natural compounds have been overlooked for drug discovery. For successful drug development of complicated structures, several hurdles must be overcome, including the supply problem and target identification. Another complication is that because of variable environmental conditions; the same organism may produce various metabolites at different times. The fact that the bioactive compounds are produced by microbes living in the marine mammal, rather than the invertebrate sea hosts, is a huge obstacle [166]. A sustainable supply of separated and recognized lead compounds can be a challenge if the lead compound is only present in small quantities and/or is difficult to isolate technically [167]. The required quantity for any of the compound's intended uses (drug, cosmetic, etc.) might range from a few grams for preclinical drug development and safety investigations in various setups to kilograms for clinical studies in various phases [166]. And the quantity of the lead compound can be a significant problem.
Furthermore, obtaining intellectual property (IP) rights for natural products with relevant bioactivities can be difficult, as naturally occurring chemicals are not always patentable in their native form, while simple modifications can be. Because of the complicated structures, the supply problem, and target identification, it is still a challenge for the researchers to translate marine-derived compounds into clinical trials [168]. The effectiveness of marine natural compounds as drug leads depends on advances in technology such as sampling methods, nanoscale NMR for structure characterization, total chemical synthesis, biosynthesis, and genetic engineering. The high level of innovation in the field of marine natural products will lead to successful marine drug discovery and development, giving us reason to believe that marine natural products will form a new wave of drugs that will flood the market and pharmacies in the future.