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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Trypanocidal Activity of Marine Natural Products</title><author><name sortKey="Jones, Amy J" sort="Jones, Amy J" uniqKey="Jones A" first="Amy J." last="Jones">Amy J. Jones</name></author><author><name sortKey="Grkovic, Tanja" sort="Grkovic, Tanja" uniqKey="Grkovic T" first="Tanja" last="Grkovic">Tanja Grkovic</name></author><author><name sortKey="Sykes, Melissa L" sort="Sykes, Melissa L" uniqKey="Sykes M" first="Melissa L." last="Sykes">Melissa L. Sykes</name></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24152565</idno><idno type="pmc">3826150</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826150</idno><idno type="RBID">PMC:3826150</idno><idno type="doi">10.3390/md11104058</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">004B32</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004B32</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Trypanocidal Activity of Marine Natural Products</title><author><name sortKey="Jones, Amy J" sort="Jones, Amy J" uniqKey="Jones A" first="Amy J." last="Jones">Amy J. Jones</name></author><author><name sortKey="Grkovic, Tanja" sort="Grkovic, Tanja" uniqKey="Grkovic T" first="Tanja" last="Grkovic">Tanja Grkovic</name></author><author><name sortKey="Sykes, Melissa L" sort="Sykes, Melissa L" uniqKey="Sykes M" first="Melissa L." last="Sykes">Melissa L. Sykes</name></author><author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M." last="Avery">Vicky M. Avery</name></author></analytic><series><title level="j">Marine Drugs</title><idno type="eISSN">1660-3397</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Marine natural products are a diverse, unique collection of compounds with immense therapeutic potential. This has resulted in these molecules being evaluated for a number of different disease indications including the neglected protozoan diseases, human African trypanosomiasis and Chagas disease, for which very few drugs are currently available. This article will review the marine natural products for which activity against the kinetoplastid parasites; <italic>Trypanosoma brucei brucei</italic>, <italic>T.b. rhodesiense</italic> and <italic>T. cruzi</italic> has been reported. As it is important to know the selectivity of a compound when evaluating its trypanocidal activity, this article will only cover molecules which have simultaneously been tested for cytotoxicity against a mammalian cell line. Compounds have been grouped according to their chemical structure and representative examples from each class were selected for detailed discussion.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lozano, R" uniqKey="Lozano R">R. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mar Drugs</journal-id><journal-id journal-id-type="iso-abbrev">Mar Drugs</journal-id><journal-id journal-id-type="publisher-id">marinedrugs</journal-id><journal-title-group><journal-title>Marine Drugs</journal-title></journal-title-group><issn pub-type="epub">1660-3397</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24152565</article-id><article-id pub-id-type="pmc">3826150</article-id><article-id pub-id-type="doi">10.3390/md11104058</article-id><article-id pub-id-type="publisher-id">marinedrugs-11-04058</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Trypanocidal Activity of Marine Natural Products</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Amy J.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Grkovic</surname><given-names>Tanja</given-names></name></contrib><contrib contrib-type="author"><name><surname>Sykes</surname><given-names>Melissa L.</given-names></name></contrib><contrib contrib-type="author"><name><surname>Avery</surname><given-names>Vicky M.</given-names></name><xref rid="c1-marinedrugs-11-04058" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-marinedrugs-11-04058">Eskitis Institute for Drug Discovery, Griffith University, Nathan, Brisbane 4111, Australia; E-Mails:<email>a.jones@griffith.edu.au</email> (A.J.J.);<email>t.grkovic@griffith.edu.au</email> (T.G.);<email>m.sykes@griffith.edu.au</email> (M.L.S.)</aff><author-notes><corresp id="c1-marinedrugs-11-04058"><label>*</label> Author to whom correspondence should be addressed; E-Mail: <email>v.avery@griffith.edu.au</email>; Tel.: +61-(0)-737356056; Fax: +61-(0)-73756001.</corresp></author-notes><pub-date pub-type="epub"><day>22</day><month>10</month><year>2013</year></pub-date><pub-date pub-type="collection"><month>10</month><year>2013</year></pub-date><volume>11</volume><issue>10</issue><fpage>4058</fpage><lpage>4082</lpage><history><date date-type="received"><day>16</day><month>8</month><year>2013</year></date><date date-type="rev-recd"><day>09</day><month>10</month><year>2013</year></date><date date-type="accepted"><day>10</day><month>10</month><year>2013</year></date></history><permissions><copyright-statement>© 2013 by the authors; licensee MDPI, Basel, Switzerland.</copyright-statement><copyright-year>2013</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/3.0/">http://creativecommons.org/licenses/by/3.0/</ext-link>).</license-p></license></permissions><abstract><p>Marine natural products are a diverse, unique collection of compounds with immense therapeutic potential. This has resulted in these molecules being evaluated for a number of different disease indications including the neglected protozoan diseases, human African trypanosomiasis and Chagas disease, for which very few drugs are currently available. This article will review the marine natural products for which activity against the kinetoplastid parasites; <italic>Trypanosoma brucei brucei</italic>, <italic>T.b. rhodesiense</italic> and <italic>T. cruzi</italic> has been reported. As it is important to know the selectivity of a compound when evaluating its trypanocidal activity, this article will only cover molecules which have simultaneously been tested for cytotoxicity against a mammalian cell line. Compounds have been grouped according to their chemical structure and representative examples from each class were selected for detailed discussion.</p></abstract><kwd-group><kwd>human African trypanosomiasis</kwd><kwd>sleeping sickness</kwd><kwd>chagas disease</kwd><kwd>marine natural products</kwd><kwd>drug discovery</kwd></kwd-group></article-meta></front><body><sec><title>1. Introduction</title><p>The trypanosomatid diseases human African trypanosomiasis (HAT) and Chagas disease account for over 19,000 deaths and the loss of over 100,000 disability adjusted life years (DALYs) annually [<xref ref-type="bibr" rid="B1-marinedrugs-11-04058">1</xref>,<xref ref-type="bibr" rid="B2-marinedrugs-11-04058">2</xref>]. The etiological agents of the disease are kinetoplastid parasites of the genus <italic>Trypanosoma</italic>. <italic>Trypanosoma brucei gambiense</italic> and <italic>Trypanosoma brucei rhodesiense</italic> are responsible for HAT, while infection with <italic>Trypanosoma cruzi</italic> is the causative agent of Chagas disease. Both diseases rely on insect vectors for their transmission; tsetse flies (<italic>Glossina</italic> spp.) are the vectors for HAT, whereas a number of <italic>Triatoma</italic> bug species transmit <italic>T. cruzi</italic> [<xref ref-type="bibr" rid="B3-marinedrugs-11-04058">3</xref>,<xref ref-type="bibr" rid="B4-marinedrugs-11-04058">4</xref>]. HAT is prevalent throughout 36 sub-Saharan African countries whilst Chagas disease primarily occurs in Southern parts of North America, and South America [<xref ref-type="bibr" rid="B5-marinedrugs-11-04058">5</xref>,<xref ref-type="bibr" rid="B6-marinedrugs-11-04058">6</xref>].</p><p>Initially, inoculation of the parasites into human hosts results in acute disease. In HAT, this is characterized by the presence of the parasites in the vasculature and lymphatic systems. Patients experience fever, nausea, headaches and lymphedema [<xref ref-type="bibr" rid="B7-marinedrugs-11-04058">7</xref>]. Without treatment the parasites penetrate the blood brain barrier (BBB) and invade the central nervous system (CNS) initiating chronic or CNS stage disease. CNS stage disease manifests as mental disturbances, anxiety, hallucinations and a characteristic disruption of the sleep-wake cycle [<xref ref-type="bibr" rid="B7-marinedrugs-11-04058">7</xref>,<xref ref-type="bibr" rid="B8-marinedrugs-11-04058">8</xref>,<xref ref-type="bibr" rid="B9-marinedrugs-11-04058">9</xref>,<xref ref-type="bibr" rid="B10-marinedrugs-11-04058">10</xref>]. Without treatment the disease is considered fatal [<xref ref-type="bibr" rid="B11-marinedrugs-11-04058">11</xref>].</p><p>In contrast to HAT, acute Chagas disease is often asymptomatic and as such is not often diagnosed [<xref ref-type="bibr" rid="B12-marinedrugs-11-04058">12</xref>]. Approximately one third of infected individuals go on to develop the chronic form of the disease which can remain asymptomatic for 10 to 30 years [<xref ref-type="bibr" rid="B12-marinedrugs-11-04058">12</xref>]. The chronic stage can manifest as cardiac or cardiodigestive disorders (megacolon, megaeosphagus), or a combination of these [<xref ref-type="bibr" rid="B13-marinedrugs-11-04058">13</xref>]. Chagas related heart disease is one of the major causes of morbidity and mortality in endemic areas [<xref ref-type="bibr" rid="B14-marinedrugs-11-04058">14</xref>].</p><p>Despite the morbidity and mortality inflicted by HAT and Chagas disease, very few effective drugs are currently available (<xref ref-type="fig" rid="marinedrugs-11-04058-f001">Figure 1</xref>). Acute <italic>T.b. gambiense</italic> and <italic>T.b. rhodesiense</italic> infections are treated with pentamidine and suramin, respectively [<xref ref-type="bibr" rid="B15-marinedrugs-11-04058">15</xref>]. CNS <italic>T.b. rhodesiense</italic> infections are treated with melarsoprol, while <italic>T.b. gambiense</italic> infections are treated with either eflornithine or a nifurtimox/eflornithine combination therapy (NECT) [<xref ref-type="bibr" rid="B15-marinedrugs-11-04058">15</xref>]. However, none of these treatments are ideal. Melarsoprol is extremely toxic, resulting in the death of 5% of all patients to whom the drug is administered, and eflornithine has a complicated, protracted administration schedule requiring 56 slow intravenous (i.v.) infusions over 14 days [<xref ref-type="bibr" rid="B16-marinedrugs-11-04058">16</xref>,<xref ref-type="bibr" rid="B17-marinedrugs-11-04058">17</xref>]. The development of NECT reduced the administration schedule of eflornithine to 14 i.v. infusions over seven days, plus oral nifurtimox every eight hours for 10 days [<xref ref-type="bibr" rid="B18-marinedrugs-11-04058">18</xref>,<xref ref-type="bibr" rid="B19-marinedrugs-11-04058">19</xref>]. However, NECT is not ideal as parenteral administration is still required and patients must be hospitalized for the duration of treatment. Acute and chronic Chagas diseases are treated with either nifurtimox or benznidazole. Both drugs have lengthy administration schedules requiring bi- or tri-daily administration for 60 to 90 days [<xref ref-type="bibr" rid="B20-marinedrugs-11-04058">20</xref>]. Patients frequently experience vomiting, nausea, hepatic intolerance, convulsions and skin disease manifestations [<xref ref-type="bibr" rid="B21-marinedrugs-11-04058">21</xref>]. The unpleasant side effects experienced by patients, coupled with administration schedules, result in many patients failing to complete the treatment regimes [<xref ref-type="bibr" rid="B22-marinedrugs-11-04058">22</xref>,<xref ref-type="bibr" rid="B23-marinedrugs-11-04058">23</xref>].</p><fig id="marinedrugs-11-04058-f001" position="float"><label>Figure 1</label><caption><p>Drugs currently registered and in development for the treatment of human African trypanosomiasis (HAT) and Chagas disease.</p></caption><graphic xlink:href="marinedrugs-11-04058-g001"></graphic></fig><p>The paucity of safe, effective and easily administrable drugs for HAT and Chagas disease is partly due to a lack of interest by large pharmaceutical companies. HAT and Chagas disease primarily affect poor, disadvantaged people, with limited access to health care and very little means to pay for drugs. Consequently, there is little incentive for pharmaceutical companies to invest in the research and development of new compounds for these disease indications. It has only been in the last decade, with the establishment of non-for-profit organizations such as the Drugs for Neglected Diseases initiative (DND<italic>i</italic>) and the Bill and Melinda Gates Foundation, that substantial investment and progress has been made in drug discovery for HAT and Chagas disease. As a result, one compound, fexinidazole, is now in phase II/III clinical trials for HAT, while a second compound, SCYX-7158, is in phase I clinical trials [<xref ref-type="bibr" rid="B24-marinedrugs-11-04058">24</xref>,<xref ref-type="bibr" rid="B25-marinedrugs-11-04058">25</xref>]. In addition, during the past five years numerous drug targets have been identified and validated in <italic>T.b. brucei</italic> which are discussed in detail in a recent review [<xref ref-type="bibr" rid="B26-marinedrugs-11-04058">26</xref>]. Promising targets described include, the enzymes S-adenosylmethionine decarboxylase (AdoMetDC) [<xref ref-type="bibr" rid="B27-marinedrugs-11-04058">27</xref>,<xref ref-type="bibr" rid="B28-marinedrugs-11-04058">28</xref>], N-myristoyltransferase (NMT) [<xref ref-type="bibr" rid="B29-marinedrugs-11-04058">29</xref>,<xref ref-type="bibr" rid="B30-marinedrugs-11-04058">30</xref>] and trypanothione synthetase-amidase (TrySyn) [<xref ref-type="bibr" rid="B31-marinedrugs-11-04058">31</xref>]. For Chagas disease, K777 is currently in pre-clinical trials [<xref ref-type="bibr" rid="B32-marinedrugs-11-04058">32</xref>], whilst clinical trials with posaconazole are due for completion in 2013 [<xref ref-type="bibr" rid="B33-marinedrugs-11-04058">33</xref>]. Target identification studies have indicated that cysteine protease is the target of K777, thus validating further development of this class of inhibitors. Posaconazole inhibits <italic>T. cruzi</italic> sterol 14α-demethylase (CYP51) [<xref ref-type="bibr" rid="B34-marinedrugs-11-04058">34</xref>], and research continues to identify further inhibitors of this specific target [<xref ref-type="bibr" rid="B35-marinedrugs-11-04058">35</xref>,<xref ref-type="bibr" rid="B36-marinedrugs-11-04058">36</xref>,<xref ref-type="bibr" rid="B37-marinedrugs-11-04058">37</xref>]. Azole antifungals with CYP51 activity have previously entered clinical trials, however, have not demonstrated curative activity [<xref ref-type="bibr" rid="B38-marinedrugs-11-04058">38</xref>]. Few validated targets have been identified against <italic>T. cruzi</italic> and studies to determine new targets will be of benefit for Chagas disease research. Cloning of recombinant proteins based on the identified genome sequence could facilitate this process [<xref ref-type="bibr" rid="B39-marinedrugs-11-04058">39</xref>]. The mitochondria and mitochondrial metabolism [<xref ref-type="bibr" rid="B40-marinedrugs-11-04058">40</xref>] have been identified as potential sources of new targets for <italic>T. cruzi</italic> drug discovery research, as well as enzymes involved in pentose phosphate and thymidine synthesis [<xref ref-type="bibr" rid="B41-marinedrugs-11-04058">41</xref>].</p><p>Non-for profit organizations have highlighted the plight of HAT and Chagas disease patients and have provided the financial resources required for new therapeutics to be identified and developed. However, numerous problems still exist which impede drug development for HAT and Chagas disease. A large proportion of the molecules identified by phenotypic high-throughput screening (HTS) campaigns have undesirable chemical properties and biological characteristics, which makes them unsuitable for further development. Structure activity relationship (SAR) studies are frequently undertaken in order to improve a molecule’s physiochemical properties, but this often results in a significant loss of trypanocidal activity. In the last five years, multiple drug targets have been identified in <italic>T. brucei</italic> spp. and <italic>T. cruzi</italic>. However, the targets are often inaccessible and it is difficult to develop small molecule inhibitors, which are capable of reaching and interacting with the target. Target-based screening can be utilized to identify potent inhibitors of targets but often the molecules lack trypanocidal activity when subsequently screened against the whole parasite, as they are unable to penetrate the parasites and reach the intracellular target.</p><p>The high attrition rate associated with drug discovery and development and the difficulties encountered, means that there still exists a critical need to identify novel compounds for HAT and Chagas disease. Natural products including, marine organisms and metabolites, are one potential source from which unique trypanocidal compounds could be identified.</p><p>Natural products are attractive chemical starting points for drug discovery. They have been investigated for a number of different disease indications and biological targets resulting in the identification of both lead molecules and drugs suitable for entry into the drug discovery pipeline. Between 1981 and 2010 natural products and synthetic small molecules either derived from a natural product or based on a natural product, pharmacophore, accounted for over 50% of new chemical entities [<xref ref-type="bibr" rid="B42-marinedrugs-11-04058">42</xref>]. Research into the chemistry, pharmacology and therapeutic potential of marine natural products began with the development of self-contained breathing apparatus (SCUBA) in the 1960s and has continued to progress and develop with thousands of compounds now identified [<xref ref-type="bibr" rid="B43-marinedrugs-11-04058">43</xref>]. The first marine natural product to be registered by the United States (US) Food and Drugs Administration (FDA) was cytarabine (1β-arabinofuranosylcytosine), a chemotherapeutic agent, in 1969. Since then six other marine natural product based drugs have been approved by the FDA; vidarabine (anti-cancer and anti-viral), ziconotide (an analgesic agent), eribulin mesylate (anti-cancer), brentuximab vedotin (for the treatment of Hodgkin’s lymphoma and large cell lymphoma) and the omega-3-ethyl ester preparations, lovaza and vascepa (triglyceride lowering agents). In addition, one further compound, trabectedin (anti-cancer), has been approved by the European Medicines Agency (EMA).</p><p>Cytarabine (1β-arabinofuranosylcytosine) and vidarabine (adenine arabinoside) (<xref ref-type="fig" rid="marinedrugs-11-04058-f002">Figure 2</xref>) are synthetic pyrimidine and purine nucleosides, respectively, developed from nucleosides isolated from the Caribbean sponge <italic>Tethya crypta</italic> [<xref ref-type="bibr" rid="B44-marinedrugs-11-04058">44</xref>,<xref ref-type="bibr" rid="B45-marinedrugs-11-04058">45</xref>]. Cytarabine is used for the treatment of acute myeloid and lymphocytic leukemia, while vidarabine was approved in 1976 for the treatment of acute keratoconjunctivitis and recurrent epithelial keratitis caused by <italic>Herpes simplex</italic> viruses [<xref ref-type="bibr" rid="B46-marinedrugs-11-04058">46</xref>,<xref ref-type="bibr" rid="B47-marinedrugs-11-04058">47</xref>,<xref ref-type="bibr" rid="B48-marinedrugs-11-04058">48</xref>]. The therapeutic effects of cytarabine and vidarabine are thought to arise due to inhibition of DNA polymerase and DNA synthesis [<xref ref-type="bibr" rid="B49-marinedrugs-11-04058">49</xref>,<xref ref-type="bibr" rid="B50-marinedrugs-11-04058">50</xref>].</p><fig id="marinedrugs-11-04058-f002" position="float"><label>Figure 2</label><caption><p>Examples of small molecule-based marine natural products or their derivatives which have received Food and Drug Administration (FDA) or European Medicines Agency (EMA) approval.</p></caption><graphic xlink:href="marinedrugs-11-04058-g002"></graphic></fig><p>Twenty-eight years after the registration of vidarabine, ziconotide, a synthetic equivalent of a peptide originally isolated from the venom of the cone snail <italic>Conus magus</italic>, was approved by the FDA [<xref ref-type="bibr" rid="B51-marinedrugs-11-04058">51</xref>]. The drug is a powerful analgesic due to its ability to selectively and specifically block N-type voltage sensitive calcium channels and is used to manage chronic pain in cancer and AIDS patients [<xref ref-type="bibr" rid="B52-marinedrugs-11-04058">52</xref>]. Also in 2004, lovaza, the first drug containing the fish derived omega-3-ethyl fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was approved for the reduction of triglyceride levels in severe hypertriglyceridemia [<xref ref-type="bibr" rid="B53-marinedrugs-11-04058">53</xref>]. This was followed by the registration of vascepa, containing only EPA, in 2012 [<xref ref-type="bibr" rid="B54-marinedrugs-11-04058">54</xref>]. Omega-3-ethyl fatty acids are found in all fish species but are most abundant in oily fish, such as salmon, mackerel and herring [<xref ref-type="bibr" rid="B55-marinedrugs-11-04058">55</xref>]. The mechanism of action (MOA) for the hypotriglyceridemic effect of omega-3-ethyl fatty acids is not fully understood but has been attributed to the suppression of hepatic lipogenesis, an increase in fatty β-oxidation and down regulation of hepatic nuclear factor-4α (HNF-4α) [<xref ref-type="bibr" rid="B56-marinedrugs-11-04058">56</xref>,<xref ref-type="bibr" rid="B57-marinedrugs-11-04058">57</xref>,<xref ref-type="bibr" rid="B58-marinedrugs-11-04058">58</xref>,<xref ref-type="bibr" rid="B59-marinedrugs-11-04058">59</xref>,<xref ref-type="bibr" rid="B60-marinedrugs-11-04058">60</xref>]. In 2010, eribulin mesylate, a synthetic macro-cyclic ketone analogue of halichondrin B, a molecule isolated from the marine sponge <italic>Halichondria okadai</italic>, received FDA approval for the treatment of metastatic breast cancer [<xref ref-type="bibr" rid="B61-marinedrugs-11-04058">61</xref>]. Eribulin induces cell death by inhibiting microtubule growth and sequestering tubulin into nonproductive aggregates [<xref ref-type="bibr" rid="B62-marinedrugs-11-04058">62</xref>,<xref ref-type="bibr" rid="B63-marinedrugs-11-04058">63</xref>,<xref ref-type="bibr" rid="B64-marinedrugs-11-04058">64</xref>]. Brentuximab vedotin, a CD30 specific antibody-drug conjugate received FDA approval for the treatment of Hodgkin’s lymphoma in 2011. Brentuximab vedotin is composed of monomethylauristatin E (MMAE), a synthetic analogue of the marine natural product dolastatin 10 conjugated with the chimeric anti-CD30 monoclonal antibody, SGN-30 [<xref ref-type="bibr" rid="B65-marinedrugs-11-04058">65</xref>]. Dolastatin 10 was originally isolated from the Indian Ocean sea hare <italic>Dolabella auricularia</italic> in 1987 [<xref ref-type="bibr" rid="B66-marinedrugs-11-04058">66</xref>]. MMAE is an anti-tubulin agent which binds to tubulin and prevents microtubule polymerization leading to G<sub>2</sub>-M phase growth arrest and apoptosis [<xref ref-type="bibr" rid="B67-marinedrugs-11-04058">67</xref>]. Trabectedin (ecteinascidin) (<xref ref-type="fig" rid="marinedrugs-11-04058-f002">Figure 2</xref>) has been approved in the European Union (EU) by the EMA. The compound was isolated from the ascidian <italic>Ecteinascidia turbinata</italic> and is an anti-cancer agent used in the treatment of soft tissue sarcoma and platinum-sensitive ovarian cancer [<xref ref-type="bibr" rid="B68-marinedrugs-11-04058">68</xref>]. The MOA of trabectedin is not fully elucidated, however, the compound has been shown to bind to the minor groove of DNA and interact with different binding proteins of the Nucleotide Excision Repair System (NERS) [<xref ref-type="bibr" rid="B69-marinedrugs-11-04058">69</xref>,<xref ref-type="bibr" rid="B70-marinedrugs-11-04058">70</xref>,<xref ref-type="bibr" rid="B71-marinedrugs-11-04058">71</xref>,<xref ref-type="bibr" rid="B72-marinedrugs-11-04058">72</xref>]. In addition to the marine natural products which have received regulatory approval and progressed to the market, numerous molecules are currently in clinical development [<xref ref-type="bibr" rid="B73-marinedrugs-11-04058">73</xref>].</p><p>To date, no marine natural products or derivatives have entered pre-clinical development specifically for trypanosomatid diseases. However, numerous marine natural products which exhibit anti-trypanosomal activity have been reported in the literature.</p><p>In this article, the natural products isolated from marine sources for which activity against the protozoan parasites; <italic>T.b. brucei</italic>, <italic>T.b. rhodesiense</italic> and <italic>T. cruzi</italic> has been reported, is reviewed. The majority of the compounds have been identified through phenotypic screening campaigns, which have recently been reviewed in detail [<xref ref-type="bibr" rid="B74-marinedrugs-11-04058">74</xref>,<xref ref-type="bibr" rid="B75-marinedrugs-11-04058">75</xref>]. It should be noted that although <italic>T.b. brucei</italic> primarily infects domestic mammals and antelopes and is not the human infective subspecies responsible for HAT, it is frequently used in early drug discovery screening campaigns to identify active compounds [<xref ref-type="bibr" rid="B76-marinedrugs-11-04058">76</xref>,<xref ref-type="bibr" rid="B77-marinedrugs-11-04058">77</xref>]. Compounds active against <italic>T.b. brucei</italic> would ultimately be evaluated against the human infective forms of the parasite, <italic>T.b. rhodesiense</italic> and <italic>T.b. gambiense</italic>. The bloodstream form of <italic>T. brucei</italic> spp. is used in phenotypic screening assays, as this is the clinically relevant form of the parasite (<xref ref-type="fig" rid="marinedrugs-11-04058-f003">Figure 3</xref>A). In <italic>T. cruzi</italic> infection, the amastigote and the trypomastigote life cycle stages are both found within the human host (<xref ref-type="fig" rid="marinedrugs-11-04058-f003">Figure 3</xref>B). All lifecycle stages of <italic>T. cruzi</italic> can be used in assays to evaluate the activity of compounds. However, activity against the amastigote form of the parasite has been deemed to be of primary importance in many assays, with activity against the trypomastigote stage also considered favorable or necessary [<xref ref-type="bibr" rid="B78-marinedrugs-11-04058">78</xref>,<xref ref-type="bibr" rid="B79-marinedrugs-11-04058">79</xref>,<xref ref-type="bibr" rid="B80-marinedrugs-11-04058">80</xref>]. Herein, only activity against the human infective forms, namely amastigotes and trypomastigotes are considered. Many assay formats used in <italic>T. cruzi</italic> research are based on the method by Buckner <italic>et al.</italic>, whereby compounds are added two hours after addition of <italic>T. cruzi</italic> β-galactosidase transfected trypomastigotes to host cells [<xref ref-type="bibr" rid="B81-marinedrugs-11-04058">81</xref>]. Cells are incubated for seven days before detection of released trypomastigotes via lysis of cells and detection of β-galactosidase activity. This assay may affect both host cell infection and/ or development of amastigotes. The <italic>T. cruzi</italic> assays discussed in this article are based on this assay format, unless a modification is discussed.</p><fig id="marinedrugs-11-04058-f003" position="float"><label>Figure 3</label><caption><p>(<bold>A</bold>) The life cycle of <italic>T. brucei</italic> spp. (modified content from [<xref ref-type="bibr" rid="B82-marinedrugs-11-04058">82</xref>]). (<bold>B</bold>) The life cycle of <italic>T. cruzi</italic> (modified content from [<xref ref-type="bibr" rid="B83-marinedrugs-11-04058">83</xref>]).</p></caption><graphic xlink:href="marinedrugs-11-04058-g003"></graphic></fig><p>In drug discovery screening campaigns for HAT and Chagas disease, a compound is only classed as a “hit”, if it has an IC<sub>50</sub> < 10 µM [<xref ref-type="bibr" rid="B84-marinedrugs-11-04058">84</xref>,<xref ref-type="bibr" rid="B85-marinedrugs-11-04058">85</xref>,<xref ref-type="bibr" rid="B86-marinedrugs-11-04058">86</xref>,<xref ref-type="bibr" rid="B87-marinedrugs-11-04058">87</xref>]. Compounds with an IC<sub>50</sub> ≥ 10 µM would not be considered suitable for progression along the drug discovery pipeline and would only be used as tools or probes. In this review, the trypanocidal activity of compounds is described according to their IC<sub>50</sub> values and are defined as: IC<sub>50</sub> < 10 µM = promising trypanocidal activity, 10 µM ≤ IC<sub>50</sub> < 20 µM = moderate activity, 20 µM ≤ IC<sub>50</sub> < 30 µM = marginal activity, 30 µM ≤ IC<sub>50</sub> < 40 µM = limited activity, IC<sub>50</sub> ≥ 40 µM = no activity/inactive. When evaluating the activity of compounds against a human pathogen or disease target it is important that the cytotoxicity of the compound is also investigated against a mammalian cell line to allow the selectivity index (SI) of the compound to be determined. The SI for selecting compounds with anti-trypanosomal activity is the ratio of the IC<sub>50</sub> value obtained for mammalian cells divided by the IC<sub>50</sub> against trypanosome species. We have considered herein that an SI < 10 suggests that the compound may be exerting a generally toxic effect. If the SI is ≥10, the compound is considered to have some selective activity against the parasite. However, a significantly greater SI is required in order for molecules to progress along the drug discovery pipeline and eventually into clinical studies.</p><p>This article will focus on compounds which have an IC<sub>50</sub> < 40 µM against <italic>T.b. brucei</italic>, <italic>T.b.</italic><italic>rhodesiense</italic> or <italic>T. cruzi</italic> and which have also been evaluated against a mammalian cell line. Compounds have been grouped according to their chemical structures into three categories; terpenes, polyketides and xanthones, and alkaloids. Representative examples for each category are discussed in terms of their trypanocidal activity and SI. To allow the activity of compounds to be compared independently of their molecular weight, all literature values have been converted into micromolar concentrations (µM).</p></sec><sec><title>2. Marine Natural Products with Reported <italic>in Vitro</italic> Activity against the <italic>Trypanosome</italic> Species <italic>T. cruzi</italic>, <italic>T. brucei</italic> or <italic>T.b. rhodesiense</italic></title><sec><title>2.1. Terpenes</title><p>The marine sponges <italic>Spongia</italic> sp. and <italic>Ircinia</italic> sp. collected from the Turkish coastline of the Aegean Sea yielded a series of linear furanoterpenes and meroterpenes, as well as di- and tri-terpenes all of which were assessed for growth inhibitory activity against a series of protozoan parasites (<xref ref-type="fig" rid="marinedrugs-11-04058-f004">Figure 4</xref>) [<xref ref-type="bibr" rid="B88-marinedrugs-11-04058">88</xref>]. 4-hydroxy-3-tetraprenylphenylacetic acid (<bold>1</bold>) was the most active and selective molecule with an IC<sub>50</sub> value of 1.4 µM against <italic>T.b. rhodesiense</italic> and a selectivity index (SI) of >150, <italic>versus</italic> mammalian L6 rat skeletal muscle cells. The related structure heptaprenyl-<italic>p</italic>-quinol (<bold>2</bold>) possessing a longer isoprene chain and a hydroquinone terminal unit showed promising activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 5.9 µM, however had no selectivity with an almost equivalent IC<sub>50</sub> value of 4.4 µM observed against L6 cells. Demethylfurospongin-4 (<bold>3</bold>) was selectively active against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 11.8 µM and an SI > 18. The diterpene 11β-acetoxyspongi-12-en-16-one (<bold>4</bold>) exhibited moderate activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 11.5 µM but had no selectivity with an IC<sub>50</sub> of 9.2 µM against L6 cells [<xref ref-type="bibr" rid="B88-marinedrugs-11-04058">88</xref>]. A number of trypanocidal molecules with varying degrees of activity have been identified from <italic>Agelas</italic> sp. marine sponges. The sterol 24-ethyl-cholest-5α-7-en-3-β-ol (<bold>5</bold>) isolated from the <italic>n</italic>-hexane extract of the Turkish sponge <italic>Agelas oroides</italic> showed limited activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 34.2 µM [<xref ref-type="bibr" rid="B89-marinedrugs-11-04058">89</xref>]. Compound <bold>5</bold> was inactive against both <italic>T. cruzi</italic> (IC<sub>50</sub> > 72 µM) and L6 cells (IC<sub>50</sub> > 217 µM). These authors used the <italic>T. cruzi</italic> β-galactosidase assay to estimate compound activity [<xref ref-type="bibr" rid="B81-marinedrugs-11-04058">81</xref>].</p><p>A series of steroidal saponins characterized by a 2-hydroxycyclopentenone ring D and a glucuronic acid substituent at C-3 isolated from the Caribbean sponge <italic>Pandaros acanthifolium</italic> have demonstrated wide-ranging biological activity, including inhibition of both <italic>T.b. brucei</italic> and <italic>T. cruzi</italic>. Notably, pandaroside G methyl ester (<bold>6</bold>) had sub-micromolar activity against both <italic>T.b. rhodesiense</italic> and <italic>T. cruzi</italic> with IC<sub>50</sub> values of 0.038 and 0.77 µM, respectively [<xref ref-type="bibr" rid="B90-marinedrugs-11-04058">90</xref>]. However, the molecule was not specific for <italic>T.b. rhodesiense</italic> or <italic>T. cruzi</italic> as it also inhibited mammalian L6 cells with an IC<sub>50</sub> value of 0.22 µM, suggesting the natural product was generally toxic. Related steroidal saponins, the acanthifolisides, were also isolated as minor components from the same sponge collection [<xref ref-type="bibr" rid="B91-marinedrugs-11-04058">91</xref>]. Acanthifolioside E (<bold>7</bold>) showed moderate activity against <italic>T. cruzi</italic>, with an IC<sub>50</sub> value of 10.6 µM, and marginal activity against <italic>T.b. rhodesiense</italic>, with an IC<sub>50</sub> of 27.4 µM. In contrast, the trisaccharide acanthifolioside F methyl ester (<bold>8</bold>) had promising activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 6.4 µM but only displayed marginal activity against <italic>T. cruzi</italic>, IC<sub>50</sub> = 22.2 µM. Both compounds showed pan-panel activity against a series of other protozoa, as well as low SI values (<3) against mammalian L6 cells.</p><fig id="marinedrugs-11-04058-f004" position="float"><label>Figure 4</label><caption><p>The structure of terpenes of marine origin which have exhibited activity against <italic>T.b. rhodesiense</italic> (<bold>1</bold>–<bold>8</bold>) and <italic>T. cruzi</italic> (<bold>6</bold>–<bold>8</bold>).</p></caption><graphic xlink:href="marinedrugs-11-04058-g004"></graphic></fig></sec><sec><title>2.2. Polyketides and Xanthones</title><p>A series of marine-derived polyketide endoperoxides have shown potent activity and good selectivity against trypanosomes (<xref ref-type="fig" rid="marinedrugs-11-04058-f005">Figure 5</xref>). Plakortide P (<bold>9</bold>) isolated from a Brazilian collection of the sponge <italic>Plakortis angulospiculatus</italic> inhibited <italic>T. cruzi</italic> with an IC<sub>50</sub> value of 6.3 μM but had a poor SI of 7 [<xref ref-type="bibr" rid="B92-marinedrugs-11-04058">92</xref>]. These authors utilized the soluble tetrazolium salt, MTT, to detect the metabolic activity of host cell-free trypomastigotes. 11,12-didehydro-13-oxo-plakortide Q (<bold>10</bold>) and 10-carboxy-11,12,13,14-tetranor-plakortide Q (<bold>11</bold>) isolated from an Australian collection of the sponge <italic>Plakortis</italic> sp. showed activity against <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 0.049 and 0.940 μM, respectively, and favorable selectivity indices, with compound <bold>10</bold> displaying a SI of 105 times and compound <bold>11</bold> <88 times over the human embryonic kidney cells, HEK-293 [<xref ref-type="bibr" rid="B93-marinedrugs-11-04058">93</xref>]. Interestingly, a substitution of the enone functionality in <bold>10</bold> with that of a carboxylic acid group in <bold>11</bold> resulted in a 20-fold reduction of activity against <italic>T.b. brucei</italic>. Related structures, manadoperoxides and peroxyplakoric ester B3 isolated from the Indonesian sponge <italic>Plakortis</italic> cfr. <italic>lita</italic> were also found to inhibit <italic>T.b. rhodesiense</italic> at low micro-molar concentrations [<xref ref-type="bibr" rid="B94-marinedrugs-11-04058">94</xref>]. Manadoperoxides B (<bold>12</bold>), C (<bold>13</bold>), F (<bold>14</bold>), H (<bold>15</bold>), I (<bold>16</bold>), and K (<bold>17</bold>) exhibited IC<sub>50</sub> values of 0.0088, 2.2, 2, 1, 0.17, and 0.2 μM respectively, with favorable selectivity indices of > 3000, >15, >13, >27, >161 and >115, against human mammary epithelial cells (HMEC). Manadoperoxide G (<bold>18</bold>) as well as the peroxyplakoric ester B3 (<bold>19</bold>) were demonstrated to have moderate activity against <italic>T.b. rhodesiense</italic> with IC<sub>50</sub> values of 5.6 and 11 µM, but exhibited very poor selectivity (< 5). The availability of ten structurally related analogues of manadoperoxide B gave an insight into the structure-activity relationship for this chemical class of compounds, suggesting that both the polarity of the side-chain and the presence of a C-4 methyl substituent were crucial for trypanocidal activity.</p><fig id="marinedrugs-11-04058-f005" position="float"><label>Figure 5</label><caption><p>The structure of endoperoxide polyketides of marine origin for which activity against <italic>T. cruzi</italic> (<bold>9</bold>), <italic>T.b. brucei</italic> (<bold>10</bold>–<bold>11</bold>), and <italic>T.b. rhodesiense</italic> (<bold>12</bold>–<bold>19</bold>) has been described.</p></caption><graphic xlink:href="marinedrugs-11-04058-g005"></graphic></fig><p>Tetronic acid-containing tetromycin B (<bold>20</bold>) as well as tetromycins 1 (<bold>21</bold>), and 3 (<bold>22</bold>) isolated from <italic>Streptomyces axinellae</italic> Po1001 cultivated from the Mediterranean sponge <italic>Axinella polypoides</italic>, showed limited activity against <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 34, 32, and 30 µM, respectively (<xref ref-type="fig" rid="marinedrugs-11-04058-f006">Figure 6</xref>) [<xref ref-type="bibr" rid="B95-marinedrugs-11-04058">95</xref>]. Compounds <bold>20</bold> and <bold>23</bold> had poor selectivity (SI < 2) against 293T kidney cells, with the most selective compound <bold>21,</bold> having a SI > 3. Three new heterocyclic-substituted xanthone analogues (<bold>23</bold>–<bold>25</bold>) were isolated from the fungus <italic>Chaetomium</italic> sp. which was obtained from an algal species collected in Greece [<xref ref-type="bibr" rid="B96-marinedrugs-11-04058">96</xref>]. Of the series, compound <bold>23</bold> was the most active and selective for <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> of 13.3 µM and a SI of 13 <italic>versus</italic> L6 cells. In contrast, the molecule had marginal activity against <italic>T. cruzi</italic> with an IC<sub>50</sub> value >28 µM. Compound <bold>25</bold> had the greatest activity and selectivity against <italic>T. cruzi</italic> with an IC<sub>50</sub> value of 3.8 µM and SI of 31, while <bold>24</bold> exhibited a similar activity against both parasites with IC<sub>50</sub> values of 25 and 19 µM against <italic>T. cruzi</italic> and <italic>T.b. brucei</italic>, respectively, and a SI > 10 [<xref ref-type="bibr" rid="B96-marinedrugs-11-04058">96</xref>].</p><fig id="marinedrugs-11-04058-f006" position="float"><label>Figure 6</label><caption><p>The structure of tetromycins (<bold>20</bold>–<bold>22</bold>) and xanthone analogues (<bold>23</bold>–<bold>25</bold>) of marine origin for which activity against <italic>T.b. brucei</italic> (<bold>20</bold>–<bold>22</bold>), <italic>T.b. rhodesiense</italic> (<bold>23</bold>–<bold>24</bold>), <italic>T. cruzi</italic> (<bold>23</bold>–<bold>25</bold>) has been described.</p></caption><graphic xlink:href="marinedrugs-11-04058-g006"></graphic></fig></sec><sec><title>2.3. Alkaloids</title><p>A number of indole-, bromopyrrole-, and purine-based alkaloids have shown a range of anti-trypanosomal activity (<xref ref-type="fig" rid="marinedrugs-11-04058-f007">Figure 7</xref>). An indole alkaloid tryptophol (<bold>26</bold>) isolated from the Turkish, Aegean Sea sponge <italic>Ircinia spinulosa</italic> [<xref ref-type="bibr" rid="B97-marinedrugs-11-04058">97</xref>] showed broad-spectrum inhibitory activity against a panel of parasitic protozoa, including <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 36.6 µM, while showing no significant toxicity against L6 cells (SI > 11) [<xref ref-type="bibr" rid="B88-marinedrugs-11-04058">88</xref>]. Three other indole alkaloids sourced from the marine bacterium <italic>Bacillus pumilus</italic>, isolated from a Panamanian collection of the black coral <italic>Anthiphates</italic> sp., namely 3-formylindole (<bold>27</bold>), 3-hydroxyacetylindole (<bold>28</bold>) and <italic>N</italic>-acetyl-β-oxotryptamine (<bold>29</bold>) showed marginal activity against <italic>T. cruzi</italic> (in a modification of the β-galactosidase method, whereby trypomastigotes are washed off before addition of compound to infected host cells) with IC<sub>50</sub> values of 26.9, 20.6 and 19.4 µM, respectively, although the selectivity of the compounds was very poor (SI < 4) [<xref ref-type="bibr" rid="B98-marinedrugs-11-04058">98</xref>]. A New Zealand collection of the ascidian <italic>Pseudodistoma opacum</italic> yielded three alkylguanidine-substituted β-carboline alkaloids, opacalines A–C [<xref ref-type="bibr" rid="B99-marinedrugs-11-04058">99</xref>]. Opacaline A (<bold>30</bold>) and the <italic>N</italic>-hydroxy analogue opacaline B (<bold>31</bold>) showed marginal inhibition of <italic>T.b. rhodesiense</italic> with IC<sub>50</sub> values of 30 and 27 µM, but had poor selectivity (<5). Compound <bold>32</bold>, a synthetically-prepared de-bromo analogue of <bold>30</bold> had improved activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 12 µM and a slightly higher SI of 7 <italic>versus</italic> mammalian L6 cells [<xref ref-type="bibr" rid="B99-marinedrugs-11-04058">99</xref>].</p><fig id="marinedrugs-11-04058-f007" position="float"><label>Figure 7</label><caption><p>The structure of indole-, bromopyrrole-, and purine-based alkaloids of marine origin which have shown activity against <italic>T.b. rhodesiense</italic> (<bold>26</bold>, <bold>30</bold>–<bold>38</bold>), <italic>T. cruzi</italic> (<bold>27</bold>–<bold>29</bold>, <bold>33</bold>, <bold>39</bold>) and <italic>T.b. brucei</italic> (<bold>39</bold>).</p></caption><graphic xlink:href="marinedrugs-11-04058-g007"></graphic></fig><p>The Turkish sponge, <italic>Agelas oroides</italic> collected in the Northern Aegean Sea yielded a series of bromopyrrole derivatives [<xref ref-type="bibr" rid="B89-marinedrugs-11-04058">89</xref>]. Moderate activity against both <italic>T.b. rhodesiense</italic> and <italic>T. cruzi</italic> with IC<sub>50</sub> values of 17 and 18 µM, respectively, was observed for amino-1-(aminoimidazoyl)-prop-1-ene (<bold>33</bold>). However, the molecule displayed significant cytotoxicity towards L6 cells with an IC<sub>50</sub> value of 5 µM. Oroidin trifluoroacetate salt (<bold>34</bold>) inhibited <italic>T.b. rhodesiense</italic> growth with an IC<sub>50</sub> value of 25 µM, with no activity demonstrated against <italic>T. cruzi</italic> (IC<sub>50</sub> > 62 µM) and L6 cells (IC<sub>50</sub> = 157 µM). Bromopyrroles <bold>35</bold>–<bold>38</bold> sourced from another study of Turkish sponges belonging to the genera <italic>Agelas</italic> and <italic>Axinella</italic> displayed a range of activities against <italic>T.b. rhodesiense</italic> and <italic>T. cruzi</italic>, utilising an assay where <italic>T.</italic><italic>cruzi</italic> trypomastigotes were washed off infected host cells before addition of compound [<xref ref-type="bibr" rid="B100-marinedrugs-11-04058">100</xref>]. The alkaloid longamide B (<bold>35</bold>) obtained from <italic>Agelas dispar</italic> [<xref ref-type="bibr" rid="B101-marinedrugs-11-04058">101</xref>] was active against <italic>T.b. rhodesiense</italic>, IC<sub>50</sub> = 4.3 µM and displayed moderate cytotoxicity against L6 cells with an IC<sub>50</sub> of 28 µM [<xref ref-type="bibr" rid="B100-marinedrugs-11-04058">100</xref>]. The compound displayed no activity against <italic>T. cruzi</italic> (IC<sub>50</sub> > 94 µM). The hydroxyl analogue, longamide A (<bold>36)</bold> isolated from <italic>Agelas longissima</italic> [<xref ref-type="bibr" rid="B102-marinedrugs-11-04058">102</xref>] was over sixty-times less active against <italic>T.b. rhodesiense</italic> (IC<sub>50</sub> > 290 µM) suggesting the importance of the carboxymethyl substituent for trypanocidal activity [<xref ref-type="bibr" rid="B100-marinedrugs-11-04058">100</xref>]. The oroidin dimer dibromopalau’amine, extracted from <italic>Axinella verrucosa</italic> [<xref ref-type="bibr" rid="B103-marinedrugs-11-04058">103</xref>], (<bold>37</bold>) exhibited sub-micromolar selective activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 0.8 µM and a SI of 10 compared with mammalian L6 cells [<xref ref-type="bibr" rid="B100-marinedrugs-11-04058">100</xref>]. As with previous bromoryrroles, the compound had no activity against <italic>T. cruzi</italic> with an IC<sub>50</sub> value of 119 µM. A second oroidin dimer, sceptrin (<bold>38</bold>), obtained from <italic>Agelas sceptrum</italic> [<xref ref-type="bibr" rid="B104-marinedrugs-11-04058">104</xref>] also showed selective activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 15.7 µM and again no activity against <italic>T. cruzi</italic> (IC<sub>50</sub> = 97 µM) or the mammalian L6 cell line (IC<sub>50</sub> > 145 µM) [<xref ref-type="bibr" rid="B100-marinedrugs-11-04058">100</xref>]. Synthetically prepared agelasine D (<bold>39</bold>) a bicyclic diterpenoid purine, originally isolated from the Okinawan sea sponge <italic>Agelas nakamurai</italic> [<xref ref-type="bibr" rid="B105-marinedrugs-11-04058">105</xref>], inhibited both <italic>T.b. brucei</italic> and <italic>T. cruzi</italic> growth with IC<sub>50</sub> values of 1.8 and 9 µM, respectively [<xref ref-type="bibr" rid="B106-marinedrugs-11-04058">106</xref>]. However, the selectivity of <bold>39</bold> was poor with an SI of <7 against MRC-5 human fetal lung fibroblasts cells.</p><p>Two brominated β-phenyl ethylamine-based alkaloids, convolutamines I (<bold>40</bold>) and J (<bold>41</bold>), were reported from a Tasmanian bryozoan <italic>Amathia tortusa</italic> with IC<sub>50</sub> values against <italic>T.b. brucei</italic> of 1.1 and 13.7 µM, respectively (<xref ref-type="fig" rid="marinedrugs-11-04058-f008">Figure 8</xref>) [<xref ref-type="bibr" rid="B107-marinedrugs-11-04058">107</xref>]. However, only convolutamine I (<bold>40</bold>) had a favorable SI of 18 against HEK-293 cells, with convolutamine J demonstrating cytotoxicity (SI > 3). As part of a HTS screen of a pre-fractionated natural product library to identify inhibitors of <italic>T.b. brucei</italic>, two cinnamoyl amino acids, iotrochotamides A (<bold>42</bold>) and B (<bold>43</bold>), were reported from an Australian marine sponge <italic>Iotrochota</italic> sp. [<xref ref-type="bibr" rid="B108-marinedrugs-11-04058">108</xref>]. Compounds <bold>42</bold> and <bold>43</bold> showed low micromolar activity against <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 3.4 and 4.7 µM, respectively, while exhibiting mild cytotoxicity against, HEK-293 with 85% inhibition at 50 µM for <bold>42</bold> and 100% inhibition at 70 µM for <bold>43</bold>. Decahydroquinoline alkaloids lepadins D–F (<bold>44</bold>–<bold>46)</bold>, were reported from a Great Barrier Reef collection of an ascidian <italic>Didemnum</italic> sp. [<xref ref-type="bibr" rid="B109-marinedrugs-11-04058">109</xref>]. Compounds <bold>45</bold> and <bold>46</bold> exhibited selective sub-micromolar activity against <italic>T.b. rhodesiense</italic> with IC<sub>50</sub> values of 0.9 and 0.55 µM, respectively, and selectivity indices >40 <italic>versus</italic> mammalian L6 cells. Lepadins also displayed activity against <italic>T. cruzi</italic>, with IC<sub>50</sub> values of 5.2 and 6.2 µM reported for <bold>45</bold> and <bold>46</bold>, but the SI was only 7 [<xref ref-type="bibr" rid="B109-marinedrugs-11-04058">109</xref>]. The presence of the 2E-octenoic acid ester functionality in <bold>45</bold> and <bold>46</bold> was concluded to be essential for the anti-trypanosomal activity of the series as the hydroxyl analogue <bold>44</bold> was observed to be over 20-fold less active against <italic>T.b. rhodesiense</italic> (IC<sub>50</sub> = 19 µM) and was inactive against <italic>T. cruzi</italic> (IC<sub>50</sub> = 125 µM). A synthetic preparation of a 3-alkylpyridinium alkaloid, viscosamine (<bold>47</bold>), originally isolated from the Arctic sponge <italic>Haliclona viscosa</italic> [<xref ref-type="bibr" rid="B110-marinedrugs-11-04058">110</xref>], displayed sub-micromolar, selective activity against <italic>T.b. brucei</italic> with an IC<sub>50</sub> of 0.41 µM and SI of 63 against HEK-293 [<xref ref-type="bibr" rid="B111-marinedrugs-11-04058">111</xref>]. The pentacyclic bis-indole alkaloid fascaplysin (<bold>48</bold>) isolated from a Fijian collection of the sponge <italic>Hyrtios</italic> cf. <italic>erecta</italic> exhibited wide-ranging biological activity, including potent, selective activity against <italic>T.b. rhodesiense</italic> with an IC<sub>50</sub> value of 0.46 μM and SI of 15 <italic>versus</italic> L6 cells [<xref ref-type="bibr" rid="B112-marinedrugs-11-04058">112</xref>]. Pyridoacridines ascididemnin (<bold>49</bold>) and 12-deoxyascididemnin (<bold>50</bold>), isolated from an Australian ascidian <italic>Polysyncraton echinatum</italic> also displayed selective sub-micromolar activity against <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 0.032 and 0.077 μM, respectively, and selectivity indices >45, against HEK-293 [<xref ref-type="bibr" rid="B113-marinedrugs-11-04058">113</xref>]. Eilatin (<bold>51</bold>) an analogue of ascididemnin was over 40 fold less active against <italic>T.b. brucei</italic> with an IC<sub>50</sub> of 1.33 µM [<xref ref-type="bibr" rid="B113-marinedrugs-11-04058">113</xref>].</p><fig id="marinedrugs-11-04058-f008" position="float"><label>Figure 8</label><caption><p>The structure of alkaloids of marine origin for which activity against <italic>T.b. brucei</italic> (<bold>40</bold>–<bold>43</bold>, <bold>47</bold>, <bold>49</bold>–<bold>51</bold>), <italic>T.b. rhodesiense</italic> (<bold>44</bold>–<bold>46</bold>, <bold>48</bold>) and <italic>T. cruzi</italic> (<bold>45</bold>, <bold>46</bold>) has been described.</p></caption><graphic xlink:href="marinedrugs-11-04058-g008"></graphic></fig><p>A series of dimethylthio (<bold>52</bold>), spiro-pentacyclic (<bold>53</bold>) and fused penta- and hexacyclic diketopiperazines (<bold>54</bold>–<bold>56</bold>) isolated from the marine-derived fungus <italic>Aspergillus fumigatus</italic> sourced from a Vanuatu sediment showed varying activity against <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 8.5, 5.7, 12.9, 6.4 and 19.5 µM, respectively [<xref ref-type="bibr" rid="B114-marinedrugs-11-04058">114</xref>] (<xref ref-type="fig" rid="marinedrugs-11-04058-f009">Figure 9</xref>). The cytotoxicity of the compounds also varied with compounds <bold>52</bold> and <bold>55</bold> having a SI > 10, while <bold>53</bold>, <bold>54</bold> and <bold>56</bold> were considerably cytotoxic with SI < 8. A dimethylthio (<bold>57</bold>) and two disulfide diketopiperazines, verticilin B (<bold>58</bold>) and chaetocin (<bold>59</bold>) were isolated from the marine fungus <italic>Nectria inventa</italic> which was obtained from a dredge sample of deep-water Californian sediment [<xref ref-type="bibr" rid="B114-marinedrugs-11-04058">114</xref>]. Compound <bold>57</bold> had low micromolar, selective activity against <italic>T.b. brucei</italic> with an IC<sub>50</sub> of 5.9 µM and SI of 16, while verticilin B (<bold>58</bold>) and chaetocin (<bold>59</bold>) exhibited potent, sub-micromolar activity against <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 0.007 and 0.002 μM, respectively [<xref ref-type="bibr" rid="B114-marinedrugs-11-04058">114</xref>]. However, the molecules exhibited pronounced cytotoxicity against Jurkat T Lymphocytes (IC<sub>50</sub> < 0.6 µM) preventing further evaluation of their therapeutic potential.</p><fig id="marinedrugs-11-04058-f009" position="float"><label>Figure 9</label><caption><p>The structure of diketopiperazines of marine origin which have shown activity against <italic>T.b. brucei</italic> (<bold>52</bold>–<bold>59</bold>).</p></caption><graphic xlink:href="marinedrugs-11-04058-g009"></graphic></fig><p>Two cyclic hexapeptides, venturamides A (<bold>60</bold>) and B (<bold>61</bold>) were isolated from the Panamanian collection of the marine cyanobacterium <italic>Oscillatoria</italic> sp. [<xref ref-type="bibr" rid="B115-marinedrugs-11-04058">115</xref>] (<xref ref-type="fig" rid="marinedrugs-11-04058-f010">Figure 10</xref>). The two compounds showed moderate activity against <italic>T. cruzi</italic> with IC<sub>50</sub> values of 14.6 and 15.8 µM, respectively, and mild cytotoxicity to mammalian Vero (monkey kidney epithelial) cells with IC<sub>50</sub> values of 86 and 56 µM, respectively, and thus an SI of < 6. Related cyclic peptides aerucyclamides B (<bold>62</bold>) and C (<bold>63</bold>) isolated from the cyanobacterium <italic>Microrcystis aeruginosa</italic> also displayed anti-trypanosomal activity with IC<sub>50</sub> values of 15.9 and 9.2 µM, respectively, reported for <italic>T.b. rhodesiense</italic> [<xref ref-type="bibr" rid="B116-marinedrugs-11-04058">116</xref>]. Aerucyclamide C had a SI of 12 against L6 cells, whilst the SI of <bold>62</bold> was lower at 8. In a study using natural products as chemical probes to identify the molecular targets of small molecules, two linear peptides, almiramides B (<bold>64</bold>) and C (<bold>65</bold>) extracted from a Panamanian collection of the marine cyanobacterium <italic>Lyngbya majuscula</italic> were found to be low micromolar inhibitors of <italic>T.b. brucei</italic> with IC<sub>50</sub> values of 6 and 3 µM, respectively [<xref ref-type="bibr" rid="B117-marinedrugs-11-04058">117</xref>]. Almiramide C displayed a SI of 11 compared to Vero cells while the SI for almiramide B was slightly lower at 9. Moreover, through a series of target based affinity probes, and fluorescence site localisation imaging studies, the compounds were shown to disrupt glycosome function in the parasite. Glycolysis is an essential pathway in trypanosomatids, and glycosomal enzymes have been identified as a potential drug target in trypanosomes [<xref ref-type="bibr" rid="B118-marinedrugs-11-04058">118</xref>].</p><fig id="marinedrugs-11-04058-f010" position="float"><label>Figure 10</label><caption><p>The structure of peptides of marine origin for which activity has been reported against <italic>T. cruzi</italic> (<bold>60</bold>–<bold>61</bold>), <italic>T.b. rhodesiense</italic> (<bold>62</bold>–<bold>63</bold>) and <italic>T.b. brucei</italic> (<bold>64</bold>–<bold>65</bold>).</p></caption><graphic xlink:href="marinedrugs-11-04058-g010"></graphic></fig></sec></sec><sec><title>3. Conclusions</title><p>A large number of structurally diverse marine natural products have been identified with trypanocidal activity. The manadoperoxides isolated from the marine sponge <italic>Plakortis cfr. lita</italic> are the most promising compounds for HAT. Manadoperoxide B (<bold>12</bold>) was the most active and selective molecule of the series exhibiting sub-micromolar activity against <italic>T.b. rhodesiense</italic> whilst highly selective against mammalian cells [<xref ref-type="bibr" rid="B94-marinedrugs-11-04058">94</xref>]. This compound was also demonstrated to possess anti-malarial activity, however, it is reported to be more than 700-fold less active against <italic>Plasmodium falciparum</italic> (D10) than <italic>T.b. rhodesiense</italic> [<xref ref-type="bibr" rid="B119-marinedrugs-11-04058">119</xref>]. As manadoperoxide B has sub-micromolar activity against <italic>T.b. rhodesiense</italic> and is not cytotoxic, one would anticipate that the physiochemical properties of the molecule, together with the biological activity are being investigated further to ensure the molecule possesses the required characteristics to meet the final target product profile.</p><p>The heterocyclic-substituted xanthone analogue <bold>25</bold> isolated from the marine fungus <italic>Chaetomium</italic> sp. was the most active and selective, marine derived compound for <italic>T. cruzi</italic> [<xref ref-type="bibr" rid="B96-marinedrugs-11-04058">96</xref>]. However, xanthones have been reported to have activity against multiple organisms and disease indications through interacting with a plethora of enzymes and targets [<xref ref-type="bibr" rid="B120-marinedrugs-11-04058">120</xref>]. This promiscuous activity may prevent further development of the compounds for Chagas disease.</p><p>In the last decade numerous molecules, both natural and synthetic, have been identified with trypanocidal activity. However, only two, have entered pre-clinical development for HAT. Furthermore, despite the identification of new targets and a multitude of <italic>in vitro</italic> and <italic>in vivo</italic> studies having been conducted, candidates for Chagas disease have failed to progress to the advanced stages of clinical development. Many of the molecules identified with potent trypanocidal activity, cannot be developed further as they possess unsuitable and undesirable structural and pharmacokinetic properties. This highlights the need to continue to explore other avenues for new chemical entities, whilst reviewing the approaches currently undertaken and the potential reasons for the lack of success. Evaluation of the current <italic>in vitro</italic> assays used to identify new compounds, in particular the life cycle stage for Chagas disease, is warranted. This is particularly true for the <italic>in vivo</italic> models where the parasite strain, administration route and duration of the study can impact on the outcomes.</p><p>Marine natural products have provided the pharmaceutical industry with many incredibly potent compounds—some developed into therapeutics whilst others providing valuable insights into the biology of disease and desired attributes of the compounds required to ameliorate it. Whilst compounds isolated from this source have yet to progress to pre-clinical development for trypanosomatid diseases, collectively the improvements to the <italic>in vitro</italic> assays used to identify them, the <italic>in vivo</italic> models used to evaluate them, and the methodology required for isolating them could change this situation.</p></sec></body><back><notes><title>Conflicts of Interest</title><p>The authors declare no conflicts of interest.</p></notes><ref-list><title>References</title><ref id="B1-marinedrugs-11-04058"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lozano</surname><given-names>R.</given-names></name><name><surname>Naghavi</surname><given-names>M.</given-names></name><name><surname>Foreman</surname><given-names>K.</given-names></name><name><surname>Lim</surname><given-names>S.</given-names></name><name><surname>Shibuya</surname><given-names>K.</given-names></name><name><surname>Aboyans</surname><given-names>V.</given-names></name><name><surname>Abraham</surname><given-names>J.</given-names></name><name><surname>Adair</surname><given-names>T.</given-names></name><name><surname>Aggarwal</surname><given-names>R.</given-names></name><name><surname>Ahn</surname><given-names>S.Y.</given-names></name><etal></etal></person-group><article-title>Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010</article-title><source>Lancet</source><year>2012</year><volume>380</volume><fpage>2095</fpage><lpage>2128</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(12)61728-0</pub-id><pub-id pub-id-type="pmid">23245604</pub-id></element-citation></ref><ref id="B2-marinedrugs-11-04058"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Murray</surname><given-names>C.J.L.</given-names></name><name><surname>Vos</surname><given-names>T.</given-names></name><name><surname>Lozano</surname><given-names>R.</given-names></name><name><surname>Naghavi</surname><given-names>M.</given-names></name><name><surname>Flaxman</surname><given-names>A.D.</given-names></name><name><surname>Michaud</surname><given-names>C.</given-names></name><name><surname>Ezzati</surname><given-names>M.</given-names></name><name><surname>Shibuya</surname><given-names>K.</given-names></name><name><surname>Salomon</surname><given-names>J.A.</given-names></name><name><surname>Abdalla</surname><given-names>S.</given-names></name><etal></etal></person-group><article-title>Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: A systematic analysis for the global burden of disease study 2010</article-title><source>Lancet</source><year>2012</year><volume>380</volume><fpage>2197</fpage><lpage>2223</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(12)61689-4</pub-id><pub-id pub-id-type="pmid">23245608</pub-id></element-citation></ref><ref id="B3-marinedrugs-11-04058"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pepin</surname><given-names>J.</given-names></name><name><surname>Meda</surname><given-names>H.A.</given-names></name></person-group><article-title>The epidemiology and control of human African trypanosomiasis</article-title><source>Adv. 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