{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:11:50Z","timestamp":1782486710636,"version":"3.54.5"},"reference-count":24,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2013,9,9]],"date-time":"2013-09-09T00:00:00Z","timestamp":1378684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A (2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC50 3.1 \u03bcM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 3.3 \u03bcM) while exhibiting low levels of cytotoxicity (L6, IC50 167 \u03bcM). A series of C-7 amide and \u03942(3) analogues were prepared that explored the influence of lipophilicity and oxidation state on observed anti-protozoal activity and selectivity. Little variation in anti-malarial potency was observed (IC50 0.62\u20136.5 \u03bcM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and  \u03942(3)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while \u03942(3)-phenethylamide 8e (IC50 0.67 \u03bcM, SI 78) exhibited improved potency and selectivity towards T. brucei rhodesiense compared to the natural product hit. A second series of analogues were prepared that replaced the quinoline ring of 2 with benzofuran or benzothiophene moieties. While esters 10a\/10b and 15 were once again found to exhibit cytotoxicity, carboxylic acid analogues exhibited potent anti-Pf activity (IC50 0.34\u20130.035 \u03bcM) combined with excellent selectivity (SI 560\u20134000). In vivo evaluation of a furan carboxylic acid analogue against P. berghei was undertaken, demonstrating 85.7% and 47% reductions in parasitaemia with ip or oral dosing respectively.<\/jats:p>","DOI":"10.3390\/md11093472","type":"journal-article","created":{"date-parts":[[2013,9,9]],"date-time":"2013-09-09T12:02:47Z","timestamp":1378728167000},"page":"3472-3499","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Discovery and Evaluation of Thiazinoquinones as  Anti-Protozoal Agents"],"prefix":"10.3390","volume":"11","author":[{"given":"Cary","family":"Lam","sequence":"first","affiliation":[{"name":"School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Pearce","sequence":"additional","affiliation":[{"name":"School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, Basel CH-4002, Switzerland"},{"name":"University of Basel, Basel CH-4003, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5492-5269","authenticated-orcid":false,"given":"Brent","family":"Copp","sequence":"additional","affiliation":[{"name":"School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1475-2875-10-S1-S2","article-title":"How can natural products serve as a viable source of lead compounds for the development of new\/novel anti-malarials?","volume":"10","author":"Guantai","year":"2011","journal-title":"Malar. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1016\/j.bmc.2008.10.072","article-title":"Synthetic medicinal chemistry of selected antimalarial natural products","volume":"17","author":"Kumar","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1111\/j.1365-2125.2006.02673.x","article-title":"Reflections on the \u201cdiscovery\u201d of the antimalarial qinghao","volume":"61","author":"Hsu","year":"2006","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nrmicro2331","article-title":"Artemisinin resistance: Current status and scenarios for containment","volume":"8","author":"Dondorp","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3390\/md8010047","article-title":"Inhibitory activity of marine sponge-derived natural products against parasitic protozoa","volume":"8","author":"Orhan","year":"2010","journal-title":"Mar. Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.copbio.2010.09.015","article-title":"The structural diversity and promise of antiparasitic invertebrate-derived small molecules","volume":"21","author":"Watts","year":"2010","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3390\/md7020130","article-title":"Marine antimalarials","volume":"7","author":"Fattorusso","year":"2009","journal-title":"Mar. Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1016\/j.bmc.2011.12.053","article-title":"Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, Dihydro analogues and photo-dimers","volume":"20","author":"McCracken","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9151","DOI":"10.1021\/jo201654h","article-title":"Anti-inflammatory and antimalarial Meroterpenoids from the New Zealand ascidian Aplidium scabellum","volume":"76","author":"Chan","year":"2011","journal-title":"J. Org. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1021\/np200509g","article-title":"Antimalarial \u03b2-carbolines from the New Zealand ascidian Pseudodistoma opacum","volume":"74","author":"Chan","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1021\/np1008619","article-title":"Didemnidines A and B, indole spermidine alkaloids from the New Zealand ascidian Didemnum sp","volume":"74","author":"Finlayson","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.bmcl.2010.12.056","article-title":"Chemical and biological explorations of the electrophilic reactivity of the bioactive marine natural product halenaquinone with biomimetic nucleophiles","volume":"21","author":"Wang","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1016\/j.tet.2008.04.012","article-title":"Orthidines A\u2013E, tubastrine, 3,4-dimethoxyphenethyl-\u03b2-guanidine, and 1,14-sperminedihomovanillamide: potential anti-inflammatory alkaloids isolated from the New Zealand ascidian Aplidium orthium that act as inhibitors of neutrophil respiratory burst","volume":"64","author":"Pearce","year":"2008","journal-title":"Tetrahedron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.bmcl.2012.11.072","article-title":"Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds","volume":"23","author":"Liew","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ejmech.2013.07.055","article-title":"Synthesis and in vitro and in vivo evaluation of antimalarial polyamines","volume":"69","author":"Liew","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1021\/np060626o","article-title":"Anti-inflammatory thiazine alkaloids isolated from the New Zealand ascidian Aplidium sp.: Inhibitors of the neutrophils respiratory burst in a model of gouty arthritis","volume":"70","author":"Pearce","year":"2007","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s10822-005-8694-y","article-title":"Virtual computational chemistry laboratory\u2014design and description","volume":"19","author":"Tetko","year":"2005","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_18","unstructured":"(2005). ALOGPS 2.1, Virtual Computational Chemistry Laboratory."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1021\/np300790g","article-title":"Biomimetic synthesis of thiaplidiaquinones A and B","volume":"75","author":"Khalil","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9179","DOI":"10.1021\/jo301738u","article-title":"Biomimetic synthesis of the apoptosis-inducing thiazinoquinone thiaplidiaquinone A","volume":"77","author":"Carbone","year":"2012","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.bmc.2009.11.063","article-title":"Synthesis of structurally simplified analogues of aplidinone A, a pro-apoptotic marine thiazinoquinone","volume":"18","author":"Aiello","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1002\/jhet.5570180620","article-title":"Studies on quinones. VII. Synthesis of some benzo[b]thiophene-4,7-diones","volume":"18","author":"Ruiz","year":"1981","journal-title":"Heterocyclic Chem."},{"key":"ref_23","unstructured":"Peters, W. (1987). Chemotherapy, and Drug Resistance in Malaria, Academic Press, Inc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.molbiopara.2004.04.007","article-title":"A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle","volume":"137","author":"Trueman","year":"2004","journal-title":"Mol. Biochem. Parasitol."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/11\/9\/3472\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:49:11Z","timestamp":1760219351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/11\/9\/3472"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,9]]},"references-count":24,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2013,9]]}},"alternative-id":["md11093472"],"URL":"https:\/\/doi.org\/10.3390\/md11093472","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,9]]}}}