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Mar. Drugs 2013, 11(9), 3472-3499;

Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, Basel CH-4002, Switzerland
University of Basel, Basel CH-4003, Switzerland
Current address: Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia.
Author to whom correspondence should be addressed.
Received: 12 August 2013 / Revised: 20 August 2013 / Accepted: 30 August 2013 / Published: 9 September 2013
(This article belongs to the Special Issue Antiprotozoal Marine Natural Products)
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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 μM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 3.3 μM) while exhibiting low levels of cytotoxicity (L6, IC50 167 μM). A series of C-7 amide and Δ2(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 0.62–6.5 μM), and no correlation was apparent between anti-malarial and anti-T. brucei activity. Phenethylamide 7e and Δ2(3)-glycine analogue 8k exhibited similar anti-Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while Δ2(3)-phenethylamide 8e (IC50 0.67 μM, 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 0.34–0.035 μM) combined with excellent selectivity (SI 560–4000). 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. View Full-Text
Keywords: marine natural products; protozoa; malaria; Plasmodium falciparum; Trypanosoma brucei rhodesiense; quinone; dioxothiazine; alkaloid marine natural products; protozoa; malaria; Plasmodium falciparum; Trypanosoma brucei rhodesiense; quinone; dioxothiazine; alkaloid

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Lam, C.F.C.; Pearce, A.N.; Tan, S.H.; Kaiser, M.; Copp, B.R. Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents. Mar. Drugs 2013, 11, 3472-3499.

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