title: Discovery and evaluation of thiazinoquinones as anti-protozoal agents.
abstract: 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.
authors.affiliation: School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Cary F C
authors.initials: CF
authors.lastname: Lam
authors.forename: A Norrie
authors.initials: AN
authors.lastname: Pearce
authors.forename: Shen H
authors.initials: SH
authors.lastname: Tan
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Brent R
authors.initials: BR
authors.lastname: Copp
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects
chemical_list: D000962:Antimalarials; D011809:Quinones; D014344:Trypanocidal Agents
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