%0 Journal Article
%T Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents
%A Cary F. C. Lam
%A A. Norrie Pearce
%A Shen H. Tan
%A Marcel Kaiser
%A Brent R. Copp
%J Marine Drugs
%D 2013
%I MDPI AG
%R 10.3390/md11093472
%X Pure compound screening has identified the dioxothiazino-quinoline-quinone ascidian metabolite ascidiathiazone A ( 2) to be a moderate growth inhibitor of Trypanosoma brucei rhodesiense (IC 50 3.1 ¦ÌM) and Plasmodium falciparum (K1 dual drug resistant strain) (IC 50 3.3 ¦ÌM) while exhibiting low levels of cytotoxicity (L6, IC 50 167 ¦ÌM). A series of C-7 amide and ¦¤ 2(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 (IC 50 0.62¨C6.5 ¦ÌM), and no correlation was apparent between anti-malarial and anti- T. brucei activity. Phenethylamide 7e and ¦¤ 2(3)-glycine analogue 8k exhibited similar anti- Pf activity to 2 but with slightly enhanced selectivity (SI 72 and 93, respectively), while ¦¤ 2(3)-phenethylamide 8e (IC 50 0.67 ¦ÌM, 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 (IC 50 0.34¨C0.035 ¦ÌM) combined with excellent selectivity (SI 560¨C4000). 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.
%K marine natural products
%K protozoa
%K malaria
%K Plasmodium falciparum
%K Trypanosoma brucei rhodesiense
%K quinone
%K dioxothiazine
%K alkaloid
%U http://www.mdpi.com/1660-3397/11/9/3472