Discovery and evaluation of thiazinoquinones as anti-protozoal agents

• Published in: Marine drugs 2013-09, Vol.11 (9), p.3472-3499
• Main Authors: Lam, Cary F C, Pearce, A Norrie, Tan, Shen H, Kaiser, Marcel, Copp, Brent R
• Format: Article
• Language: English
• Subjects: alkaloid; Antimalarials - chemistry; Antimalarials - pharmacology; dioxothiazine; Inhibitory Concentration 50; malaria; marine natural products; Parasitic Sensitivity Tests - methods; Plasmodium falciparum; Plasmodium falciparum - drug effects; protozoa; quinone; Quinones - chemistry; Quinones - pharmacology; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei rhodesiense; Trypanosoma brucei rhodesiense - drug effects
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md11093472

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.