Discovery and Evaluation of Thiazinoquinones as Anti-Protozoal Agents

Cary Lam,A Pearce,Shen Tan,Brent Copp,Marcel Kaiser

doi:10.3390/md11093472

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.

Highlights

Natural products have historically played an important role in the discovery of new treatments for malaria [1]
In the hunt for novel scaffolds from which to develop the generation of anti-malarials, a structurally-diverse array of natural products, including those obtained from marine organisms, have been reported to exhibit activity towards Plasmodium falciparum [5,6,7]
As part of our own continuing search for new leads for the development of treatments for neglected human diseases [8,9,10,11,12] we have screened a library of synthesized and isolated marine natural products against a panel of four parasitic protozoa: Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum K1 dual drug-resistant strain, with concurrent counter-screening for toxicity towards the non-malignant L6 rat myoblast cell line

Summary

Introduction

Natural products have historically played an important role in the discovery of new treatments for malaria [1]. In the hunt for novel scaffolds from which to develop the generation of anti-malarials, a structurally-diverse array of natural products, including those obtained from marine organisms, have been reported to exhibit activity towards Plasmodium falciparum [5,6,7]. As part of our own continuing search for new leads for the development of treatments for neglected human diseases [8,9,10,11,12] we have screened a library of synthesized and isolated marine natural products against a panel of four parasitic protozoa: Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum K1 dual drug-resistant strain, with concurrent counter-screening for toxicity towards the non-malignant L6 rat myoblast cell line. We recently disclosed details of the first hit from this screen, the previously reported anti-inflammatory polyamine diamide ascidian metabolite orthidine F (1) [13,14,15] (Figure 1)

Methods

Results

Conclusion