Journal
MARINE DRUGS
Volume 12, Issue 6, Pages 3138-3160Publisher
MDPI AG
DOI: 10.3390/md12063138
Keywords
marine natural products; protozoa; malaria; Plasmodium falciparum; Trypanosoma brucei rhodesiense; polyamine; indolglyoxamide; alkaloid
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Funding
- University of Auckland Biopharma Thematic Research Initiative [76639]
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Pure compound screening has previously identified the indolglyoxy lamidospermidine ascidian metabolites didemnidine A and B (2 and 3) to be weak growth inhibitors of Trypanosoma brucei rhodesiense (IC50 59 and 44 mu M, respectively) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 41 and 15 mu M, respectively), but lacking in selectivity (L6 rat myoblast, IC50 24 mu M and 25 mu M, respectively). To expand the structure-activity relationship of this compound class towards both parasites, we have prepared and biologically tested a library of analogues that includes indoleglyoxyl and indoleacetic capping acids, and polyamines including spermine (PA3-4-3) and extended analogues PA3-8-3 and PA3-12-3. 7-Methoxy substituted indoleglyoxylamides were typically found to exhibit the most potent antimalarial activity (IC50 10-92 nM) but with varying degrees of selectivity versus the L6 rat myoblast cell line. A 6-methoxyindolglyoxylamide analogue was the most potent growth inhibitor of T. brucei (IC50 0.18 mu M) identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 mu M). There was no apparent correlation between antimalarial and anti-T. brucei activity in the series. In vivo evaluation of one analogue against Plasmodium berghei was undertaken, demonstrating a modest 20.9% reduction in parasitaemia.
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