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Mar. Drugs 2014, 12(6), 3138-3160; doi:10.3390/md12063138

Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents

1
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
2
Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, Basel CH-4002, Switzerland
3
University of Basel, Basel CH-4003, Switzerland
*
Author to whom correspondence should be addressed.
Received: 10 April 2014 / Revised: 30 April 2014 / Accepted: 4 May 2014 / Published: 28 May 2014
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Abstract

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 μM, respectively) and Plasmodium falciparum (K1 dual drug resistant strain) (IC50 41 and 15 μM, respectively), but lacking in selectivity (L6 rat myoblast, IC50 24 μM and 25 μM, 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 μM) identified in the study: it, however, also exhibited poor selectivity (L6 IC50 6.0 μM). 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. View Full-Text
Keywords: marine natural products; protozoa; malaria; Plasmodium falciparum; Trypanosoma brucei rhodesiense; polyamine; indolglyoxamide; alkaloid marine natural products; protozoa; malaria; Plasmodium falciparum; Trypanosoma brucei rhodesiense; polyamine; indolglyoxamide; alkaloid
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MDPI and ACS Style

Wang, J.; Kaiser, M.; Copp, B.R. Investigation of Indolglyoxamide and Indolacetamide Analogues of Polyamines as Antimalarial and Antitrypanosomal Agents. Mar. Drugs 2014, 12, 3138-3160.

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