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

Abstract

Pure compound screening has previously identified the indolglyoxylamidospermidine 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.

6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers

“…exhibited more pronounced activity than the non-polyamine (13) or shorter chained (10,11,12,14,15) derivatives. Within the polyamine examples, the presence of only one mid-chain nitrogen (4) reduced potency towards yeast, while the length of the polyamine mid-section gave maximal potency at PA3-10-3, with 8…”

“…Our screening identified two 6-bromoindolglyoxylamide compounds, spermine 3 13 and spermidine 4 13 (Fig. 1) that exhibited good antimicrobial activity against two Gram-positive strains bacteria Staphylococcus intermedius (MIC 3.125 and 3.125 µM, respectively) and S. aureus (MIC 6.25 and 3.125 µM, respectively) and moderate to strong antifungal activity towards Candida albicans (MIC 17.2 µM for 3) and Cryptococcus neoformans (MIC 1.1 and 50 M, respectively) ( Table 1).…”

“…Mechanism of action studies suggest squalamine (1) functions by disruption of the outer-membrane of Gram-negative bacteria while ianthelliformisamine C (2), in contrast, inhibits efflux pumps. 7,10 Being suitably intrigued by these findings and given our ongoing interest in biologically active polyamine derivatives, [11][12][13][14] we screened an in-house library of polyamine alkaloids related to the natural product ianthelliformisamine C (2)) for antimicrobial and antifungal properties and for the ability to restore the antibiotic activity of doxycycline towards P. aeruginosa. Herein we present this preliminary data, a structure-activity relationship study that explores the influence of the polyamine core on observed intrinsic antimicrobial properties and the ability to potentiate the action of doxycycline, and mechanism of action studies that evaluated compound influence on membrane permeability and polarization.…”

Methionine is required for cAMP‐PKA‐mediated morphogenesis and virulence of Candida albicans

“…As spermidine and spermine are the most predominant polyamines in eukaryotic cells, SAMDC is a popular target for therapeutics against some eukaryotic pathogens, such as Leishmania and Trypanosoma species (J€ anne et al, 1991;Marton and Pegg, 1995;Pegg and McCann, 1992;Svensson et al, 1997). Polyamine metabolism has also been proposed as a target for treatment of Plasmodium falciparum (causing malaria) (Wang et al, 2014). However, an apparent correlation between antimalarial and antitrypanosomal activity is not yet available for polyamine synthesis targeting therapeutics (Wang et al, 2014).…”

“…Polyamine metabolism has also been proposed as a target for treatment of Plasmodium falciparum (causing malaria) (Wang et al, 2014). However, an apparent correlation between antimalarial and antitrypanosomal activity is not yet available for polyamine synthesis targeting therapeutics (Wang et al, 2014). This might be due to the special feature of this parasite; it encodes one single open reading frame for SAMDC and ODC activities.…”