| Summary: | The marine natural product ianthelliformisamine C is a bis-cinnamido substituted spermine derivative that exhibits intrinsic antimicrobial properties and can enhance the action of doxycycline towards the Gram-negative bacterium <i>Pseudomonas aeruginosa</i>. As part of a study to explore the structure–activity requirements of these activities, we have synthesized a set of analogues that vary in the presence/absence of methoxyl group and bromine atoms and in the polyamine chain length. Intrinsic antimicrobial activity towards <i>Staphylococcus aureus</i>, methicillin-resistant <i>S. aureus</i> (MRSA) and the fungus <i>Cryptococcus neoformans</i> was observed for only the longest polyamine chain examples of non-brominated analogues while all examples bearing either one or two bromine atoms were active. Weak to no activity was typically observed towards Gram-negative bacteria, with exceptions being the longest polyamine chain examples <b>13f</b>, <b>14f</b> and <b>16f</b> against <i>Escherichia coli</i> (MIC 1.56, 7.2 and 5.3 µM, respectively). Many of these longer polyamine-chain analogues also exhibited cytotoxic and/or red blood cell hemolytic properties, diminishing their potential as antimicrobial lead compounds. Two of the non-toxic, non-halogenated analogues, <b>13b</b> and <b>13d</b>, exhibited a strong ability to enhance the action of doxycycline against <i>P. aeruginosa</i>, with >64-fold and >32-fold enhancement, respectively. These results suggest that any future efforts to optimize the antibiotic-enhancing properties of cinnamido-polyamines should explore a wider range of aromatic ring substituents that do not include bromine or methoxyl groups.
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