The Antimicrobial and Antibiotic Potentiating Properties of Lipophilic Polyamine Analogues

Abstract

The combination of increasing bacterial drug resistance and simulatenous decrease in the development of new antibacterial agents has led to an urgent need for new antimicrobials. An ongoing project within the Copp group has been the synthesis of polyamine derivatives with modified “capping” groups, which have shown promising biological results for both antimicrobial and antibiotic potentiating properties. The first succinyl-primaquine (SPQ) end group possessed weak antimicrobial activity with moderate to excellent antibiotic potentiating properties (MIC: 6.25 μM) in a doxycycline/P. aeruginosa potentiating assay. As a result, simplified SPQ analogues containing quinolines, pyridines and naphthalene subunits were prepared. None exhibited antibiotic potentiating activity, though 1.19, 1.21, 1.23, 1.28 and 1.29 exhibited improved antimicrobial activity towards S. aureus and C. neoformans at an MIC of ≤0.25 μg/mL. To add to the set of simplified SPQ polyamines, analogues centered upon di-aryl and tri-aryl end groups were prepared. Biological activity of capping groups containing substituted-quinoline rings were only weak antimicrobial and antibiotic potentiating agents, although, the 4-aminobiphenyl analogues, in particular 2.65, exhibited excellent antimicrobial activity against S. aureus and C. neoformans (MIC: ≤0.25 μg/mL), with no detectable cytotoxicity or haemolytic properties. In the case of 3,3-diphenylpropylamine analogues 1.28 and 1.29, potent broad-spectrum antimicrobial activity as well as moderate doxycycline/P. aeruginosa potentiation were observed, and so following this, additional examples of diphenyl and triphenyl end groups were prepared. Only diphenyl analogue 3.38 exhibited significant antibiotic enhancing properties in combination with doxycycline (MIC of 475 μM to 47.5 μM), however, extremely potent antimicrobial activity against S. aureus and E. coli (≤0.25 μg/mL) with no cytotoxicity and no haemolytic properties were observed with other diphenyl analogues 3.41, 3.42, 3.43, 3.44 and 3.45. For the even more lipophilic triphenyl capping groups, they also exhibited potent broad-spectrum antimicrobial properties but were found to be potently cytotoxic and haemolytic. Analysis of the results observed for this study suggested that the requirements for selective antimicrobial properties were the presence of two protonatable polyamine chain amines, clogP between 6–9 and an average of 3.5–6.5 rotatable bonds per aromatic ring in the structure.