In this study, α-ω-disubstituted polyamines exhibit a range of potentially useful biological activities, including antimicrobial and antibiotic potentiation properties. We have prepared an expanded set of diarylbis(thioureido)polyamines that vary in central polyamine core length, identifying analogues with potent methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Acinetobacter baumannii and Candida albicans growth inhibition properties, in addition to the ability to enhance action of doxycycline towards Gram-negative bacterium Pseudomonas aeruginosa. The observation of associated cytotoxicity/hemolytic properties prompted synthesis of an alternative series of diacylpolyamines that explored aromatic head groups of varying lipophilicity. Examples bearing terminal groups each containing two phenyl rings (15a–f, 16a–f) were found to have optimal intrinsic antimicrobial properties, with MRSA being the most susceptible organism. A lack of observed cytotoxicity or hemolytic properties for all but the longest polyamine chain variants identified these as non-toxic Gram-positive antimicrobials worthy of further study. Analogues bearing either one or three aromatic-ring-containing head groups were either generally devoid of antimicrobial properties (one ring) or cytotoxic/hemolytic (three rings), defining a rather narrow range of head group lipophilicity that affords selectivity for Gram-positive bacterial membranes versus mammalian. Analogue 15d is bactericidal and targets the Gram-positive bacterial membrane.

As part of our search for new antimicrobials and antibiotic enhancers, a series of naphthyl- and biphenyl-substituted polyamine conjugates have been synthesized. The structurally-diverse library of compounds incorporated variation in the capping end groups and in the length of the polyamine (PA) core. Longer chain (PA-3-12-3) variants containing both 1-naphthyl and 2-naphthyl capping groups exhibited more pronounced intrinsic antimicrobial properties against methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.29 µM) and the fungus Cryptococcus neoformans (MIC ≤ 0.29 µM). Closer mechanistic study of one of these analogues, 20f, identified it as a bactericide. In contrast to previously reported diarylacyl-substituted polyamines, several examples in the current set were able to enhance the antibiotic action of doxycycline and/or erythromycin towards the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli. Two analogues (19a and 20c) were of note, exhibiting greater than 32-fold enhancement in activity. This latter result suggests that α,ω-disubstituted polyamines bearing 1-naphthyl- and 2-naphthyl-capping groups are worthy of further investigation and optimization as non-toxic antibiotic enhancers.

The marine environment represents a rich source of novel antimicrobial compounds. This study investigated the isolation and synthesis of antimicrobial agents from the New Zealand ascidian Pseudodistoma opacum to identify natural products and derivatives with potential pharmacological applications. Screening of a marine natural product library and related synthetic analogues revealed several compounds exhibiting antibiotic-potentiating activity in combination with doxycycline against Pseudomonas aeruginosa. To further explore these findings, the most active natural product, opacaline A (1), was synthesized, and a structure–activity relationship (SAR) study was conducted to identify key structural features required for activity. This work reports the first total synthesis of opacaline A (1) and racemic 7-bromohomotrypargine (3). Biological evaluation demonstrated that the presence of a bromine substituent and a free amine or guanidine group is essential for both intrinsic antimicrobial activity and antibiotic potentiation. Additionally, both oxidation states of the β-carboline ring (aromatic and tetrahydro-) were found to retain activity. These findings provide insight into the structural requirements for activity and support further development of these compounds as antimicrobial adjuvants.

New therapeutic options to combat the growing incidence of antimicrobial resistance are urgently needed. A 2015 publication reported the isolation and biological evaluation of two diketopiperazine natural products, cyclo(l-Trp-l-Arg) (CDP 2) and cyclo(d-Trp-d-Arg) (CDP 3), from an Achromobacter sp. bacterium, finding that the latter metabolite in particular exhibited strong antibacterial activity towards a range of wound-related microorganisms and could synergize the action of ampicillin. Intrigued by these biological activities and noting inconsistencies in the structural characterization of the natural products, we synthesized the four diastereomers of cyclo(Trp-Arg) and evaluated them for antimicrobial and antibiotic enhancement properties. The detailed comparison of spectroscopic data raises uncertainty regarding the structure of CDP 2 and disproves the structure of CDP 3. In our hands, none of the four stereoisomers of cyclo(Trp-Arg) exhibited detectable intrinsic antimicrobial properties towards a range of Gram-positive and Gram-negative bacteria or fungi nor could they potentiate the action of antibiotics. These discrepancies in biological properties, compared with the activities reported in the literature, reveal that these specific cyclic dipeptides do not represent viable templates for the development of new treatments for microbial infections.