Investigation of tetrasubstituted heterocycles reveals hydantoins as a promising scaffold for development of novel antimicrobials with membranolytic properties

Mimics of antimicrobial peptides (AMPs) have been proposed as a promising class of antimicrobial agents. We report the analysis of five tetrasubstituted, cationic, amphipathic heterocycles as potential AMP mimics. The analysis showed that the heterocyclic scaffold had a strong influence on the haemo...

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Published in:European journal of medicinal chemistry 2023-03, Vol.249, p.115147-115147, Article 115147
Main Authors: Langer, Manuel K., Rahman, Ataur, Dey, Hymonti, Anderssen, Trude, Blencke, Hans-Matti, Haug, Tor, Stensvåg, Klara, Strøm, Morten B., Bayer, Annette
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Anti-Infective Agents - pharmacology
Antimicrobial Cationic Peptides - chemistry
Antimicrobial peptides (AMP)
Gram-Negative Bacteria
Hydantoin
Hydantoins - pharmacology
Membranolytic
Microbial Sensitivity Tests
Peptidomimetics
Synthetic mimics of antimicrobial peptides (SMAMPs)
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Summary:Mimics of antimicrobial peptides (AMPs) have been proposed as a promising class of antimicrobial agents. We report the analysis of five tetrasubstituted, cationic, amphipathic heterocycles as potential AMP mimics. The analysis showed that the heterocyclic scaffold had a strong influence on the haemolytic activity of the compounds, and the hydantoin scaffold was identified as a promising template for drug lead development. Subsequently, a total of 20 hydantoin derivatives were studied for their antimicrobial potency and haemolytic activity. We found 19 of these derivatives to have very low haemolytic toxicity and identified three lead structures, 2dA, 6cG, and 6dG with very promising broad-spectrum antimicrobial activity. Lead structure 6dG displayed minimum inhibitory concentration (MIC) values as low as 1 μg/mL against Gram-positive bacteria and 4–16 μg/mL against Gram-negative bacteria. Initial mode of action (MoA) studies performed on the amine derivative 6cG, utilizing a luciferase-based biosensor assay, suggested a strong membrane disrupting effect on the outer and inner membrane of Escherichia coli. Our findings show that the physical properties and structural arrangement induced by the heterocyclic scaffolds are important factors in the design of AMP mimics. [Display omitted] •The hydantoin scaffold was the most promising AMP mimetic of five heterocycles studied.•n-Butyl linkers combined with guanidine head groups delivered the highest antimicrobial potency.•Lead structures 6 cG and 6 dG delivered high selectivity indices.•Disruption of the bacterial cytoplasmic membrane was their main mode of action.
ISSN:0223-5234
1768-3254
1768-3254
DOI:10.1016/j.ejmech.2023.115147