Synthetic mimics of antimicrobial peptides from triaryl scaffolds

Abstract

In this report, we describe the synthesis of a new series of small amphiphilic aromatic compounds that mimic the essential properties of cationic antimicrobial peptides using Suzuki-Miyaura coupling. The new design allowed the easy tuning of the conformational restriction, controlled by introduction of intramolecular hydrogen bonds, and the overall hydrophobicity by modifications to the central ring and the side chains. This approach allowed us to better understand the influence of these features on the antimicrobial activity and selectivity. We found that the overall hydrophobicity had a more significant impact on antimicrobial and hemolytic activity than the conformational stiffness. A novel compound was discovered which has MICs of 0.78 μg/mL against S. Aureus and 6.25 μg/mL against E. Coli, similar to the well-known antimicrobial peptide, MSI-78.

Figure 1

Representative scaffold showing design principles.

Figure 2

Aryl oligomers with β-alanine polar side chain and different central rings.

Figure 3

Aryl oligomers prepared for investigating the effect of different polar side groups.

Figure 4

Acetyl derivatives of oligomers used for H-bond investigation.

Figure 5

Influence of the solvent composition on the amide proton chemical shift. Compounds a) 6b vs. b) 7b.

Figure 6

Partial NOESY spectra of compound 7b in DMSO-d₆ solvent. Only NHb shows a NOE effect with ArHd, meanwhile there is no signal between NHa and ArHc, which proves the ability of the intramolecular H-bonding to restrict the rotation around the biaryl bond of the backbone.

Scheme 1

Synthetic pathway for pyridazine oligomers. i) pinacolborane, PdCl₂(dppf)·CH₂Cl₂, Et₃N, dioxane, 100°C, 3h; ii) 3,6-dibromopyridazine, PdCl₂(dppf)/CH₂Cl₂, Na₂CO₃aq, DMF, 90°C, 18h; iii) a,c. Boc-β-Ala-OH, EDC/HOBT, CH₂Cl₂, r.t., overnight; b. Boc-β-Ala-OH, POCl₃, Pyridine, 0°C, 1h; iv) TFA/CH₂Cl₂ (1:3), r.t., 1h.