An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone: toward a versatile antimicrobial materials screening platform

Abstract

This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr₂ and Me₆TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-aminoethyl)-1,3-di-Boc-guanidine, 1-(3-aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 μg mL⁻¹ (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C₁₂ and 2C₁₂ oligomers exhibiting greater lysis against the red blood cells (HC₁₀ values between 7.1 and 43 μg mL⁻¹) than their imidazole and tertiary amine counterparts (HC₁₀ of >217 μg mL⁻¹). Oligomers showed the greatest selectivity for C. neoformans, with the C₁₂- and 2C₁₂-tertiary amine and C₁₂-imidazole oligomers possessing the greatest selectivity of >54–109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure–property relationships for antibacterial and antifungal materials.