Highly efficient microwave synthesis of rhodanine and 2-thiohydantoin derivatives and determination of relationships between their chemical structures and antibacterial activity

Abstract

Here we report studies on the synthesis of 12 new heterocyclic derivatives that differ in three structural motifs and the simultaneous evaluation of the impact of these three variables on the biological properties. The examined compounds are based on rhodanine and 2-thiohydantoin cores equipped with hydrogen or carboxymethyl substituents at the N-3 position and linked to a triphenylamine moiety through 1,4-phenylene, 1,4-naphthalenylene and 1,9-anthracenylene spacers at the C-5 position of the heterocycles. All the compounds were synthesized very quickly, selectively and in high yields according to the developed microwave-assisted Knoevenagel condensation protocol, and they were characterized thoroughly with NMR, FT-IR and ESI-HRMS techniques. The derivatives were tested for their activity against selected strains of Gram-positive and Gram-negative bacteria and yeast. Two compounds showed good activity against Gram-positive bacteria, and all of them showed low cytotoxicity against three cell lines of the human immune system. Based on membrane permeability assays it was demonstrated that the active compounds do not penetrate the cell membrane, and thus they must act on the bacterial cell surface. Finally, we proved that the evaluated structure modifications had a synergistic effect and the simultaneous presence of a 1,4-phenylene spacer and carboxymethyl group at N-3 caused the highest boost in antimicrobial activity.