Conjugation of a New Series of Dithiocarbazate Schiff Base Copper(II) Complexes with Vectors Selected to Enhance Antibacterial Activity.
Résumé
A new series of six Schiff bases derived from S-methyldithiocarbazate and S-benzyldithiocarbazate with methyl levulinate, levulinic acid and 4-carboxybenzaldehyde were reacted with copper(II), producing complexes of general formula ML2 (M = Cu(II), L = ligand). All compounds were characterized using established physico-chemical and spectroscopic methods. Crystal structures were determined for most of the Schiff bases and two Cu(II) complexes. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. The parent ligands and their respective copper(II) complexes exhibited moderate antibacterial activity against both Gram-negative and Gram-positive bacteria. The most active ligand and its analogous S-methyl derivative were conjugated with various vector moieties: polyarginines (R1, R4, R9 and RW9), oligoethylene glycol (OEG) and an efflux pump blocker, phenylalanine-arginine-β-naphthylamide (PAβN). Among the conjugates, nonarginine (R9) derivatives showed the most encouraging synergistic effect upon conjugation and complexation with copper ion with enhanced water solubility, bacteria cell membrane permeability and bioactivity. These Cu(II)-R9 derivatives display remarkable antibacterial activity against a wide spectrum of bacteria and in particular, are highly efficacious against Staphylococcus aureus with minimum inhibition concentration (MIC) values of 1-0.5 µM. This pioneer study clearly indicates that the conjugation of cell-penetrating peptides (CPPs) to dithiocarbazate compounds greatly enhances their therapeutic potential.