Conjugation of a new series of dithiocarbazate Schiff base Copper(II) complexes with vectors selected to enhance antibacterial activity.
A new series of six Schiff bases derived from S-methyldithiocarbazate (SMDTC) and S-benzyldithiocarbazate (SBDTC) with methyl levulinate (SMML, SBML), levulinic acid (SMLA, SBLA), and 4-carboxybenzaldehyde (SM4CB, SB4CB) were reacted with copper(II), producing complexes of general formula ML2 (M = Cu(II), L = ligand). All compounds were characterized using established physicochemical and spectroscopic methods. Crystal structures were determined for three Schiff bases (SMML, SBML, SBLA) and two Cu(II) complexes (Cu(SMML)2 and Cu(SMLA)2). In order to provide more insight into the behavior 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 (SB4CB) and its analogous S-methyl derivative (SM4CB) 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). Nonaarginine (R9) derivatives showed the most encouraging synergistic effects upon conjugation and complexation with copper ion including 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 inhibitory concentration (MIC) values of 0.5-1 μM. This pioneer study clearly indicates that the conjugation of cell-penetrating peptides (CPPs) to dithiocarbazate compounds greatly enhances their therapeutic potential.
Laboratoire des BioMolécules, UMR 7203, CNRS, Université Pierre et Marie Curie , Ecole Normale Supérieure, Départment de Chimie, 24 rue Lhomond, 75005 Paris, France.
May Lee
ML
Low
Laure
L
Maigre
Pierre
P
Dorlet
Régis
R
Guillot
Jean-Marie
JM
Pagès
Karen A
KA
Crouse
Clotilde
C
Policar
Nicolas
N
Delsuc
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D057846:Cell-Penetrating Peptides / Q000737:chemistry; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D003460:Crystallization; D004563:Electrochemistry / Q000379:methods; D004578:Electron Spin Resonance Spectroscopy; D006834:Hydrazines / Q000737:chemistry*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D009942:Organometallic Compounds / Q000737:chemistry*; D060327:Solid-Phase Synthesis Techniques; D012996:Solutions; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D057846:Cell-Penetrating Peptides; D056831:Coordination Complexes; D006834:Hydrazines; D008024:Ligands; D009942:Organometallic Compounds; D012996:Solutions; C016573:methyldithiocarbazate; D003300:Copper