Département de chimie moléculaire

Objectives: The authors report the synthesis, antibacterial activity and toxicity of 24 bis-indolic derivs. obtained during the development of new ways of synthesis of marine bis-indole alkaloids from the spongotine, topsentin and hamacanthin classes. Methods: Innovative ways of synthesis and further structural optimizations led to bis-indoles presenting either the 1-(1H-indol-3'-yl)-1,2-diaminoethane unit or the 1-(1H-indol-3-yl)ethanamine unit. MIC detn. was performed for ref. and clin. strains of Staphylococcus aureus and CoNS species. MBC, time-kill kinetics, soly., hydrophobicity index, plasma protein-binding and cytotoxicity assays were performed for lead compds. Inhibition of the S. aureus NorA efflux pump was also tested for bis-indoles with no antistaphylococcal activity. Results: Lead compds. were active against both S. aureus and CoNS species, with MICs between 1 and 4 mg/L. Importantly, the same MICs were found for MRSA and vancomycin-intermediate S. aureus strains. Early concn.-dependent bactericidal activity was obsd. for lead derivs. Compds. with no intrinsic antibacterial activity could inhibit the S. aureus NorA efflux pump, which is involved in resistance to fluoroquinolones. At 0.5 mg/L, the most effective compd. led to an 8-fold redn. of the ciprofloxacin MIC for the SA-1199B S. aureus strain, which overexpresses NorA. However, the bis-indole compds. displayed a high hydrophobicity index and high plasma protein binding, which significantly reduced antibacterial activity. Conclusions: The authors have synthesized and characterized novel bis-indole derivs. as promising candidates for the development of new antistaphylococcal treatments, with preserved activity against MDR S. aureus strains.