4-[(E)-2-(1-Pyrenyl)Vinyl]Pyridine Complexes: How to Modulate the Toxicity of Heavy Metal Ions to Target Microbial Infections.

Pyrene derivatives are regularly proposed for use in biochemistry as dyes due to their photochemical characteristics. Their antibacterial properties are, however, much less well understood. New complexes based on 4-[(E)-2-(1-pyrenyl)vinyl]pyridine (PyPe) have been synthesized with metal ions that are known to possess antimicrobial properties, such as zinc(II), cadmium(II), and mercury(II). The metal ion salts, free ligand, combinations thereof, and the coordination compounds themselves were tested for their antibacterial properties through microdilution assays. We found that the ligand is able to modulate the antibacterial properties of transition metal ions, depending on the complex stability, the distance between the ligand and the metal ions, and the metal ions themselves. The coordination by the ligand weakened the antibacterial properties of heavy metal ions (Cd(II), Hg(II), Bi(III)), allowing the bacteria to survive higher concentrations thereof. Mixing the ligand and the metal ion salts without forming the complex beforehand enhanced the antibacterial properties of the cations. Being non-cytotoxic itself, the ligand therefore balances the biological consequences of heavy metal ions between toxicity and therapeutic weapons, depending on its use as a coordinating ligand or simple adjuvant.

Silver(I) complexes with 4,7-phenanthroline efficient in rescuing the zebrafish embryos of lethal Candida albicans infection.

Five novel silver(I) complexes with 4,7-phenanthroline (4,7-phen), [Ag(NO3-O)(4,7-phen-µ-N4,N7)]n (1), [Ag(ClO4-О)(4,7-phen-µ-N4,N7)]n (2), [Ag(CF3COO-O)(4,7-phen-µ-N4,N7)]n (3), [Ag2(H2O)0.58(4,7-phen)3](SbF6)2 (4) and {[Ag2(H2O)(4,7-phen-µ-N4,N7)2](BF4)2}n (5) were synthesized, structurally elucidated and biologically evaluated. These complexes showed selectivity towards Candida spp. in comparison to the tested bacteria and effectively inhibited the growth of four different Candida species, particularly of C. albicans strains, with minimal inhibitory concentrations (MICs) in the range of 2.0-10.0 µM. In order to evaluate the therapeutic potential of 1-5, in vivo toxicity studies were conducted in the zebrafish model. Based on the favorable therapeutic profiles, complexes 1, 3 and 5 were selected for the evaluation of their antifungal efficacy in vivo using the zebrafish model of lethal disseminated candidiasis. Complexes 1 and 3 efficiently controlled and prevented fungal filamentation even at sub-MIC doses, while drastically increased the survival of the infected embryos. Moreover, at the MIC doses, both complexes totally prevented C. albicans filamentation and rescued almost all infected fish of the fatal infection outcome. On the other side, complex 5, which demonstrated the highest antifungal activity in vitro, affected the neutrophils occurrence of the infected host, failed to inhibit the C. albicans cells filamentation and showed a poor potential to cure candidal infection, highlighting the importance of the in vivo activity evaluation early in the therapeutic design and development process. The mechanism of action of the investigated silver(I) complexes was related to the induction of reactive oxygen species (ROS) response in C. albicans, with DNA being one of the possible target biomolecules.