Multifunctional Silver(I) Complexes with Metronidazole Drug Reveal Antimicrobial Properties and Antitumor Activity against Human Hepatoma and Colorectal Adenocarcinoma Cells

Abstract

Silver salts and azole derivatives are well known for their antimicrobial properties. Recent evidence has demonstrated also their cytotoxic and genotoxic potential toward both normal and cancer cells. Still, little is known about the action of complexes of azoles with silver(I) salts. Thus, the goal of the study was to compare the chemical, cytotoxic and antimicrobial properties of metronidazole complexes with silver(I) nitrate and silver(I) sulfate to metronidazole and pure silver(I) salts. We synthetized a novel complex, [Ag(MTZ)2]2SO4, and confirmed its chemical structure and properties using 1H and 13C NMR spectroscopy and X-Ray, IR and elemental analysis. To establish the stability of complexes [Ag(MTZ)2NO3] and [Ag(MTZ)2]2SO4, they were exposed to daylight and UV-A rays and were visually assessed. Their cytotoxicity toward human cancer cells (HepG2, Caco-2) and mice normal fibroblasts (Balb/c 3T3 clone A31) was determined by MTT, NRU, TPC and LDH assays. The micro-dilution broth method was used to evaluate their antimicrobial properties against Gram-positive and Gram-negative bacteria. A biofilm eradication study was also performed using the crystal violet method and confocal laser scanning microscopy. The photo-stability of the complexes was higher than silver(I) salts. In human cancer cells, [Ag(MTZ)2]2SO4 was more cytotoxic than Ag2SO4 and, in turn, AgNO3 was more cytotoxic than [Ag(MTZ)2NO3]. For Balb/c 3T3 cells, Ag2SO4 was more cytotoxic than [Ag(MTZ)2]2SO4, while the cytotoxicity of AgNO3 and [Ag(MTZ)2NO3] was similar. Metronidazole in the tested concentration range was non-cytotoxic for both normal and cancer cells. The complexes showed increased bioactivity against aerobic and facultative anaerobic bacteria when compared to metronidazole. For the majority of the tested bacterial strains, the silver(I) salts and complexes showed a higher antibacterial activity than MTZ; however, some bacterial strains presented the reverse effect. Our results showed that silver(I) complexes present higher photo-stability, cytotoxicity and antimicrobial activity in comparison to MTZ and, to a certain extent, to silver(I) salts.

Synthesis of Gingerol-Metals Complex and in-vitro Cytotoxic Activity on Human Colon Cancer Cell Line

“… 39 Several studies indicated that silver(I) complexes show better cytotoxicity against tumor cells including myeloid leukemia cells K562, MCF-7 breast cancer, colorectal Adenocarcinoma Cells Caco-2 cells, and human Hepatoma HepG2. 40 , 41 Our study suggested that gingerol-metal complex-Ag has the potential to be developed as chemotherapeutic agent against colorectal cancers.…”

Silver(i) complexes containing antifungal azoles: significant improvement of the anti-Candida potential of the azole drug after its coordination to the silver(i) ion

“…The antimicrobial potential of silver(I) complexes is well known, and recent studies have also demonstrated their cytotoxic and genotoxic potential toward normal and cancer cells. 47,48 In comparison to simple silver(I) salt, it was found that silver(I) complexes with organic-based ligands exhibit more varied chemical properties. 47 Moreover, the use of simple silver(I) salts has been limited since they undergo fast dissociation, leading to the precipitation of AgCl under physiological conditions, a process that prevents the antimicrobial action of silver(I) ion in accordance with the pathways previously described.…”

“…47,48 In comparison to simple silver(I) salt, it was found that silver(I) complexes with organic-based ligands exhibit more varied chemical properties. 47 Moreover, the use of simple silver(I) salts has been limited since they undergo fast dissociation, leading to the precipitation of AgCl under physiological conditions, a process that prevents the antimicrobial action of silver(I) ion in accordance with the pathways previously described. 34 To determine the influence of the coordinated silver(I) ion on the antimicrobial activity of complexes 1-3, the biological properties of these complexes were compared with those of the corresponding antifungal azoles (Table 2).…”

Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment

“…Moreover, silver(I) complexes with metronidazole (MTZ) and miconazole (MCZ) have demonstrated more diverse biochemical properties compared to free ligands and silver(I) salts alone [18][19][20][21][22][23]. Miconazole (Figure 1) is a broad-spectrum azole antifungal with some additional activity against Gram-positive bacteria.…”

“…This is an important consideration when applying metronidazole composites with silver nanoparticles as antibacterials, as they do not demonstrate toxic side effects toward mammalian cells and tissues [36]. were synthetized by our group and further studied [18][19][20][21][22][23], along with their potential cytostatic activity in A375 human skin cancer cells and normal BJ cells. In addition, to comprehensively assess their potential as anticancer agents, this study also evaluates their impact on blood coagulation and red blood cell hemolysis.…”