Novel benzyl-substituted N-heterocyclic carbene-silver acetate complexes: synthesis, cytotoxicity and antibacterial studies.
From the reaction of 1-methylimidazole (1a), 4,5-dichloro-1H-imidazole (1b(I)) and 1-methylbenzimidazole (1c) with p-cyanobenzyl bromide (2a), non-symmetrically substituted N-heterocyclic carbene (NHC) [(3a-c)] precursors, 5,6-dimethyl-1H-benzimidazole (1d) and 4,5-diphenyl-1H-imidazole (1e) with p-cyanobenzyl bromide (2a) and benzyl bromide (2b), symmetrically substituted N-heterocyclic carbene (NHC) [(3d-f)] precursors were synthesised. These NHC-precursors were then reacted with silver(i) acetate to yield the NHC-silver complexes (1-methyl-3-(4-cyanobenzyl)imidazole-2-ylidene)silver(i)acetate (4a), (4,5-dichloro-1-(4-cyanobenzyl)-3-methyl)imidazole-2-ylidene)silver(i)acetate (4b), (1-methyl-3-(4-cyanobenzyl)benzimidazole-2-ylidene)silver(i)acetate (4c), (1,3-bis(4-cyanobenzyl)5,6-dimethylbenzimidazole-2-ylidene) silver(i) acetate (4d), (1,3-dibenzyl-5,6-dimethylbenzimidazole-2-ylidene) silver(i) acetate (4e) and (1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene) silver(i) acetate (4f) respectively. Three NHC-precursors 3c-e and four NHC-silver complexes 4b and 4d-f were characterised by single crystal X-ray diffraction. Preliminary in vitro antibacterial activity of the NHC-precursors and NHC-silver complexes was investigated against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative Kirby-Bauer disk-diffusion method. NHC-silver complexes have shown very high antibacterial activity compared to the NHC-precursors. All six NHC-silver complexes were tested for their cytotoxicity through MTT based in vitro tests on the human renal-cancer cell line Caki-1 in order to determine their IC₅₀ values. NHC-silver complexes 4a-f were found to have IC₅₀ values of 6.2 (±1.0), 7.7 (±1.6), 1.2 (±0.6), 10.8 (±1.9), 24.2 (±1.8) and 13.6 (±1.0) μM, respectively. These values represent improved cytotoxicity against Caki-1, most notably for 4c, which is a three times more cytotoxic than cisplatin (IC₅₀ value = 3.3 μM) itself.
Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and Chemical Biology (CSCB), UCD School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland.
Siddappa
S
Patil
Anthony
A
Deally
Brendan
B
Gleeson
Helge
H
Müller-Bunz
Francesca
F
Paradisi
Matthias
M
Tacke
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008697:Methane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D018030:Silver Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D014961:X-Ray Diffraction
D000085:Acetates; D000900:Anti-Bacterial Agents; D001593:Benzyl Compounds; D006571:Heterocyclic Compounds; D007093:Imidazoles; D018030:Silver Compounds; C103100:silver acetate; C030011:carbene; D008697:Methane