Synthesis, Cytotoxicity and Antibacterial Studies of Novel Symmetrically and Nonsymmetrically 4-(Methoxycarbonyl)benzyl-Substituted N-Heterocyclic Carbene-Silver Acetate Complexes

From the reaction of 1H-imidazole (1a), 4,5-dichloro-1H-imidazole (1b), 1H-benzimidazole (1c), 1-methyl-1H-imidazole (1d), and 1-methyl-1H-benzimidazole (1f) with methyl 4-(bromomethyl)benzoate (2), symmetrically and nonsymmetrically 4-(methoxycarbonyl) benzyl-substituted N-heterocyclic carbene (NHC) precursors, 3a-3f, were synthesized. These NHC precursors were then reacted with silver(I) acetate (AgOAc) to yield the NHC-silver acetate complexes (acetato-kappa O){1,3-bis[4-(methoxycarbonyl)benzyl]imidazol-2-ylidene}silver (4a), (acetato-kappa O){4,5-dichloro-1,3-bis[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-imidazol-2-yl}silver (4b), (acetato-kappa O){1,3-bis[ 4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-benzimidazol-2-yl}silver (4c), (acetato-kappa O){1-[4-(methoxycarbonyl)benzyl]-3-methyl-2,3-dihydro-1H-imidazol-2-yl}silver (4d), (acetato-kappa O){4,5-dichloro-1-[4-(methoxycarbonyl)benzyl]-3-methyl-2,3-dihydro-1H-imidazol-2-yl}silver (4e), and (acetato-kappa O){1-[ 4-(methoxycarbonyl)benzyl]-3-methyl-2,3-dihydro-1H-benzimidazol-2-yl}silver (4f), respectively. The three NHC-AgOAc complexes 4a, 4c, and 4d were characterized by single-crystal X-ray diffraction. All compounds studied in this work were preliminarily screened for their antimicrobial activities in vitro against Gram-positive bacteria Staphylococcus aureus, and Gram-negative bacteria Escherichia coli using the qualitative disk-diffusion method. All NHC-AgOAc complexes exhibited weak-to-medium antibacterial activity with areas of clearance ranging from 4 to 7 mm at the highest amount used, while the NHC precursors showed significantly lower activity. In addition, NHC-AgOAc complexes 4a and 4b, and 4d-4f exhibited in preliminary cytotoxicity tests on the human renal-cancer cell line Caki-1 medium-to-high cytotoxicities with IC50 values ranging from 3.3 +/- 0.4 to 68.3 +/- 1 mu M.