Nonsymmetrically substituted N-heterocyclic carbene (NHC) precursors 1a–d and 3a–d were synthesised by first reacting 1H-(benz)imidazole with p-cyanobenzyl bromide to give 4-(1H-imidazole-1-ylmethyl)benzonitrile (1) and 4-(1H-benzimidazole-1-ylmethyl)benzonitrile (3) and afterwards introducing benzyl bromide, 1-(bromomethyl)-4-methylbenzene, 1-(bromomethyl)-4-methoxybenzene, and methyl 4-(bromomethyl)benzoate. The NHC-silver(I) acetate complexes (1-benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (2a), (1-(4-cyanobenzyl)-3-(4-methylbenzyl)-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (2b), (1-(4-cyanobenzyl)-3-[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-imidazole-2-ylidene) silver(I) acetate (2c), (1-benzyl-3-(4-cyanobenzyl)-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4a), (1-(4-cyanobenzyl)-3-(4-methylbenzyl)-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4b), (1-(4-cyanobenzyl)-3-(4-methoxybenzyl)-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4c), and (1-(4-cyanobenzyl)-3-[4-(methoxycarbonyl)benzyl]-2,3-dihydro-1H-benzimidazole-2-ylidene) silver(I) acetate (4d) were yielded by reacting these NHC precursors with silver(I) acetate. The silver(I) acetate complex 4b was characterised by single crystal X-ray diffraction. Preliminary in vitro antibacterial studies against the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Escherichia coli, using the Kirby-Bauer disc diffusion method, were carried out on the seven NHC-silver(I) acetate complexes 2a–c and 4a–d. Also the IC50 values of these seven complexes were determined by an MTT-based assay against the human renal cancer cell line Caki-1. The complexes 2a–c and 4a–c revealed the following IC50 values, respectively, 25 (±1), 15 (±2), 5.4 (±0.8), 16 (±2), 7.1 (±1), 20 (±4), and 14 (±1)？μM. 1. Introduction N-Heterocyclic carbenes (NHCs) are versatile ligands in silver complexes exhibiting antimicrobial activity, in particular for the possible treatment of pulmonary infections accompanying cystic fibrosis (CF) and chronic lung infections [1–3] and maybe in the treatment of cancer [4]. Youngs’ research group have reported antimicrobial activity of NHC-silver complexes derived from 1H-imidazole, 4,5-dichloro-1H-imidazole and xanthines against a panel of highly resistant pathogens recovered from the respiratory tract of cystic fibrosis (CF) patients [1, 3, 5]. Another important contribution by the Ghosh research group led to the synthesis and antimicrobial evaluation of NHC-silver complexes derived from
References
[1]
K. M. Hindi, T. J. Siciliano, S. Durmus et al., “Synthesis, stability, and antimicrobial studies of electronically tuned silver acetate N-heterocyclic carbenes,” Journal of Medicinal Chemistry, vol. 51, no. 6, pp. 1577–1583, 2008.
[2]
A. Kascatan-Nebioglu, M. J. Panzner, C. A. Tessier, C. L. Cannon, and W. J. Youngs, “N-Heterocyclic carbene-silver complexes: A new class of antibiotics,” Coordination Chemistry Reviews, vol. 251, no. 5-6, pp. 884–895, 2007.
[3]
A. Kascatan-Nebioglu, A. Melaiye, K. Hindi et al., “Synthesis from caffeine of a mixed N-heterocyclic carbene-silver acetate complex active against resistant respiratory pathogens,” Journal of Medicinal Chemistry, vol. 49, no. 23, pp. 6811–6818, 2006.
[4]
W. J. Youngs, D. A. Medvetz, K. M. Hindi, M. J. Panzner, A. J. Ditto, and Y. H. Yun, “Anticancer activity of Ag(I) N-heterocyclic carbene complexes derived from 4,5-dichloro-1H-imidazole,” Metal-Based Drugs, vol. 2008, Article ID 384010, 2008.
[5]
A. Melaiye, R. S. Simons, A. Milsted et al., “Formation of water-soluble pincer silver(I)-carbene complexes: a novel antimicrobial agent,” Journal of Medicinal Chemistry, vol. 47, no. 4, pp. 973–977, 2004.
[6]
S. Ray, R. Mohan, J. K. Singh et al., “Anticancer and antimicrobial metallopharmaceutical agents based on palladium, gold, and silver N-heterocyclic carbene complexes,” Journal of the American Chemical Society, vol. 129, no. 48, pp. 15042–15053, 2007.
[7]
C. L. Cannon, L. A. Hogue, R. K. Vajravelu et al., “In vitro and murine efficacy and toxicity studies of nebulized SCC1, a methylated caffeine-silver(I) complex, for treatment of pulmonary infections,” Antimicrobial Agents and Chemotherapy, vol. 53, no. 8, pp. 3285–3293, 2009.
[8]
S. Roland, C. Jolivalt, T. Cresteil et al., “Investigation of a series of silver-N-Heterocyclic carbenes as antibacterial agents: Activity, synergistic effects, and cytotoxicity,” Chemistry—A European Journal, vol. 17, no. 5, pp. 1442–1446, 2011.
[9]
B. Thati, A. Noble, B. S. Creaven et al., “In vitro anti-tumour and cyto-selective effects of coumarin-3-carboxylic acid and three of its hydroxylated derivatives, along with their silver-based complexes, using human epithelial carcinoma cell lines,” Cancer Letters, vol. 248, no. 2, pp. 321–331, 2007.
[10]
H. L. Zhu, X. M. Zhang, X. Y. Liu et al., “Clear Ag-Ag bonds in three silver(I) carboxylate complexes with high cytotoxicity properties,” Inorganic Chemistry Communications, vol. 6, no. 8, pp. 1113–1116, 2003.
[11]
J. J. Liu, P. Galettis, A. Farr et al., “In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake,” Journal of Inorganic Biochemistry, vol. 102, no. 2, pp. 303–310, 2008.
[12]
S. Patil and M. Tacke, “NHC-silver(I) acetates as bioorganometallic anticancer and antibacterial drugs,” in Insights into Coordination, Bioinorganic and Applied Inorganic Chemistry, M. Melník, P. Seg？a, and M. Tatarko, Eds., pp. 555–566, Press of Slovak University of Technology, Bratislava, Slovakia, 2011.
[13]
S. Patil, A. Deally, B. Gleeson et al., “Synthesis, cytotoxicity and antibacterial studies of novel symmetrically and non-symmetrically p-nitrobenzyl-substituted N-heterocyclic carbene-silver(i) acetate complexes,” Zeitschrift fur Anorganische und Allgemeine Chemie, vol. 637, no. 3-4, pp. 386–396, 2011.
[14]
S. Patil, A. Deally, B. Gleeson, H. Müller-Bunz, F. Paradisi, and M. Tacke, “Novel benzyl-substituted N-heterocyclic carbene–silver acetate complexes: synthesis, cytotoxicity and antibacterial studies,” Metallomics, vol. 3, no. 1, pp. 74–88, 2011.
[15]
S. Patil, K. Dietrich, A. Deally et al., “Synthesis, cytotoxicity and antibacterial studies of novel symmetrically and nonsymmetrically 4-(methoxycarbonyl)benzyl-substituted n-heterocyclic carbene-silver acetate complexes,” Helvetica Chimica Acta, vol. 93, no. 12, pp. 2347–2364, 2010.
[16]
S. Patil, A. Deally, B. Gleeson, H. Müller-Bunz, F. Paradisi, and M. Tacke, “Synthesis, cytotoxicity and antibacterial studies of symmetrically and non-symmetrically benzyl- or p-cyanobenzyl-substituted N-Heterocyclic carbene—silver complexes,” Applied Organometallic Chemistry, vol. 24, no. 11, pp. 781–793, 2010.
[17]
S. Patil, J. Claffey, A. Deally et al., “Synthesis, cytotoxicity and antibacterial studies of p-methoxybenzyl- substituted and benzyl-substituted n-heterocyclic carbene-silver complexes,” European Journal of Inorganic Chemistry, no. 7, pp. 1020–1031, 2010.
[18]
L. Kaps, B. Biersack, H. Müller-Bunz et al., “Gold(I)-NHC complexes of antitumoral diarylimidazoles: Structures, cellular uptake routes and anticancer activities,” Journal of Inorganic Biochemistry, vol. 106, no. 1, pp. 52–58, 2012.
[19]
S. Patil, A. Deally, F. Hackenberg et al., “Novel benzyl- or 4-cyanobenzyl-substituted N-heterocyclic (Bromo)(carbene)silver(I) and (Carbene)(chloro)gold(I) complexes: Synthesis and preliminary cytotoxicity studies,” Helvetica Chimica Acta, vol. 94, no. 9, pp. 1551–1562, 2011.
[20]
Agilent Technologies, “Program CrysalisPro Version 1.171.34.49,” 2011.
[21]
G. M. Sheldrick, “A short history of SHELX,” Acta Crystallographica Section A, vol. 64, no. 1, pp. 112–122, 2007.
[22]
A. Bondi, H. E. Spaulding, E. D. Smith, and C. C. Dietz, “A routine method for the rapid determination of susceptibility to penicillin and other antibiotics,” The American Journal of the Medical Science, vol. 213, no. 2, pp. 221–225, 1947.
[23]
S. E. Luria, “Recent advances in bacterial genetics,” Bacteriological Reviews, vol. 11, no. 1, pp. 1–40, 1947.
[24]
W. A. Herrmann and C. Kocher, “N-heterocyclic carbenes,” Angewandte Chemie International Edition, vol. 36, no. 20, pp. 2162–2187, 1997.
[25]
A. J. Arduengo, H. V. Rasika Dias, J. C. Calabrese, and F. Davidson, “Homoleptic carbene-silver(I) and carbene-copper(I) complexes,” Organometallics, vol. 12, no. 9, pp. 3405–3409, 1993.
[26]
C. C. Scarborough, B. V. Popp, I. A. Guzei, and S. S. Stahl, “Development of 7-membered N-heterocyclic carbene ligands for transition metals,” Journal of Organometallic Chemistry, vol. 690, no. 24-25, pp. 6143–6155, 2005.
[27]
M. J. Panzner, A. Deeraksa, A. Smith et al., “Synthesis and in vitro efficacy studies of silver carbene complexes on biosafety level 3 bacteria,” European Journal of Inorganic Chemistry, no. 13, pp. 1739–1745, 2009.
[28]
B. Gleeson, J. Claffey, D. Ertler et al., “Novel organotin antibacterial and anticancer drugs,” Polyhedron, vol. 27, no. 18, pp. 3619–3624, 2008.
