ARTICLE DOI: 10.1002/zaac.201300082 Copper(II) Complex with the Tridentate Ligand N,N-bis(2-ethyl-4-methyl- imidazol-5-ylmethyl)phenylethylamine (biaq). X-ray Crystal Structure and Biological Activity on Bacillus subtilis of [Cu(biaq)Cl 2 ]. Ángeles Mendoza, [a] Guillermo Mendoza-Díaz,* [b] Mario Pedraza-Reyes, [c] and Sylvain Bernès [d] Keywords: Antibacterial properties; Copper; Imidazole derivatives; Mutagenic activity Abstract. The ligand N,N-bis(2-ethyl-4-methyl-imidazol-5-ylmethyl)- 1-phenylethylamine (biaq) was prepared by Mannich reaction of 2- ethyl-4-methyl-1H-imidazole, (R)-1-phenylethylamine and formalde- hyde. It was characterized by FTIR and NMR spectroscopy. This li- gand reacts with CuCl 2 to give a coordination compound with formula [Cu(biaq)Cl 2 ]. In this compound, biaq acts as a tridentate ligand with one tertiary amine and two azole nitrogen atoms coordinated to the central metal atom. The complex was characterized by FTIR spec- troscopy, elemental analysis, and X-ray diffraction. The X-ray struc- 1 Introduction Imidazole-based ligands have been matter of medical inter- est because they may have some biological activities as anti- bacterial and antiparasitic agents. Also, the development of such ligands is related to the preparation of small molecules that may mimic some copper-containing enzymes, and there- fore may have some interesting catalytic effects. The interest in having a better understanding of how central copper atoms work in biological systems, in order to develop new metal- based drugs, is still a growing topic. In particular, this interest has been directed toward the synthesis of copper complexes with imidazole derivatives. Some of these imidazole-based li- gands, NL 3 (L = imidazole [1–3] ), have a tripodal shape. The interest in this type of ligands comes from the fact that in * Prof. Dr. G. Mendoza-Díaz E-Mail: mendozag@ugto.mx [a] Departamento de Química División de Ciencias Naturales y Exactas Campus Guanajuato, Universidad de Guanajuato Noria Alta s/n Guanajuato, Gto. 36050, Mexico [b] Departamento de Ingenierías Química Electrónica y biomédica, División de Ciencias e Ingenierías Campus León, Universidad de Guanajuato Loma del Bosque 103 Lomas del Campestre, León, Guanajuato. 37150, Mexico [c] Departamento de Biología División de Ciencias Naturales y Exactas Campus Guanajuato, Universidad de Guanajuato Noria Alta s/n Guanajuato, Gto. 36050 Mexico [d] DEP Facultad de Ciencias Químicas, UANL Guerrero y Progreso s/n Col. Treviño 64570 Monterrey, NL, Mexico Z. Anorg. Allg. Chem. 2013, 639, (8-9), 1455–1460 © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1455 ture of [Cu(biaq)Cl 2 ] shows a pentacoordinate cooper(II) atom, where two chloride ions and the three nitrogen atoms of the biaq ligand are coordinated in a distorted square pyramidal arrangement. The bio- logical activity of the complex [Cu(biaq)Cl 2 ] was tested using the Gram positive bacterium Bacillus subtilis as a model. Results revealed that the copper complex interfered with bacterial growth, inducing cell death, most probably by altering the primary structure of the chromo- some, since a significant increase of the mutation frequency to rifampi- cin resistance was observed. many copper metalloproteins imidazole residues from histidine appear to be coordinated to copper. [4,5] Therefore, the synthesis of small complexes that could mimic the coordination environ- ment, catalytic behavior or spectroscopic properties of such metalloproteins, is currently a challenge for many groups. Se- lected examples of ligands and complexes reported in the literature related to the present work may be cited: The linear tridentate ligand N,N-bis(2-ethyl-5-methylimidazol-4-yl- methyl)aminopropane (biap) and the coordination compounds of biap with Co II , Ni II , Zn II , [6] Fe III , [7] and Cu II[8] have been reported. The copper complex of biap has been used success- fully for modeling nitrite reductase. [9] Similar ligands as N,N-bis(2-ethyl-5-methylimidazol-4-ylmethyl)aminomethane (biam), N,N-bis(2-ethyl-5-methylimidazol-4-ylmethyl)amino- ethanol (biae), and N,N-bis(2-ethyl-5-methylimidazol-4-yl- methyl)amino-2-ethylpyridine (biapy) form complexes with copper(II) featuring a distorted square pyramidal environ- ment. [8] All the above mentioned ligands were prepared by a Mannich condensation, a straightforward reaction using simple reagents like formaldehyde, amines, and imidazoles. [6,9] in a one pot procedure. On the other hand, antibiotic rifampicin, a potent inhibitor of prokaryotic transcription [10] has been used as a highly clini- cally effective drug, particularly in the treatment of tuberculo- sis. Mutations conferring rifampicin resistance (Rif R ) occur at specific clusters within the gene encoding the β subunit of the prokaryotic RNA polymerase. Rif R RNA polymerases have been extensively characterized in E. coli; these have altered properties in transcription elongation and/or termination. [11] In E. coli, Rif R mutations are usually located in the central region