Copper complexes of pyridine derivatives with superoxide scavenging and antimicrobial activities.

Superoxide anions are reactive oxygen species that can attack biomolecules such as DNA, lipids and proteins to cause many serious diseases. This study reports the synthesis of copper complexes of nicotinic acid with related pyridine derivatives. The copper complexes were shown to possess superoxide dismutase (SOD) and antimicrobial activities. The copper complexes exerted SOD activity in range of 49.07-130.23 microM. Particularly, copper complex of nicotinic acid with 2-hydroxypyridine was the most potent SOD mimic with an IC(50) of 49.07 microM. In addition, the complexes exhibited antimicrobial activity against Bacillus subtilis ATCC 6633 and Candida albicans ATCC 90028 with MIC range of 128-256 microg/mL. The SOD activities were well correlated with the theoretical parameters as calculated by density functional theory at the B3LYP/LANL2DZ level of theory. Interestingly, the SOD activity of the copper complexes was demonstrated to be inversely correlated with the electron affinity, but was well correlated with both HOMO and LUMO energies. The vitamin-metal complexes described in this report are great examples of the value-added benefits of vitamins for medicinal applications.

[1]  Weimin Hu,et al.  Augmented inhibition of Candida albicans growth by murine neutrophils in the presence of a tryptophan metabolite, picolinic acid , 2004, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[2]  A. Nafady,et al.  The protective effect of copper complexes against gastric mucosal ulcer in rats. , 1993, Biochemical pharmacology.

[3]  D. Silverman,et al.  Characterization of the Product-inhibited Complex in Catalysis by Human Manganese Superoxide Dismutase* , 1999, The Journal of Biological Chemistry.

[4]  P. Fernandes,et al.  Cu, Zn Superoxide dismutase: distorted active site binds substrate without significant energetic cost , 2006 .

[5]  J. Rawson,et al.  The coordination chemistry of 2-pyridone and its derivatives , 1995 .

[6]  Apilak Worachartcheewan,et al.  Antimicrobial and Antioxidative Activities of Bioactive Constituents from Hydnophytum formicarum Jack , 2008, Molecules.

[7]  P. Aggett,et al.  An in vitro study of the effect of picolinic acid on metal translocation across lipid bilayers. , 1981, The Journal of nutrition.

[8]  M. Cathcart,et al.  Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[9]  A. Khlebnikov,et al.  Decomposition of reactive oxygen species by copper(II) bis(1-pyrazolyl)methane complexes , 2006, JBIC Journal of Biological Inorganic Chemistry.

[10]  S. Hazen,et al.  Oxidative and nitrosative events in asthma. , 2003, Free radical biology & medicine.

[11]  P. Hamilton,et al.  Antiviral, cytotoxic and apoptotic activities of picolinic acid on human immunodeficiency virus-1 and human herpes simplex virus-2 infected cells. , 2001, Anticancer research.

[12]  Chartchalerm Isarankura-Na-Ayudhya,et al.  Copper Complexes of Nicotinic-Aromatic Carboxylic Acids as Superoxide Dismutase Mimetics , 2008, Molecules.

[13]  Hong-yu Zhang,et al.  A theoretical study on Cu(II) binding modes and antioxidant activity of mammalian normal prion protein. , 2004, Chemical research in toxicology.

[14]  A. Banerjee,et al.  In vitro study of antioxidant activity of Syzygium cumini fruit , 2005 .

[15]  K. N. Thimmaiah,et al.  Stereochemistry and fungitoxicity of complexes of p-anisaldehydethiosemicarbazone with Mn(II), Fe(II), Co(II) and Ni(II) , 1985 .

[16]  F. Bricaire,et al.  Neurodegenerative diseases and oxidative stress. , 2004, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[17]  B. Mikhaĭlov,et al.  Antiviral activity of boron chelates obtained from 2-aminopyridine , 1982, Pharmaceutical Chemistry Journal.

[18]  S. Pastorino,et al.  Antifungal activity of macrophages engineered to produce IFNγ: inducibility by picolinic acid , 2003, Medical Microbiology and Immunology.

[19]  G. Mohan,et al.  Syntheses and anti-inflammatory activity of Diphenylamine-2,2′-dicarboxylic acid and its metal complexes , 2005, Journal of enzyme inhibition and medicinal chemistry.

[20]  R. Morris,et al.  Effect of the Ligand and Metal on the pKa Values of the Dihydrogen Ligand in the Series of Complexes [M(H2)H(L)2]+, M = Fe, Ru, Os, Containing Isosteric Ditertiaryphosphine Ligands, L , 1994 .

[21]  Raghuvir Singh,et al.  Synthesis and characterization of divalent manganese, cobalt, nickel, copper and zinc complexes with nicotinic acid , 1981 .

[22]  P. Geerlings,et al.  Electron affinities of the first- and second-row atoms: Benchmark ab initio and density-functional calculations , 1999, physics/9902026.

[23]  H. Tomioka,et al.  Effects of picolinic acid on the antimicrobial functions of host macrophages against Mycobacterium avium complex. , 2007, International journal of antimicrobial agents.

[24]  Gary Hardiman,et al.  Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. , 2008, Cancer cell.

[25]  A. Nafady,et al.  A novel therapeutic drug (copper nicotinic acid complex) for non‐alcoholic fatty liver , 2007, Liver international : official journal of the International Association for the Study of the Liver.

[26]  A. Wierzbicki,et al.  The relationship between serum copper and ceruloplasmin in routine clinical practice , 2007, International journal of clinical practice.

[27]  Chartchalerm Isarankura-Na-Ayudhya,et al.  Metalloantibiotic Mn(II)-bacitracin complex mimicking manganese superoxide dismutase. , 2006, Biochemical and biophysical research communications.

[28]  R. Gu,et al.  Predicting the binding capability of benzothiazoline-2-thione and its derivatives with gold: a DFT and FT-Raman combined studies. , 2008, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[29]  Bao-dui Wang,et al.  Synthesis, Characterization and Anti-oxidative Activity of Cobalt(II), Nickel(II) and Iron(II) Schiff Base Complexes , 2005 .

[30]  Hong-yu Zhang,et al.  Computational note on the SOD-like antioxidant potential of nicotine–copper(II) complexes , 2007 .

[31]  H. Hemmings,et al.  The Effects of General Anesthetics on Norepinephrine Release from Isolated Rat Cortical Nerve Terminals , 2002, Anesthesia and analgesia.

[32]  Hong-yu Zhang,et al.  A new strategy to combat Alzheimer's disease. Combining radical-scavenging potential with metal-protein-attenuating ability in one molecule. , 2005, Bioorganic & medicinal chemistry letters.

[33]  T. Franklin,et al.  Biochemistry of Antimicrobial Action , 1975, Springer US.

[34]  R. Gambino,et al.  Associations of dietary and serum copper with inflammation, oxidative stress, and metabolic variables in adults. , 2008, The Journal of nutrition.

[35]  Y. Chen,et al.  Ethylenediamine-palladium(II) complexes with pyridine and its derivatives: synthesis, molecular structure and initial antitumor studies. , 1999, Journal of inorganic biochemistry.

[36]  K. Owzar,et al.  Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection. , 2008, Free radical biology & medicine.

[37]  D. Leibfritz,et al.  Free radicals and antioxidants in normal physiological functions and human disease. , 2007, The international journal of biochemistry & cell biology.

[38]  N. Sayınalp,et al.  Copper deficiency with increased hematogones mimicking refractory anemia with excess blasts. , 2008, Leukemia research.

[39]  Gokare A. Ravishankar,et al.  Effect of pretreatment with chromium picolinate on haematological parameters during dengue virus infection in mice. , 2007, The Indian journal of medical research.

[40]  P. Beale,et al.  Studies on the activity of three palladium(II) compounds of the form: trans-PdL2Cl2 where L=2-hydroxypyridine, 3-hydroxypyridine, and 4-hydroxypyridine. , 2007, Journal of inorganic biochemistry.

[41]  M. Anadkat,et al.  A pilot study of the safety and efficacy of picolinic acid gel in the treatment of acne vulgaris , 2007, The British journal of dermatology.

[42]  P. Fernandes,et al.  Density-functional calculations of the Cu, Zn superoxide dismutase redox potential: The influence of active site distortion , 2005 .

[43]  I. Sóvágó,et al.  Copper(II) and zinc(II) complexes of the peptides Ac-HisValHis-NH2 and Ac-HisValGlyAsp-NH2 related to the active site of the enzyme CuZnSOD. , 2004, Journal of inorganic biochemistry.