ABSTRACT
The synthesis, characterization and comparative biological study of a series of antibacterial copper complexes with heterocyclic sulfonamides were reported. Two kinds of complexes were obtained with the stoichiometries [Cu(L)2] . H2O and [Cu(L)2(H2O)4] . nH2O. They were characterized by infrared and electronic spectroscopies and the crystal structure of [Cu(sulfisoxazole)2(H2O)4] . 2H2O was determined by single crystal X-ray diffraction. It crystallized in the C2/c with Z = 8 monoclinic space group C2/c with Z = 8. The Cu(II) is in a slightly tetragonal distorted octahedron formed by four oxygen atoms from water molecules and two nitrogen atoms from two isoxazole rings. The antimicrobial activity was evaluated for all the synthesized complexes and ligands using the agar dilution test. The results showed that the complexes with five-membered heterocyclic rings were more active than the free sulfonamides while the pyrimidine, pyridine and pyridazine complexes had similar or less activity than the free ligands. In order to find an explanation for this behavior lipophilicity and superoxide dismutase-like activity were tested, showing that the [Cu(sulfamethoxazol)2(H2O)4] . 3H2O presented the highest antimicrobial potency and a superoxide dismutase-like activity comparable with pharmacological active compounds.
Subject(s)
Copper/chemistry , Heterocyclic Compounds/chemistry , Organometallic Compounds/chemistry , Sulfacetamide/analogs & derivatives , Sulfonamides/chemistry , Superoxide Dismutase/chemical synthesis , Crystallography, X-Ray , Escherichia coli/drug effects , Microbial Sensitivity Tests , Models, Molecular , Spectrophotometry, Infrared , Staphylococcus aureus/drug effects , Sulfacetamide/chemistry , Superoxide Dismutase/chemistry , Superoxide Dismutase/pharmacology , Water/chemistryABSTRACT
The synthesis and antiviral properties of pyridinioalkanoyl thioester (PATE) compounds that target nucleocapsid p7 protein (NCp7) of the human immunodeficiency virus type 1 (HIV-1) have been described previously (Turpin, J. A., Song, Y., Inman, J. K., Huang, M., Wallqvist, A., Maynard, A., Covell, D. G., Rice, W. G., and Appella, E. (1999) J. Med. Chem. 42, 67-86). In the present study, fluorescence and electrospray ionization-mass spectrometry were employed to determine the mechanism of modification of NCp7 by two lead compounds, N-[2-(5-pyridiniovaleroylthio)benzoyl]sulfacetamide bromide and N-[2-(5-pyridiniovaleroylthio)benzoyl]-4-(4-nitrophenylsulfonyl )anili ne bromide (compounds 45 and 47, respectively). Although both compounds exhibit antiviral activity in cell-based assays, we failed to detect appreciable ejection of zinc from NCp7 under conditions in which previously described NCp7-active disulfides readily eject zinc. However, upon "activation" by Ag(+), compound 45 reacted with NCp7 resulting in the zinc ejection from both zinc fingers. The reaction followed a two-step mechanism in which zinc was ejected from the carboxyl-terminal zinc finger faster than from the amino-terminal zinc finger. Both compounds covalently modified the protein with pyridinioalkanoyl groups. Compound 45 modified cysteines 36 and 49 of the carboxyl-terminal zinc finger. The results obtained herein demonstrate that PATE compounds can be constructed that selectively target only one of the two zinc fingers of NCp7, thus providing an impetus to pursue development of highly selective zinc finger inhibitors.
Subject(s)
Anti-HIV Agents/pharmacology , Capsid Proteins , Capsid/antagonists & inhibitors , Capsid/chemistry , Gene Products, gag/antagonists & inhibitors , Gene Products, gag/chemistry , HIV-1/physiology , Pyridinium Compounds/pharmacology , Sulfacetamide/analogs & derivatives , Sulfones/pharmacology , Viral Proteins , Amino Acid Sequence , Anti-HIV Agents/chemistry , Humans , Kinetics , Mass Spectrometry , Molecular Sequence Data , Protein Conformation , Pyridinium Compounds/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Spectrometry, Mass, Secondary Ion , Sulfacetamide/chemistry , Sulfacetamide/pharmacology , Sulfones/chemistry , Zinc/analysis , Zinc Fingers , gag Gene Products, Human Immunodeficiency VirusABSTRACT
The structural spectroscopic, and thermal properties of a complex of sulfacetamide (Hsacm) with Cu(II) have been investigated. The complex [Cu(Hsacm)2(NO3)2] crystallizes in the monoclinic system, space group P2(1)/n. The cell dimensions are a = 7.696(7) A, b = 8.017(7) A, c = 19.230(10), beta = 110.80(1) degree, V = 1109(1) A3, Z = 2, and Dx = 1.84 g/cm3. The structure was refined to R = 0.0776. Cu(Hsacm)2(NO3)2 molecules form a long polymeric chain extended along the b-axis. The copper(II) coordinated geometry is tetragonally distorted octahedral with two amino nitrogens from Hsacm and two oxygens from nitrato anions in the basal plane and two acetamido oxygens from neighbor Hsacm molecules in the apical position. Each sulfacetamide, acting as a bidentate ligand, links two Cu(II) ions as a bridge through the Namino and the Oacetamido atoms. The complex proved to possess higher bacteriostatic activity than the corresponding ligand.
