title: Synthesis, structural analysis and anticonvulsant activity of a ternary Cu(II) mononuclear complex containing 1,10-phenanthroline and the leading antiepileptic drug valproic acid.
abstract: The synthesis and characterization of the binary complex of copper(II) with the antiepileptic drug valproic acid sodium salt (Valp) and the related ternary complex with 1,10-phenanthroline (phen) are reported, as well as the anticonvulsant properties of the latter. The characterization was carried out by means of elemental analyses, infrared (IR), UV-visible (UV-vis) spectrophotometry and Electron Paramagnetic Resonance (EPR). The X-ray crystal structure of the mononuclear complex bis(2-propylpentanoate)(1,10-phenanthroline)copper(II) [Cu(Valp)(2)phen] is showed for the first time. It crystallized in C2/c space group with unit cell dimensions of a = 14.939(1) A, b = 19.280(1) A, c = 9.726(1) A, beta = 97.27(2) degrees , V = 2778.8(4) A(3) and Z = 8. The carboxylates bond in an asymmetric chelating mode and the copper atom adopts a highly distorted octahedral coordination, characterized by the sum of the angles of 365.9 degrees around Cu(II) and its nearest atoms in the CuN(2)O(2) + O(2) chromophore instead of the expected 360 degrees for a basal square planar geometry found in most Cu(II) complexes. Molecules assemble three by three through slipped pi-pi stacking of the aromatic phen with respectively 3.519 and 3.527 A distances, in a head-to-tail arrangement. Studies of the anticonvulsant properties of this bioligand chelate evidenced its lack of efficacy in preventing MES-induced seizures. Interestingly, complex 4 protected mice against the Minimal Clonic seizures at doses that do not cause Rotorod toxicity, with an ED(50) documenting very potent anticonvulsant activity in this model of seizure, a particularly useful pharmacological profile of activity for the treatment of Petit Mal seizures.
authors: Laboratoire de Synthèse Organique et Pharmacochimie, BioCIS, CNRS UMR 8076, Université Paris Sud, Faculté de Pharmacie, 5, rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry Cedex, France.
authors: Maité
authors: M
authors: Sylla-Iyarreta Veitía
authors: Françoise
authors: F
authors: Dumas
authors: Georges
authors: G
authors: Morgant
authors: John R J
authors: JR
authors: Sorenson
authors: Yves
authors: Y
authors: Frapart
authors: Alain
authors: A
authors: Tomas
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D010618:Phenanthrolines / Q000737:chemistry*; D051381:Rats; D012640:Seizures / Q000188:drug therapy*; D014635:Valproic Acid / Q000737:chemistry*
chemical_list: D000927:Anticonvulsants; D009942:Organometallic Compounds; D010618:Phenanthrolines; D014635:Valproic Acid; D003300:Copper; C025205:1,10-phenanthroline