title: Palladium-benzodiazepine derivatives as promising metallodrugs for the development of antiepileptic therapies.
abstract: We synthesized two organometallic diazepam-palladium(II) derivatives by C-H activation of diazepam (DZP) with palladium salts, i.e., PdCl2 and Pd(OAc)2 (OAc=acetate). Both compounds obtained are air stable and were isolated in good yields. The anticonvulsant potential of the complexes, labeled [(DZP)PdCl]2 and [(DZP)PdOAc]2, was evaluated through two animal models: pentylenetetrazole (PTZ)- and picrotoxin (PTX)-induced convulsions. The organometallic DZP-palladium(II) acetate complex, [(DZP)PdOAc]2, significantly increased (p<0.01 or p<0.001) latencies and protected the animals against convulsions induced by PTZ and PTX, while the analogous chloro derivative, [(DZP)PdCl]2, was effective (p<0.01) only in the PTZ model. These effects appear to be mediated through the GABAergic system. The possible mechanism of action of the DZP-palladium(II) complexes was also confirmed with the use of flumazenil (FLU), a GABAA-benzodiazepine receptor complex site antagonist. Herein, we present the first report of the anticonvulsant properties of organometallic DZP-palladium(II) complexes as well as evidence that these compounds may play an important role in the study of new drugs to treat patients with epilepsy.
authors.affiliation: Grupo de Catálise e Reatividade Química (GCaR), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil. Electronic address: walleska_bismaida@hotmail.com.
authors.forename: Walleska Bismaida Zacarias Galvão
authors.initials: WB
authors.lastname: Barros
authors.affiliation: Grupo de Catálise e Reatividade Química (GCaR), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil. Electronic address: allyssonhaide@hotmail.com.
authors.forename: Allysson Haide Queiroz
authors.initials: AH
authors.lastname: da Silva
authors.affiliation: Grupo de Catálise e Reatividade Química (GCaR), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil; Laboratoire de Chimie et Systémique Organo-Métalliques, Institut de Chimie, UMR7177, 4 rue Blaise Pascal, Strasbourg 67000, France. Electronic address: anasoraya.farma@yahoo.com.br.
authors.forename: Ana Soraya Lima
authors.initials: AS
authors.lastname: Barbosa
authors.affiliation: Grupo de Catálise e Reatividade Química (GCaR), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil. Electronic address: magalhaes.abner@gmail.com.
authors.forename: Ábner Magalhães
authors.initials: ÁM
authors.lastname: Nunes
authors.affiliation: Grupo de Catálise e Reatividade Química (GCaR), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil. Electronic address: trapima@gmail.com.
authors.forename: José Rui Machado
authors.initials: JR
authors.lastname: Reys
authors.affiliation: Laboratório de Neurociências e Ensaios Farmacológicos (LANEF), Departamento de Fisiologia, Universidade Federal de Sergipe (UFS), Av. Marechal Rondom, s/n, São Cristóvão, Sergipe CEP 49.000-100, Brazil. Electronic address: heitorgaf@gmail.com.
authors.forename: Heitor Gomes
authors.initials: HG
authors.lastname: de Araújo-Filho
authors.affiliation: Laboratório de Neurociências e Ensaios Farmacológicos (LANEF), Departamento de Fisiologia, Universidade Federal de Sergipe (UFS), Av. Marechal Rondom, s/n, São Cristóvão, Sergipe CEP 49.000-100, Brazil. Electronic address: jullyanas@yahoo.com.br.
authors.forename: Jullyana
authors.initials: J
authors.lastname: de Souza Siqueira Quintans
authors.affiliation: Laboratório de Neurociências e Ensaios Farmacológicos (LANEF), Departamento de Fisiologia, Universidade Federal de Sergipe (UFS), Av. Marechal Rondom, s/n, São Cristóvão, Sergipe CEP 49.000-100, Brazil. Electronic address: lucindojr@gmail.com.
authors.forename: Lucindo José
authors.initials: LJ
authors.lastname: Quintans-Júnior
authors.affiliation: Laboratoire de Chimie et Systémique Organo-Métalliques, Institut de Chimie, UMR7177, 4 rue Blaise Pascal, Strasbourg 67000, France. Electronic address: pfeffer@unistra.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Pfeffer
authors.affiliation: Laboratório de Cristalografia e Modelagem Molecular (LaboCrMM), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil. Electronic address: vrsm@qui.ufal.br.
authors.forename: Valéria Rodrigues
authors.initials: VR
authors.lastname: Dos Santos Malta
authors.affiliation: Grupo de Catálise e Reatividade Química (GCaR), Instituto de Química e Biotecnologia, Universidade Federal de Alagoas, Av. Lourival de Melo Mota, s/n, Maceió, Alagoas CEP: 57.072-970, Brazil. Electronic address: mrm@qui.ufal.br.
authors.forename: Mario Roberto
authors.initials: MR
authors.lastname: Meneghetti
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry*; D008297:Male; D051379:Mice; D010165:Palladium / Q000737:chemistry*
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D010165:Palladium
keywords: Benzodiazepine; Convulsion; Diazepam; Epilepsy; Palladacycles