Sulfamidas Anticonvulsivas. Diseño, Síntesis y Actividad biológica de aminoácidos funcionalizados

GAVERNET LUCIANA; SELLA CRAVERO MARIANA; SAMAJA GISELA; PASTORE VALENTINA; BRUNO-BLANCH LUIS E.

Montevideo, Uruguay

Congreso; I Reunión Latinoamericana de Química Medicinal; 2007

The incomplete information about the cellular basis of human epilepsy makes it difficult to find a common way to identify new drugs. The alternative rational design of new antiepileptic drugs (AED) based on pharmacophoric patterns has proven to be efficient in the discovery of new chemical entities. Recently we and coworkers have considered structures that belong to the family of aryl and alkyl sulfamides, as new target of antiepileptic drugs. The selection was supported by a nonclassical bioisosteric replacement of the groups that contribute to the definition of the pharmacophore. Compounds bearing this functionality were active against maximal electroshock (MES) test, which is mainly used to target an inhibition of the neuronal voltage-dependent Na channels. In conjunction with the subcutaneous pentylenetetrazole (PTZ) test, the MES test is the assay most widely used to characterize the anticonvulsant activity at preclinical phases. As part of our study of this kind of compounds as AED, we have considered in this investigation sulfamides that include amino acids in their structure.  Amino acids and their derivatives have been investigated in their anticonvulsant action and some of them have proven to be potent AED.3 We used the sulfamide function to incorporate lipophilic tails in order to promote better transport properties through cellular membranes. We also replace the amide bond between two amino acids in dipeptides by the sulfamide functionality, in order to increase the stability towards proteolysis by peptidases. The compounds were synthesized following two general synthetic routes, and they were evaluated against MES and PTZ test. Toxicity was also tested in vivo using Rotorod test. The results pointed to this class of derivatives as new anticonvulsant agents.