Síntesis, resolución y estudio de la actividad anticonvulsionante y neurotoxicidad de fenil amidas

Abstract

Epilepsy is one of the most common neurological disorders affecting around 1 % of the worldwide population. Approximately 70% of the patients with epilepsy are successfully treated, however 20 to 30 % of epileptics are refractory to antiepileptics, hence the need to develop new antiepileptic drugs. The compound DL-3-hydroxy-3-ethyl-3-phenyl propionamide (DL-HEPP) is a broad spectrum anticonvulsant. Incorporation of hydrophobic groups in the phenyl ring of DL-HEPP increased its anticonvulsant activity. Therefore, a hydrophobic group (CF3) has been introduced in the phenyl ring of DL-HEPP and DL-HEPB (a homologue of HEPP) to give the fluorobencenamides DL-CF3-HEPP and DL-CF3-HEPB. It was also made the resolution of the anticonvulsant DL-HEPA, a homologue of DL-HEPP. DL-CF3-HEPP, DL-HEPA and its enantiomers were characterized through 1H-NMR, 13C-RMN and IR spectroscopy. The results confirmed the proposed structure. The anticonvulsant activity was determined using pentylentetrazole (80 mg/kg) intraperitoneally and maximal electroshock test (MES) in male Swiss Webster mice. The effective doses 50 (ED50) obtained for DL-CF3-HEPB, DL-HEPP, DL-HEPA, (-) HEPA and phenobarbital (PB) in the MES test were 62,138, 109.5, 125 and 19 mg/kg respectively. In the rotarod ataxia test the TD50 values obtained for DL-CF3-HEPP, DL-HEPP and PB were 66, 212 and 69 mg/kg. In conclusion, the inclusion of the trifluoromethyl group in the phenyl ring of DL-HEPP increased its anticonvulsant activity.