Structure-activity relationships of the aromatic site in novel anticonvulsant pyrrolo[1,2-a]pyrazine derivatives

Abstract

Novel, chiral derivatives of pyrrolo[1,2-a]pyrazine with aromatic substituents at carbon C-4 were synthesized by a short synthetic sequence involving Ugi multicomponent reaction. The compounds were evaluated for their in vivo efficacy in animal models of epilepsy within the Anticonvulsant Screening Program (ASP). High activity in 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests was characteristic for meta-substituted analogs. On the other hand, efficacy of compounds in the 6 Hz model of pharmacoresistant limbic seizures was only marginally affected by the orientation of substituents in the phenyl moiety. The most active derivative, 5a, displayed an ED50 value of 32.24 mg/kg and a protective index of 6.6 (PI) in the 6 Hz test. It was also active in a pilocarpine-induced status prevention model of pharmacoresistant status epilepticus.

Keywords: 2,6-Diketopiperazine; 2,6-Piperazinedione; Anticonvulsant activity; Multicomponent reactions; Pyrrolo[1,2-a]pyrazine; Ugi reaction.