title: Novel fluorinated pyrrolo[1,2-a]pyrazine-2,6-dione derivatives: synthesis and anticonvulsant evaluation in animal models of epilepsy.
abstract: A series of fluorinated analogs of the potent investigative anticonvulsant agent (4S,8aS)-4-phenylperhydropyrrolo[1,2-a]pyrazine-2,6-dione 1 was prepared and characterized by IR, 1H, 13C NMR and mass spectral data. The compounds have been evaluated in the in vivo rodent models of epilepsy. They displayed high activity in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6Hz model of pharmacoresistant limbic seizures. The results showed that incorporating fluorine atoms into the phenyl ring of 1 can be beneficial for the anticonvulsant potency. The most promising meta-trifluoromethyl and meta-trifluoromethoxy derivatives (4S,8aS)-5h and (4S,8aS)-5l, respectively, displayed very broad spectra of activity across the preclinical seizure models.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland. Electronic address: maciej.dawidowski@wum.edu.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dawidowski
authors.affiliation: Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Chońska
authors.affiliation: Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland.
authors.forename: Weronika
authors.initials: W
authors.lastname: Mika
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1 Str., 02-097 Warszawa, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D054879:Halogenation; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole; D010862:Pilocarpine; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D006845:Hydrocarbons, Fluorinated; D011719:Pyrazines; D011758:Pyrroles; C000596443:pyrrolo(1,2-a)pyrazine-2,6-dione; D010862:Pilocarpine; D010433:Pentylenetetrazole
keywords: Anticonvulsant agent; Antiseizure agent; Broad spectrum; Fluorine derivatives; Multicomponent reaction; Pyrrolo[1,2-a]pyrazine