Synthesis and Anticonvulsant Properties of New 3,3-Diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetamides and 3,3-Diphenyl-propionamides.
The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a-t) and 3,3-diphenyl-propionic acid (3a-t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the "classical" maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test. Additionally, several compounds were studied also in the 6-Hz seizures recognized as the animal model of human pharmacoresistant epilepsy. In this series, compound 3q displayed a broad spectrum of activity across the preclinical seizure models (ED50MES = 31.64 mg/kg; ED50scPTZ = 75.41 mg/kg, ED506-Hz (32 mA) = 38.15 mg/kg). Consequently, compound 3q revealed a wider spectrum of protection, higher activity or/and a better safety profile than the commonly used antiepileptic drugs such as phenytoin, ethosuximide, valproic acid, or/and levetiracetam. Notably, the in vitro studies showed that the most possible mechanism of action of 3q may be connected to the interaction with neuronal voltage-sensitive sodium channels (site 2). Other substances were active predominantly in the chemically induced seizures. The results of the current studies indicate that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable for anticonvulsant activity.
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Jolanta
J
Obniska
Faculty of Pharmacy, Department of Pharmacodynamics, Jagiellonian University Medical College, Kraków, Poland.
Anna
A
Rapacz
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Sabina
S
Rybka
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Małgorzata
M
Góra
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Paweł
http://orcid.org/0000-0003-3594-1241
P
Żmudzki
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Krzysztof
http://orcid.org/0000-0003-2103-371X
K
Kamiński
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012640:Seizures / Q000188:drug therapy*
C000618654:1-(4-(2-hydroxyethyl)piperazin-1-yl)-3,3-diphenylpropan-1-one; D000081:Acetamides; D000577:Amides; D000927:Anticonvulsants; D010879:Piperazines
Anticonvulsant activity; In vitro studies; In vivo studies; Pyrrolidine-2,5-dione; Succinimide