Asymmetric synthesis and in vivo/in vitro characterization of new hybrid anticonvulsants derived from (2,5-dioxopyrrolidin-1-yl)phenylacetamides
| Autor: | Marta Struga, Michał Abram, Rafał M. Kamiński, Dagmara Otto-Ślusarczyk, Justyna Kalinowska-Tłuścik, Gniewomir Latacz, Bartłomiej Szulczyk, Anna Rapacz, Krzysztof Kamiński |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Stereochemistry Cell Survival medicine.medical_treatment Voltage-Gated Sodium Channels 01 natural sciences Biochemistry Mice Structure-Activity Relationship In vivo Seizures Drug Discovery medicine Potency Animals Humans Molecular Biology ED50 Cells Cultured Electroshock Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry In vitro toxicology Enantioselective synthesis In vitro 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry Anticonvulsant Anticonvulsants Enantiomer |
| Zdroj: | Bioorganic chemistry. 109 |
| ISSN: | 1090-2120 |
| Popis: | In the current studies we carried out an optimized multistep asymmetric synthesis of R-enantiomers (eutomers) for a previously identified series of racemic hybrid anticonvulsants. The spatial structure of selected enantiomers was solved by the use of crystallographic methods. The compound (R)-16 was identified as a lead, which revealed broad-spectrum protective activity in a range of epilepsy models with the following ED50 values: the maximal electroshock (MES) test (36.0 mg/kg), the 6 Hz (32 mA) seizure model (39.2 mg/kg), and the pentylenetetrazole-induced seizure model (scPTZ) (54.8 mg/kg). Furthermore, (R)-16 displayed a low potency for the induction of motor impairment in the rotarod test (TD50 = 468.5 mg/kg), resulting in potentially very beneficial therapeutic window. Finally, (R)-16 showed satisfying ADME-Tox properties in the in vitro assays. Therefore, the data obtained in the current studies justify the further preclinical development of (R)-16 as candidate for potentially broad-spectrum and safe anticonvulsant. |
| Databáze: | OpenAIRE |
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