Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 10, Pages 2548-2561Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.03.038
Keywords
Pyrrolidine-2,5-dione; Hybrid compounds; Anticonvulsant activity; In vivo studies; In vitro studies; Metabolic stability
Funding
- Polish National Scientific Centre [DEC-2012/05/D/NZ7/02328]
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The purpose of this study was to synthesize the library of 33 new N-benzyl-2-(2,5-dioxopyrrolidin-1-yl) propanamides, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl) propanamides, and 2-(2,5-dioxopyrrolidin-1-yl) butanamides as potential new hybrid anticonvulsant agents. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. The coupling reaction of the 2-(2,5-dioxopyrrolidin-1-yl) propanoic acid, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl) propanoic acid, or 2-(2,5-dioxopyrrolidin-1-yl) butanoic acid with the appropriately substituted benzylamines in the presence of the coupling reagent, N,N-carbonyldiimidazole (CDI) generated the final compounds 4-36. Spectral data acquired via H-1 NMR, C-13 NMR, and LC-MS confirmed the chemical structures of the newly prepared compounds. The initial anticonvulsant screening was performed in mice intraperitoneally (ip), using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The rotarod test determined the acute neurological toxicity (NT). The results of preliminary pharmacological screening revealed that 25 compounds showed protection in half or more of the animals tested in the MES and/or scPTZ seizure models at the fixed dose of 100 mg/kg. The broad spectra of activity across the preclinical seizure models displayed compounds 4, 7, 8, 13, 15-18, 24, and 26. The quantitative pharmacological studies in mice demonstrated the highest protection for compounds 4 (ED50 MES = 67.65 mg/kg, ED50 scPTZ = 42.83 mg/kg); 8 (ED50 MES = 54.90 mg/kg, ED50 scPTZ = 50.29 mg/kg); and 20 (ED50 scPTZ = 47.39 mg/kg). These compounds were distinctly more potent and provided better safety profiles in the rotarod test compared to valproic acid or ethosuximide, which were used as model AEDs. Compound 8 underwent only a slight metabolic change by the human liver microsomes (HLMs), and also did not affect the activity of human cytochrome P450 isoform, CYP3A4, in the in vitro assays. (C) 2015 Elsevier Ltd. All rights reserved.
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