Design, synthesis and biological evaluation of new hybrid anticonvulsants derived from N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives

Bioorg Med Chem. 2015 May 15;23(10):2548-61. doi: 10.1016/j.bmc.2015.03.038. Epub 2015 Mar 21.

Abstract

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 (1)H NMR, (13)C 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 100mg/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, ED50scPTZ=42.83 mg/kg); 8 (ED50 MES=54.90 mg/kg, ED50scPTZ=50.29 mg/kg); and 20 (ED50scPTZ=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.

Keywords: Anticonvulsant activity; Hybrid compounds; In vitro studies; In vivo studies; Metabolic stability; Pyrrolidine-2,5-dione.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / pharmacology
  • Benzylamines / chemistry
  • Convulsants / administration & dosage
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design
  • Electroshock
  • Humans
  • Imidazoles / chemistry
  • Male
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Motor Activity / drug effects
  • Pentylenetetrazole / administration & dosage
  • Propionates / chemistry
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacology
  • Rotarod Performance Test
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Seizures / physiopathology
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Amides
  • Anticonvulsants
  • Benzylamines
  • Convulsants
  • Imidazoles
  • Propionates
  • Pyrrolidines
  • Small Molecule Libraries
  • N,N-carbonyldiimidazole
  • Pentylenetetrazole