Synthesis and anticonvulsant activity of 4-(2-(2,6-dimethylphenylamino)-2-oxoethylamino)-N-(substituted)butanamides: a pharmacophoric hybrid approach.

Abstract

A series of pharmacophoric hybrids of ameltolide-gamma-aminobutyric acid (GABA)-amides was designed, synthesized, and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (ip) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. All the compounds had improved lipophilicity and the pharmacological activity profile confirmed their blood-brain barrier penetration. The titled compounds showed promising activity in scPIC screen indicating the involvement of GABA-mediation. Compound 4-(2-(2,6-dimethylaminophenylamino)-2-oxoethylamino)-N-(2,6-dimethylphenyl) butanamide (7) emerged as the most potent derivative effective in all the three animal models of seizure with no neurotoxicity at the anticonvulsant dose.

• Authors: Perumal Yogeeswari, Dharmarajan Sriram, Puppala Sahitya, Jegadeesan Vaigunda Ragavendran, Velagaleti Ranganadh
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 17 Issue 13 Pg. 3712-5 (Jul 01 2007) ISSN: 0960-894X [Print] England
• PMID: 17481896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(2-(2,6-dimethylaminophenylamino)-2-oxoethylamino)-N-(2,6-dimethylphenyl) butanamide
• Anticonvulsants
• Ethanol
• gamma-Aminobutyric Acid

Topics

• Animals
• Anticonvulsants (chemical synthesis, chemistry, pharmacology)
• Blood-Brain Barrier
• Chemistry, Pharmaceutical (methods)
• Drug Design
• Ethanol (chemistry)
• Mice
• Models, Chemical
• Molecular Structure
• Motor Activity (drug effects)
• Neurons (metabolism)
• Seizures (drug therapy)
• Structure-Activity Relationship
• gamma-Aminobutyric Acid (analogs & derivatives, chemical synthesis, pharmacology)