title: 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.affiliation: Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India. pyogee@bits-pilani.ac.in <pyogee@bits-pilani.ac.in>
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Puppala
authors.initials: P
authors.lastname: Sahitya
authors.forename: Jegadeesan Vaigunda
authors.initials: JV
authors.lastname: Ragavendran
authors.forename: Velagaleti
authors.initials: V
authors.lastname: Ranganadh
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D000431:Ethanol / Q000737:chemistry; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C522502:4-(2-(2,6-dimethylaminophenylamino)-2-oxoethylamino)-N-(2,6-dimethylphenyl) butanamide; D000927:Anticonvulsants; D000431:Ethanol; D005680:gamma-Aminobutyric Acid