title: Synthesis of N-1', N-3'-disubstituted spirohydantoins and their anticonvulsant activities in pilocarpine model of temporal lobe epilepsy.
abstract: Herein we report the synthesis and anticonvulsant activity of a library of eighteen new compounds that are structural mimics of phenytoin. These class of compounds contain a N-1', N-3'-disubstituted spirohydantoin scaffold, where the N-1' and N-3' positions are modified with an alkyl group or aryl group. Of the eighteen compounds synthesized and tested, compound 5c showed the best anticonvulsant activity. It completely prevented the precursor events of motor seizure in the pilocarpine model of temporal lobe epilepsy. Additionally, ten of the analogs were more effective than phenytoin when compared using the Racine's score in the pilocarpine model. Based on the structure activity relationship (SAR), we concluded that alkyl groups (ethyl, propyl or cyclopropyl) at N-3' position and 4-nitro phenyl group at N-1' position are desirable.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439,USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439,USA.
authors.forename: Francis A X
authors.initials: FAX
authors.lastname: Schanne
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439,USA. Electronic address: yoganats@stjohns.edu.
authors.forename: Sabesan
authors.initials: S
authors.lastname: Yoganathan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439,USA; Department of Chemistry, St. John's College of Liberal Arts and Sciences, St. John's University, Queens, NY 11439,USA. Electronic address: stephanr@stjohns.edu.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Stephani
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy*; D015394:Molecular Structure; D010862:Pilocarpine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012640:Seizures / Q000188:drug therapy*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D013141:Spiro Compounds; D010862:Pilocarpine
keywords: Anticonvulsant; Epilepsy; N,N′-Disubstituted ureas; Seizure; Spirohydantoin