Design, synthesis, and anticonvulsant activity of 1-(pyrid-3-ylsulfonamido)-2-nitroethylenes.
The lipophilic 1-cycloalkylamino-1-(pyrid-3-yl-sulfonamido)-2-nitr oethylenes were synthesized as bioisosteres of BM-34, an anticonvulsant sulfonylthiourea. Compound 17 (ip) emerged from the maximal electroshock seizure (MES) test with a 50% effective dose (ED50) of 8.25 mg/kg. Its anticonvulsant profile was similar to that of phenytoin (ED50 = 9.51 mg/kg) and of BM-34 (ED50 = 1.19 mg/kg): active in the MES test and inactive in seizures induced by subcutaneous injection of pentetrazole, strychnine, bicuculline, picrotoxin, or N-methyl-D,L-aspartate. The neurotoxicity of 17 (TD50 = 113.8 mg/kg) was lower than that of phenytoin (TD50 = 65.5 mg/kg) but higher than that of BM-34 (TD50 = 147.2 mg/kg). Crystallographic study revealed that BM-401 (17) was a zwitterionic structure. Its sulfonamido nitroethylene side chain adopted a conformation which placed the two cycloalkyl rings face to face to form a single hydrophobic area.
Masereel
B
B
Department of Pharmacy and Laboratory of Molecular Structures, University of Namur, FUNDP, 61, rue de Bruxelles, 5000 Namur, Belgium. bernard.masereel@fundp.ac.be
Wouters
J
J
Pochet
L
L
Lambert
D
D
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003292:Convulsants; D018360:Crystallography, X-Ray; D015195:Drug Design; D004597:Electroshock; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000927:Anticonvulsants; D003292:Convulsants; D009498:Neurotoxins; C104938:BM 34; D010672:Phenytoin; D013890:Thiourea