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.