Synthesis and anticonvulsant activities of alpha-acetamido-N-benzylacetamide derivatives containing an electron-deficient alpha-heteroaromatic substituent.
Recent studies have demonstrated that C(alpha)-substituted alpha-acetamido-N-benzylacetamides displayed excellent anticonvulsant activities in mice. Analysis of the structure-activity relationship for this series of compounds has shown that placement of small, electron-rich aromatic and heteroaromatic groups at the C(alpha) site led to pronounced protection against MES-induced seizures. In this note, synthetic protocols are reported for the preparation of three novel nonnaturally occurring electron-deficient C(alpha)-aza aromatic alpha-acetamido-N-benzylacetamides (i.e., pyrid-2-yl (11), pyrazin-2-yl (12), pyrimid-2-yl (13)). Expedient syntheses for 12 and 13 were developed using a phase-transfer, nucleophilic aromatic substitution process. All three adducts exhibited potencies comparable to or greater than phenytoin in the MES test (mice, ip). These findings required us to modify in part the previously proposed structure-activity relationship for this class of anticonvulsants.
Bardel
P
P
Department of Chemistry, University of Houston, Texas 77204-5641.
Bolanos
A
A
Kohn
H
H
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
D000081:Acetamides; D000927:Anticonvulsants