Synthesis and anticonvulsant activities of alpha-heterocyclic alpha-acetamido-N-benzylacetamide derivatives.
Earlier studies showed that (R,S)-alpha-acetamido-N-benzylacetamides (2) containing a five- and six-membered aromatic or heteroaromatic group appended at the C(alpha) site displayed outstanding activity in the maximal electroshock-induced seizure (MES) test in mice. An expanded set of C(alpha)-heteroaromatic analogues of 2 have been prepared and evaluated. The observed findings extended the structure-activity relationships previously discerned for this novel class of anticonvulsants and have validated previous trends. The alpha-furan-2-yl (4), alpha-oxazol-2-yl (18), and alpha-thiazol-2-yl (19) alpha-acetamido-N-benzylacetamides afforded excellent protection against MES-induced seizures in mice. The ED50 and PI values for these adducts rivaled those reported for phenytoin. The outstanding properties provided by 4 led to an in-depth examination of the effect of structural modification at key sites within this compound on biological activity. The pharmacological data in this series indicated that stringent steric and electronic requirements existed for maximal activity and revealed the outstanding activity of (R)-(-)-alpha-acetamido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)aceta mide [(R)-30].
Kohn
H
H
Department of Chemistry, University of Houston, Texas 77204-5641.
Sawhney
K N
KN
Bardel
P
P
Robertson
D W
DW
Leander
J D
JD
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology*; D044482:Benzeneacetamides; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012640:Seizures / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D000927:Anticonvulsants; D044482:Benzeneacetamides; D001593:Benzyl Compounds; D005663:Furans; D006571:Heterocyclic Compounds; C084129:alpha-acetamido-N-benzyl-alpha-(furan-2-yl)acetamide; C084130:alpha-acetamido-N-(4-fluorobenzyl)-alpha-(furan-2-yl)acetamide