Synthesis and biological evaluation of chiral alpha-aminoanilides with central antinociceptive activity.
Tocainide and related optically active chiral alpha-aminoanilides were synthesized and tested in vivo via the hot plate test to evaluate their central analgesic action. The aims of the study were to verify if a) the increase in lipophilicity, obtained by the introduction of an alkyl group on the steric center (3f-i), and the replacement of the C=O group with the C=S (10) group as well as the introduction of a methyl or ethyl group on the amidic nitrogen atom (8a-c) would produce an increase in central analgesic efficacy with respect to Tocainide; b) the 2,6-xylidide moiety is crucial for high analgesic activity (3b-e); c) the hydrogen atom bonded to the amidic nitrogen moiety is an essential pharmacophoric element for analgesic activity. Among all the synthesized compounds, 3f showed antinociceptive properties with a good enantioselective index.
Corbo
Filomena
F
Department of Pharmaceutical Chemistry, University of Bari, Via E. Orabona n.4, 70125 Bari, Italy.
Franchini
Carlo
C
Lentini
Giovanni
G
Muraglia
Marilena
M
Ghelardini
Carla
C
Matucci
Rosanna
R
Galeotti
Nicoletta
N
Vivoli
Elisa
E
Tortorella
Vincenzo
V
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D006860:Hydrogen Bonding; D008297:Male; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000700:Analgesics; D000813:Anilides; C520346:N(1)-(2,6-dimethylphenyl)valinamide; D014633:Valine