Synthesis and biological activity of a series of diaryl-substituted alpha-cyano-beta-hydroxypropenamides, a new class of anthelmintic agents.
A series of alpha-cyano-beta-hydroxypropenamides was prepared and tested for anthelmintic activity. alpha-Cyano-beta-hydroxy-N-[4- (trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]propenamide (1) showed good activity against the nematode Nematospirodes dubius in a mixed parasite infection in mice; several of the analogues were also effective against the cestode Hymenolepis nana. In sheep trials, 1 caused 100% reduction of the hematophagous nematode Haemonchus contortus after a single dose of 20 mg/kg but did not show satisfactory control of Trichostrongylus colubriformis or Ostertagia circumcincta. Against the liver fluke Fasciola hepatica, 1 suppressed egg production but only temporarily, suggesting that the adult flukes were not eliminated. Mechanism of action studies on 1 using Ascaris mitochondria showed it to be an uncoupler of oxidative phosphorylation.
Sjogren
E B
EB
Syntex Research, Palo Alto, California 94304.
Rider
M A
MA
Nelson
P H
PH
Bingham
S
S
Poulton
A L
AL
Emanuel
M A
MA
Komuniecki
R
R
D000577:Amides / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis* / Q000627:therapeutic use; D005260:Female; D008297:Male; D051379:Mice; D009349:Nematode Infections / Q000188:drug therapy; D009570:Nitriles / Q000138:chemical synthesis* / Q000627:therapeutic use; D012756:Sheep; D013329:Structure-Activity Relationship
D000577:Amides; D000871:Anthelmintics; D009570:Nitriles; C071839:alpaha-cyano-beta-hydroxy-N-(4-(trifluoromethyl)phenyl)-3-(4-(trifluoromethyl)phenyl)propenamide