Benzylated 1,2,3-triazoles as anticoccidiostats.
Substituted 5-amino-4-carbamoyl-1,2,3-triazoles 3a-w were prepared by two synthetic schemes and evaluated in vivo for anticoccidial activity. Both schemes proceeded by brominating appropriately substituted toluenes 4a-s,v to 5a-s,v. In Scheme I, the brominated benzyl analogues 5 were converted to the corresponding benzyl azides 6, which were treated with cyanoacetamide to yield 1-substituted-5-amino-4-carbamoyl-1,2,3-triazoles 3. In Scheme II, the benzyl halides 5 were employed to alkylate the sodium salt of 5-amino-4-carbamoyl-1,2,3-triazole (7). Preliminary screening data against Eimeria acervulina and E. tenella in chickens suggested structural requirements for maximizing activity. Further evaluation against a relatively resistant series of eight Eimeria field isolates revealed L-651,582 (3a) to be a highly effective coccidiostat. However, unacceptable tissue residues precluded further development. Mechanistic studies on this series of 5-amino-4-carbamoyl-1,2,3-triazoles and, in particular, on L-651,582 (3a) revealed that its mode of action does not involve inhibition of IMP dehydrogenase, but probably interferes with host cell calcium entry. In addition, L-651,582 has been found to have antiproliferative activity in several disease models and was recently reported to possess antimetastatic activity in a model of ovarian cancer progression.
Bochis
R J
RJ
Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065-0900.
Chabala
J C
JC
Harris
E
E
Peterson
L H
LH
Barash
L
L
Beattie
T
T
Brown
J E
JE
Graham
D W
DW
Waksmunski
F S
FS
Tischler
M
M
D000478:Alkylation; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002645:Chickens; D003049:Coccidiostats / Q000737:chemistry; D004539:Eimeria / Q000187:drug effects; D005260:Female; D010051:Ovarian Neoplasms / Q000188:drug therapy; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D003049:Coccidiostats; D014230:Triazoles; D000620:Aminoimidazole Carboxamide; C062058:carboxyamido-triazole