title: Benzylated 1,2,3-triazoles as anticoccidiostats.
abstract: 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065-0900.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bochis
authors.forename: J C
authors.initials: JC
authors.lastname: Chabala
authors.forename: E
authors.initials: E
authors.lastname: Harris
authors.forename: L H
authors.initials: LH
authors.lastname: Peterson
authors.forename: L
authors.initials: L
authors.lastname: Barash
authors.forename: T
authors.initials: T
authors.lastname: Beattie
authors.forename: J E
authors.initials: JE
authors.lastname: Brown
authors.forename: D W
authors.initials: DW
authors.lastname: Graham
authors.forename: F S
authors.initials: FS
authors.lastname: Waksmunski
authors.forename: M
authors.initials: M
authors.lastname: Tischler
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D003049:Coccidiostats; D014230:Triazoles; D000620:Aminoimidazole Carboxamide; C062058:carboxyamido-triazole