Benzylated 1,2,3-triazoles as anticoccidiostats

• Published in: Journal of medicinal chemistry 1991-09, Vol.34 (9), p.2843-2852
• Main Authors: Bochis, Richard J, Chabala, John C, Harris, Ellwood, Peterson, Louis H, Barash, Louis, Beattie, Thomas, Brown, Jeannette E, Graham, Donald W, Waksmunski, Frank S
• Format: Article
• Language: English
• Subjects: Alkylation; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Animals; Antineoplastic Agents - therapeutic use; Chemistry; Chickens; Coccidiostats - chemistry; Eimeria - drug effects; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Organic chemistry; Ovarian Neoplasms - drug therapy; Preparations and properties; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00113a024

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.