Inhibition of purine biosynthesis by analogues of 4(5)-aminoimidazole-5(4)-carboxamide

Abstract

Twenty-three compounds were synthesized as possible antimetabolites of 4(5)-aminoimidazole-5(4)-carboxamide (AIC). The activity of the new compounds was compared with that of 4(5)-diazoimidazole-5(4)-carboxamide, 4(5)-amino-1,2,3-triazole-5(4)-carboxamide, 4(5)-diazo-1,2,3-triazole-5(4)-carboxamide, and 6-mercaptopurine, all of which have been tested by other investigators against nucleic acid synthesis or neoplasms. Activity was judged by retardation of E. coli growth, inhibition of conversion of glycine-14C to hypoxanthine by pigeon liver homogenates, and prolongation of survival of mice following injection of Ehrlich ascites cells. Although none of the new analogues was highly active in the test systems, a number showed comparable or superior activity to the four previously tested inhibitors which were used as standards in this study. 4(5)-Nitroimidazole-5(4)-carboxyhydrazide, 4(5)-acetylamino-1,2,3-triazole 5(4) carboxamide, 4(5)-diazo-1,2,3,-triazole-5(4)-carboxyhydrazide, and 4(5)-diazo-1,2,3-triazole-5(4)-nitrile showed >50% inhibition of glycine-14C conversion at 3 × 10−3 M or less, while 4(5)-nitroimidazole-5(4)-carboxyhydrazide, 4(5)-amino-1,2,3-triazole-5(4)-carboxamidine, 4(5)-amino-1,2,3-triazole-5(4)-nitrile, and 1-benzyl-5-amino-1,2,3-triazole-4-carboxyhydrazide showed >50% inhibition of E. coli growth at 10−3 M. None of the nine compounds of which there was sufficient quantity to be tested against growth of Ehrlich ascites tumor appreciably prolonged the survival of mice following intraperitoneal injection of the cells.