The synthesis of novel nonclassical reversed bridge quinazoline antifolates as inhibitors of thymidylate synthase [1a,b]

2-Amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one (3, AG337) a lipophilic thymidylate synthase inhibitor, is currently in clinical trials as an antitumor agent. On the basis of the crystal structure of 3 and the c lassical inhibitor 10-propargyl-5,8-dideazafolic acid (1, PDDF) with thymid ylate synthase, we designed and synthesized a series of nonclassical 2-amin o-6-substituted-3H-quinazolin-4-ones 4-13, with a variety of electron withd rawing groups in the side chain (with the exception of compound 4). Molecul ar modeling indicates that these reversed bridge (N9-C10) 6-substituted ana logues orient their side chain C10-substituent such that it lies between th at of 1 and 3. These compounds were obtained by reductive amination of 6-am inoquinazoline 16 and the appropriate aryl aldehyde 17 or aryl ketone 18. F or analogues 11-13, the yield depended on the substitutents on the aryl ket one 18 (comparison of 11 and 13). With the exception of analogue 13, all th e compounds in the series were poor inhibitors of thymidylate synthase from Lactobacillus casei, Pneumocystis carinii and human sources.