Structure-activity relationships in the formation of amides from substituted N-benzylanilines

1. The in vitro hepatic microsomal metabolism of certain substituted N-benzylanilines was studied in the male hamster to establish the mechanism(s) and process(es) involved in the formation of the corresponding amides. 2. N-Benzyl-2,4,6-trihalogeno, N-benzyl-4-cyano- and N-benzyl-4-nitroanilines were only metabolized by N-debenzylation. However, N-benzyl-4-methyl- and N-benzyl-2,4,6-trimethylanilines gave rise to both the corresponding amide and nitrone metabolites together with dealkylation products. These latter two substrates also produced hydroxymethyl metabolites as major products. Metabolism of N-(2,4,6,-trimethylbenzyl)aniline also led to the formation of an amide metabolite. The dealkylation products, the corresponding imine and an unknown metabolite, probably an hydroxylated product were also detected with this substrate. 3. N-(2,4-Dichlorobenzyl) and N-(2,6-dichlorobenzyl) anilines yielded the corresponding nitrone metabolites; but no amide metabolite was detected. Oxidative dealkylation leading to the formation of the corresponding primary anilines and aldehydes, together with para hydroxylation of aniline rings, were established as major routes of metabolism for both compounds. Similarly, neither N-(2,4,6-trifluorobenzyl) nor N-(4-nitrobenzyl) anilines produced any amide metabolite although dealkylation products were detected. 4. The pattern of amide formation observed for these N-benzylsubstituted anilines is discussed in terms of the steric and electronic effects of their aromatic substituents.