Anti-influenza active and low toxic N-phenyl-substituted [beta]-amidoamidines structurally related to natural antibiotic amidinomycin

A set of racemic N-phenyl-substituted [beta]-amidoamidines hydrochlorides 4, which are structurally related to natural antiviral agent amidinomycin (1), was synthesized in four steps starting from methacryloyl anilide (5). In the final step of the synthetic route, an uncommon monoacylation of [beta]-aminoamidine 8 at the less reactive [beta]-phenylamino-group took place. To rationalize this result, a mechanism which involves initial acylation at the more active amidine-function followed by intramolecular acyl-group transfer to [beta]-phenylamino-group was suggested. All three [beta]-amidoamidines 4daf bearing long linear aliphatic chain (from n-C8H17 to n-C12H25) revealed significant in vitro activity against influenza A virus (H3N2) and modest cytotoxicity. The in vitro antiviral potency of 4d,e is 6a20 times greater than that of commercial rimantadine with lower EC50 values and higher therapeutic index. The non-toxic in vivo compounds 4daf showed a beneficial protective effect in influenza A (H3N2) infected mice.