Anti-influenza active and low toxic N-phenyl-substituted ¦Â-amidoamidines structurally related to natural antibiotic amidinomycin

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• 作者：Edward E. Korshin^a ; ^b ; ^{edward.korshin@weizmann.ac.il} ; Lyubov G. Zakharova^b ; Yakov A. Levin^b ; Marina P. Shulaeva^c ; Oskar K. Pozdeev^b ; ^c
• 关键词：Influenza A ; Antiviral activity ; Imidoyl chloride ; Amidine ; Amide
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 April, 2013
• 年：2013
• 卷：23
• 期：8
• 页码：2357-2361
• 全文大小：526 K

文摘

A set of racemic N-phenyl-substituted ¦Â-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 ¦Â-aminoamidine 8 at the less reactive ¦Â-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 ¦Â-phenylamino-group was suggested. All three ¦Â-amidoamidines 4d-f 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 6-20 times greater than that of commercial rimantadine with lower EC₅₀ values and higher therapeutic index. The non-toxic in vivo compounds 4d-f showed a beneficial protective effect in influenza A (H3N2) infected mice.