Camphor-based symmetric diimines as inhibitors of influenza virus reproduction

• Published in: Bioorganic & medicinal chemistry 2014-04, Vol.22 (7), p.2141-2148
• Main Authors: Sokolova, Anastasiya S., Yarovaya, Оlga I., Korchagina, Dina V., Zarubaev, Vladimir V., Tretiak, Tatiana S., Anfimov, Pavel M., Kiselev, Oleg I., Salakhutdinov, Nariman F.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antivirals; Camphor; Camphor - chemistry; Diimine derivatives; Dogs; Dose-Response Relationship, Drug; Imines - chemical synthesis; Imines - chemistry; Imines - pharmacology; Influenza; Influenza A virus; Influenza A virus - drug effects; Influenza virus; Madin Darby Canine Kidney Cells; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.02.038

Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The purpose of the study was synthesis and investigation of antiviral activity of camphor-based symmetric diimines and diamines. A set of C2-symmetric nitrogen-containing camphor derivatives have been synthesized. The antiviral activity of these compounds was studied against rimantadine- and amantadine-resistant influenza virus A/California/7/09 (H1N1)pdm09 in MDCK cells. The highest efficacy in virus inhibiting was shown for compounds 2a–e with cage moieties bound by aliphatic linkers. The therapeutic index (selectivity index) for 2b exceeded that for reference compounds amantadine, deitiforin and rimantadine almost 10-fold. As shown by structure–activity analysis, the length of the linker has a dramatic effect on the toxicity of compounds. Compound 2e with –C12H24– linker exhibited the lowest toxicity (CTD50=2216μM). Derivatives of camphor, therefore, can be considered as prospective antiinfluenza compounds active against influenza viruses resistant to adamantane-based drugs.