Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: influenza life-cycle and currently available drugs

GASPARINI, R.; AMICIZIA, D.; LAI, PL.; BRAGAZZI, NL.; PANATTO, D.

There are several potentially effective drugs, which act as HA inhibitors. However, only one medication, the small indole derivative Arbidol (ARB) or Umifenovir (Figs. 2, 3) , or ethyl-6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2[(phenylthio)methyl]-indole-3-carboxylatehydrochloride monohydrate, has been licensed [232] [233] [234] [235] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] [246] [247] [248] . ARB was created by the Center for Drug Chemistry in Moscow [246] , has been licensed in Russia 20 years ago and since 2006 has been used in China for the prophylaxis and treatment of pneumonia caused by influenza viruses A and B [234] . ARB probably exerts a multiple antiviral action: a direct virucidal effect, a block of the virus at the level of cell-entry (attachment and internalization), and impairment of viral replication, because of its ability to bind with proteins and lipids [232] [233] [234] [235] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] [246] [247] [248] . Several studies have demonstrated that ARB is also effective against other enveloped and non-enveloped viruses, such as Hepatitis B Virus (HBV), HCV, RSV, some Picornavirus (such as rhinovirus 14), Poliovirus 1, Coxsackievirus B5), parainfluenza type 3 (PIV3), as well as the avian coronavirus, infectious bronchitis virus, Chikungunya virus, Reovirus, Hantaan virus, Vesicular stomatitis virus (VSV) and Marek disease virus, an avian oncogenic herpesvirus [234] . It is metabolized in the liver and redistributed in the body tissues. The principal biotransformation pathways include sulfoxidation, dimethylamine N-demethylation, glucuronidation, and sulfate conjugation. The major metabolite is sulfinylarbidol, followed by unmetabolized arbidol, Ndemethylsulfinylarbidol, and sulfonylarbidol. CYP3A4 is the major isoform involved in ARB metabolism, whereas the other P450s and flavin-containing monooxygenases (FMOs) play minor roles. Plasma half-life is long (up to 25 hours) [243] .