Efficacy of (R)-6-Adamantane-Derivatives of 1,3-Oxazinan-2-One and Piperidine-2,4-Dione in The Treatment of Mice Infected by the A/California/04/2009 influenza Virus

The World Health Organization (WHO) recommends antivirals as an additional line of defense against influenza. One of such drugs is rimantadine. However, most of the circulating strains of influenza A viruses are resistant to this drug. Thus, a search for analogs effective against rimantadine-resistant viruses is of the utmost importance. Here, we examined the efficiency of two adamantane azaheterocyclic rimantadine derivatives on a mouse model of pneumonia caused by the rimantadine-resistant influenza A virus /California/ 04/2009 (H1N1). BALB/c mice inoculated with the virus were treated with two doses (15 mg and 20 mg/kg a day) of tested analogs via oral administration for 5 days starting 4 hours before the infection. The efficacy was assessed by survival rate, mean day to death, weight loss, and viral titer in the lungs. Oral treatment with both compounds in both doses protected 60–100% of the animals, significantly increased the survival rate, and abolished weight loss. The treatments also inhibited virus titer in the lungs in comparison to the control group. This treatment was more effective compared to rimantadine at the same scheme and dosage. Moreover, the study of the sensitivity of the virus isolated from the lungs of the treated mice and grown in MDCK cells showed that no resistance had emerged during the 5 days of treatment with both compounds.