PROTECTIVE ACTIVITY OF NOVEL BENZIMIDAZOLE DERIVATIVES AT EXPERIMENTAL INFLUENZA INFECTION

Abstract

Influenza is an acute respiratory viral infection, which represents an important health problem. Every year, influenza causes epidemics and pandemics, leading to increase in morbidity and mortality in all regions of the globe. Due to the segmental organization of the genome and low accuracy of its replication, the influenza virus is capable of escaping the host’s immune response (antigenic drift), as well as the selection of drug-resistant variants. This calls for constant monitoring of the sensitivity of viral isolates to antiviral drugs and the development of new etiotropic antiviral agents that have alternative targets and mechanisms of activity. The purpose of this study was to characterize the new aminobenzimidazole derivatives as protective agents in lethal influenza infection in white mice. The efficacy of the compounds was assessed by their ability to reduce specific mortality of animals in the course of lethal influenza pneumonia caused by the influenza A/Puerto Rico/8/34 (H1N1) irus, increase the life duration of animals, and normalize the morphological structure of lung tissue comparing to the placebo group. For all the compounds studied, a decrease in the specific mortality of animals (from 20 to 60%) has been shown. The reference drug (oseltamivir phosphate) reduced the mortality of mice by 80%. The benzimidazole derivative 2519 demonstrated the highest indices of protective activity, its use reduced the mortality of animals by 60% and increased their mean day of death by 1.6 days in comparison with the control group. Morphological analysis showed that the activity of derivative 2519 was manifested in the normalization of the morphological structure of lung tissue in the course of influenza pneumonia. On day 5 after infection, the cells of the bronchial epithelium looked intact, in contrast to destroyed cells with numerous viral inclusions in control animals. The foci of inflammation themselves occupied a smaller area compared to the control. At the same time, there was no correlation between the previously obtained data on the virus-inhibiting effect of these compounds in vitro and the data obtained in animals. This suggests that despite the presence of direct antiviral activity detected previously in in vitro experiments, the protective properties of the studied aminobenzimidazoles on animals are caused, in addition to the etiotropic effect, by other pathogenetic factors. In conclusion, amino derivatives of benzimidazole should be considered as compounds that are promising for further development and introduction as an anti-influenza agents.