PROTECTIVE ACTIVITY OF NOVEL BENZIMIDAZOLE DERIVATIVES AT EXPERIMENTAL INFLUENZA INFECTION

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.