Activity of Ingavirin (6-[2-(1H-imidazol-4-yl)ethylamino]-5-oxohexanoic acid) against human respiratory viruses in in vivo experiments

Respiratory viral infections constitute the most frequent reason for medical consultations in the World. They can be associated with a wide range of clinical manifestations ranging from self-limited upper respiratory tract infections to more devastating conditions such as pneumonia. In particular, in serious cases influenza A leads to pneumonia, which is particularly fatal in patients with cardiopulmonary diseases, obesity, young children and the elderly. In the present study, we show a protective effect of the low-molecular weight compound Ingavirin (6-[2-(1H-imidazol-4-yl)ethylamino]-5-oxohexanoic acid) against influenza A (H1N1) virus, human parainfluenza virus and human adenovirus infections in animals. Mortality, weight loss, infectious titer of the virus in tissues and tissue morphology were monitored in the experimental groups of animals. The protective action of Ingavirin was observed as a reduction of infectious titer of the virus in the lung tissue, prolongation of the life of the infected animals, normalization of weight dynamics throughout the course of the disease, lowering of mortality of treated animals compared to a placebo control and normalization of tissue structure. In case of influenza virus infection, the protective activity of Ingavirin was similar to that of the reference compound Tamiflu. Based on the results obtained, Ingavirin should be considered as an important part of anti-viral prophylaxis and therapy. © 2011 by the authors; licensee MDPI, Basel, Switzerland

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) virus, 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. © 2018 Saint Petersburg Pasteur Institute. All rights reserved

Features of oxa-bridge cleavage in hexahydro-3a,6-epoxyisoindol-1(4H)-ones: A concise method to access acetylisoindolones possessing anti-viral activity

Unusual stereo- and regioselective methods for epoxy-bridge cleavage in perhydro-3a,6-epoxyisoindolones, under the action of the BF3·Et2O/Ac2O system, were discovered. The reaction pathway strongly depends on the characteristics of the isoindolone ring substituents and allows the synthesis of a wide diversity of isoindole-containing heterocycles. The obtained isoindolinones belong to a new class of anti-viral agents possessing a high activity against influenza virus A/Puerto Rico/8/34 (H1N1) in in vitro experiments. © 2019 Elsevier Lt

First example of the cascade acylation/IMDAV/ene reaction sequence, leading to N-arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral activity

The reaction between readily accessible N-aryl-3-phenylallylamines and maleic anhydride led to unexpected products – polysubstituted hydrogenated benzo[f]isoindole-4-carboxylic acids. This transformation proceeds through a previously unknown sequence of steps: N-acylation of the allylamine with maleic anhydride, intramolecular Diels-Alder reaction of the vinylarene in the intermediate N-maleamide, and Alder-ene reaction of the products of the previous two steps. Selected benzo[f]isoindoles displayed antiviral activity. © 2018 Elsevier Lt

First example of the cascade acylation/IMDAV/ene reaction sequence, leading to N-arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral activity

The reaction between readily accessible N-aryl-3-phenylallylamines and maleic anhydride led to unexpected products – polysubstituted hydrogenated benzo[f]isoindole-4-carboxylic acids. This transformation proceeds through a previously unknown sequence of steps: N-acylation of the allylamine with maleic anhydride, intramolecular Diels-Alder reaction of the vinylarene in the intermediate N-maleamide, and Alder-ene reaction of the products of the previous two steps. Selected benzo[f]isoindoles displayed antiviral activity. © 2018 Elsevier Lt

Synthesis of d-(+)-camphor-based: N -acylhydrazones and their antiviral activity

The design and synthesis of a series of novel d-(+)-camphor N-acylhydrazones exhibiting inhibitory activity against vaccinia and influenza viruses are presented. An easy pathway to camphor-based N-acylhydrazones containing in their structure aliphatic, aromatic, and heterocyclic pharmacophore scaffolds has been developed. The conformation and configuration of the synthesized hydrazones were thoroughly characterized by a complete set of spectral characterization techniques, including 2D NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis. In vitro screening for activity against vaccinia virus (VV) and influenza H1N1 virus was carried out for the obtained compounds. It was revealed that the derived N-acylhydrazones exhibited significant antiviral activity with a selectivity index >280 against VV for the most promising compound. © 2018 The Royal Society of Chemistry