CYTOPROTECTIVE ACTIVITY OF NEWLY SYNTHESIZED 3-(ARYLMETHYLAMINO)-6-METHYL-4-PHENYLPYRIDIN-2(1H)-ONES DERIVATIVES

Currently, studies are being conducted on the possible role of the cytoprotective effect of biologically active substances in conditions of cerebral hypoxia or cardiomyopathies. At the same time, oxidative stress is considered one of the important mechanisms of cellular cytotoxicity and a target for the action of cytoprotectors. The aim of this study is to search for derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones. The probability of cytoprotective action was assessed by measuring cell viability using two tests (with neutral red dye and MTT test). It was found that some derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones under the conditions of our experiment had a pronounced cytoprotective activity, providing better cell survival in vitro, including the MTT test and conditions of blood hyperviscosity. To correlate the obtained results in vitro, molecular docking of the synthesized derivatives was also carried out. The standard drug omeprazole (co-crystallized with the enzyme) was used as a standard. It was shown that all synthesized derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones had higher affinity for the selected protein than the standard gastro-cytoprotector omeprazole. The studied derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones also fully satisfy Lipinski’s rule of five (RO5), which increases their chances for possible use as orally active drugs with good absorption ability and moderate lipophilicity. Thus, the results obtained make it possible to evaluate derivatives of 3-(arylmethylamino)-6-methyl-4-phenylpyridin-2(1H)-ones as having a relatively high cytoprotective potential

Tilorone and Cridanimod Protect Mice and Show Antiviral Activity in Rats despite Absence of the Interferon-Inducing Effect in Rats

The synthetic compounds, Tilorone and Cridanimod, have the antiviral activity which initially had been ascribed to the capacity to induce interferon. Both drugs induce interferon in mice but not in humans. This study investigates whether these compounds have the antiviral activity in mice and rats since rats more closely resemble the human response. Viral-infection models were created in CD-1 mice and Wistar rats. Three strains of Venezuelan equine encephalitis virus were tested for the performance in these models. One virus strain is the molecularly cloned attenuated vaccine. The second strain has major virulence determinants converted to the wild-type state which are present in virulent strains. The third virus has wild-type virulence determinants, and in addition, is engineered to express green fluorescent protein. Experimentally infected animals received Tilorone or Cridanimod, and their treatment was equivalent to the pharmacopoeia-recomended human treatment regimen. Tilorone and Cridanimod show the antiviral activity in mice and rats and protect the mice from death. In rats, both drugs diminish the viremia. These drugs do not induce interferon-alpha or interferon-beta in rats. The presented observations allow postulating the existence of an interferon-independent and species-independent mechanism of action