The dissertation is related to the research of anti-herpetic and apoptotic-inducing activity of newly synthesized fluorinated compounds of nucleoside nature (derivatives based on triazoles, uracils, tiosugars) and non-nucleoside nature (derivatives of amino acids). Antiviral activity studies were performed on the model of herpes simplex virus type 1 (HSV-1) infection, acute and chronic Epstein-Barr virus (EBV) infection; apoptosis-inducing potential was investigated on models of latent and chronic EBV infection.
For the first time, using PASS, it has been predicted that uracil derivatives (G26 and G27) can to have the highest indexes of potential antiviral activity (Pa/Pi), namely, against herpesviruses, Pa/Pi for G26 and G27 compounds were 0,445/0,019 and 0,372/0,044. Tiosugars derivatives (SBIO6, SBIO7) have a slightly lower activity - 0,379/0,045. According to the forecast, the probability of antiviral activity of compounds 10S-20 and 10S-21 (amino acids derivatives) was 0,294/0,005 and 0,214/0,084, respectively. It should be added that it was found the probability of antitumor activity for the compounds of nucleoside nature; Pa/Pi was from 0,495/0,011 to 0,257/0,025. It has been found that a list of potential targets for fluorine-containing compounds contains in the vast majority nucleic acid synthesis proteins, apoptotic proteins and enzymes that play an important role in activating/inhibiting the activity of the protein.
For the first time, it was established, derivatives of triazoles (G8 and G9) and amino acids (10S-20) have a pronounced antiviral effect concerning HSV-1, and their selectivity indexes were 18, 17 and 11, respectively. Under conditions of acute EBV infections, uracil derivatives (G26 and G27), tiosugars (SBIO6 and SBIO7) and amino acids (10S-20) effectively inhibited the replication of the virus, their selectivity indexes were in the range of 10 to 114. On the model of chronic EBV infection, only the compound of SBIO6 was effective (selectivity indexe = 16).
For the first time it has been shown that derivatives of triazoles (G8 and G9) on the model of herpetic meningoencephalitis in mice effectively inhibited the development of HSV-1 infection. In the minimum dose tested for both compounds (0,4 and 0,5 mg/kg), the index of efficiency was 100%. It has been determined that the use of triazole derivatives increased the level of interleukin 2 compared with the virus control (HSV-1) and was 25 pg/ml. An increase in the INFγ level under the action of G9 was detected, while compound G8 had a less pronounced immunostimulatory effect.
It was found that compounds G27, SBIO6 and 10S-21 on the model of both latent (Raji cells) and chronic (В95-8 cells) EBV infection effectively induce the development of apoptotic death of cells already at 24 and 48 hours of research (40% and 80%). For the first time, in Raji and B95-8 cells under the conditions of induction of lytic EBV infection, it was determined that the compound of SBIO6 (derivative of tiosugar) effectively induces apoptosis, the amount of Raji apoptotic cells reached 30%, in B95-8 cells it reached 40% at 24 hours.
The obtained and analyzed results testify to the prospect of further research of fluorinated compounds, as anti-herpetic and antitumor agents.
