N-methylisatin-beta-thiosemicarbazone derivative (SCH 16) is an inhibitor of Japanese encephalitis virus infection in vitro and in vivo

Background: During the early and mid part of 20(th) century, several reports described the therapeutic effects of N-methylisatin-beta-Thiosemicarbazone (MIBT) against pox viruses, Maloney leukemia viruses and recently against HIV. However, their ability to inhibit flavivirus replication has not been investigated. Hence the present study was designed to evaluate the antiviral activity of 14 MIBT derivatives against Flaviviruses that are prevalent in India such as Japanese Encephalitis Virus (JEV), Dengue-2 (Den-2) and West Nile viruses (WNV). Results: Amongst the fourteen Mannich bases of MIBT derivatives tested one compound-SCH 16 was able to completely inhibit in vitro Japanese encephalitis virus (JEV) and West Nile virus (WNV) replication. However no antiviral activity of SCH 16 was noted against Den-2 virus replication. This compound was able to inhibit 50% of the plaques (IC50) produced by JEV and WNV at a concentration of 16 mu gm/ml (0.000025 mu M) and 4 mu gm/ml (0.000006 mu M) respectively. Furthermore, SCH 16 at a concentration of 500 mg/kg body weight administered by oral route twice daily was able to completely (100%) prevent mortality in mice challenged with 50LD(50) JEV by the peripheral route. Our experiments to understand the mechanism of action suggest that SCH 16 inhibited JEV replication at the level of early protein translation. Conclusion: Only one of the 14 isatin derivatives -SCH 16 exhibited antiviral action on JEV and WNV virus infection in vitro. SCH 16 was also found to completely inhibit JEV replication in vivo in a mouse model challenged peripherally with 50LD50 of the virus. These results warrant further research and development on SCH 16 as a possible therapeutic agent.