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.

Background: Japanese encephalitis is a major public health problem in several parts of Asia, particularly India, Nepal, Sri Lanka and Myanmar (Burma). Despite its public health implications, there are no effective antiviral drugs available. Methods: The present study evaluated the effect of mycophenolic acid on Japanese encephalitis virus (JEV) using an in vitro cytopathic effect inhibition assay, plaque reduction assay and virus yield reduction assay, and its therapeutic potential was also assessed in vivo in a mouse model. Results: Analysis of the results obtained in the in vitro and in vivo experiments suggests that mycophenolic acid has significant antiviral activity against JEV, with an IC₅₀ of 3.1 µg/ml, a therapeutic index of 16 and a 75% protection against lethal challenge of JEV. Conclusion: The study concludes that this compound significantly inhibited the replication of JEV in vitro and protected mice in vivo.

Several investigations have shown that pentoxifylline possesses broad-spectrum antiviral activity against a range of RNA and DNA viruses. However, its ability to inhibit Japanese encephalitis virus (JEV) replication has not yet been studied. The present study was designed to investigate the antiviral activity of pentoxifylline against JEV in vitro and in vivo. The activity of pentoxifylline against JEV was evaluated in vitro using cytopathic effect inhibition and plaque reduction assays. Pentoxifylline was able to inhibit JEV replication in a dose-dependent manner at a 50% inhibitory concentration (IC(50)) of 50.3microg/mL (0.00018microM) and a therapeutic index (TI) of 10. Experiments to study the mechanism of antiviral action of pentoxifylline using in vitro translation of viral mRNA suggested that the drug did not interfere either with early or late protein synthesis but most likely exerted its action on virus assembly and/or release. Furthermore, the in vivo study showed that pentoxifylline at a concentration of 100mg/kg and 200mg/kg body weight was able to protect completely mice challenged with 50 x 50% lethal dose (LD(50)) of JEV.

Aim:  To investigate the drug to drug interaction of N‐methylisatin‐β‐thiosemicarbazone (MIBT) derivative (SCH16) with ribavirin, mycophenolic acid and pentoxifylline against Japanese encephalitis virus in vitro. Our earlier studies have reported significant antiviral activity of these compounds against Japanese encephalitis virus in vitro and in vivo. Methods and Results:  An in vitro drug to drug combination analysis was carried out to investigate whether or not the direct antiviral effect shown by the individual MIBT derivative could be effectively increased when lower concentrations of two compounds in combination were used. The results of this study showed that the combination of MIBT derivative (SCH16) with ribavirin or mycophenolic acid significantly enhanced the antiviral activity of SCH16 against JEV in vitro. In contrast, the combination of SCH16 and pentoxifylline resulted in antagonism. Conclusion:  The antiviral activity showed by SCH16 was enhanced in the presence of ribavirin and mycophenolic Acid. Significance and Impact of the Study:  Studying the synergistic/additive interaction of the compounds in combination would help in lowering the effective concentration so as to overcome the concern of toxicity.

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