Design, synthesis, and biological evaluation of itaconic acid derivatives as potential anti-influenza agents.

Influenza A viruses (IAVs) have caused worldwide epidemics and pandemics by reassortment and generation of drug-resistant mutants, which renders antivirals and current vaccinations no longer usable. In this study, an itaconic acid derivative 1 was identified from a chemical library of 20,000 compounds by performing a cell-based screening assay as a lead agent exhibiting anti-influenza A activity. Accordingly, a series of itaconic acid derivatives were designed and synthesized by adopting a rational design strategy to obtain more potent anti-influenza agents. The results of an in vitro pharmacological study showed that compounds 4 and 8 exhibited the most potent anti-IAV effect with EC50 values of 0.14 and 0.11 µM, respectively, in Madin-Darby canine kidney cells. Mechanisms of action studies showed that lead agents 1 and 4 reduced virus replication by directly targeting IAV nucleoproteins and disrupting virus ribonucleoprotein export from nucleus to cytosol. On the basis of its high potential as an anti-IAV agent and its selectivity index > 785, compound 4 was found to be a promising candidate for further development against IAVs.