Design, Synthesis, and Biological Evaluation of Itaconic Acid Derivatives as Potential Anti-Influenza Agents
- 12 February 2019
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 62 (5), 2390-2403
- https://doi.org/10.1021/acs.jmedchem.8b01683
Abstract
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.Keywords
Funding Information
- Ministry of Science and Technology (106-2320-B-182-004-MY3, 106-2632-B-182-001, 107-3017-F-182-001)
- Chang Gung Memorial Hospital, Linkou (CMRPD1E0041-3, CMRPD1F0561-2, CMRPD1G0301-3, BMRP416)
- Chang Gung University (BMRP416, BMRPB23)
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