Design, Synthesis, and Biological Evaluation of Itaconic Acid Derivatives as Potential Anti-Influenza Agents

J Med Chem. 2019 Mar 14;62(5):2390-2403. doi: 10.1021/acs.jmedchem.8b01683.

Bidyadhar Sethy, Chung-Fan Hsieh, Ta-Jen Lin, Po-Yuan Hu, Yu-Li Chen, Chia-Yi Lin, Sung-Nain Tseng, Jim-Tong Horng ¹ ², Pei-Wen Hsieh ² ³

Affiliations

1 Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, College of Medicine , Chang Gung University , Linkou 333 , Taiwan.
2 Research Center for Chinese Herbal Medicine , Chang Gung University of Science and Technology , Taoyuan 33303 , Taiwan.
3 Department of Anesthesiology , Chang Gung Memorial Hospital , Linkou 333 , Taiwan.

PMID: 30753063 DOI: 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 render 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 half-maximal effective concentration values of 0.14 and 0.11 μM, respectively, in Madin-Darby canine kidney cells. The mechanism of action studies showed that lead agents 1 and 4 reduced virus replication by directly targeting IAV nucleoproteins and disrupting virus ribonucleoprotein export from the nucleus to the 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.

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