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  3. Development of chalcone-like derivatives and their biological and mechanistic investigations as novel influenza nuclear export inhibitors

Development of chalcone-like derivatives and their biological and mechanistic investigations as novel influenza nuclear export inhibitors

  • Eur J Med Chem. 2023 Sep 29:261:115845. doi: 10.1016/j.ejmech.2023.115845.
Chuanfeng Liu 1,  Ying Zhang 2,  Ping Li 3,  Huinan Jia 2,  Han Ju 2,  Jiwei Zhang 2,  Edeildo Ferreira da Silva-Júnior 4,  Sunanda Samanta 5,  Parimal Kar 6,  Bing Huang 7,  Xinyong Liu 8,  Peng Zhan 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; Suzhou Research Institute of Shandong University, Room607, Building B of NUSP, NO.388 Ruoshui Road, SIP, Suzhou, Jiangsu, 215123, PR China.
  • 2 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 3 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
  • 4 Research Group of Biological and Molecular Chemistry, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, AC. Simões Campus, 57072-970, Alagoas, Maceió, Brazil.
  • 5 Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Indore, 453552, Madhya Pradesh, India.
  • 6 Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Indore, 453552, Madhya Pradesh, India. Electronic address: parimal@iiti.ac.in.
  • 7 China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: hbind@163.com.
  • 8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
  • 9 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
PMID: 37804770 DOI: 10.1016/j.ejmech.2023.115845
Abstract

Concerning the emergence of resistance to current anti-influenza drugs, our previous phenotypic-based screening study identified the compound A9 as a promising lead compound. This chalcone analog, containing a 2,6-dimethoxyphenyl moiety, exhibited significant inhibitory activity against oseltamivir-resistant strains (H1N1 pdm09), with an EC50 value of 1.34 μM. However, it also displayed notable cytotoxicity, with a CC50 value of 41.46 μM. Therefore, compound A9 was selected as a prototype structure for further structural optimization in this study. Initially, it was confirmed that the substituting the α,β-unsaturated ketone with pent-1,4-diene-3-one as a linker group significantly reduced the cytotoxicity of the final compounds. Subsequently, the penta-1,4-dien-3-one group was utilized as a privileged fragment for further structural optimization. Following two subsequent rounds of optimizations, we identified compound IIB-2, which contains a 2,6-dimethoxyphenyl- and 1,4-pentadiene-3-one moieties. This compound exhibited inhibitory effects on oseltamivir-resistant strains comparable to its precursor (compound A9), while demonstrating reduced toxicity (CC50 > 100 μM). Furthermore, we investigated its mechanism of action against anti-influenza virus through immunofluorescence, Western blot, and surface plasmon resonance (SPR) experiments. The results revealed that compound IIB-2 can impede virus proliferation by blocking the export of Influenza Virus Nucleoprotein. Thusly, our findings further emphasize influenza nuclear export as a viable target for designing novel chalcone-like derivatives with potential inhibitory properties that could be explored in future lead optimization studies.

Keywords

Anti-influenza; Influenza virus; MM/PBSA; Nucleoprotein; Ribonucleoprotein complex; SPR.

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