Anti-influenza activity of phenethylphenylphthalimide analogs derived from thalidomide.

Abstract

Swine-origin influenza A virus has caused pandemics throughout the world and influenza A is regarded as a serious global health issue. Hence, novel drugs that will target these viruses are very desirable. Influenza A expresses an RNA polymerase essential for its transcription and replication which comprises PA, PB1, and PB2 subunits. We identified potential novel anti-influenza agents from a screen of 34 synthesized phenethylphenylphthalimide analogs derived from thalidomide (PPT analogs). For this screen we used a PA endonuclease inhibition assay, a PB2 pathogenicity-determinant domain-binding assay, and an anti-influenza A virus assay. Three PPT analogs, PPT-65, PPT-66, and PPT-67, were found to both inhibit PA endonuclease activity and retard the growth of influenza A, suggesting a correlation between their activities. PPT-28 was also found to inhibit the growth of influenza A. These four analogs have a 3,4-dihydroxyphenethyl group in common. We also discuss the possibility that 3,4-dihydroxyphenethyl group flexibility may play an important functional role in PA endonuclease inhibition. Another analog harboring a dimethoxyphenethyl group, PPT-62, showed PB2 pathogenicity-determinant domain-binding activity, but did not inhibit the growth of the virus. Our present results indicate the utility of the PA endonuclease assay in the screening of anti-influenza drugs and are therefore useful for future strategies to develop novel anti-influenza A drugs and for mapping the function of the influenza A RNA polymerase subunits.

• Authors: Yuma Iwai, Hitoshi Takahashi, Dai Hatakeyama, Kazunori Motoshima, Minoru Ishikawa, Kazuyuki Sugita, Yuichi Hashimoto, Yuichi Harada, Shigeyuki Itamura, Takato Odagiri, Masato Tashiro, Yoshihisa Sei, Kentaro Yamaguchi, Takashi Kuzuhara
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 14 Pg. 5379-90 (Jul 15 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20538468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antiviral Agents
• Phthalimides
• Stilbenes
• Thalidomide
• DNA-Directed RNA Polymerases

Topics

• Animals
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• DNA-Directed RNA Polymerases (metabolism)
• Dogs
• Humans
• Influenza A virus (drug effects, enzymology)
• Influenza, Human (drug therapy)
• Orthomyxoviridae Infections (drug therapy)
• Phthalimides (chemical synthesis, chemistry, pharmacology)
• Stilbenes (chemical synthesis, chemistry, pharmacology)
• Thalidomide (chemical synthesis, chemistry, pharmacology)