tetano
Editor, Senior Moderator
ChemMedChem. 2018 Sep 5. doi: 10.1002/cmdc.201800511. [Epub ahead of print]
[h=1]Synthesis of Trifluoromethyl-α,β-unsaturated Lactones and Pyrazolinones and Discovery of Influenza Virus Polymerase Inhibitors.[/h] Mizuta S[SUP]1[/SUP], Makau JN[SUP]2[/SUP], Kitagawa A[SUP]2[/SUP], Kitamura K[SUP]2[/SUP], Otaki H[SUP]2[/SUP], Nishi K[SUP]2[/SUP], Watanabe K[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] To explore potential biological activities of trifluoromethyl heterocycles, we recently developed a synthetic approach to assess a series of α-trifluoromethyl-α,β-unsaturated lactones and trifluoromethyl pyrazolinones. The compounds were tested for their antimicrobial activity, and we found that some compounds had anti-influenza viral activity. The β-aryl-α-trifluoromethyl α,β-unsaturated lactone derivatives 5g, 7b and the trifluoromethyl pyrazolinone 12c possessed promising inhibitory activity against influenza virus type A, strain A/WSN/33 (H1N1). These hit compounds 5g, 7b, and 12c were successfully optimized, and we identified that the most potent compound 5h showed inhibitory activity against various types of influenza A and B viruses in the low-micromolar range without showing cytotoxicity. Moreover, 5h was more effective against the clinical isolate A/California/7/2009 (H1N1pdm) strain than the influenza viral polymerase inhibitor, favipiravir (T-705). We also delineated the structure-activity relationship and obtained mechanistic insights into inhibition of the viral polymerase.
[h=4]KEYWORDS:[/h] Inhibitors; RNA-dependent RNA polymerase; cross-coupling; influenza virus; trifluoromethyl group
PMID: 30182456 DOI: 10.1002/cmdc.201800511
[h=1]Synthesis of Trifluoromethyl-α,β-unsaturated Lactones and Pyrazolinones and Discovery of Influenza Virus Polymerase Inhibitors.[/h] Mizuta S[SUP]1[/SUP], Makau JN[SUP]2[/SUP], Kitagawa A[SUP]2[/SUP], Kitamura K[SUP]2[/SUP], Otaki H[SUP]2[/SUP], Nishi K[SUP]2[/SUP], Watanabe K[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] To explore potential biological activities of trifluoromethyl heterocycles, we recently developed a synthetic approach to assess a series of α-trifluoromethyl-α,β-unsaturated lactones and trifluoromethyl pyrazolinones. The compounds were tested for their antimicrobial activity, and we found that some compounds had anti-influenza viral activity. The β-aryl-α-trifluoromethyl α,β-unsaturated lactone derivatives 5g, 7b and the trifluoromethyl pyrazolinone 12c possessed promising inhibitory activity against influenza virus type A, strain A/WSN/33 (H1N1). These hit compounds 5g, 7b, and 12c were successfully optimized, and we identified that the most potent compound 5h showed inhibitory activity against various types of influenza A and B viruses in the low-micromolar range without showing cytotoxicity. Moreover, 5h was more effective against the clinical isolate A/California/7/2009 (H1N1pdm) strain than the influenza viral polymerase inhibitor, favipiravir (T-705). We also delineated the structure-activity relationship and obtained mechanistic insights into inhibition of the viral polymerase.
[h=4]KEYWORDS:[/h] Inhibitors; RNA-dependent RNA polymerase; cross-coupling; influenza virus; trifluoromethyl group
PMID: 30182456 DOI: 10.1002/cmdc.201800511