Structure-activity relationship studies of 1-(1'-hydroxyalkyl)rupestonic acid methyl esters against influenza viruses.

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1484-1487. doi: 10.1016/j.bmcl.2016.06.011. Epub 2016 Jun 6.

Li G1, Zhao JY2, Niu C2, Nie LF2, Dong CZ3, Aisa HA4.

Author information

1

The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; Université Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Paris Cedex 13, France.

2

The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China.

3

Université Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR 7086 CNRS, 15 rue J-A de Baïf, 75205 Paris Cedex 13, France. Electronic address: dong@univ-paris-diderot.fr.

4

The Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China. Electronic address: haji@ms.xjb.ac.cn.

Abstract

A series of 1-(1'-hydroxyalkyl)rupestonic acid methyl esters were synthesized via the condensation of methyl rupestonate with various aldehydes in the presence of LDA. This mixed aldol reaction was highly stereoselective and all the new compounds were elucidated by detailed NMR and MS analyses. The absolute configurations of the newly formed stereocenters were further confirmed by X-ray crystallographic analysis of 3d, the results of which were found to be opposite to the prediction based on Zimmerman-Traxler's and Houk's models. All the compounds synthesized were then evaluated for their in vitro inhibitory activities against influenza A (H1N1 and H3N2) and B viruses. The data showed that 3p displayed the highest activity against influenza A H1N1 (IC50=0.69μg/mL) and H3N2 (IC50=0.69μg/mL) viruses, which were even better than Ribavirin and Oseltmivir. On the other hand, both 3c and 3o were found to show comparable activities with the reference drugs in inhibiting both influenza A and B viruses. Further studies will focus on reducing the cytotoxicity of the hits reported in this work.

Copyright © 2016 Elsevier Ltd. All rights reserved.

KEYWORDS:

Anti-influenza viruses; Rupestonic acid; Synthesis; X-ray crystallographic analysis

PMID:

 

28196702

 

DOI:

 

10.1016/j.bmcl.2016.06.011