Synthesis and In Vitro Evaluation of C-7 and C-8 Luteolin Derivatives as Influenza Endonuclease Inhibitors
Abstract
Influenza is a causative agent of upper respiratory tract infection that causes 290 000 - 650 000 deaths worldwide annually. Because of its high virulence and mutation rate, the H5N1, H1N1, and H3N2strains has made a likelihood of human influenza pandemic and the possible socio-economic impact remain major worldwide concern.2These strains have also developed resistance again highly efficient neuraminidase inhibitor (Oseltamivir) and M2 ion channel blocker(Amantidine).
Recently, the highly conserved endonuclease site ofPA-subunit of RNA dependent RNA polymerase became a promising target for influenza treatment, since its function is dependent onMg2+ or Mn2+ ions. To facilitate its function, Mg2+ or Mn2+ ions are essential for the endonuclease activity.3 There is currently only oneFDA-approved inhibitor of this metalloenzyme known as Xofluza (baloxavir barboxil).
Herein, based on X-ray structural analysis of PA subunit-luteolin andPA subunit-orientin complexes we proposed and prepared series of luteolin and orientin bioisosters using unique synthetic approach