Design, synthesis, biophysical and biological evaluation of original condensed pyrrolopyrimidine and pyrrolopyridine ligands as anti-SARS-CoV-2 agents targeting G4

Abstract

The design and synthesis of novel bis[(substituted-aminomethyl)phenyl]phenyl pyrrolopyrimidines, pyrrolopyridines, pyrazolopyrimidines, imidazopyrimidines, and tris[(substituted-aminomethyl)phenyl]phenyl pyrrolopyrimidines are reported here. These original G-quadruplex (G4) ligands have been then subjected to a screening on SARS-CoV-2 using a competition HTRF assay by targeting the SUD-NM/TRF2 RNA G4 interaction. The more promising derivatives have been evaluated in vitro to determine their potential antiviral effect on two different cell lines infected by two SARS-CoV-2 strains. This study revealed a clear correlation between their antiviral property and their efficacy to prevent the SUD/G4 interaction. This correlation supports the choice of SUD/RNA G4 complexes formed during SARS-CoV-2 infection as new antiviral targets.

Keywords: Antiviral molecule; COVID-19; FRET-melting; G4 ligands; Guanine quadruplex; HTRF; Nsp3; Pyrrolopyridine; Pyrrolopyrimidine; SARS-CoV-2.