ABSTRACT
Quadrupolar probes derived from 8-dimethylamino-quinoline (8-DMAQ) having a pegylated fluorene core were prepared and studied under "one-photon" (λ=365â nm) and "two-photon" (TP) (λ=730â nm) irradiation conditions. Compound 1 a was identified as the most efficient probe by UV activation that showed sequential release of acetic acid as a model. Although the probe showed high two-photon absorption it stayed inert under femtosecond irradiation conditions. Fast and selective photolysis was observed, however, by using picosecond irradiation conditions with a remarkably high TP uncaging cross-section (δu =2.3â GM).
ABSTRACT
The NS5B RNA-dependent RNA polymerase (RdRp) is a key enzyme for Hepatitis C Virus (HCV) replication. In addition to the catalytic site, this enzyme is characterized by the presence of at least four allosteric pockets making it an interesting target for development of inhibitors as potential anti-HCV drugs. Based on a previous study showing the potential of the naturally occurring aurones as inhibitors of NS5B, we pursued our efforts to focus on pseudodimeric aurones that have never been investigated so far. Hence, 14 original compounds characterized by the presence of a spacer between the benzofuranone moieties were synthesized and investigated as HCV RdRp inhibitors by means of an in vitro assay. The most active inhibitor, pseudodimeric aurone 4, induced high inhibition activity (IC50 = 1.3 µM). Mutagenic and molecular modeling studies reveal that the binding site for the most active derivatives probably is the palm pocket I instead of the thumb pocket I as for the monomeric derivatives.