Synthesis of New Acridone Derivatives, Inhibitors of NS3 Helicase, Which Efficiently and Specifically Inhibit Subgenomic HCV Replication

Abstract

A new goup of acridone derivatives, obtained by reaction of acridone-4-carboxylic acid derivatives with aromatic amines, was tested to determine the inhibitory properties toward the NS3 helicase of hepatitis C virus (HCV). Six compounds inhibited the NS3 helicase at low concentrations (IC(50) from 1.5 to 20 microM). The acridone derivatives probably act via intercalation into double-stranded nucleic acids with a strong specificity for double-stranded RNA, although an interaction with the enzyme cannot be excluded. Testing in the subgenomic HCV replicon system revealed that compounds 10 and 13 are efficient RNA replication inhibitors, with EC(50) of 3.5 and 1 microM and therapeutic indexes of >28 and 20, respectively. Compound 16, with EC(50) < 1 microM and TI > 1000, is extremely specific and practically noncytotoxic at the concentrations tested, proving that the acridone derivatives may be regarded as potential antiviral agents. Although the mechanism of action of 16 in the replicon system remains unclear, it is the key lead compound for further development of anti-HCV drugs.

Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

“…This 170 could be explained by the way acridones usually act against virus infection. Some authors argue 171 that their nucleic acid intercalation ability and interaction with viral enzymes are the main 172 mechanisms by which these compounds act (Adams, 2002;Stankiewicz-Drogon et al, 2010;workers (Stankiewicz-Drogon et al, 2010;Stankiewicz-Drogon et al, 2008) reinforces this 175 assumption. Acridones showed inhibition of NS3 helicase, T7 RNA polymerase (topology and 176 function similar to HCV NS5B) and strong double-stranded RNA intercalation property.…”

“…Some acridones from Rutaceae plants showed great 153 antiviral activity against viruses with DNA genomes like herpes simplex virus serotypes 1 and 2 154 (HSV-1 and HSV-2), human cytomegalovirus (HCMV) and Epstein-Barr virus (Chansriniyom et 155 al., 2009;Itoigawa et al, 2003;Takemura et al, 1995;Yamamoto et al, 1989). For RNA 156 viruses, acridones presented activity against HIV-1, bovine viral diarrhea virus (BVDV), all 157 serotypes of dengue virus (DENV) and HCV, the last three belonging to the Flaviviridae family 158 (Fujiwara et al, 1999;Houe, 2003;Mazzucco et al, 2015;Raney et al, 2010;Sepulveda et al, 159 2008;Stankiewicz-Drogon et al, 2010;Stankiewicz-Drogon et al, 2008;Tabarrini et al, 2006;160 Turpin et al, 1998). 161 Our results showed that Fac4 inhibited up to 92% of HCV replication in the context of either the 162 subgenomic replicon or full length JFH1 HCVcc.…”

“…Some acridones described in the literature present dsRNA intercalation property, 180 others show inhibition of NS3 helicase and NS5B polymerase, and some present both effects 181 (Manfroni et al, 2009;Stankiewicz-Drogon et al, 2010). However, all these studies performed 182 in isolated assays, evaluating inhibition of enzymatic activity or dsRNA intercalation 183…”

“…The T7 polymerase presents similar topology and function to the HCV RdRp NS5B 327 (Stankiewicz-Drogon et al, 2010;Stankiewicz-Drogon et al, 2008). In order to evaluate 328 whether Fac4 interacts with T7 consequently inhibiting viral replication, we tested the effects of 329 FAC4 on in vitro RNA transcription.…”

Acridone suppresses the proliferation of human breast cancer cells in�vitro via ATP-binding cassette subfamily G member 2

“…There are numerous functions of the acridone nucleus in addition to its derivatives that have been reported in previous studies, including anticancer (13-16), anti-herpes (17), anti-malarial (18,19), antivirus (20), anti-allergy (21) and anti-leishmanial (22) activities. These features are attributed to the semi planar heterocyclic structure, which interacts with different biomolecular targets.…”