Synthesis and anti-BVDV activity of acridones as new potential antiviral agents.
In this study we report the design, synthesis, and activity against bovine viral diarrhea virus (BVDV) of a novel series of acridone derivatives. BVDV is responsible for major losses in cattle. The virus is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. Some of the synthesized acridones elicited selective anti-BVDV activity with EC(50) values ranging from 0.4 to 4 microg/mL and were not cytotoxic at concentrations that were 25- to 200-fold higher (CC(50) >100 microg/mL). It was proven that the most potent acridone derivative 10 was able to not only protect cells from virus-induced cytopathic effect but also reduce the production of infectious virus and extracellular viral RNA. Furthermore, compound 10, as well as a number of other analogues, inhibited HCV replication to some extent. However, there was no direct correlation between anti-BVDV and anti-HCV activity. Thus, the acridone scaffold, when appropriately functionalized, can yield compounds with selective activity against pestiviruses and related viruses such as the HCV.
Tabarrini
Oriana
O
Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. oriana.t@unipg.it
Manfroni
Giuseppe
G
Fravolini
Arnaldo
A
Cecchetti
Violetta
V
Sabatini
Stefano
S
De Clercq
Erik
E
Rozenski
Jef
J
Canard
Bruno
B
Dutartre
Hélène
H
Paeshuyse
Jan
J
Neyts
Johan
J
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054831:Acridones; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects*; D015195:Drug Design; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000166:Acridines; D054831:Acridones; D000998:Antiviral Agents; C041300:acridone