Synthesis and evaluation of N-substituted acridones as antiviral agents against haemorrhagic fever viruses.
BACKGROUND
In the present study, a series of N-substituted acridone derivatives was synthesized and evaluated against two haemorrhagic fever viruses (HFV).


METHODS
Compounds were tested against Junin virus (JUNV), an arenavirus agent of Argentine haemorrhagic fever, and dengue virus (DENV), a flavivirus agent of the most prevalent arthropod-borne viral disease in humans.


RESULTS
Among tested compounds, two N-allyl acridones (derivatives 3c and 3f) elicited a potent and selective antiviral activity against JUNV (strain 1V4454) and DENV-2 (strain NGC) with 50% effective concentration values between 2.5 and 5.5 microM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1,000 microM, resulting in selectivity indices >181.8-400.0. Both acridones were effective against a wide spectrum of arenaviruses and the four serotypes of DENV. Furthermore, 3c and 3f failed to inactivate virus before cell infection as well as to induce a refractory state by cell pretreatment, indicating that the inhibitory effect was exerted through a blockade in virus multiplication during the infectious process.


CONCLUSIONS
These data are the first demonstration that acridone derivatives have a potent antiviral activity that block in vitro multiplication of HFV belonging to Arenaviridae and Flaviviridae, such as JUNV and DENV.
Sepúlveda
Claudia S
CS
Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina.
Fascio
Mirta L
ML
Mazzucco
María B
MB
Palacios
Maite L Docampo
ML
Pellón
Rolando F
RF
García
Cybele C
CC
D'Accorso
Norma B
NB
Damonte
Elsa B
EB
D054831:Acridones / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001117:Arenaviridae Infections / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003716:Dengue Virus / Q000187:drug effects*; D018051:Junin virus / Q000187:drug effects*; D019595:Severe Dengue / Q000188:drug therapy; D014709:Vero Cells; D010948:Viral Plaque Assay
D054831:Acridones; D000998:Antiviral Agents