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 IV4454) and DENV-2 (strain NGC) with 50% effective concentration values between 2.5 and 5.5 µM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1,000 µM, 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. Conclusion: 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.