Synthesis and Evaluation of N-Substituted Acridones as Antiviral Agents against Haemorrhagic Fever Viruses

Abstract

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.

Inhibition of Lassa Virus Glycoprotein Cleavage and Multicycle Replication by Site 1 Protease-Adapted α1-Antitrypsin Variants

“…In principle, every step in the viral life cycle is a potential target for antiviral inhibitors. While current antiviral strategies in the arenavirus field mainly target virus entry [58,59,60,61] or replication and assembly [62,63,64,65,66,67], inhibition studies of the glycoprotein activating endoprotease and its impact on viral replication are largely unexploited. Due to its central role in the arenavirus life cycle [23,26,33,34], S1P should be considered as a cellular target for antiviral drug development.…”

Host Cell Factors as Antiviral Targets in Arenavirus Infection

“…With respect to arenaviruses, a screening of antiviral activity of diverse novel N -substituted acridone derivatives identified a group of 10-allyl-9(10 H )-acridones as effective and very selective inhibitors of arenaviruses [57]. In particular, the 10-allyl-6-chloro-4-methoxy-9(10 H )-acridone, designated 3f , was the most active compound that blocked replication of the pathogenic arenaviruses JUNV and LCMV as well as the four serotypes of dengue virus, another HF-causing RNA virus belonging to the family Flaviviridae .…”

Antimalarial activity of new acridinone derivatives

“…Our tested compounds exhibited weaker activity than those acridinones and the reference drugs (chloroquine and artemisinin). However, our compounds showed very low cytotoxicity against MRC-5 cell line (CC 50 > 64 mM) and VERO cells, CC 50 greater than 1000 mM [12]. Previously synthesized antimalarial 10-N-substituted acridinones exhibited higher cytotoxicity.…”

“…Taking into account these facts and our experience in the synthesis and characterization of acridinone core [11] we focus attention on new synthesized acridinones derivatives, some of them possessing high antiviral [12] and moderate trypanocidal activity [13]. In this paper we report the in vitro activity of 12 derivatives of 10-allyl-, 10-(3-methyl-2-butenyl)-and 10-(1,2propadienyl)-9(10H)-acridinone, against P. falciparum.…”