Acridones as Antiviral Agents Against Emerging Hemorrhagic Fever Viruses

E. DAMONTE; C. SEPÚLVEDA; M. MAZZUCCO; C. GARCÍA; M. FASCIO; N. D´ACCORSO; M. DOCAMPO PALACIOS; R. PELLÓN

Toulon, Francia

Simposio; 15th International Symposium on HIV and Emerging Infectious Diseases; 2008

Acridones as antiviral agents effective against emerging hemorrhagic fever viruses. E.B. Damonte1, C.S. Sepúlveda1, M.B. Mazzucco1, C.C. García1, M.L. Fascio2, N.B. D’Accorso2, M.L. Docampo Palacios3, R.F. Pellón3. 1Laboratorio de Virología, Depto. Química Biológica, FCEN, UBA, Ciudad Universitaria, 1428 Buenos Aires, Argentina, 2CIHIDECAR (CONICET), Depto. Química Orgánica, Ciudad Universitaria, FCEN, UBA, 1428 Buenos Aires, Argentina, 3Centro de Química Farmacéutica, Ap. 16042, 11600 La Habana, Cuba.   Hemorrhagic fever viruses (HFV) constitute a heterogeneous group of enveloped viruses with RNA genome including agents of severe emerging infectious diseases such as dengue virus (DENV) and the arenavirus Junin (JUNV). JUNV is responsible of the annual outbreaks of Argentine hemorrhagic fever, whereas DENV is the agent of the most prevalent arthropod-borne viral human disease, with an increasing global emergence in the last decade producing about 50 million annual cases of dengue fever and 250,000 cases of the life-threatening dengue hemorrhagic fever. Since no specific and safe chemotherapy is currently available, the search for antiviral compounds against these viruses is a demanding effort. In the present study, a series of novel acridone derivatives were synthesized and evaluated against DENV and JUNV. Among tested compounds, two N-substituted acridones (10-allyl-6-chloro-9(10H)-acridone and 10-allyl-6-chloro-4-methoxi-9(10H)-acridone, named 3c and 3f, respectively) elicited a potent and selective antiviral activity against JUNV, strain IV4454, and DENV-2, strain NGC. The effective concentration 50% (EC50) values were in the range 2.5-11.5 µM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1000 µM, resulting in selectivity indices (ratio cytotoxicity/antiviral activity) greater than 87-400. This activity was independent of the input multiplicity of infection. Both acridones were also effective against a wide spectrum of arenaviruses and the four serotypes of DENV. Mechanistic studies demonstrated that addition of acridones to infected cells between 1 and 4 h after virus adsorption caused total inhibition of virus production whereas drug treatment at later times resulted in a time-dependent decrease of the antiviral effect. Furthermore, 3c and 3f failed to inactivate virus before cell infection as well as to induce a refractory state by cell pretreatment. Thus, the antiviral action of acridones was exerted through a blockade during intracellular multiplication (RNA/protein synthesis or virus assembly) of HFV infectious process.