Identification and evaluation of 4-anilinoquin(az)olines as potent inhibitors of both dengue virus (DENV) and Venezuelan equine encephalitis virus (VEEV)

There is an urgent need for novel strategies for the treatment of emerging arthropod-borne viral infections, including those caused by dengue virus (DENV) and Venezuelan equine encephalitis virus (VEEV). We prepared and screened focused libraries of 4-anilinoquinolines and 4-anilinoquinazolines for antiviral activity and identified three potent compounds. N-(2,5-dimethoxyphenyl)-6-(trifluoromethyl)quinolin-4-amine (10) inhibited DENV infection with an EC50 = 0.25 µM, N-(3,4-dichlorophenyl)-6-(trifluoromethyl)quinolin-4-amine (27) demonstrated an EC50 = 0.50 µM against VEEV, and an advanced lead, N-(3-ethynyl-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine (54) had a potent antiviral activity (EC50 = 0.60 µM) for VEEV. These series of compounds demonstrated nearly no toxicity with CC50 values greater than 10 µM in all cases. These promising results provide a future prospective to develop a clinical compound against these emerging viral threats.