Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus

In a previous study, twelve antimalarial compounds, amodiaquine (AQ) and derivatives, were shown to have potent anti-dengue viral (DENV) activity by using the stable DENV2 Renilla luciferase reporter replicon expressing BHK-21 cells, infectivity (plaque), and the qRT-PCR assays. In this study, we performed molecular modeling on these compounds to determine their stereo-electronic properties required for optimal antiviral activity. Based on the similarity of calculated stereo-electronic profiles, specifically the electrostatic potential profiles of the compounds, and in silico screening of related compounds from literature, we identified three additional compounds, Quinacrine (QC), Mefloquine (MQ), and GSK369796. Analysis of their antiviral activities indicated that all three compounds have high anti-DENV activity in the DENV2 replicon expressing cells with EC₅₀ values of 5.30 ± 1.31 μM (QC), 3.22 ± 0.37 μM (MQ), and 5.06 ± 0.86 μM (GSK369796). The infectivity assays revealed the EC₅₀ values of 7.09 ± 1.67 μM (QC), 4.36 ± 0.31 μM (MQ) and 3.03 ± 0.35 μM (GSK369796). The mode of action of these compounds is through inhibition of autophagy, thereby affecting DENV2 replication. Moreover, these compounds also showed antiviral activity against the rapidly emerging Zika virus (ZIKV) with EC₅₀ values of 2.27 ± 0.14 μM (QC), 3.95 ± 0.21 μM (MQ), and 2.57 ± 0.09 μM (GSK369796).