Identification of 4-Amino-7-chloroquinoline Derivative with In Vitro Activity Against Chikungunya Virus

Abstract

Arboviruses such as chikungunya virus (CHIKV), Zika virus (ZIKV), and Mayaro virus (MAYV) represent significant global health challenges due to the lack of effective antiviral therapies. Quinoline-based compounds have emerged as promising scaffolds for antiviral drug development. In this study, five 4-amino-7-chloroquinoline derivatives were synthesized and evaluated for their in vitro antiviral activity against CHIKV, ZIKV, and MAYV in Vero cells. Cytotoxicity and antiviral effects were assessed using a tetrazolium-based assay, followed by complementary analyses including cytopathic effect inhibition, virucidal assay, and viral load quantification by RT-qPCR. Among the tested compounds, derivative 6 demonstrated the most pronounced anti-CHIKV activity, with a low micromolar effective concentration and moderate selectivity index. This compound significantly reduced viral replication, preserved cell monolayer integrity, and decreased viral titers, achieving substantial viral load reduction confirmed by RT-qPCR. No virucidal activity was observed. In contrast, compound 6 inhibited the virus-induced cytopathic effect when administered after viral adsorption, suggesting that its antiviral activity is unlikely to result from interference with viral attachment or adsorption but rather from inhibition of a post-adsorption stage of the viral replication cycle. Overall, these findings highlight 4-amino-7-chloroquinoline derivatives as a promising class of antiviral agents and identify compound 6 as a potential lead candidate for further development against CHIKV.