Synthesis and antiviral evaluation of cytisine derivatives against dengue virus types 1 and 2

Abstract

Dengue virus (DENV) causes about 50–100 million cases per year worldwide. However, there is still a big challenge in developing antiviral drugs against DENV infection. Some derivatives of alkaloid (−)-cytisine, like other alkaloid analogs, have been proposed for their antiviral potential. This study investigated antiviral activity and mechanisms of the cytisine derivatives, and discovered the structure–activity relationship against DENV. The antiviral assays were performed using one strain of DENV1 and DENV2, and two cell lines Vero E6 and A549. The structure–activity relationship of the effective compounds was also evaluated using combination of time-of-addition/removal assay and molecular docking. Compounds 3, 4, 12 (N-allylcytisine-3-thiocarbamide), 16, and 20 exhibited the high antiviral activity with IC50 values of lower than 3 μM against DENV1 and DENV2. Of them, the derivative 12 showed the highest antiviral activities against DENV1 (IC50 = 0.14 μM) and DENV-2 (IC50 = <0.1 μM), exhibiting the potent inhibition on virus attachment and entry stages. Meanwhile, the compounds 4 and 20 had a strong inhibition at the post-entry stage (IC50 = <0.1 μM). A correlation between the experimental pIC50 values and predicted pKi calculated by docking of compounds into DENV E protein was significant, correlating with the impact of compound 12 on the attachment stage, but compounds 4, and 20 on post-entry stage. The results provided the insight into the directions of synthetic modifications of starting (−)-cytisine as the inhibitors of DENV E protein at attachment and entry stages of DENV life cycle.