Design, synthesis and discovery of andrographolide derivatives against Zika virus infection.

The Zika endemic established by imported and local transmission is of significant concern and effective anti-ZIKV drugs remain an urgent unmet need. As andrographolide was identified to be an inhibitor of DENV and CHIKV and the importance of quinoline structure against infectious diseases was considered, we are interested in studying its andrographolide derivatives with quinoline moiety against Zika virus infection. In addition to screening eight in-house derivatives of andrographolide, sixteen new derivatives were designed, synthesized and tested against Zika virus infection. Among these compounds, two most potent anti-Zika compounds of 19-acetylated 14α-(5',7'-dichloro-8'-quinolyloxy) derivative 17b and 14β-(8'-quinolyloxy)-3,19- diol derivative 3 with the highest selectivity were discovered. The SAR analysis indicates that rational and optimal combined modification/s at 3-, 14-, or 19-positions can make derivatives less toxic and more potent against Zika infection, and both of 3 and 17b are suitable as leads for designing new generation of andrographolide derivatives with quinoline or its structure- and property-related moieties against Zika virus and other arboviruses.