Synthesis and biological evaluation of novel tricyclic matrinic derivatives as potential anti-filovirus agents

摘要

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structure—activity relationship analysis indicated: (i) 12N-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound >7d exhibited the most potent potency against EBOV with an IC50 value of 5.29 μmol/L and an SI value of over 37.8. Further in vivo anti-EBOV assay of >7d identified its high effectiveness, and in vivo anti-MARV assay of >7d suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.