Synthesis, bioactivity and mode of action of 5(A)5(B)6(C) tricyclic spirolactones as novel antiviral lead compounds

摘要

BACKGROUND Plant viral diseases cause tremendous decreases in yield and quality. Natural polycyclic compounds such as those containing carbocycles are often very important lead compounds for drug and pesticide development. Tricyclic spiranoid lactones with 5(A)5(B)6(C)-ring fusion topologies possess various bioactivities. In this study, 33 new 5(A)5(B)6(C) tricyclic spirolactones were rationally designed, synthesized, characterized and evaluated for antiviral activities. RESULT CONCLUSION SchemeFigure These compounds showed no apparent toxicity against Italian honeybees up to 2.73 mu g bee(-1). Spirolactones 14, 16, 19, 23 and 28 at a concentration of 100 mu g mL(-1) inactivated 90% of tobacco mosaic virus (TMV) infection, making these compounds much more potent than the positive controls. Significantly, compound 19 displayed the best inactivation activity causing inhibition of up to 98%. The results of the bioassays and QSAR studies indicated that the carbon-containing cyclic moiety was the antiviral pharmacophore, and derivative 19, which showed the best inactivation activity, could emerge as a potential antiviral agent against TMV. In vitro capsid protein (CP) assembly and TMV assembly inhibition determinations indicated that these compounds induced crosslinking in the TMV and prevented its uncoating, which was a putative new mode of action for TMV inactivation. (c) 2018 Society of Chemical Industry