First Discovery and Stucture-Activity Relationship Study of Phenanthroquinolizidines as Novel Antiviral Agents against Tobacco Mosaic Virus (TMV)

Ziwen Wang,Lizhong Wang,Mingbo Cui,Yuxiu Liu,Qingmin Wang,Anzheng Feng,Daniel S Sem

doi:10.1371/journal.pone.0052933

Abstract

A series of phenanthroquinolizidine alkaloids 1–24 were prepared and first evaluated for their antiviral activity against tobacco mosaic virus (TMV). The bioassay results showed that most of these compounds exhibited good to excellent in vivo anti-TMV activity, of which compounds 1, 2, 15 and 16 displayed significantly higher activity than (R)-antofine and commercial Ningnanmycin at the same test condition. The substituents on the phenanthrene moiety play an important role for maintaining high in vivo antiviral activity. The introduction of 6-hydroxyl, which is proposed to interact with TMV RNA, did increased anti-TMV activity. The 14aR-configuration was confirmed to be the preferred antiviral configuration for phenanthroquinolizidine alkaloids. Introduction of hydroxy group at 15-position of phenanthroquinolizidine alkaloids increased activity for S-configuration but decreased activity for R-configuration. Present study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.

Highlights

Plant viruses cause numerous diseases in a wide range of crop plant species and lead to an estimated $600 billion in annual losses worldwide [1]
In order to further evaluate the effect of 6-hydroxy group on antiviral activity, which is proposed to interact with Tobacco mosaic virus (TMV) RNA [26], phenanthroquinuolizidine alkaloids 16 and 17 were designed and synthesized
The 6-position of the phenanthrene moiety, which is proposed to interact with TMV RNA [26], really is a sensitive site: removal of 6-O methyl increased the antiviral activity, which indicated that the 6-position may be a hydrogen donor site; replacement of 6-O methyl with 6-O cyclopropyl methyl significantly decreased the antiviral activity, which indicated that the steric effect is a very important factor

Summary

Introduction

Plant viruses cause numerous diseases in a wide range of crop plant species and lead to an estimated $600 billion in annual losses worldwide [1]. Because of the unsatisfactory cure rate (30–60%) of common antiviral agents (Ningnanmycin, Ribavirin, Virus A, et al.) and economic loss of tobacco, many efforts have been done to develop novel, potent and structure concise antiviral agents. Some chemicals, such as triazolyl compounds [3], pyrazole derivatives [4,5], cyanoacrylate derivatives [5,6], a-aminophosphonate derivatives [5,7], N-(pyrimidin-5-yl)-N9-phenylureas [8], and some natural products [9,10,11], have been found to possess antiviral activity. Based on the above findings, a series of phenanthroquinolizidine alkaloids 1–24 were prepared and systematically evaluated for their antiviral activity against TMV

Results and Discussion

Materials and Methods

Conclusion