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

<div><p>A series of phenanthroquinolizidine alkaloids <b>1</b>–<b>24</b> were prepared and first evaluated for their antiviral activity against <em>tobacco mosaic virus</em> (TMV). The bioassay results showed that most of these compounds exhibited good to excellent <em>in vivo</em> anti-TMV activity, of which compounds <b>1</b>, <b>2</b>, <b>15</b> and <b>16</b> displayed significantly higher activity than (<em>R</em>)-antofine and commercial Ningnanmycin at the same test condition. The substituents on the phenanthrene moiety play an important role for maintaining high <em>in vivo</em> antiviral activity. The introduction of 6-hydroxyl, which is proposed to interact with TMV RNA, did increased anti-TMV activity. The 14a<em>R</em>-configuration was confirmed to be the preferred antiviral configuration for phenanthroquinolizidine alkaloids. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052933#s1">Introduction</a> of hydroxy group at 15-position of phenanthroquinolizidine alkaloids increased activity for <em>S</em>-configuration but decreased activity for <em>R</em>-configuration. Present study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.</p> </div

<i>In vitro</i> and <i>in vivo</i> anti-TMV activity of 15-hydroxyphenanthroquinolizidine alkaloids 19–24.

<p><i>In vitro</i> and <i>in vivo</i> anti-TMV activity of 15-hydroxyphenanthroquinolizidine alkaloids 19–24.</p

<i>In vitro</i> and <i>in vivo</i> anti-TMV activity of chiral phenanthroquinolizidine alkaloids 2, 3, 5, 6, 8 and 9.

<p><i>In vitro</i> and <i>in vivo</i> anti-TMV activity of chiral phenanthroquinolizidine alkaloids 2, 3, 5, 6, 8 and 9.</p

Synthesis of compounds 10–14.

<p>Synthesis of compounds 10–14.</p

<i>In vitro</i> and <i>in vivo</i> anti-TMV activity of racemic phenanthroquinolizidine alkaloids 1, 4, 7, and 10–18.

<p><i>In vitro</i> and <i>in vivo</i> anti-TMV activity of racemic phenanthroquinolizidine alkaloids 1, 4, 7, and 10–18.</p

Chemical structures of compounds 1–24, Ribavirin, Ningnanmycin, Cryptopleuridine and (<i>R</i>)-Antofine.

<p>Chemical structures of compounds 1–24, Ribavirin, Ningnanmycin, Cryptopleuridine and (<i>R</i>)-Antofine.</p

Synthesis of compound 17.

<p>Synthesis of compound 17.</p

Synthesis of compound 15.

<p>Synthesis of compound 15.</p

Synthesis of compound 16.

<p>Synthesis of compound 16.</p