Design, Synthesis, and Anti-tobacco Mosaic Virus (TMV) Activity of Phenanthroindolizidines and Their Analogues

On the basis of our previous structure–activity relationship (SAR) and antiviral mechanism studies, a series of phenanthroindolizidines and their analogues <b>3</b>–<b>20</b> were designed, targeting tobacco mosaic virus (TMV) RNA, synthesized, and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds displayed good anti-TMV activity, and some of them exhibited higher antiviral activity than that of commercial Ningnanmycin (perhaps the most successful registered antiplant viral agent). Especially, (<i>S</i>)-deoxytylophorinine (<b>5</b>) with excellent anti-TMV activity (inactivation activity, 59.8%/500 μg mL^–1 and 40.3%/100 μg mL^–1; curative activity, 65.1%/500 μg mL^–1 and 43.7%/100 μg mL^–1; and protection activity, 70.2%/500 μg mL^–1 and 51.3%/100 μg mL^–1) emerged as a potential inhibitor of the plant virus. Compound <b>20</b> exhibited a strong <i>in vivo</i> protection effect against TMV at 100 μg mL^–1, which indicated that phenanthroindolizidine analogues with a seven-membered D ring have a new and interesting structural scaffold and have great potential for further development as tobacco protection agents

D and E Rings May Not Be Indispensable for Antofine: Discovery of Phenanthrene and Alkylamine Chain Containing Antofine Derivatives as Novel Antiviral Agents against Tobacco Mosaic Virus (TMV) Based on Interaction of Antofine and TMV RNA

On the basis of the interaction of antofine and tobacco mosaic virus (TMV) RNA, a series of phenanthrene and alkylamine chain containing antofine derivatives <b>1</b>–<b>41</b> were designed, synthesized, and systematically evaluated for their antiviral activity against TMV. The results showed that most of these compounds exhibited good to excellent anti-TMV activity, which indicated that the D and E rings of antofine may not be indispensable. Phenanthrene is important for these compounds, but not the more the better. Phenanthrene, benzene rings, and alkylamine chain containing compounds exhibited good antiviral activity. The optimum compounds, <b>10</b>, <b>18</b>, and <b>19</b>, displayed higher activity than precursor antofine and commercial ribavirin, thus emerging as new lead compounds. The novel concise structure provides another new template for antiviral studies

Design, Synthesis, and Biological Activities of Novel Coumarin Derivatives as Pesticide Candidates

Food security is an important issue in the 21st century; preventing and controlling crop diseases and pests are the key to solve this problem. The creation of new pesticides based on natural products is an important and effective method. Herein, coumarins were selected as parent structures, and a series of their derivatives were designed, synthesized, and evaluated for their antiviral activities, fungicidal activities, and insecticidal activities. We found that coumarin derivatives exhibited good to excellent antiviral activities against tobacco mosaic virus (TMV). The antiviral activities of I-1, I-2a, I-4b, II-2c, II-2g, II-3, and II-3b are better than that of ribavirin at 500 μg/mL. Molecular docking research showed that these compounds had a strong interaction with TMV CP. These compounds also showed broad-spectrum fungicidal activities against 14 plant pathogenic fungi. The EC50 values of I-1, I-2a, I-3c, and II-2d are in the range of 1.56–8.65 μg/mL against Rhizoctonia cerealis, Physalospora piricola, Sclerotinia sclerotiorum, and Pyricularia grisea. Most of the compounds also displayed good insecticidal activities against Mythimna separata. Pesticide-likeness analysis showed that these compounds are following pesticide-likeness and have the potential to be developed as pesticide candidates. The present work lays a foundation for the discovery of novel pesticide lead compounds based on coumarin derivatives

Application of “Hydrogen Bonding Interaction” in New Drug Development: Design, Synthesis, Antiviral Activity, and SARs of Thiourea Derivatives

A series of simple thiourea derivatives were designed based on the structure of natural product harmine and lead compound and synthesized from amines in one step. The antiviral activity of these thiourea derivatives was evaluated. Most of them exhibited significantly higher anti-TMV activity than commercial plant virucides ribavirin, harmine, and lead compound. The hydrogen bond was found to be important but not the more the better. The optimal compound (<i>R</i>,<i>R</i>)-<b>20</b> showed the best anti-TMV activity in vitro and in vivo (in vitro activity, 75%/500 μg/mL and 39%/100 μg/mL; inactivation activity, 71%/500 μg/mL and 35%/100 μg/mL; curative activity, 73%/500 μg/mL and 37%/100 μg/mL; protection activity, 69%/500 μg/mL and 33%/100 μg/mL), which is significantly higher than that of Ningnanmycin. The systematic study provides strong evidence that these simple thiourea derivatives could become potential TMV inhibitors

Application of “Hydrogen-Bonding Interaction” in Drug Design. Part 2: Design, Synthesis, and Structure–Activity Relationships of Thiophosphoramide Derivatives as Novel Antiviral and Antifungal Agents

On the basis of the structure of natural product harmine, lead compound <b>18</b>, and the structure of compounds in part 1, a series of thiophosphoramide derivatives <b>1</b>–<b>17</b> were designed and synthesized from various amines in one step. Their antiviral and antifungal activities were evaluated. Most of the compounds showed significantly higher antiviral activity against tobacco mosaic virus (TMV) than commercial virucide ribavirin. Compound (<i>R</i>,<i>R</i>)-<b>17</b> showed the best anti-TMV activity <i>in vitro</i> (70%/500 μg/mL and 33%/100 μg/mL) and <i>in vivo</i> (inactivation effect, 68%/500 μg/mL and 30%/100 μg/mL; curative effect, 64%/500 μg/mL and 31%/100 μg/mL; protection effect, 66%/500 μg/mL and 31%/100 μg/mL), which is higher than that of ningnanmycin and lead compound <b>18</b>. The antiviral activity of (<i>R</i>,<i>R</i>)-<b>17</b>·HCl is about similar to that of (<i>R</i>,<i>R</i>)-<b>17</b>. However, the antifungal activity of (<i>R</i>,<i>R</i>)-<b>17</b>·HCl against Puccinia sorghi is slightly lower than that of (<i>R</i>,<i>R</i>)-<b>17</b>. The systematic study provides compelling evidence that these simple thiophosphoramide compounds could become efficient antiviral and antifungal agents

<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

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

Synthesis of compounds 10–14.

<p>Synthesis of compounds 10–14.</p

Design, Synthesis, Antiviral Activity, and SARs of 14-Aminophenanthroindolizidines

Based on our previous structure–activity relationship and antiviral mechanism studies, a series of 14-aminophenanthroindolizidines (<b>1a</b>–<b>i</b>, <b>2</b>, and <b>3</b>) were designed, targeting tobacco mosaic virus (TMV) RNA, and synthesized and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds exhibited good to excellent in vivo anti-TMV activity, of which compounds <b>1d</b> and <b>1h</b> displayed significantly higher activity than commercial ningnanmycin, and thus emerged as potential inhibitors of plant virus. The introduction of amino groups at the 14-position of phenanthroindolizidines, which is proposed to interact with arginine residues around the TMV RNA, increased anti-TMV activity