7 research outputs found

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

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    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

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    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

    Discovery of Topsentin Alkaloids and Their Derivatives as Novel Antiviral and Anti-phytopathogenic Fungus Agents

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    Topsentin alkaloids and their derivatives were designed, synthesized, and characterized on the basis of NMR and mass spectroscopy. The antiviral activities against tobacco mosaic virus (TMV) and anti-phytopathogenic fungus activities of these alkaloids were evaluated for the first time. Alkaloids <b>1c</b>, <b>1e</b>, <b>2b</b>, and <b>2d</b> displayed significantly higher antiviral activities against TMV than Ribavirin, emerging as new lead compounds for anti-TMV research. Further fungicidal activity tests against 14 kinds of phytopathogenic fungi revealed that these alkaloids displayed broad-spectrum fungicidal activities. Topsentin derivative <b>2d</b> with 4–5 mg/kg EC<sub>50</sub> values against Sclerotinia sclerotiorum (Lib.), Rhizoctonia solani (Kuhn), and Botrytis cinerea (Pers.) emerged as a new lead compound for fungicidal research. Current studies provide support for the application of topsentin alkaloids as novel agrochemicals

    Enantioselective Synthesis of <i>trans</i>-Dihydrobenzofurans via Primary Amine-Thiourea Organocatalyzed Intramolecular Michael Addition

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    A primary amine-thiourea organocatalyzed intramolecular Michael addition access was developed for the synthesis of <i>trans</i>-dihydrobenzofurans. Under the catalysis of an (<i>R</i>,<i>R</i>)-1,2-diphenylethylamine derived primary amine-thiourea bearing a glucosyl scaffold, the corresponding <i>trans</i>-dihydrobenzofurans were obtained in high yields with excellent level of enantioselectivities (94 to >99% ee). Moreover, an in situ isomerization occurring at high temperature gave good to excellent <i>trans</i>/<i>cis</i> ratios as well (<i>trans</i>/<i>cis</i>: 84/16–96/4)

    Design, Synthesis, and Biological Evaluation of Novel Derivatives of the Marine Natural Product Laurene

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    Plant pathogenic fungi and viruses are seriously threatening agricultural production. There is an urgent need to develop novel fungicides and antiviral agents with low toxicity and high efficiency. In this study, we designed and synthesized 32 thiazole-, hydrazone-, and amide-containing derivatives of laurene and systematically evaluated their antiviral activities and fungicidal activities. Structure-simplified compounds 5a–5c, 5i, 5k, 5l, 11a, 11j, and 12c displayed higher antiviral activities than that of ningnanmycin. Compound 11a with a simple chemical structure, convenient synthetic route, and excellent antiviral activity emerged as a secondary lead compound. The docking results show that compounds 5i, 5k, and 11a have strong interactions with the tobacco mosaic virus coat protein (TMV CP). These compounds also exhibited significant fungicidal activities. Compounds 5g, 5k, 11j, and 11l displayed 9.15–17.45 μg/mL EC50 values against Pyricularia grisea, and compounds 5h (EC50: 8.01 μg/mL) and 11i (EC50: 15.23 μg/mL) exhibited a similar level of EC50 values with chlorothalonil (EC50: 7.33 μg/mL) against Physalospora piricola. Preliminary fungicidal mechanism research indicated that compound 5h has a certain destructive effect on the hyphae of P. piricola. This work lays a foundation for the application of laurene derivatives in plant protection

    Marine-Natural-Product Development: First Discovery of Nortopsentin Alkaloids as Novel Antiviral, Anti-phytopathogenic-Fungus, and Insecticidal Agents

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    Nortopsentin alkaloids were found to have potent antiviral, anti-phytopathogenic-fungus, and insecticidal activities for the first time. Antiviral-activity tests revealed that these compounds were very sensitive to substituents, so a series of nortopsentin derivatives were designed, synthesized, and systematically evaluated for their antiviral activities against TMV, their fungicidal activities, and their insecticidal activities on the basis of a structural-diversity-derivation strategy. Compounds <b>2e</b> (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 50, 59, and 56%, respectively, at 500 μg/mL) and <b>2k</b> (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 60, 58, and 52%, respectively, at 500 μg/mL), with excellent antiviral activities and good physicochemical properties, emerged as new lead compounds for novel-antiviral-agent development. Further fungicidal-activity tests revealed that these alkaloids displayed broad-spectrum fungicidal activities. Compounds <b>2f</b>, <b>2h</b>, and <b>2j</b> emerged as new lead compounds for antifungal-activity research. Additionally, all the compounds displayed good insecticidal activities against five kinds of insects, including <i>Mythimna separate</i>, <i>Helicoverpa armigera</i>, <i>Ostrinia nubilalis</i>, <i>Plutella xylostella</i>, and <i>Culex pipiens pallens</i>

    Structural Optimization of the Natural Product: Discovery of Almazoles C–D and Their Derivatives as Novel Antiviral and Anti-phytopathogenic Fungus Agents

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    Plant diseases seriously affect the growth of crops and the quality and yield of agricultural products. The search for plant-derived pesticide candidates based on natural products is a hot topic of current research. Marine natural products almazoles C–D were efficiently prepared and selected as the lead compounds in this work. Two series of almazole derivatives were designed and synthesized, and their antiviral and fungicidal activities were systematically evaluated. The results of anti-tobacco mosaic virus (anti-TMV) activity showed that almazoles C–D and their derivatives had good anti-TMV activities. Compounds 6, 15, 16a, 16b, 16g, 16l, 16n, 20a, 20d, 20i, and 20n exhibited better anti-TMV activities than the commercial antiviral agent ribavirin. Anti-TMV mechanism studies showed that compound 16b could induce the polymerization of 20S CP (coat protein, CP), thereby affecting the assembly of TMV virus particles. Molecular docking results showed that compounds 15, 16b, and 20n could combine with amino acid residues through hydrogen bonds to achieve an excellent anti-TMV effect. In addition, most of the almazole derivatives were found to have broad-spectrum fungicidal activities against eight kinds of plant pathogens (Fusarium oxysporum f. sp. cucumeris, Cercospora arachidicola Hori, Physalospora piricola, Rhizoctonia cerealis, Alternaria solani, Pyricularia grisea, Phytophthora capsici, and Sclerotinia sclerotiorum). This study provides an important evidence for the research and development of almazole alkaloids containing indole and oxazole structural groups as novel agrochemicals
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