7 research outputs found
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
Discovery of Topsentin Alkaloids and Their Derivatives as Novel Antiviral and Anti-phytopathogenic Fungus Agents
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
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
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
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
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