RESUMEN
A series of ferulic acid dimers were designed, synthesized, and evaluated for anti-TMV activity. Biological assays demonstrated that compounds A6, E3, and E5 displayed excellent inactivating against tobacco mosaic virus (TMV) with EC50 values of 62.8, 94.4, and 85.2 µg mL-1, respectively, which were superior to that of ningnanmycin (108.1 µg mL-1). Microscale thermophoresis indicated that compounds A6, E3, and E5 showed strong binding capacity to TMV coat protein with binding affinity values of 1.862, 3.439, and 2.926 µM, respectively. Molecular docking and molecular dynamics simulation revealed that compound A6 could firmly bind to the TMV coat protein through hydrogen and hydrophobic bonds. Transmission electron microscopy and self-assembly experiments indicated that compound A6 obviously destroyed the integrity of the TMV particles and blocked the virus from infecting the host. This study revealed that A6 can be used as a promising leading structure for the development of antiviral agents by inhibiting TMV self-assembly.
Asunto(s)
Antivirales , Ácidos Cumáricos , Simulación del Acoplamiento Molecular , Virus del Mosaico del Tabaco , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacología , Proteínas de la Cápside/química , Proteínas de la Cápside/metabolismo , Enfermedades de las Plantas/virología , Ensamble de Virus/efectos de los fármacos , Dimerización , Simulación de Dinámica MolecularRESUMEN
Tobacco mosaic virus (TMV), as one of the most traditional and extensive biological stresses, poses a serious threat to plant growth and development. In this work, a series of 1-phenyl/tertbutyl-5-amino-4-pyrazole oxadiazole and arylhydrazone derivatives was synthesized. Bioassay evaluation demonstrated that the title compounds (P1-P18) without a "thioether bond" lost their anti-TMV activity, while some of the ring-opening arylhydrazone compounds exhibited superior in vivo activity against TMV in tobacco. The EC50 value of title compound T8 for curative activity was 139 µg/mL, similar to that of ningnanmycin (NNM) (EC50 = 152 µg/mL). Safety analysis revealed that compound T8 had no adverse effects on plant growth or seed germination at a concentration of 250 µg/mL. Morphological observation revealed that compound T8 could restore the leaf tissue of a TMV-stressed host and the leaf stomatal aperture to normal. A mechanism study further revealed that compound T8 not only restored the photosynthetic and growth ability of the damaged host to normal levels but also enhanced catalase (CAT) activity and reduced the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in the damaged host, thereby reducing the oxidation damage to the host. TMV-green fluorescent protein (GFP) experiments further demonstrated that compound T8 not only slowed the transmission speed of TMV in the host but also inhibited its reproduction. All of the experimental results demonstrated that compound T8 could reduce the oxidative damage caused by TMV stress and regulate the photosynthetic ability of the host, achieving the ability to repair damage, to make the plant grow normally.
Asunto(s)
Antivirales , Hidrazonas , Nicotiana , Oxadiazoles , Enfermedades de las Plantas , Virus del Mosaico del Tabaco , Virus del Mosaico del Tabaco/efectos de los fármacos , Virus del Mosaico del Tabaco/fisiología , Oxadiazoles/química , Oxadiazoles/farmacología , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Nicotiana/virología , Nicotiana/efectos de los fármacos , Enfermedades de las Plantas/virología , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Diseño de Fármacos , Relación Estructura-Actividad , Hojas de la Planta/química , Hojas de la Planta/efectos de los fármacos , Estructura MolecularRESUMEN
The tobacco mosaic virus coat protein (TMV-CP) is indispensable for the virus's replication, movement and transmission, as well as for the host plant's immune system to recognize it. It constitutes the outermost layer of the virus particle, and serves as an essential component of the virus structure. TMV-CP is essential for initiating and extending viral assembly, playing a crucial role in the self-assembly process of Tobacco Mosaic Virus (TMV). This research employed TMV-CP as a primary target for virtual screening, from which a library of 43,417 compounds was sourced and SH-05 was chosen as the lead compound. Consequently, a series of α-amide phosphate derivatives were designed and synthesized, exhibiting remarkable anti-TMV efficacy. The synthesized compounds were found to be beneficial in treating TMV, with compound 3g displaying a slightly better curative effect than Ningnanmycin (NNM) (EC50 = 304.54 µg/mL) at an EC50 of 291.9 µg/mL. Additionally, 3g exhibited comparable inactivation activity (EC50 = 63.2 µg/mL) to NNM (EC50 = 67.5 µg/mL) and similar protective activity (EC50 = 228.9 µg/mL) to NNM (EC50 = 219.7 µg/mL). Microscale thermal analysis revealed that the binding of 3g (Kd = 4.5 ± 1.9 µM) to TMV-CP showed the same level with NNM (Kd = 5.5 ± 2.6 µM). Results from transmission electron microscopy indicated that 3g could disrupt the structure of TMV virus particles. The toxicity prediction indicated that 3g was low toxicity. Molecular docking showed that 3g interacted with TMV-CP through hydrogen bond, attractive charge interaction and π-Cation interaction. This research provided a novel α-amide phosphate structure target TMV-CP, which may help the discovery of new anti-TMV agents in the future.
Asunto(s)
Antivirales , Proteínas de la Cápside , Fosfatos , Virus del Mosaico del Tabaco , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Fosfatos/química , Fosfatos/farmacología , Relación Estructura-Actividad , Estructura Molecular , Proteínas de la Cápside/antagonistas & inhibidores , Proteínas de la Cápside/química , Proteínas de la Cápside/metabolismo , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Simulación del Acoplamiento MolecularRESUMEN
Based on the broad-spectrum biological activities of echinopsine and acylhydrazones, a series of echinopsine derivatives containing acylhydrazone moieties have been designed, synthesized and their biological activities were evaluated for the first time. The bioassay results indicated that most of the compounds showed moderate to good antiviral activities against tobacco mosaic virus (TMV), among which echinopsine (I) (inactivation activity, 49.5 ± 4.4%; curative activity, 46.1 ± 1.5%; protection activity, 42.6 ± 2.3%) and its derivatives 1 (inactivation activity, 44.9 ± 4.6%; curative activity, 39.8 ± 2.6%; protection activity, 47.3 ± 4.3%), 3 (inactivation activity, 47.9 ± 0.9%; curative activity, 43.7 ± 3.1%; protection activity, 44.6 ± 3.3%), 7 (inactivation activity, 46.2 ± 1.6%; curative activity, 45.0 ± 3.7%; protection activity, 41.7 ± 0.9%) showed higher anti-TMV activity in vivo at 500 mg/L than commercial ribavirin (inactivation activity, 38.9 ± 1.4%; curative activity, 39.2 ± 1.8%; protection activity, 36.4 ± 3.4%). Some compounds exhibited insecticidal activities against Plutella xylostella, Mythimna separate and Spodoptera frugiperda. Especially, compounds 7 and 27 displayed excellent insecticidal activities against Plutella xylostell (mortality 67 ± 6% and 53 ± 6%) even at 0.1 mg/L. Additionally, most echinopsine derivatives exhibited high fungicidal activities against Physalospora piricola and Sclerotinia sclerotiorum.
Asunto(s)
Diseño de Fármacos/métodos , Hidrazonas/química , Quinolonas/síntesis química , Quinolonas/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Animales , Antifúngicos , Antivirales , Ascomicetos/efectos de los fármacos , Granulovirus/efectos de los fármacos , Insecticidas , Quinolonas/química , Spodoptera/efectos de los fármacosRESUMEN
A new compound classified as one new azaphilone derivative, nigirpexin E (1), was obtained from the soil-derived fungus Trichoderma afroharzianum LTR-2, together with seven known compounds (2-8). The structures of 1-8 were determined by their HRESIMS, optical rotation, and NMR spectroscopic data. The absolute configuration of nigirpexin E (1) was determined on the basis of comparisons of experimental and theoretically calculated ECD spectra. Compound 3 was firstly isolated from Trichoderma. Bioactivities of the isolated compounds were assayed their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 1 exhibited significant inactivation effect against TMV with an inhibition rate of 67.25% (0.5 mg ml-1), which was higher than that of positive control ribavirin (56.74%). This is the first report of the anti-TMV activity of azaphilone derivatives.
Asunto(s)
Antivirales/farmacología , Hypocreales/química , Virus del Mosaico del Tabaco/efectos de los fármacos , Benzopiranos , Dicroismo Circular , Fermentación , Espectroscopía de Resonancia Magnética , Estructura Molecular , Pigmentos Biológicos , Ribavirina/farmacología , Microbiología del SueloRESUMEN
Phrymarolin II, a furofuran lignan isolated from Phryma leptostachya L., features a 3,7-dioxabicyclo[3.3.0]octane skeleton. Herein, we report an alternative total synthesis of (±)-phrymarolin II (2), which was performed in 9 steps from commercially available sesamol. The key steps of the synthesis included a zinc-mediated Barbier-type allylation and a copper-catalyzed anomeric O-arylation. Our total synthesis allowed the synthesis of analogues of (±)-phrymarolin II. Most derivatives displayed good to excellent in vivo activity against tobacco mosaic virus (TMV). (±)-Phrymarolin II (2) and compounds (±)-31d and (±)-31g exhibited similar or higher activity than commercial ningnanmycin, which indicated that phrymarolin lignans are a promising new class of plant virus inhibitors.
Asunto(s)
Antivirales/síntesis química , Lignanos/síntesis química , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/farmacología , Benzodioxoles , Lignanos/farmacologíaRESUMEN
A series of new ferulic acid derivatives bearing an oxadiazole ether was synthesized by introducing a structure of oxadiazole into trans-ferulic acid via an ether linkage. The synthesized target compounds were evaluated in vivo for their anti-TMV (tobacco mosaic virus) activity, which indicated that some synthesized compounds displayed strong activity for controlling TMV. For protective activity, compounds 6f and 6h had the most activities of 65% and 69.8% at 500 mg L-1, respectively. Compounds 6a, 6b, 6e, 6f and 6h showed > 60% curative activities at 500 mg L-1. Preliminary proteomics analysis showed that compound 6h could regulate the phenylpropanoid biosynthesis pathway and chloroplast function. These results indicated that synthesized novel ferulic acid derivatives could be used for controlling TMV.
Asunto(s)
Antivirales/farmacología , Ácidos Cafeicos/farmacología , Éteres/farmacología , Oxadiazoles/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Ácidos Cafeicos/síntesis química , Ácidos Cafeicos/química , Relación Dosis-Respuesta a Droga , Éteres/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxadiazoles/química , Relación Estructura-ActividadRESUMEN
Plant diseases caused by plant viruses and pathogens seriously affect crop yield and quality, and it is very difficult to control them. The discovery of new leads based on natural products is an important way to innovate pesticides. Based on the resveratrol is a kind of natural phytoalexin, but it cannot be used as candidate for the development of new drug due to its poor druggability. The phenolic hydroxyl groups in the resveratrol structure are easily destroyed by oxidation, in order to improve its stability, ester formation is the most commonly used modification method in drug design. Their structures were characterized by 1H NMR, 13C NMR and HRMS. The activity against tobacco mosaic virus (TMV) of these ester derivatives has been tested for the first time. The bioassay results showed part of the target compounds exhibited good to excellent in vivo activities against TMV. The optimum compounds III-2 (inhibitory rates of 50, 53, and 59% at 500 µg/mL for inactivation, curative, and protection activities in vivo, respectively), III-4 (inhibitory rates of 57, 59, and 51% at 500 µg/mL, respectively), and II-5 (inhibitory rates of 54, 52, and 51% at 500 µg/mL, respectively) displayed higher activity than commercial plant virucide ribavirin (inhibitory rates of 38, 37, and 40% at 500 µg/mL, respectively). Compounds I-9 and I-10 also showed excellent activities. The systematic study provides strong evidence that these simple resveratrol derivatives could become potential TMV inhibitors. The novel concise structure provides another new template for antiviral studies.
Asunto(s)
Antifúngicos/farmacología , Antivirales/farmacología , Resveratrol/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Insecticidas/farmacología , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/terapia , Enfermedades de las Plantas/virología , Resveratrol/análogos & derivadosRESUMEN
Understanding the role of H2 S in host defense mechanisms against RNA viruses may provide opportunities for the development of antivirals to combat viral infections. Here, we have developed a green-emitting fluorogenic probe, which exhibits a large fluorescence response at 520â nm (>560-fold) when treated with 100â µM H2 S for 1â h. It is highly selective for H2 S over biothiols (>400-fold F/F0 ) and has a detection limit of 12.9â nM. We demonstrate the application of the probe for endogenous H2 S detection inâ vivo for the understanding of its roles in antiviral host defense. Such virus-induced H2 S inhibits viral replication by reducing gene expression of RNA-dependent RNA polymerase (RdRp) and coat protein (CP). Additionally, a H2 S donor GYY4137 showed significantly antiviral activity as ribavirin, a broad-spectrum drug against RNA viruses. Furtherly, we propose a possible molecular mechanism for the TMV-induced H2 S biogenesis. This work provides a proof-of-principle in support of further studies identifying endogenous H2 S and its donors as potential antivirals toward RNA viruses.
Asunto(s)
Antivirales/análisis , Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/análisis , Virus del Mosaico del Tabaco/metabolismo , Antivirales/farmacología , Colorantes Fluorescentes/metabolismo , Sulfuro de Hidrógeno/farmacología , Pruebas de Sensibilidad Microbiana , Virus del Mosaico del Tabaco/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
To further study the structure-activity relationship of gossypol, hemigossypol (1) and its derivatives (2-23) were successfully designed via structure simplification and chemically synthesized. The anti-tobacco mosaic virus (TMV), fungicidal, and insecticidal activities of them were tested systematically. Most of these derivatives exhibited excellent anti-TMV activity. Furthermore, these compounds also exhibited broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. In particular, hemigossypol acid lactone (7) was stable in the air. In terms of biological activity, it not only showed anti-TMV activity (inhibitory rates of 70.3, 65.4 and 72.4% at 500 µg/mL for inactivation, curative, and protection activity in vivo, respectively) comparable to ningnanmycin but also exhibited higher insecticidal activity against mosquito larvae (60%/0.25 mg/kg) than the commercial species rotenone. None of hemigossypol and the tested derivatives showed antitumor activities.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antivirales/síntesis química , Antivirales/farmacología , Fungicidas Industriales/síntesis química , Fungicidas Industriales/farmacología , Insecticidas/síntesis química , Insecticidas/farmacología , Animales , Antineoplásicos/química , Antivirales/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Productos Biológicos/farmacología , Línea Celular Tumoral , Culicidae/efectos de los fármacos , Culicidae/crecimiento & desarrollo , Diseño de Fármacos , Hongos/efectos de los fármacos , Hongos/crecimiento & desarrollo , Fungicidas Industriales/química , Gosipol/química , Gosipol/farmacología , Humanos , Insecticidas/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/virología , Relación Estructura-Actividad , Virus del Mosaico del Tabaco/efectos de los fármacosRESUMEN
Based on the structure of the natural product cysteine, a series of thiazolidine-4-carboxylic acids were designed and synthesized. All target compounds bearing thiazolidine-4-carboxylic acid were characterized by 1H-NMR, 13C-NMR, and HRMS techniques. The antiviral and antifungal activities of cysteine and its derivatives were evaluated in vitro and in vivo. The results of anti-TMV activity revealed that all compounds exhibited moderate to excellent activities against tobacco mosaic virus (TMV) at the concentration of 500 µg/mL. The compounds cysteine (1), 3-4, 7, 10, 13, 20, 23, and 24 displayed higher anti-TMV activities than the commercial plant virucide ribavirin (inhibitory rate: 40, 40, and 38% at 500 µg/mL for inactivation, curative, and protection activity in vivo, respectively), especially compound 3 (inhibitory rate: 51%, 47%, and 49% at 500 µg/mL for inactivation, curative, and protection activity in vivo, respectively) with excellent antiviral activity emerged as a new antiviral candidate. Antiviral mechanism research by TEM exhibited that compound 3 could inhibit virus assembly by aggregated the 20S protein disk. Molecular docking results revealed that compound 3 with higher antiviral activities than that of compound 24 did show stronger interaction with TMV CP. Further fungicidal activity tests against 14 kinds of phytopathogenic fungi revealed that these cysteine derivatives displayed broad-spectrum fungicidal activities. Compound 16 exhibited higher antifungal activities against Cercospora arachidicola Hori and Alternaria solani than commercial fungicides carbendazim and chlorothalonil, which emerged as a new candidate for fungicidal research.
Asunto(s)
Alternaria/efectos de los fármacos , Antifúngicos/farmacología , Antivirales/farmacología , Ascomicetos/efectos de los fármacos , Cisteína/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Antifúngicos/síntesis química , Antifúngicos/química , Antivirales/síntesis química , Antivirales/química , Cisteína/síntesis química , Cisteína/química , Descubrimiento de Drogas , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
Phytochemistry investigations on Ailanthus altissima (Mill.) Swingle, a Simaroubaceae plant that is recognized as a traditional herbal medicine, have afforded various natural products, among which C20 quassinoid is the most attractive for their significant and diverse pharmacological and biological activities. Our continuous study has led to the isolation of two novel quassinoid glycosides, named chuglycosides J and K, together with fourteen known lignans from the samara of A. altissima. The new structures were elucidated based on comprehensive spectra data analysis. All of the compounds were evaluated for their anti-tobacco mosaic virus activity, among which chuglycosides J and K exhibited inhibitory effects against the virus multiplication with half maximal inhibitory concentration (IC50) values of 56.21 ± 1.86 and 137.74 ± 3.57 µM, respectively.
Asunto(s)
Ailanthus/química , Antivirales/farmacología , Glicósidos/farmacología , Nicotiana/efectos de los fármacos , Extractos Vegetales/farmacología , Cuassinas/química , Virus del Mosaico del Tabaco/efectos de los fármacos , Lignanos/farmacología , Corteza de la Planta/química , Nicotiana/virologíaRESUMEN
The discovery of novel, effective, and botanical pesticides is one of the main strategies for modern plant protection and insect pest control. During the search for novel botanical pesticides from natural sources, the seeds of Sophora tonkinensis were systematically investigated to obtain 11 new matrine-type alkaloids (1-11), including one novel matrine-type alkaloid featuring an unprecedented 5/6/6/6 tetracyclic skeleton (1), along with 16 known compounds (12-27). Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HRESIMS), ECD calculations, and single-crystal X-ray diffraction. The anti-tobacco mosaic virus (TMV) activity and insecticidal activities against Aphis fabae and Tetranychus urticae of the compounds were also respectively screened using the half-leaf method and spray method. Biological tests indicated that compounds 2, 4, 6, and 26 displayed significant anti-TMV biological activities compared with the positive control ningnanmycin. Compounds 7, 17, and 26 presented moderate activities against A. fabae with LC50 values of 38.29, 18.63, and 23.74 mg/L, respectively. Moreover, compounds 13 and 26 exhibited weak activities against T. urticae.
Asunto(s)
Alcaloides/farmacología , Antivirales/farmacología , Insecticidas/farmacología , Extractos Vegetales/farmacología , Quinolizidinas/farmacología , Sophora/química , Alcaloides/química , Animales , Antivirales/química , Insectos/efectos de los fármacos , Insectos/crecimiento & desarrollo , Insecticidas/química , Extractos Vegetales/química , Quinolizidinas/química , Semillas/química , Virus del Mosaico del Tabaco/efectos de los fármacos , Virus del Mosaico del Tabaco/crecimiento & desarrolloRESUMEN
Natural elicitors derived from pathogenic microorganisms represent an ecologic strategy to achieve resistance in plants against diseases. Glucosylceramides (GlcCer) are classified as neutral glycosphingolipids. GlcCer were isolated and purified from Fusarium oxysporum mycelium. F. oxysporum is a plant pathogenic fungus, abundant in soil and causing severe losses in economically important crops such as corn, tobacco, banana, cotton and passion fruit. In this study we evaluate the capacity of GlcCer in inducing resistance in N. tabacum cv Xanthi plants against Tobacco mosaic virus (TMV). Spraying tobacco plants with GlcCer before virus infection reduced the incidence of necrotic lesions caused by TMV. In addition, plants already infected with the virus showed a reduction in hypersensitive response (HR) lesions after GlcCer treatment, suggesting an antiviral effect of GlcCer. Our investigations showed that GlcCer stimulates the early accumulation of H2O2 and superoxide radicals. In addition, the expression of PR-1 (pathogenesis-related 1, with suggested antifungal action), PR-2 (ß-1,3-glucanase), PR-3 (Chitinase), PR-5 (Osmotin), PAL (Phenylalanine ammonia-lyase), LOX (Lipoxygenase) and POX (Peroxidase) genes was highly induced after treatment of tobacco plants with GlcCer and induction levels remained high throughout a period of 6 to 120 hours. Our experiments demonstrate that GlcCer induces resistance in tobacco plants against infection by TMV.
Asunto(s)
Antivirales/farmacología , Fusarium/química , Enfermedades de las Plantas/prevención & control , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/química , Glucosilceramidas , Peróxido de Hidrógeno/metabolismo , Enfermedades de las Plantas/microbiología , Hojas de la Planta/efectos de los fármacos , Hojas de la Planta/virología , Superóxidos/química , Nicotiana/efectos de los fármacos , Nicotiana/virología , Virus del Mosaico del Tabaco/patogenicidadRESUMEN
Globally, the citrus industry produces various wastes, which contain a great deal of limonoids. In order for the sustainable development of the citrus industry, and considering the diverse bioactivities of limonoids, a series of ester derivatives were constructed by structural modification of limonin in the B ring. Furthermore, two seven-membered lactone derivatives of limonin and obacunone with a novel skeleton in the B ring were obtained by the Baeyer-Villiger oxidation rearrangement. The steric structures of six key compounds 3a, 3b, 4m, 4n, 6, and 7 were determined by X-ray crystallography. It demonstrated that the molar ratio of 3a (7α-isomer) and 3b (7ß-isomer) depended on the mixed solvents in the reduction system. The anti-tobacco mosaic virus (TMV) activities under three different modes of action for most of the tested compounds were as the following sequence: inactivation effect > protection effect > curative effect. It was noteworthy that compound 4aa displayed the most potent anti-TMV/insect growth inhibitory activities, which indicated that the introduction of the phenylacryloyloxy group at the C-7ß position of limonin could significantly improve its agricultural biological activities. This study will pave the way for future value-added application of citrus industrial wastes and provide strong evidence for the discovery of sustainable biopesticides based on limonoids.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Citrus/química , Insecticidas/síntesis química , Insecticidas/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Agricultura , Animales , Antivirales/química , Residuos Industriales/análisis , Insectos/efectos de los fármacos , Insectos/crecimiento & desarrollo , Insecticidas/química , Estructura Molecular , Virus del Mosaico del Tabaco/crecimiento & desarrollo , Residuos/análisisRESUMEN
Two structurally unique polyphenols, alatains A (1) and B (2), were isolated from the bark of Cassia alata. Their structures were elucidated on the basis of spectroscopic analysis. Compounds 1 and 2 represent a new type of hetero-dimeric polyphenols with a C-14-C-5' linkage, biogenetically formed by an unusual intermolecular oxidative phenol-coupling reaction between a chromone unit and an isocoumarin moiety. Moreover, compounds 1 and 2 showed significant anti-tobacco mosaic virus (anti-TMV) inhibition IC50 values of 18.8 and 11.4 µM, respectively. Alatains A and B also exhibited promising protective effects on TMV infection of the host plants (Nicotiana tabacum) with the inhibition rates of 54.6% and 69.7% at the concentration of 20 µM, respectively. The results provided a new structural template for potential anti-TMV agent discovery.
Asunto(s)
Antivirales/farmacología , Cassia/química , Polifenoles/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Antivirales/aislamiento & purificación , China , Cromonas , Isocumarinas , Estructura Molecular , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Corteza de la Planta/química , Polifenoles/aislamiento & purificación , Nicotiana/virologíaRESUMEN
Plant diseases are seriously endangering agricultural production. The emergence of drug resistance has brought great challenges to the prevention and control of plant diseases. There is an urgent need for the emergence of new drug candidates. In this work, we achieved the efficient synthesis of pulmonarins A and B in 64% and 59% overall yield, respectively. Pulmonarins A and B were found to have good antiviral activities against tobacco mosaic virus (TMV) for the first time. A series of pulmonarin derivatives were designed, synthesized, and evaluated for their antiviral and fungicidal activities systematically. Most compounds displayed higher anti-TMV activities than commercial ribavirin. Compounds 6a, 6c, and 6n with better inactivation effects than ningnanmycin emerged as new antiviral candidates. We selected 6c for further antiviral mechanism research, which revealed that it could inhibit virus assembly by interacting with TMV coat protein (CP). The molecular docking results further confirmed that these compounds could interact with CP through hydrogen bonding. These compounds also displayed broad spectrum fungicidal activities. Especially compound 6u with prominent antifungal activity emerged as a new fungicidal candidate for further research. The current work provides a reference for understanding the application of pulmonarin alkaloids in plant protection.
Asunto(s)
Antivirales/farmacología , Productos Biológicos/farmacología , Bromobencenos/farmacología , Fungicidas Industriales/farmacología , Antivirales/síntesis química , Antivirales/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Bromobencenos/síntesis química , Bromobencenos/química , Hongos/efectos de los fármacos , Hongos/crecimiento & desarrollo , Fungicidas Industriales/síntesis química , Fungicidas Industriales/química , Simulación del Acoplamiento Molecular , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/virología , Relación Estructura-Actividad , Virus del Mosaico del Tabaco/efectos de los fármacos , Virus del Mosaico del Tabaco/crecimiento & desarrolloRESUMEN
On the basis of the scaffolds widely used in drug design, a series of novel spirooxindole derivatives containing hydantoin, thiohydantoin, urea, and thiourea moieties have been designed, synthesized, characterized, and first evaluated for their biological activities. The diastereoselectivity mechanism is proposed, and the systematic conformational analysis is performed. The bioassay results show that the target compounds possess moderate to good antiviral activities against tobacco mosaic virus (TMV), among which compound 22 shows the highest antiviral activity in vitro as well as inactivation, curative, and protection activities in vivo (45 ± 1, 47 ± 3, 50 ± 1, and 51 ± 1%, 500 mg/L, respectively), higher than ribavirin (38 ± 1, 36 ± 1, 38 ± 1, and 36 ± 1%, 500 mg/L, respectively). Thus, compound 22 is a promising candidate for anti-TMV development. Most of these compounds show broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi and selective fungicidal activities against Physalospora piricola, Sclerotinia sclerotiorum, and Rhizoctonia cerealis. Additionally, some of these compounds exhibit insecticidal activity against Culex pipiens pallens, Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis. Compound 17 exhibits the highest larvicidal activity (LC50 was 0.32 mg/L) against C. pipiens pallens.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Fungicidas Industriales/síntesis química , Fungicidas Industriales/farmacología , Insecticidas/síntesis química , Insecticidas/farmacología , Animales , Antivirales/química , Culex/efectos de los fármacos , Diseño de Fármacos , Hongos/efectos de los fármacos , Fungicidas Industriales/química , Hidantoínas/química , Insecticidas/química , Estructura Molecular , Mariposas Nocturnas/efectos de los fármacos , Relación Estructura-Actividad , Tiohidantoínas/química , Tiourea/química , Virus del Mosaico del Tabaco/efectos de los fármacos , Urea/químicaRESUMEN
Plant diseases caused by viruses and fungi have posed a serious threat to global agricultural production. The discovery of new leads based on natural products is an important way to innovate pesticides. In this work, natural product luotonin A was found to have good antiviral activity against tobacco mosaic virus (TMV) for the first time. A series of luotonin A derivatives were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities systematically. Most compounds displayed better antiviral activities against TMV than commercial ribavirin. Compounds 9k, 12b, and 12d displayed about similar inhibitory effects as ningnanmycin (inhibitory rates of 55, 57, and 59% at 500 µg/mL for inactivation, curative, and protection activities in vivo, respectively), the best antiviral agent at present, and emerged as novel antiviral leads for further research. We selected 9k for further antiviral mechanism research via transmission electron microscopy and molecular docking, which revealed that compound 9k can interact with TMV coat protein through the hydrogen bond, leading to its polymerization, thus preventing virus assembly. Further fungicidal activity tests showed that these compounds also showed broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. Especially, compound 14 with a 100% antifungal effect against Botrytis cinereal emerged as a lead for further research. This work provides a reference for the development of agricultural active ingredients based on Chinese medicine plants.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Enfermedades de las Plantas/virología , Pirroles/química , Pirroles/farmacología , Quinonas/química , Quinonas/farmacología , Virus del Mosaico del Tabaco/efectos de los fármacos , Diseño de Fármacos , Hongos/efectos de los fármacos , Hongos/fisiología , Fungicidas Industriales/química , Fungicidas Industriales/farmacología , Relación Estructura-Actividad , Virus del Mosaico del Tabaco/fisiologíaRESUMEN
The objectives of the present work are to design, syhthesize and introduce novel urea/thiourea derivatives of 2-(piperazine-1-yl)-pyrimidine and 1-(4-Fluoro/4-Chloro phenyl)-piperazine molecules as tobacco mosaic virus (TMV) inhibitors. A series of urea/thiourea derivatives containing pyrimidine and piperazine moieties were synthesized, characterized using Fourier-transform infrared (FTIR) mass spectra, nuclear magnetic resonance (NMR) spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. The anti-viral bioassay of the title compounds showed an antiviral activity against TMV. The compounds synthesized, 9j, 6g and 3d, showed highly-potential curative, protective, and inhibitory activities against TMV at 500 mg/mL formulation. All these compounds were allowed to quantum-polarized-ligand (quantum mechanical and molecular mechanical (QM/MM)) docking experiments. The compounds 9j, 6g and 3d structurally exhibited identical higher affinity towards TMV-Helicase and TMV-Coat proteins. The docking interactions proposed had two stage inhibition of TMV virus by binding to coat protein and helicase for inhibition of RNA replication. The long-range molecular dynamics (150 ns) simulations has revealed more consistency by 9j, 6g and 3d. The present study outcomes good binding propensity for active-tunnel of TMV-Hel enzyme, by these thiourea, urea derivatives, 9j, 6g and 3d, to suggest that the designed and synthesized were ideal for proposing as selective novel inhibitors to target for TMV.