Anti-tobacco Mosaic Virus Activity Research Articles

Brusatol's anticancer activity and its molecular mechanism: a research update.

Brusatol (BT) is a quassinoid compound extracted from Brucea javanica that is a traditional Chinese herbal medicine. Brusatol possesses biological and medical activity, including antitumor, antileukemia, anti-inflammatory, antitrypanosomal, antimalarial, and antitobacco mosaic virus activity. To summarize and discuss the antitumor effects of BT and its mechanisms of actions, we compiled this review by combining the extensive relevant literature and our previous studies. We searched and retrieved the papers that reported the pharmacological effects of BT and the mechanism of BT antitumor activity from PubMed until July 2023. Numerous studies have shown that BT is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor that acts on various signaling pathways and has good antitumor properties. Brusatol shows great potential in cancer therapy by inhibiting cell proliferation, blocking the cell cycle, promoting tumor cell differentiation, accelerating tumor cell apoptosis, inducing autophagy, suppressing angiogenesis, inhibiting tumor invasion and metastasis, and reversing multidrug resistance. This review summarizes recent updates on the antitumor activity and molecular mechanisms of BT and provides references for future development and clinical translation of BT and its derivatives as antitumor drugs.

Design, synthesis, and anti–tobacco mosaic virus activity evaluation of quinazolinone derivatives containing purine moieties

In this study, a series of quinazolinone derivatives containing purine molecules were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and HRMS (High Resolution Mass Spectrometer). Antiviral bioassays against plant viruses indicated that some target compounds exhibited higher in vivo antiviral activity against tobacco mosaic virus (TMV) than the commercial drug ribavirin. At a concentration of 500 mg/L, compound A2 exhibited good activity against TMV, with therapeutic and protective activity values of 65.2 % and 60.2 %, respectively, and these values were superior to those of ribavirin (50.1 % and 57.2 %, respectively). Among these compounds, A2 demonstrated significant therapeutic bioactivity against TMV in vivo, with an EC50 (half-maximum effective concentration) value of 162.3 mg/L, which was superior to that of ribavirin (314.4 mg/L). In conclusion, quinazolinone derivatives containing purine molecules may provide a basis for further research on antiviral drugs.

Three new flavones from the whole plants of Cassia auriculata Linn. and their antiviral activities

Cassia auriculata, a widely grown medicinal plant in China, has not been fully studied in terms of its secondary metabolites. In our pursuit of new bioactive metabolites from Cassia plants, we conducted a phytochemical reinvestigation on C. auriculata. This investigation resulted in the isolation of three new (1−3) and six known (4−9) flavones. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D NMR techniques. Interestingly, Compounds 1-3 are rare flavones bearing an unusual (4-methylfuran-2-yl)methyl moiety. In addition, Compounds 1-3 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that Compounds 1–3 exhibited potential anti-TMV activities with inhibition rates of 26.8%, 30.5% and 34.6% at a concentration of 20 μM, respectively, and these rates are close to that of the positive control. Compounds 1-9 were also tested for their anti-rotavirus activities. The results revealed that 1–9 exhibited potential anti-rotavirus activity with therapeutic index (TI) values in the range of 13.3–20.8. These values are lower than that of the positive control (with a therapeutic index of 23.4).

Five quinolizidine alkaloids with anti-tobacco mosaic virus activities from two species of Sophora

Three novel matrine-type alkaloids (1–3) and two unprecedented aloperine-type alkaloids (4 and 5) were isolated from the root of Sophora tonkinensis and the seeds of Sophora alopecuroides respectively. Notably, compound 1 possessed an unprecedented 6/5/6 tricyclic skeleton, while compounds 2 and 3 characterized by rare 6/6/5/6 tetracyclic system and 6/6/6/6/6 pentacyclic system respectively. Moreover, compound 4 possessed an unprecedented 6/7/6/6 tetracyclic core, and compound 5 characterized by rare 6/6/6/6 tetracyclic skeleton. Their structures were elucidated by comprehensive spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Biological tests indicated that compound 5 displayed significant anti-tobacco mosaic virus (TMV) activity compared with the positive control ningnanmycin.

Design, synthesis, and antiviral activities evaluation of novel quinazoline derivatives containing sulfonamide moiety

Abstract A series of novel quinazoline derivatives bearing sulfonamide moiety was designed and synthesized, and their structure were characterized by 1H NMR, 13C NMR, and HRMS techniques. Among them, the structure of compound E1 was further confirmed through X-ray single-crystal diffraction analyses. Their anti-Tobacco mosaic virus (TMV) activities were evaluated through half-leaf method. The bioassay results showed that E8 and E19 possess excellent inhibitory activity towards TMV. The EC50 of curative activities, protective activities, and inactivating activities of E8 and E19 are 132.1, 152.8, 57.4 mg/L and 278.0, 165.3, 94.5 mg/L, respectively, which are far superior than Ribavirin (318.2, 201.5, 128.6 mg/L, respectively).

Antiviral activity evaluation and action mechanism of myricetin derivatives containing thioether quinoline moiety.

A variety of myricetin derivatives containing thioether quinoline moiety were designed and synthesized. Their structures of title compounds were determined by 1H NMR, 13C NMR, 19F NMR, and HRMS. Single-crystal X-ray diffraction experiments were carried out with B4. Antiviral activity indicated that some of the target compounds exhibited remarkable anti-tobacco mosaic virus (TMV) activity. In particular, compound B6 possessed significant activity. The half maximal effective concentration (EC50) value of the curative activity of compound B6 was 169.0μg/mL, which was superior to the control agent ningnanmycin (227.2μg/mL). Meanwhile, the EC50 value of the protective activity of compound B6 was 86.5μg/mL, which was better than ningnanmycin (179.2μg/mL). Microscale thermophoresis (MST) indicated that compound B6 had a strong binding capability to the tobacco mosaic virus coat protein (TMV-CP) with a dissociation constant (Kd) value of 0.013μmol/L, which was superior to that of myricitrin (61.447μmol/L) and ningnanmycin (3.215μmol/L). And the molecular docking studies were consistent with the experimental results. Therefore, these novel myricetin derivatives containing thioether quinoline moiety could become potential alternative templates for novel antiviral agents.

Design, synthesis, bioactivity and mechanism of action of novel myricetin derivatives containing amide and hydrazide

A series of myricetin derivatives containing amide and hydrazide were designed and synthesized. All the compounds were characterized by NMR and HRMS. Bioactivity test showed that some of the target compounds had excellent anti-tobacco mosaic virus (TMV) activity. In particular, the median effective concentration (EC50) values of the anti-TMV curative and protective activities of N-(2-(2-(2-((5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-chromen-3-yl)oxy)acetyl)hydrazineyl)-2-oxoethyl)-4-(trifluoromethyl)benzamide (G9) were 202.3 and 164.0 μg/mL respectively, superior to ningnanmycin (329.1, 230.3 μg/mL). Microscale thermophoresis (MST) and molecular docking showed that G9 had an excellent binding affinity with tobacco mosaic virus coat protein (TMV-CP) (Kd = 0.158 ± 0.024 μM), which was better than that of ningnanmycin (Kd = 2.074 ± 0.818 μM). Moreover, there were many interaction forces between G9 and the key amino acid residues of TMV-CP. The chlorophyll content and peroxidase (POD) activity of tobacco leaves treated with G9 increased significantly, indicating that G9 could improve the photosynthesis of tobacco leaves and stimulate the resistance of tobacco leaves to TMV. The insecticidal activity of G9 against Mythimna separata (M. separate) was found to be 95.2% at 200 μg/mL, which was close to bufenozide (100%). The insecticidal activity of myricetin was significantly improved after the introduction of active groups of amide and hydrazide, which could be further explored.

Anti-Tobacco Mosaic Virus Indole Alkaloids from the Nicotiana tabacum-Derived Fungus Aspergillus versicolor

To explore the active metabolites from Aspergillus, we have discovered five undescribed tricyclic or tetracyclic indole alkaloids aspergillines K–O (1–5) and four known analogues (6–9) from the strain of Nicotiana tabacum-derived Aspergillus versicolor YNCA0363. The α-amino group derived from tryptophan in isolates 1–6 was changed to an oxygen atom, which is uncommon in the reported analogues. To the best of our knowledge, 4 and 5 represent the first examples of indole alkaloids possessing an isochromene moiety. Compounds 1 and 3 showed obvious anti-tobacco mosaic virus (TMV) activities with inhibition rates of 43.6% ± 2.2 and 58.5% ± 2.8 at the concentration of 20 μM, respectively, which were significantly higher than that of the positive control. Compound 3 also showed excellent potential of inducing systemic acquired resistance. Furthermore, compound 3 can increase the activities of two reactive oxygen species-scavenging enzymes, peroxidase and superoxide dismutase, and enhance tobacco resistance to TMV. Molecular docking results showed that compound 3 exhibits a stronger interaction with TMV-helicase, and showed higher antiviral activities than others. This work revealed that the above indole alkaloids, especially 3, could induce resistance in tobacco plants against the viral pathogen TMV.

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.

Synthesis and Evaluation of 11-Butyl Matrine Derivatives as Potential Anti-Virus Agents.

Matrine derivatives were reported to have various biological activities, especially the ester, amide or sulfonamide derivatives of matrine deriving from the hydroxyl or carboxyl group at the end of the branch chain after the D ring of matrine is opened. In this work, to investigate whether moving away all functional groups from the C-11 branch chain could have an impact on the bioactivities, such as anti-tobacco mosaic virus (TMV), insecticidal and fungicidal activities, a variety of N-substituted-11-butyl matrine derivatives were synthesized. The obtained bioassay result showed that most N-substituted-11-butyl matrine derivatives had obviously enhanced anti-TMV activity compared with matrine, especially many compounds had good inhibitory activity close to that of commercialized virucide Ningnanmycin (inhibition rate 55.4, 57.8 ± 1.4, 55.3 ± 0.5 and 60.3 ± 1.2% at 500 μg/mL; 26.1, 29.7 ± 0.2, 24.2 ± 1.0 and 27.0 ± 0.3% at 100 μg/mL, for the in vitro activity, in vivo inactivation, curative and protection activities, respectively). Notably, N-benzoyl (7), N-benzyl (16), and N-cyclohexylmethyl-11-butyl (19) matrine derivatives had higher anti-TMV activity than Ningnanmycin at both 500 and 100 μg/mL for the four test modes, showing high potential as anti-TMV agent. Furthermore, some compounds also showed good fungicidal activity or insecticidal activity.

Antitobacco Mosaic Virus Activity of a New Eremophilane Glucoside From the Leaves of Nicotiana tabacum L

A new eremophilane-type sesquiterpene glucoside, 13-hydroxycapsidiol 3- O- β-D-glucoside (1), was isolated from the leaves of Nicotiana tabacum L. The structure of this new metabolite was determined by one-dimensional (1D) and 2D nuclear magnetic resonance (NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and comparison with values reported in the literature. Compound 1 was the second glycosylated eremophilane sesquiterpenoid isolated from plants of the Solanaceae family and exhibited a more potent anti-tobacco mosaic virus (anti-TMV) activity, with an inhibition rate of 39.4% at 20 μM, than the positive control ningnanmycin (34.8%).

Maillard Reaction Products with Anti-Tobacco Mosaic Virus Activities Generated in Processed Thermopsis lanceolata R. Br. Seed Extract.

Six novel Maillard reaction products (MRPs) (1-6) were isolated from the processed Thermopsis lanceolata R. Br. seed extract, along with one biogenetically related intermediate (7). Compounds 1-4 possessed three rare dimerization patterns constructed by cytisine, whereas compounds 5 and 6 represented the first example of the addition products of cytisine and 5,6-dihydroxy-4-hexanolide. Their structures were elucidated by comprehensive spectroscopic data analysis and quantum chemistry calculations including GIAO 13C{1H} NMR and ECD calculation, combined with single-crystal X-ray diffraction analysis. Biologically, compound 3 displayed significant anti-tobacco mosaic virus activity compared with the positive control ningnanmycin.

Isoindolin-1-ones from the stems of Nicotiana tabacum and their antiviral activities

In previous studies, several isoindolin-1-one analogs that exhibited significant anti-tobacco mosaic virus (anti-TMV) activities were isolated from Nicotiana tabacum. Since gene-editing mutants provide a new sample for the discovery of active metabolites, we focused on the stems of YN-18-23 (a mutant N. tabacum for gene editing with the alkaloid metabolic pathway cultivated by Yunnan Tobacco Company), which led to the isolation of four new (1-4) and four known (5-8) isoindolin-1-ones. To the best of our knowledge, nicindole C (3) is the first subclass of isoindolin-1-one bearing a pentacyclic ketone, while nicindole D (4) is the first example of isoindolin-1-one bearing a methyl-pyridin-2-(1H)-one moiety. Compounds 1-4 were tested for their anti-TMV activities, and the results revealed that compounds 1, 3, and 4 exhibited high anti-TMV activities at concentrations of 20μM with inhibition rates of 48.6, 42.8, and 71.5%, respectively. These rates are higher than the inhibition rate of the positive control (33.2%). The mechanistic study of compound 4, which had the highest anti-TMV activity revealed that increased potentiation of defense-related enzyme activities and downregulation of expression of the NtHsp70 protein may induce resistance in tobacco against the viral pathogen TMV. Molecular docking studies also revealed that the isoindolin-1-one substructure is fundamental for anti-TMV activity. The methyl-pyridin-2-(1H)-one moiety in compound 4 and the 2-oxopropyl groups in compounds 1 and 3 at the N-2 position may increase inhibitory activities. This study of the structure-activity relationship is helpful for finding new anti-TMV activity inhibitors. To study whether the isoindolin-1-ones have broader antiviral activities, compounds 1-4 were also tested for their anti-rotavirus activities. Compound 4 exhibited high anti-rotavirus activity with a therapeutic index (TI) value of 20.7. This TI value is close to that of the positive control (20.2).

Isochromenes from the Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor and their anti-tobacco mosaic virus activities

Three new isochromenes, (5-methoxy-7-prenyl-1H-isochromen-3-yl)methanol (1), 3-(3-(hydroxymethyl)-5-methoxy-1H-isochromen-7-yl)propan-1-ol (2), and (5-methoxy-7-methyl-1H-isochromen-3-yl)methanol (3), along with three known analogues (4–6) were isolated from the fermentation products of a Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor. Their structures were elucidated by spectroscopic methods, including extensive 1 D and 2 D NMR techniques. Compounds 1–3 and 6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 46.4%, and this rate is higher than that of positive control. Compounds 1, 3, and 6 also showed potential anti-TMV activity with inhibition rates of 28.6, 30.5, and 26.2%, respectively. The IC50 of compounds 1–3 and 6 were also tested, and showed IC50 values of 49.3, 22.4, 42.2, and 54.1 µM, respectively.

Indole Alkaloids and Chromones from the Stem Bark of Cassia alata and Their Antiviral Activities.

The Cassia (Leguminosae) genus has attracted a lot of attention as a prolific source of alkaloids and chromones with diverse structures and biological properties. The aim of this study is to screen the antiviral compounds from Cassia alata. The extract of the stem bark of this plant was separated using silica gel, MCI, ODS C18, and Sephadex LH-20 column chromatography, as well as semi-preparative HPLC. As a result, three new indole alkaloids, alataindoleins A–C (1–3); one new chromone, alatachromone A (4); and a new dimeric chromone-indole alkaloid, alataindolein D (5) were isolated. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Interestingly, alataindolein D (5) represents a new type of dimeric alkaloid with an unusual N-2−C-16’ linkage, which is biogenetically derived from a chromone and an indole alkaloid via an intermolecular nucleophilic substitution reaction. Compounds 1–5 were tested for their anti-tobacco mosaic virus (TMV) and anti-rotavirus activities, and the results showed that compounds 2–4 showed high anti-TMV activities with inhibition rates of 44.4%, 66.5%, and 52.3%, respectively. These rates were higher than those of the positive control (with inhibition rate of 32.8%). Compounds 1 and 5 also showed potential anti-TMV activities with inhibition rates of 26.5% and 31.8%, respectively. In addition, compounds 1–5 exhibited potential anti-rotavirus activities with therapeutic index (TI) values in the range of 9.75~15.3. The successful isolation and structure identification of the above new compounds provided materials for the screening of antivirus drugs, and contributed to the development and utilization of C. alata.

Two new isoflavones from the roots of Sophora tonkinensis

Two new isoflavones (1 and 2), as well as eight known ones were isolated from the roots of Sophora tonkinensis Gagnep. Compound 1 represents an unprecedented polymerization pattern constructed by isoflavone and cytisine. Their structures were elucidated by comprehensive spectroscopic data analysis, combined with ECD calculations. Compound 1 displayed significant anti-tobacco mosaic virus (TMV) activity compared with the positive control ningnanmycin. Moreover, compound 6 exhibited potent α-glucosidase inhibitory activity with IC50 value of 47.4 mg/L.

Synthesis and Structure–Activity Relationship Studies of Nicot­lactone Analogues as Anti-TMV Agents

AbstractThe synthesis of the originally proposed structure of (±)-nicotlactone A, a potent antiviral lignan with three continuous chiral centers, is reported in 5 steps from methyl acrylate. The key steps of the synthesis included an In-catalyzed regioselective allylation and a Mn-catalyzed Mukaiyama hydration reaction. Our synthetic strategy also enabled us to get the other three epimers and investigate the structure–activity relationship. The NMR data of the synthesized compounds do not match that of the isolated sample, indicating that the structure of nicotlactone A remains to be reassigned. All the synthetic target compounds were evaluated for their anti-tobacco mosaic virus (anti-TMV) activity. Bioassay results indicated that (±)-8-demethylnicotlactone A displayed similar anti-TMV activity to the commercial agent ningnanmycin, thus being a promising candidate or lead compound for developing novel antiviral agents in crop protection.

In Silico Pesticide Discovery for New Anti-Tobacco Mosaic Virus Agents: Reactivity, Molecular Docking, and Molecular Dynamics Simulations

Considerable data are available regarding the molecular genetics of the tobacco mosaic virus. The disease caused by the tobacco mosaic virus is still out of control due to the lack of an efficient functional antagonist chemical molecule. Extensive research was carried out to try to find effective new anti-tobacco mosaic virus agents, however no study could find an effective agent which could completely inhibit the disease caused by the virus. In recent years, molecular docking, combined with molecular dynamics, which is considered to be one of the most important methods of drug discovery and design, were used to evaluate the type of binding between the ligand and its protein enzyme. The aim of the current work was to assess the in silico anti-tobacco mosaic virus activity for a selection of 41 new and 2 reference standard compounds. These compounds were chosen to examine their reactivity and binding efficiency with the tobacco mosaic virus coat protein (PDB ID: 2OM3). A comparison was made between the activity of the selected compounds and that for ningnanmycin and ribavirin, which are common inhibitors of plant viruses. The simulation results obtained from the molecular docking and molecular dynamics showed that two compounds of the antofine analogues could bind with the tobacco mosaic virus coat protein receptor better than ningnanmycin and ribavirin.

Cyclopiazonic acid type indole alkaloids from Nicotiana tabacum-derived fungus Aspergillus versicolor and their anti-tobacco mosaic virus activities

Indole alkaloids have attracted widespread attention of chemists and biologists. Therefore, the aim of this study is to screen more bioactivities indole alkaloids from the microorganisms. In this study, five undescribed CPA-type indole alkaloids, aspergillines F–J, and three known CPA-type indole alkaloids, aspergilline A, aspergilline C, and cyclopiamide E, were obtained from the Nicotiana tabacum-derived fungus Aspergillus versicolor. Notably, aspergillines F and G represent the first examples of indole alkaloids with a benzo[cd]indol-2(1H)-one skeleton, and aspergilline J is also the firstly obtained indole alkaloids bearing a N-1-(2-(1H-imidazole-5-yl)ethyl) moiety. Aspergillines F–J and cyclopiamide E were tested for their anti-TMV activities, and the results revealed that aspergillines G and J exhibited obvious anti-TMV activities with inhibition rates of 41.2 and 56.8% at the concentration of 20 μM, respectively. These rates are high than that of positive control (with inhibition rate of 32.5%). In addition, the molecular docking studies for the isolated CPA-type indole alkaloids may also reveal that the benzo[cd]indol-2(1H)-one substructure is the fundamental for anti-TMV activity and the oxygen-containing substituent groups at C-19 also increases the inhibitory activity. This study of structure-activity relationship is helpful to find new anti-TMV activity inhibitors.

Diterpenes from oriental tobacco Nicotiana tabacum ‘YNOTBS1’ and their bioactivities

Seven diterpenes including two new seco-cembranoid basmanoids A (1) and B (2), and two new labdane basmadanes A (3) and B (4), and three known compounds (–)-dehydro-nor-ambreinolid (5), (13E)-8-hydroxy-13-labden-12-one (6), and 14,15,16-dinor-7-oxolabda-8-ene-13-oic acid (7) were isolated from oriental tobacco Nicotiana tabacum ‘YNOTBS1’. Compounds 1–3 and 5 showed anti-tobacco mosaic virus (TMV) activity with inhibition rates in the range of 30–69% at the concentration of 1 mg/mL. However, none of them exhibited any inhibitory effects against nitric oxide (NO) production in LPS and IFN-γ-induced RAW 264.7 murine macrophages and anti-proliferative activities against cancer cell lines SMMC-7721 and A-549.