Design,synthesis and anti-TMV activities of novel chromone derivatives containing dithioacetal moiety

Thirty-five novel chromone derivatives containing dithioacetal moiety were designed, synthesized, and their anti-TMV activities were evaluated through half-leaf method. The results showed compound c23 illustrates highly curative, protective and inactivating activities against TMV at 500 mg/L, with the values of 68.8%, 58.8%, 86.0% respectively, which were superior to that of Ribavirin (42.3%, 49.8%, 68.4%, respectively) and similar to that of Ningnanmycin (59.4%, 52.4%, 88.4%, respectively). The EC₅₀ value of inactivating activities of compound c23 is 9.3 mg/L, which was better than that of Ribavirin (135.2 mg/L), and equivalent to that of Ningnanmycin (8.8 mg/L). Furthermore, compound c23 can destroy the integrity of TMV-CP, resulting in reduced infectivity of TMV. Meanwhile, compound c23 can combine with TMV protein coat and hydrolyze TMV protein coat to impact the process of self-assembling of TMV, with the association constant (K_d) 4.5 mg/L. This finding suggests that chromone derivatives containing dithioacetal moiety can be used as new antiviral agent.     

Antiviral properties and interaction of novel chalcone derivatives containing a purine and benzenesulfonamide moiety

A new concise and facile method was explored to synthesize a series of novel chalcone derivatives containing a purine and benzenesulfonamide moiety and their antiviral properties were evaluated against TMV and CMV. Biological assays indicated that several of the derivatives exhibited significant anti-TMV and anti-CMV activities in vivo. In particular, compound d2 displayed excellent inactivating activity against TMV, with the EC₅₀ value of 51.65?μg/mL, which was better than that of ribavirin (150.45?μg/mL). Molecular docking showed that there are four hydrogen bonds between compound d2 and TMV coat protein (TMV-CP). Compound d2 demonstrated strong binding capacity to TMV-CP with K_a?=?1.58?×?10⁵?L/mol and K_d?=?12.16?μM. These findings indicated that chalcone derivatives are worthy of further research and development as templates for new antiviral agents.     

Synthesis,antiviral activity,and molecular docking study of trans-ferulic acid derivatives containing acylhydrazone moiety

In this study, we report the synthesis and antiviral activity of trans-ferulic acid derivatives containing acylhydrazone moiety. Biological tests demonstrated that most target compounds showed potent antiviral activity against tobacco mosaic virus (TMV). Compound D4 showed remarkable inactivating activity with EC₅₀ value of 36.59 μg/mL, which was obviously superior to ribavirin (126.05 μg/mL). Molecular docking results revealed that compound D4 exhibited the optimal combining capacity with five hydrogen bonds to different amino-acid residues of TMV coat protein (TMV-CP). Docking results were consistent with the inactivating activity of target compounds against TMV.     

Design,synthesis, anti-TMV,fungicidal, and insecticidal activity evaluation of 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid derivatives based on virus inhibitors of plant sources

By drawing the creation ideas of botanical pesticides, a series of tetrahydro-β-carboline-3-carboxylic acid derivatives were designed and synthesized, and first evaluated for their anti-TMV, fungicidal and insecticidal activities. Most of these derivatives exhibited good antiviral activity against TMV both in vitro and in vivo. Especially, the activities of compounds 8 and 15 in vivo were higher than that of ribavirin. The compound 8 exhibited more than 70% fungicidal activities against Cercospora arachidicola Hori, Alternaria solani, Bipolaris maydis, and Rhizoctonia solani at 50 mg/kg, compounds 16 and 20 exhibited more than 60% insecticidal activities against Mythimna separate and Ostrinia nubilalis.     

Pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety as potential antiviral agents

A series of pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety were synthesized, characterised, and evaluated for their activity against tobacco mosaic virus (TMV). Biological assays indicated that several of the derivatives exhibited significant activity against TMV. In particularly, compounds 5y and 5aa displayed excellent inactivating activity against TMV, with half maximal effective concentration (EC₅₀) values of 70.3 and 53.65?μg/mL, respectively, which were much better than that of ribavirin (150.45?μg/mL), and 5aa was superior to ningnanmycin (EC₅₀?=?55.35?μg/mL). Interactions of compounds 5y and 5aa with TMV coat protein (TMV-CP) were investigated using microscale thermophoresis and molecular docking. Compounds 5y and 5aa displayed strong binding capability to TMV-CP with dissociation constant (K_d) values of 22.6 and 9.8?μM, respectively. These findings indicate that pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base may be potential antiviral agents.     

C ring may be dispensable for β-carboline: Design,synthesis, and bioactivities evaluation of tryptophan analog derivatives based on the biosynthesis of β-carboline alkaloids

According to our previous work and the latest research on the biosynthesis of β-carboline, and using the reverse thinking strategy, tryptophan, the biosynthesis precursor of β-carboline alkaloids, and their derivatives were synthesized, and their biological activities and structure–activity relationships were studied. This bioassay showed that these compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV); especially (S)-2-amino-3-(1H-indol-3-yl)-N-octylpropanamide (4) (63.3 ± 2.1%, 67.1 ± 1.9%, 68.7 ± 1.3%, and 64.5 ± 3.1%, 500 μg/mL) exhibited the best antiviral activity both in vitro and in vivo. Compound 4 was chosen for the field trials and the acute oral toxicity test, the results showed that the compound exhibited good anti-TMV activity in the field and low acute oral toxicity. We also found that these compounds showed antifungal activities and insecticidal activities.     

Synthesis and anti-TMV activity of novel β-amino acid ester derivatives containing quinazoline and benzothiazole moieties

Here, a series of β-amino acid ester derivatives containing quinazoline and benzothiazoles was synthesized and evaluated for anti-tobacco mosaic virus (TMV) activity. The compounds 3n, 3o, 3p and 3q showed good antiviral activity against TMV at a concentration of 500 μg/mL, with curative rates of 55.55%, 52.32%, 52.77% and 50.91%, respectively, and protection rates of 52.33%, 55.96%, 54.21% and 50.98%, respectively. These values were close to those of the commercially available antiviral agent ningnanmycin (which has curative and protection rates of 55.27% and 52.16%, respectively). To our knowledge, this is the first report of the anti-TMV activity of β-amino acid ester derivatives containing quinazoline and benzothiazoles moieties; the results indicate that these novel compounds can potentially be used as protective agents against TMV diseases.     

Antiviral flavones from the leaves of Nicotiana tabacum

Three new flavones, tabaflavones A–C (1–3), together with three known flavones (4–6), were isolated from the leaves of Nicotiana tabacum. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1–6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed compound 1 exhibited moderate anti-TMV activity with inhibition rate of 29.2%, which is close to that of the positive control. The other compounds also showed the anti-TMV activities with inhibition rates in the range of 14.2–20.8%.     

Isoflavones from the roots and stems of Nicotiana Tabacum and their anti-tobacco mosaic virus activities

Two new isoflavones, 7-hydroxy-6,3′,4′,5′-tetramethoxy-isoflavone (1) and 6-hydroxy-7,3′,4′,5′-tetramethoxy-isoflavone (2), together with seven known isoflavones were isolated from the roots and stems of Nicotiana tabacum. Their structures were determined by means of HRESIMS, extensive 1D and 2D NMR spectroscopic studies and chemical evidences. The anti-tobacco mosaic virus (anti-TMV) activities of the isoflavones were also evaluated. The results reveal that compound 9 shows high anti-TMV activity, compound 2 shows moderate anti-TMV activity, and compounds 1, 3–8 show weak anti-TMV activities.     

Design,synthesis and antifungal evaluation of novel pyrazole carboxamides with diarylamines scaffold as potent succinate dehydrogenase inhibitors

Sixteen novel pyrazole carboxamides with diarylamines scaffold were designed, synthesized and characterized in detail via ¹H NMR, ¹³C NMR and ESI-HRMS. Preliminary bioassays showed that some of the target compounds exhibited good antifungal activity against Rhizoctonia solani, Fusarium oxysporum, Phytophthora infestans and Fusarium graminearum. Among them, compound 1c exhibited the highest antifungal activities against R. solani in vitro with EC₅₀ value of 0.005?mg/L, superior to the commercially available fungicide fluxapyroxad (EC₅₀?=?0.033?mg/L). And compound 1c (IC₅₀?=?0.034?mg/L) showed higher inhibition abilities against succinate dehydrogenase than fluxapyroxad (IC₅₀?=?0.037?mg/L). This study suggests that compound 1c could be regarded as a potential succinate dehydrogenase inhibitor.     

Three new isobenzofurans from Lavandula angustifolia and their bioactivities

Three new isobenzofurans, lavandulactones A–C (1–3), together with three known ones (4–6), were isolated from the whole herb of Lavandula angustifolia. Their structures were established on the basis of detailed spectroscopic analysis (1D- and 2D-NMR, HRESIMS, UV, and IR) and comparison with data reported in the literature. New isolates were evaluated for their anti-tobacco mosaic virus (TMV) activities and cytotoxicity activities. The results revealed that compounds 1–3 showed high anti-TMV activity with inhibition rate of 31.8, 29.6 and 33.4%, respectively. These rates are higher than that of positive control. Compounds 1–3 also showed weak inhibitory activities against some tested human tumor cell lines with IC₅₀ values ranging from 1.5 to 5.7 μM.     

Screening of chalcone analogs with anti-depressant,anti-inflammatory,analgesic, and COX-2-inhibiting effects

A group of 2-methyl-4-phenylquinoline-chalcone analogs (2a–2x) was synthesized and investigated for anti-depressant, anti-inflammatory, and analgesic effects as cyclooxygenase-2 inhibitors. Pharmacological experiments identified 24 analogs that exhibited anti-depressant, anti-inflammatory, and analgesic activities. In particular, compounds 2c, 2k, and 2w markedly shortened immobility times and exhibited the most anti-depressant activity. In addition, the mechanisms of action of the analogs 2c, 2k, and 2w were likely related to increased serotonin levels in the central nervous system. Compounds 2c, 2k, and 2w displayed reasonable cyclooxygenase-2 inhibitory effects (IC₅₀ values from 0.21 to 0.29 µmol/L) similar to celecoxib (IC₅₀: 0.19 µmol/L) in vitro. A molecular docking study of compound 2k also was conducted.     

First Discovery and Stucture-Activity Relationship Study of Phenanthroquinolizidines as Novel Antiviral Agents against Tobacco Mosaic Virus (TMV)

A series of phenanthroquinolizidine alkaloids 1–24 were prepared and first evaluated for their antiviral activity against tobacco mosaic virus (TMV). The bioassay results showed that most of these compounds exhibited good to excellent in vivo anti-TMV activity, of which compounds 1, 2, 15 and 16 displayed significantly higher activity than (R)-antofine and commercial Ningnanmycin at the same test condition. The substituents on the phenanthrene moiety play an important role for maintaining high in vivo antiviral activity. The introduction of 6-hydroxyl, which is proposed to interact with TMV RNA, did increased anti-TMV activity. The 14aR-configuration was confirmed to be the preferred antiviral configuration for phenanthroquinolizidine alkaloids. Introduction of hydroxy group at 15-position of phenanthroquinolizidine alkaloids increased activity for S-configuration but decreased activity for R-configuration. Present study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.     

Chromones from the stems of Cassia fistula and their anti-tobacco mosaic virus activities

Three new chromones, 5-methoxy-2,2-dimethyl-7-(2-oxopropyl)-2,3-dihydrochromen-4-one (1), 5-methoxy-2,2-dimethyl-8-(2-oxopropyl)-2,3-dihydrochromen-4-one (2), and 1-(3,4-dihydro-5-methoxy-2,2-dimethyl-2H-chromen-7-yl)propan-2-one (3), together with four known chromones (4–7) were isolated from the stems of Cassia fistula. Their structures were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1–5 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 5 exhibited high anti-TMV activity with inhibition rate of 30.8% at a concentration of 20 μM. The other compounds also exhibited potential anti-TMV activities with inhibition rates in the range of 15.6–22.1% at the same concentration.     

Design,synthesis, antiviral activity,and SARs of 13a-substituted phenanthroindolizidine alkaloid derivatives

On the basis of our previous structure–activity relationship (SAR) and antiviral mechanism studies, a series of 13a-substituted phenanthroindolizidine alkaloid analogues (3a–16a, 3b, 4b, 6b, 7b, 10b, and 14b) were designed targeting tobacco mosaic virus (TMV) RNA, synthesized, and evaluated for their antiviral activity against TMV for the first time. The bioassay results showed that most of the synthesized compounds (such as 4a, 6a, 7a, 11a, 14a, 6b, and 14b) exhibited good to excellent antiviral activity against TMV both in vitro and in vivo. Especially, for inactivation effect and curative effect, compounds 4a, 6a, 7a, 11a, 14a, and 14b showed higher activity at both concentrations (500 μg mL⁻¹ and 100 μg mL⁻¹) than commercial Ningnanmycin. Preliminary SARs showed that the substituted groups with hydrogen donor at 13a position were found to be favorable for keeping high antiviral activity. The present work demonstrates that 13a-substituted phenanthroindolizidines can be used as possible lead compounds for developing anti-TMV agents.     

Design,synthesis and algicides activities of thiourea derivatives as the novel scaffold aldolase inhibitors

By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) were de novo discovered based on the active site of fructose-1, 6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of the N-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14～L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1～L13). Especially, compound L14 not only shows higher CyFBA-II activity (K_i?=?0.65?μM), but also exhibits most potent in vivo activity against Synechocystis sp. PCC 6803 (EC₅₀?=?0.09?ppm), higher (7-fold) than that of our previous inhibitor (EC₅₀?=?0.6?ppm). The binding modes of compound L14 and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).     

Design,synthesis and biological evaluation of bitopic arylpiperazine-hexahydro-pyrazinoquinolines as preferential dopamine D3 receptor ligands

Three series of bitobic arylpiperazine-phenyl-hexahydropyrazinoquino- lines analogues were designed, synthesizedand evaluated as a novel class of selective ligands for the dopamine D3 receptor. Compounds 15a (K_i of 11.7 ± 1.8 and 373 nM at D3 and D2, respectively), 15c (K_i of 5.49 and 264 nM at D3 and D2, respectively), 15e (K_i of 14.9 and 325 nM at D3 and D2, respectively), 15i (K_i of 13.8 and 401 nM at D3 and D2, respectively) and 15l (K_i of 13.6 and 870 nM at D3 and D2, respectively) were found to demonstrate good binding affinity and selectivity, and especially compound 15c showeda similar binding affinity and selectivity compared with the contrast drug BP897.     

Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates

A series of novel 1,3,4-oxadiazole/thiadiazole–chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04 μM, respectively, which were comparable to that of Ninnanmycin (6.78 μM) and even better than that of Ribavirin (99.25 μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC₅₀ values of 33.66, 33.97, 33.87 and 30.57 µg/mL, respectively, which were comparable to that of Ningnanmycin (36.85 µg/mL) and superior to that of Ribavirin (88.52 µg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.     

Anti-tobacco mosaic virus phenylpropanoids from the stems of Nicotiana tabacum

Three new phenylpropanoids, 3-(6-methoxy-3-oxo-1, 3-dihydroisobenzofuran-5-yl)-3-oxopropyl acetate (1), 3-hydroxy-1-(6-methoxy-1, 3-dihydroisobenzofuran-5-yl)propan-1-one (2), and 3-hydroxy-1-(6- methyl-1, 3-dihydroisobenzofuran-5-yl)propan-1-one (3), together with three known phenylpropanoids (4–6) were isolated from the stems of Nicotiana tabacum. Their structures were examined using different spectroscopic techniques, including extensive 1D- and 2D NMR. Compounds 1–6 were also evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The anti-TMV results demonstrated that compounds 1 and 6 exhibited high anti-TMV activities, with inhibition rates of 34.6 and 35.4%, both of which were higher than the positive control (32.5%). The other compounds (2–5) also had anti-TMV activities, with inhibition rates between 16.8 and 28.6%.     

Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis,cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC₅₀ 6.78?μM and 5.25?μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC₅₀ 0.76?μM.