TMV-CP based rational design and discovery of α-Amide phosphate derivatives as anti plant viral agents.

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.

Modular synthesis of fluorinated 2H-thiophenes via [4 + 1] cyclization of enaminothiones.

An efficient and straightforward synthetic method for constructing trifluoromethyl 2H-thiophenes through [4 + 1] cycloaddition of enaminothiones with trifluoromethyl N-tosylhydrazones has been disclosed. The cycloaddition platforms were found to be compatible with a broad substrate scope and to show high regio- and stereo-selectivities under very mild reaction conditions such as room temperature, neutral media and low loading of catalyst.

The proteomics and metabolomics studies of GZU001 on promoting the Merisis of maize (Zea mays L.) roots.

BACKGROUND: Plant growth regulators are chemicals that regulate plant growth and development, which can regulate hormonal balance and affect plant growth, thereby increasing crop yield and improving crop quality. Our studies have revealed a new compound, GZU001, which could be used as a plant growth regulator. This compound has been observed to affect root elongation in maize significantly. However, the exact mechanism of this phenomenon is still being investigated. RESULTS: Metabolomics and proteomics were used in unison in this study to explore the response pathway and regulation mechanism of GZU001 in promoting maize root elongation. From the appearance, we can see that both roots and plants of maize treated with GZU001 are significantly improved. Maize root metabolism revealed 101 differentially abundant proteins and 79 differentially expressed metabolites. The current study identified altered proteins and metabolites associated with physiological and biochemical processes. GZU001 treatment has been demonstrated to promote primary metabolism, essential for carbohydrates, amino acids, energy, and secondary metabolism. The result suggests that the stimulation of primary metabolism is beneficial for the growth and development of maize and plays a significant role in sustaining metabolism and growth. CONCLUSIONS: This study recorded the changes of related proteins and metabolites in maize roots after GZU001 treatment and provided evidence for this compound's action mode and mechanism in plants.

Analysis of Therapeutic Effect of Elderly Patients with Severe Heart Failure Based on LSTM Neural Model.

In recent years, cardiovascular-related diseases have become the "number one killer" threatening human life and health and have received much attention. The timely and accurate detection and diagnosis of arrhythmias and heart failure are relatively common heart diseases, which are of great social value and research significance in improving people's quality of life by providing early treatment or intervention for those who are at risk. Based on this, this paper proposes a deep learning network architecture based on the combination of long- and short-term memory networks and deep residual neural networks for the automatic detection of heart failure. A total of 60 elderly patients with severe heart failure treated in the emergency department of our hospital from August 2019 to August 2021 were selected as the sample subjects of this study. The treatment outcomes and prognostic quality of life of the two groups of patients were compared and analyzed. Based on the unbiased test method, the accuracy of the proposed method on the authoritative open continuous heart rate database PhysioNet was 99.67% (data length 500), 98.84% (data length 1000), and 96.63% (data length 2000). This indicates that the network model can well extract the high-dimensional features of continuous heart rate and improve the accuracy of the classification model. The LSTM neural model proposed in this paper may be able to provide richer information on heart health status for portable ECG detection systems, which have very important clinical value and social significance.

A briefly overview of the research progress for the abscisic acid analogues.

Abscisic acid (ABA) is an important plant endogenous hormone that participates in the regulation of various physiological processes in plants, including the occurrence and development of somatic embryos, seeddevelopment and dormancy. ABA is called "plant stress resistance factor", while with the limitation of the rapid metabolic inactivation and photoisomerization inactivation of ABA for its large-scale use. Understanding the function and role of ABA in plants is of great significance to promote its application. For decades, scientists have conducted in-depth research on its mechanism of action and signaling pathways, a series of progress were achieved, and hundreds of ABA analogues (similar in structure or function) have been synthesized to develop highly active plant growth regulators and tools to elucidate ABA perception. In this review, we summarize a variety of ABA analogues, especially the ABA receptor analogues, and explore the mechanisms of ABA action and catabolism, which will facilitate the development of novel ABA analogues with high biological activities.

Trifluoromethylpyridine thiourea derivatives: design, synthesis and inhibition of the self-assembly of tobacco mosaic virus particles.

BACKGROUND: Devastating plant virus diseases leading to bad harvests and lower quality of crops have made feeding the beyond seven billion population a huge challenge. Nevertheless, growing resistance and cross resistance of crop protection agents have made this challenge harder. Therefore, an efficient crop protection agent with novel structure and mode of action showing higher efficiency and eco-friendly is urgently needed. RESULTS: The coat protein (CP) of a virus is a potential target for the discovery of new antiviral agents. Antiviral molecules can inhibit infection by obstructing the assembly of virus particles. A series of novel phthalamide-like thiourea derivatives containing trifluoromethylpyridine was designed and synthesized. Most of the compounds exhibited good antiviral activity against tobacco mosaic virus (TMV). Compound 7b showed notable curative, protective and inactivation activities against TMV. Its inactivation half-maximal effective concentration (EC50 ) value (20.5 µg mL-1 ) was better even than commercial ningnanmycin (23.2 µg mL-1 ). Compound 7b also had stronger TMV-CP binding ability than ningnanmycin and destroyed the external shape of TMV particles and hindered the self-assembly of TMV-CP and TMV-RNA. CONCLUSION: These phthalamide-like thiourea derivatives especially compound 7b containing trifluoromethylpyridine are potential lead compounds and inhibitors of TMV particle self-assembly. © 2021 Society of Chemical Industry.

Trifluoromethylpyridine 1,3,4-Oxadiazole Derivatives: Emerging Scaffolds as Bacterial Agents.

A new class of trifluoromethylpyridine 1,3,4-oxadiazole derivatives (6a-6v) was obtained, and their antibacterial activities were evaluated. Some of them exhibited good activity, particularly 6a, which had the highest in vitro activity against Ralstonia solanacearum (R. solanacearum) and Xanthomonas axonopodis pv. citri (Xac). The half-maximal effective concentrations (EC50) were 26.2 and 10.11 µg/mL, respectively, which were lower than those of commercial thiodiazole copper (97.2 and 35.3 µg/mL, respectively). Furthermore, 6q showed much higher activity against Xanthomonas oryzae pv. oryzae (Xoo) with an EC50 value of 7.2 µg/mL; this was superior to bismerthiazol (57.2 µg/mL). Collectively, our findings provide a foundation for the development of trifluoromethylpyridine 1,3,4-oxadiazole derivatives.

Design, Synthesis, and Mechanism of Antiviral Acylurea Derivatives Containing a Trifluoromethylpyridine Moiety.

Novel acylurea derivatives 7a-7ab were designed and synthesized by linking the active substructures trifluoromethylpyridine and anthranilic diamide via an acylurea bridge. Most of the title compounds exhibited good activity against tobacco mosaic virus (TMV), particularly compound 7x (EC50 of 211.8 µg/mL), which showed much higher curative activity than ningnanmycin (EC50 of 389.8 µg/mL), and compound 7ab, which showed excellent inactivation activity (EC50 of 36.1 µg/mL), similar to ningnanmycin (EC50 of 23.2 µg/mL). The preliminary mechanism of these derivatives was investigated. Autodocking analysis revealed that compounds 7x and 7ab had good affinity for TMV coat protein (TMV CP), with low binding energies (-7.86 and -8.59 kcal/mol) comparable to ningnanmycin (-8.75 kcal/mol). Molecular dynamics simulation showed that compound 7x had a stable system structure with a better binding free energy (-32.94 kcal/mol) than ningnanmycin (-25.62 kcal/mol). Microscale thermophoresis showed that compound 7x bound more strongly to TMV CP (Kd of 19.8 ± 7.3 µM) than ningnanmycin (Kd of 21.2 ± 7.3 µM). Transmission electron microscopy and self-assembly experiments demonstrated that compounds 7x and 7ab significantly obstructed the self-assembly of TMV RNA and TMV CP. This new acylurea derivative has excellent antiviral activity by targeting TMV CP and inhibiting TMV self-assembly and can be considered a candidate for antiviral applications.

Synthesis of trans- methyl ferulate bearing an oxadiazole ether as potential activators for controlling plant virus.

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.

Meta-analysis: Early Age at Natural Menopause and Risk for All-Cause and Cardiovascular Mortality.

AIMS: The aim of this meta-analysis was to comprehensively evaluate the association of early age at natural menopause with the risk for all-cause and cardiovascular mortality. METHODS: Literature retrieval was done on August 4, 2020. Article selection and data extraction were completed independently and in duplicate. Early age at natural menopause was grouped into premature menopause (<40 years), early menopause (40-44 years), and relatively early menopause (45-49 years). Effect-size estimates are summarized as hazard ratio (HR) or relative risk (RR) with 95% confidence interval (CI). RESULTS: Sixteen articles involving 321,233 women were meta-analyzed. Overall analyses revealed a statistically significant association of early age at natural menopause with all-cause mortality risk (HRadjusted = 1.08, 95% CI: 1.03 to 1.14, P = 0.002; RRadjusted = 1.05, 95% CI 1.01 to 1.08, P = 0.005), but not with cardiovascular mortality risk. In dose-response analyses, the association with all-cause mortality was significant for premature menopause with (HRadjusted = 1.10; 95% CI: 1.01 to 1.21; P = 0.034) and without (RRadjusted = 1.34; 95% CI: 1.08 to 1.66; P = 0.007) considering follow-up intervals. As for cardiovascular mortality, marginal significance was noted for premature menopause after considering follow-up intervals (HR = 1.09; 95% CI: 1.00-1.19; P = 0.045). Subgroup analyses indicated that gender, country, and follow-up periods were possible causes of heterogeneity. There was an overall low probability of publication bias. CONCLUSIONS: Our findings indicate that premature menopause is a promising independent risk factor for both all-cause and cardiovascular mortality.

Design, Synthesis, and Bioactivity of α-Ketoamide Derivatives Bearing a Vanillin Skeleton for Crop Diseases.

A series of novel α-ketoamide derivatives bearing a vanillin skeleton were designed and synthesized. Bioactivity tests on virus and bacteria were performed. The results indicated that some compounds exhibited excellent antitobacco mosaic virus (TMV) activities, such as compound 34 exhibited an inactivation activity of 90.1% and curative activity of 51.8% and compound 28 exhibited a curative activity of 54.8% at 500 µg mL-1, which is equivalent to that of the commercial ningnanmycin (inactivation of 91.9% and curative of 51.9%). Moreover, the in vitro antibacterial activity test illustrated that compounds 2, 22, and 33 showed much higher activities than commercial thiodiazole copper, which could be used as lead compounds or potential candidates. The findings of transmission electron microscopy and molecular docking indicated that the synthesized compounds exhibited strong and significant binding affinity to the TMV coat protein and could obstruct the self-assembly and increment of TMV particles. This study revealed that α-ketoamide derivatives bearing a vanillin skeleton could be used as a novel potential pesticide for controlling the plant diseases.

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 (Kd) 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.