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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 (EC 50 ) value (20.5 ∼g mL −1 ) was better even than commercial ningnanmycin (23.2 ∼g 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.

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.

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 (K d of 19.8 ± 7.3 μM) than ningnanmycin (K d 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.

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 ( H R adjusted = 1.08 , 95% CI: 1.03 to 1.14, P = 0.002 ; R R adjusted = 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 ( H R adjusted = 1.10 ; 95% CI: 1.01 to 1.21; P = 0.034 ) and without ( R R adjusted = 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.