Discovery of Highly Efficient Novel Antifungal Lead Compounds Targeting Succinate Dehydrogenase: Pyrazole-4-carboxamide Derivatives with an N-Phenyl Substituted Amide Fragment.

Developing environmentally friendly fungicides is crucial to tackle the issue of rising pesticide resistance. In this study, a series of novel pyrazole-4-carboxamide derivatives containing N-phenyl substituted amide fragments were designed and synthesized. The structures of target compounds were confirmed by 1H NMR, 13C NMR, and HRMS, and the crystal structure of the most active compound N-(1-(4-(4-(tert-butyl)benzamido)phenyl)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide (U22) was further determined by X-ray single-crystal diffraction. The bioassay results indicated that the 26 target compounds possessed good in vitro antifungal activity against Sclerotinia sclerotiorum with EC50 values for compounds U12, U13, U15, U16, U18, U22, and U23 being 4.17 ± 0.46, 8.04 ± 0.71, 7.01 ± 0.71, 12.77 ± 1.00, 8.11 ± 0.70, 0.94 ± 0.11, and 9.48 ± 0.83 µg·mL-1, respectively, which were the similar to controls bixafen (6.70 ± 0.47 µg·mL-1), fluxapyroxad (0.71 ± 0.14 µg·mL-1), and pydiflumetofen (0.06 ± 0.01 µg·mL-1). Furthermore, in vivo antifungal activity results against S. sclerotiorum indicated that compounds U12 (80.6%) and U22 (89.9%) possessed excellent preventative efficacy at 200 µg·mL-1, which was the same as the control pydiflumetofen (82.4%). Scanning electron microscopy and transmission electron microscopy studies found that the compound U22 could destroy the hyphal morphology and damage mitochondria, cell membranes, and vacuoles. The results of molecular docking of compound U22 and pydiflumetofen with succinate dehydrogenase (SDH) indicated they interact well with the active site of SDH. This study validated our approach and design strategy to produce compounds with an enhanced biological activity as compared to the parent structure.

Novel Dioxolane Ring Compounds for the Management of Phytopathogen Diseases as Ergosterol Biosynthesis Inhibitors: Synthesis, Biological Activities, and Molecular Docking.

Thirty novel dioxolane ring compounds were designed and synthesized. Their chemical structures were confirmed by 1H NMR, HRMS, and single crystal X-ray diffraction analysis. Bioassays indicated that these dioxolane ring derivatives exhibited excellent fungicidal activity against Rhizoctonia solani, Pyricularia oryae, Botrytis cinerea, Colletotrichum gloeosporioides, Fusarium oxysporum, Physalospora piricola, Cercospora arachidicola and herbicidal activity against lettuce (Lactuca sativa), bentgrass (Agrostis stolonifera), and duckweed (Lemna pausicostata). Among these compounds, 1-((2-(4-chlorophenyl)-5-methyl-1,3-dioxan-2-yl)methyl)-1H-1,2,4-triazole (D17), 1-(((4R)-2-(4-chlorophenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole (D20), 1-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxan-2-yl)methyl)-1H-1,2,4-triazole (D22), and 1-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole (D26) had broad spectrum fungicidal and herbicidal activity. The IC50 values against duckweed were 20.5 ± 9.0, 14.2 ± 6.7, 24.0 ± 11.0, 8.7 ± 3.5, and 8.0 ± 3.1 µM for D17, D20, D22, and D26 and the positive control difenoconazole, respectively. The EC50 values were 7.31 ± 0.67, 9.74 ± 0.83, 17.32 ± 1.23, 11.96 ± 0.98, and 8.93 ± 0.91 mg/L for D17, D20, D22, and D26 and the positive control difenoconazole against the plant pathogen R. solani, respectively. Germination experiments with Arabidopsis seeds indicated that the target of these dioxolane ring compounds in plants is brassinosteroid biosynthesis. Molecular simulation docking results of compound D26 and difenoconazole with fungal CYP51 P450 confirmed that they both inhibit this enzyme involved in ergosterol biosynthesis. The structure-activity relationships (SAR) are discussed by substituent effect, molecular docking, and density functional theory analysis, which provided useful information for designing more active compounds.

Synthesis, Crystal Structure, Herbicidal Activity, and SAR Study of Novel N-(Arylmethoxy)-2-chloronicotinamides Derived from Nicotinic Acid.

Nicotinic acid, also known as niacin, is a natural product, which is widely found in plants and animals. To discover novel natural-product-based herbicides, a series of N-(arylmethoxy)-2-chloronicotinamides were designed and synthesized. Some of the new N-(arylmethoxy)-2-chloronicotinamides exhibited excellent herbicidal activity against Agrostis stolonifera (bentgrass) at 100 µM. Compound 5f (2-chloro-N-((3,4-dichlorobenzyl)oxy)nicotinamide) possessed excellent herbicidal activity against Lemna paucicostata (duckweed), with an IC50 value of 7.8 µM, whereas the commercial herbicides clomazone and propanil had values of 125 and 2 µM, respectively. The structure-activity relationships reported in this paper could be used for the development of new herbicides against monocotyledonous weeds.

[Study on improvement provided by water extracts of Polygoni Multiflori Radix and Polygoni Multiflori Radix Praeparata on non-alcoholic steatohepatitis in mice induced by MCD].

This study aims to observe the improvement of non-alcoholic steatohepatitis(NASH) after using water extracts of Polygoni Multiflori Radix and Polygoni Multiflori Radix Praeparata and explore their preliminary mechanism. Mice were fed with methionine-choline-deficent diet(MCD) for 6 weeks for modeling, and mice were orally given with 50, 100, 200 mg·kg~(-1) of Polygoni Multiflori Radix water extract(PMRWE) or Polygoni Multiflori Radix Praeparata water extract(PMRPWE) at the last 4 weeks. During the whole experimental procedure, the body weight changes of the mice were monitored and recorded. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) activities were detected; liver histopathological evaluation and NAFLD activity score(NAS) calculation were conducted, and the levels of reactive oxygen species(ROS) in liver tissues were analyzed. The contents of triglyceride(TG) and non-esterified fatty acids(NEFA) in liver tissues were detected, and oil red O staining of the liver tissues was conducted and observed. Quantitative polymerase chain reaction(qPCR) was used to detect hepatic mRNA expression of ß-oxidation-related genes in mice. The results showed that PMRWE(100, 200 mg·kg~(-1)) and PMRPWE(50, 100, 200 mg·kg~(-1)) alleviated liver damage in MCD-induced NASH in mice. PMRWE(100, 200 mg·kg~(-1)) and PMRPWE(50, 100, 200 mg·kg~(-1)) reduced hepatic li-pid accumulation in mice with NASH. Different doses of PMRPWE inversed the decreased hepatic mRNA expression of ß-oxidation-related genes in mice with NASH. This study indicated that PMRPWE and PMRWE could ameliorate MCD-induced NASH in mice by promoting fatty acid ß oxidation, reducing liver lipid accumulation, and alleviating liver damage. Moreover, the protective effect of PMRPWE against MCD-induced NASH was better than PMRWE.