Novel Pyrazole Acyl(thio)urea Derivatives Containing a Biphenyl Scaffold as Potential Succinate Dehydrogenase Inhibitors: Design, Synthesis, Fungicidal Activity, and SAR.

As part of a program to discover novel succinate dehydrogenase inhibitor fungicides, a series of new pyrazole acyl(thio)urea compounds containing a diphenyl motif were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS, and single X-ray crystal diffraction analysis. Most of these compounds possessed excellent activity against 10 fungal plant pathogens at 50 µg mL-1, especially against Rhizoctonia solani, Alternaria solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Cercospora arachidicola. Interestingly, compounds 3-(difluoromethyl)-1-methyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9b, EC50 = 0.97 ± 0.18 µg mL-1), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50 = 2.63 ± 0.41 µg mL-1), and N-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (9g, EC50 = 1.31 ± 0.15 µg mL-1) exhibited activities against S. sclerotiorum that were better than the commercial fungicide bixafen (EC50 = 9.15 ± 0.05 µg mL-1) and similar to the positive control fluxapyroxad (EC50 = 0.71 ± 0.11 µg mL-1). These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants. Structure-activity relationships (SAR) are discussed by substituent effects/molecular docking, and density functional theory analysis indicated that these compounds are succinate dehydrogenase inhibitors.

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.

Design, Synthesis, Insecticidal Activity, and SAR of Aryl Isoxazoline Derivatives Containing Pyrazole-5-carboxamide Motif.

It is important to develop new insecticides with a new mode of action because of increasing pesticide resistance. In this study, a series of novel aryl isoxazoline derivatives containing the pyrazole-5-carboxamide motif were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Bioassays indicated that the 24 compounds synthesized possessed excellent insecticidal activity against Mythimna separate and no activity against Aphis craccivora and Tetranychus cinnabarinus. Among these aryl isoxazoline derivatives, 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrozol-3-yl)-N-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (IA-8) had the best insecticidal activity against M. separate, which is comparable with the positive control fluralaner. The molecular docking results of compound IA-8 and fluralaner with the GABA model demonstrated the same docking mode between compound IA-8 and positive control fluralaner in the active site of GABA. Molecular structure comparisons and ADMET analysis can potentially be used to design more active compounds. The structure-activity relationships are also discussed. This work provided an excellent insecticide for further optimization.