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.