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

Abstract

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 <i>Rhizoctonia solani, Alternaria solani</i>, <i>Sclerotinia sclerotiorum</i>, <i>Botrytis cinerea</i>, and <i>Cercospora arachidicola</i>. Interestingly, compounds 3-(difluoromethyl)-1-methyl-<i>N</i>-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1<i>H</i>-pyrazole-4-carboxamide (<b>9b</b>, EC₅₀ = 0.97 ± 0.18 μg mL^-1), 1,3-dimethyl-<i>N</i>-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1<i>H</i>-pyrazole-4-carboxamide (<b>9a</b>, EC₅₀ = 2.63 ± 0.41 μg mL^-1), and <i>N</i>-((4'-chloro-[1,1'-biphenyl]-2-yl)carbamoyl)-1,3-dimethyl-1<i>H</i>-pyrazole-4-carboxamide (<b>9g</b>, EC₅₀ = 1.31 ± 0.15 μg mL^-1) exhibited activities against <i>S. sclerotiorum</i> 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.