Novel pyrazole acyl(thio)urea derivatives containing a biphenyl scaffold as potential succinate dehydrogenase inhibitors: Design, synthesis, fungicidal activity and SAR

Authors: SUN, NA-BO - Zhejiang Shuren University; MIN, LI-JING - Huzhou University; SUN, ZHI-WEN - Zhejiang University Of Technology; ZHAI, ZHI-WEN - Zhejiang University Of Technology; Bajsa-Hirschel, Joanna; WEI, ZHE-CHENG - Zhejiang University Of Technology; HUA, XUE-WEN - Liaocheng University; Cantrell, Charles; XU, HAO - Zhejiang Shuren University; DUKE, STEPHEN - University Of Mississippi; LIU, XING-HAI - Zhejiang University Of Technology

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/8/2024
Publication Date: 1/29/2024
Citation: Sun, N., Min, L., Sun, Z., Zhai, Z., Bajsa Hirschel, J.N., Wei, Z., Hua, X., Cantrell, C.L., Xu, H., Duke, S.O., Liu, X. 2024. Novel pyrazole acyl(thio)urea derivatives containing a biphenyl scaffold as potential succinate dehydrogenase inhibitors: Design, synthesis, fungicidal activity and SAR. Journal of Agricultural and Food Chemistry. 72:2512-2525. https://doi.org/10.1021/acs.jafc.3c07735.
DOI: https://doi.org/10.1021/acs.jafc.3c07735

Interpretive Summary: Pesticides play important roles in modern agriculture. Discovery and development of pesticides with new modes of action or new structures is needed to combat rapidly evolving and spreading pesticide resistance. Nitrogen-containing heterocycles are important skeletons in many natural alkaloids a+nd synthetic molecules, and are thus of interest in drug and pesticide discovery. Pyrazole is a classic five-membered nitrogen-linked heterocycle, which is a key core in some pesticides. In our previous work, several pyrazole compounds were designed and synthesized with insecticidal, herbicidal or fungicidal activity. A total of twenty-four compounds were designed and synthesized in this study. Most of these compounds possessed excellent activity against ten fungal plant pathogens at 50 microg/mL. These compounds were not significantly phytotoxic to monocotyledonous and dicotyledonous plants.

Technical 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 ten fungal plant pathogens at 50 µg/mL, 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±0.18µg/mL), 1,3-dimethyl-N-((3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)carbamoyl)-1H-pyrazole-4-carboxamide (9a, EC50=2.63±0.41µg/mL) 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) exhibited activities against S. sclerotiorum, that were better than the commercial fungicide bixafen (EC50=9.15±0.05 µg/mL) and similar to the positive control fluxapyroxad (EC50=0.71±0.11 µg/mL). 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.