Novel dioxolane ring compounds for the management of phytopathogen diseases as ergosterol biosynthesis inhibitors: synthesis, biological activities and molecular docking

Authors: MIN, LI-JING - Huzhou University; WANG, HAN - Zhejiang University Of Technology; Bajsa-Hirschel, Joanna; YU, CHEN-SHENG - Zhejiang University Of Technology; WANG, BIN - Zhejiang University Of Technology; YAO, MENG-MENG - Zhejiang University Of Technology; HAN, LIANG - Zhejiang University Of Technology; Cantrell, Charles; DUKE, STEPHEN - University Of Mississippi; SUN, NA-BO - Zhejiang University Of Technology; LIU, XING-HAI - Zhejiang University Of Technology

Submitted to: Journal of Agricultural and Food Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/11/2022
Publication Date: 3/31/2022
Citation: Min, L., Wang, H., Bajsa Hirschel, J.N., Yu, C., Wang, B., Yao, M., Han, L., Cantrell, C.L., Duke, S.O., Sun, N., Liu, X. 2022. Novel dioxolane ring compounds for the management of phytopathogen diseases as ergosterol biosynthesis inhibitors: synthesis, biological activities and molecular docking. Journal of Agricultural and Food Chemistry. https://doi.org/10.1021/acs.jafc.2c00541.
DOI: https://doi.org/10.1021/acs.jafc.2c00541

Interpretive Summary: Pesticides and fertilizers play crucial roles in modern agriculture. Due to the rapid evolution and spread of pesticide resistance, discovery and development of new pesticides with new structures and/or mechanisms of actions is needed. Heterocycles with nitrogen atoms are important structural units in many pesticides. Among them, 1,2,4-triazole is an important five-membered nitrogen-containing heterocycle which has led to the discovery of many agricultural fungicides used for crop protection such as propiconazole, tebuconazole, propiconazole, and cyproconazole. In this paper, a series of 1,2,4-triazole derivatives containing dioxolane ring motif were designed and synthesized. Some of the synthetic 1,2,4-triazole derivatives exhibited good fungicidal and plant growth regulation activity. These new fungicides are structurally different from existing fungicides that act through inhibition of ergosterol synthesis.

Technical Abstract: Thirty novel dioxolane ring compounds were designed and synthesized. Their structures were confirmed by 1H NMR, HRMS and single crystal X-ray diffraction analysis. Bioassays indicated that these dioxolane ring compounds possessed excellent fungicidal activity against Pyricularia oryae, Rhizoctonia solani, Botrytis cinerea, Colletotrichum gloeosporioides, Fusarium oxysporum, Cercospora arachidicola and Physalospora piricola, 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, D26 and 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, D26 and the positive control difenoconazole against 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 that they both inhibit this enzyme involved in ergosterol synthesis. The structure-activity relationships (SAR) are also discussed. This work provided excellent pesticide lead compounds for further optimization. Density functional theory analysis can potentially be used to design more active compounds.