Novel Dioxolane Ring Compounds for the Management of Phytopathogen Diseases as Ergosterol Biosynthesis Inhibitors: Synthesis, Biological Activities, and Molecular Docking

Abstract

Thirty novel dioxolane ring compounds were designed and synthesized. Their chemical structures were confirmed by ¹H NMR, HRMS, and single crystal X-ray diffraction analysis. Bioassays indicated that these dioxolane ring derivatives exhibited excellent fungicidal activity against <i>Rhizoctonia solani</i>, <i>Pyricularia oryae</i>, <i>Botrytis cinerea</i>, <i>Colletotrichum gloeosporioides</i>, <i>Fusarium oxysporum</i>, <i>Physalospora piricola</i>, <i>Cercospora arachidicola</i> and herbicidal activity against lettuce (<i>Lactuca sativa</i>), bentgrass (<i>Agrostis stolonifera</i>), and duckweed (<i>Lemna pausicostata</i>). Among these compounds, 1-((2-(4-chlorophenyl)-5-methyl-1,3-dioxan-2-yl)methyl)-1<i>H</i>-1,2,4-triazole (<b>D17</b>), 1-(((4<i>R</i>)-2-(4-chlorophenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1<i>H</i>-1,2,4-triazole (<b>D20</b>), 1-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxan-2-yl)methyl)-1<i>H</i>-1,2,4-triazole (<b>D22</b>), and 1-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-1<i>H</i>-1,2,4-triazole (<b>D26</b>) 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 <b>D17</b>, <b>D20</b>, <b>D22</b>, and <b>D26</b> and the 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 <b>D17</b>, <b>D20</b>, <b>D22</b>, and <b>D26</b> and the positive control difenoconazole against the plant pathogen <i>R. solani</i>, respectively. Germination experiments with <i>Arabidopsis</i> seeds indicated that the target of these dioxolane ring compounds in plants is brassinosteroid biosynthesis. Molecular simulation docking results of compound <b>D26</b> and difenoconazole with fungal CYP51 P450 confirmed that they both inhibit this enzyme involved in ergosterol biosynthesis. The structure-activity relationships (SAR) are discussed by substituent effect, molecular docking, and density functional theory analysis, which provided useful information for designing more active compounds.