Design, Synthesis, and Assessment of Fungicidal Activity of Active Substructure 1,2,4-Triazole Containing Coumarin

Fragment splicing and molecular docking are important techniques in the design of new agrochemicals. Based on our former discovery of 4-(3,4-dichloroisothiazole)-7-hydroxycumarins <b>1a</b> and <b>1b</b> as fungicidal leads, following fragment splicing and molecular docking, a series of bioactive substructure 1,2,4-triazole containing coumarins were designed and synthesized. In vitro fungicidal bioassay indicated that compound <b>7e</b> was more active than <b>1b</b> against <i>Botrytis cinereal</i>, <i>Cercospora arachidicola</i>, and <i>Sclerotinia sclerotiorum</i>, with a corresponding EC₅₀ value of 4.02 vs 5.90, 6.03 vs 8.31, and 3.81 vs 5.37 μg/mL, respectively. Compound <b>7e</b> also showed an EC₅₀ value of 4.15 μg/mL against <i>Fusarium graminearum</i>. Moreover, compound <b>7e</b> demonstrated a stronger inhibition than flutriafol against <i>F. graminearum</i> 14-α demethylase, with an IC₅₀ value of 0.59 and 0.97 μM, respectively. Calculation results based on density functional theory calculation (DFT), molecular dynamics (MD), and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) studies gave a rational explanation between the activity of compound <b>7e</b> and its structure. This study demonstrates that fragment splicing of 1,2,4-triazole and coumarin is a good technique for discovering a novel fungicide lead.