Design, Synthesis, and Assessment of Fungicidal Activity of Active Substructure 1,2,4-Triazole Containing Coumarin
You Lv, Kun Li, Lei Liu, Z. Walter Yu, Rongzhang Wu, Angkun Chen, Ruixi Tian, Yuxuan Deng, Liang‐Fu Tang, Zhijin Fan
Abstract
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 1a and 1b 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 7e was more active than 1b against Botrytis cinereal, Cercospora arachidicola, and Sclerotinia sclerotiorum, with a corresponding EC 50 value of 4.02 vs 5.90, 6.03 vs 8.31, and 3.81 vs 5.37 μg/mL, respectively. Compound 7e also showed an EC 50 value of 4.15 μg/mL against Fusarium graminearum . Moreover, compound 7e demonstrated a stronger inhibition than flutriafol against F. graminearum 14-α demethylase, with an IC 50 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 7e 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.