Discovery of Benzothiazolylpyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors through Active Fragment Exchange and Link Approach

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, in this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides <b>I</b>-<b>III</b> as potent SDH inhibitors using active fragment exchange and link approach. The results of the fungicidal activity assays showed that some of the synthesized compounds exhibited excellent inhibition against the tested fungi. Systematic structure–activity relationship studies led to the discovery of compound <b>Ip</b>, <i>N</i>-(1-((4,6-difluorobenzo[<i>d</i>]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)-<i>N</i>-methoxy-1-methyl-1<i>H</i>-pyrazole-4-carboxamide, which showed higher fungicidal activity against Fusarium graminearum Schw (EC₅₀ = 0.93 μg/mL) than the commercial fungicides thifluzamide (EC₅₀ > 50 μg/mL) and boscalid (EC₅₀ > 50 μg/mL). The molecular simulation studies suggested that hydrophobic interactions were the primary driving forces between ligands and SDH. Promisingly, we found that <b>Ip</b> could stimulate the growth of wheat seedlings and Arabidopsis thaliana and increase the biomass of the treated plants. Preliminary studies on the plant growth promoter mechanism of <b>Ip</b> indicated that it could increase nitrate reductase activity <i>in planta</i>, that, in turn, stimulates the growth of plants.