Bioactivity-Guided Synthesis Accelerates the Discovery of 3-(Iso)quinolinyl-4-chromenones as Potent Fungicide Candidates

Abstract

Fungal infections could cause tremendous decreases in crop yield and quality. Natural products, including flavonoids and (iso)quinolines, have always been an important source for lead discovery in medicinal and agricultural chemistry. To promote the discovery and development of new fungicides, a series of 3-(iso)quinolinyl-4-chromenone derivatives was designed and synthesized by the active substructure splicing principle and evaluated for their antifungal activities. The lead optimization was guided by bioactivity. The bioassay data revealed that the 3-quinolinyl-4-chromenone <b>13</b> showed significant <i>in vitro</i> activities against <i>S. sclerotiorum</i>, <i>V. mali</i>, and <i>B. cinerea</i> with EC₅₀ values of 3.65, 2.61, and 2.32 mg/L, respectively. The 3-isoquinolinyl-4-chromenone <b>25</b> exhibited excellent <i>in vitro</i> activity against <i>S. sclerotiorum</i> with an EC₅₀ value of 1.94 mg/L, close to that of commercial fungicide chlorothalonil (EC₅₀ = 1.57 mg/L) but lower than that of boscalid (EC₅₀ = 0.67 mg/L). For <i>V. mali</i> and <i>B. cinerea</i>, 3-isoquinolinyl-4-chromenone <b>25</b> (EC₅₀ = 1.56, 1.54 mg/L) showed significantly higher activities than chlorothalonil (EC₅₀ = 11.24, 2.92 mg/L). In addition, <i>in viv</i>o experiments proved that compounds <b>13</b> and <b>25</b> have excellent protective fungicidal activities with inhibitory rates of 88.24 and 94.12%, respectively, against <i>B. cinerea</i> at 50 mg/L, while the positive controls chlorothalonil and boscalid showed inhibitory rates of 76.47 and 97.06%, respectively. Physiological and biochemical studies showed that the primary action of mechanism of compounds <b>13</b> and <b>25</b> on <i>S. sclerotiorum</i> and <i>B. cinerea</i> may involve changing mycelial morphology and increasing cell membrane permeability. In addition, compound <b>13</b> may also affect the respiratory metabolism of <i>B. cinerea</i><i>.</i> This study revealed that compounds <b>13</b> and <b>25</b> could be promising candidates for the development of novel fungicides in crop protection.