Antifungal Exploration of Quinoline Derivatives against Phytopathogenic Fungi Inspired by Quinine Alkaloids

Abstract

Enlightened from our previous work of structural simplification of quinine and innovative application of natural products against phytopathogenic fungi, lead structure 2,8-bis(trifluoromethyl)-4-quinolinol (<b>3</b>) was selected to be a candidate and its diversified design, synthesis, and antifungal evaluation were carried out. All of the synthesized compounds <b>Aa1-Db1</b> were evaluated for their antifungal activity against four agriculturally important fungi, <i>Botrytis cinerea</i>, <i>Fusarium graminearum</i>, <i>Rhizoctonia solani,</i> and <i>Sclerotinia sclerotiorum</i>. Results showed that compounds <b>Ac3</b>, <b>Ac4</b>, <b>Ac7</b>, <b>Ac9</b>, <b>Ac12</b>, <b>Bb1</b>, <b>Bb10</b>, <b>Bb11</b>, <b>Bb13</b>, <b>Cb1</b>. and <b>Cb3</b> exhibited a good antifungal effect, especially <b>Ac12</b> had the most potent activity with EC₅₀ values of 0.52 and 0.50 μg/mL against <i>S. sclerotiorum</i> and <i>B. cinerea</i>, respectively, which were more potent than those of the lead compound <b>3</b> (1.72 and 1.89 μg/mL) and commercial fungicides azoxystrobin (both >30 μg/mL) and 8-hydroxyquinoline (2.12 and 5.28 μg/mL). Moreover, compound <b>Ac12</b> displayed excellent <i>in vivo</i> antifungal activity, which was comparable in activity to the commercial fungicide boscalid. The preliminary mechanism revealed that compound <b>Ac12</b> might cause an abnormal morphology of cell membranes, an increase in membrane permeability, and release of cellular contents. These results indicated that compound <b>Ac12</b> displayed superior <i>in vitro</i> and <i>in vivo</i> fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.