Distinct Antifungal Ingredients Deploying β-Alkylated (Hetero)arylethylamines Inspired by Fluopyram

Inspired by the unique profiles of the succinate dehydrogenase inhibitor (SDHI) fungicides empowered by the introduction of β-arylethylamines, we elaborated new antifungal ingredients incorporating β-(hetero)arylethylamines inspired by fluopyram. Thirteen kinds of (hetero)arylethylamines, featuring various heterocycles and concomitant β-modifications, were deployed for achieving β-quinolinyl cyclohexylmethanamine as a novel pharmacophore through an antifungal screen. The subsequent fine-tuning was conducted conveniently by employing commercially inexpensive and easily available acid segments. Up to seven structurally distinct amides (<b>LN8</b>, <b>LN9</b>, <b>LN11</b>, <b>LN13</b>, <b>LN20</b>, <b>LN26</b>, and <b>LN27</b>) out of 52 new compounds were acquired as antifungal candidates specifically against <i>Sclerotinia scleotiorum</i> with EC₅₀ values ranging from 0.31 μM to 0.63 μM, which was 8-18 times more potent than the positive control fluopyram (EC₅₀, 5.46 μM). The molecular docking simulations were compared between <b>LN9</b>, <b>LN27</b>, and fluopyram, showcasing a reversed pharmacophore that was invaginated in the presumed pocket. Candidate <b>LN9</b> also demonstrated good <i>in vivo</i> activities against <i>S. sclerotiorum</i>, with curative and preventative efficacies of 63.2% and 70.6%, respectively. It could cause severe deformation of mycelial morphology, cessation of mycelial growth, and destruction of the structure and function of mitochondria in mycelial cells. Compared with fluopyram, this candidate demonstrated a parallel inhibitory activity against succinate dehydrogenase (SDH). The distinct biological profiles together with the synthetic accessibility and cost-efficacy highlighted the practical potential of β-substituted (hetero)arylethylamine as a new chemical entity in the discovery of fungicides.