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 (LN8, LN9, LN11, LN13, LN20, LN26, and LN27) out of 52 new compounds were acquired as antifungal candidates specifically against Sclerotinia scleotiorum 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 LN9, LN27, and fluopyram, showcasing a reversed pharmacophore that was invaginated in the presumed pocket. Candidate LN9 also demonstrated good in vivo activities against S. sclerotiorum, 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.