Fungicidal Activity of Novel 6-Isothiazol-5-ylpyrimidin-4-amine-Containing Compounds Targeting Complex I Reduced Nicotinamide Adenine Dinucleotide Oxidoreductase.

To discover novel inhibitors of the complex I reduced nicotinamide adenine dinucleotide (NADH) oxidoreductase as fungicides, a series of 6-isothiazol-5-ylpyrimidin-4-amine-containing compounds were designed using a computer-aided pesticide design method and splicing of substructures from diflumetorim and isotianil. In vitro fungicidal bioassays indicated that compounds - showed high inhibitory activity against with an effective concentration (EC) value falling between 2.20 and 23.85 μg/mL, which were more active than or equivalent to the lead diflumetorim with its EC of 19.80 μg/mL. In vivo antifungal bioassays demonstrated that, at a concentration of 200 μg/mL, and showed higher inhibition against than all other compounds, while exhibited the highest inhibition against . showed an approximately twofold lower inhibition potency against complex I NADH oxidoreductase than diflumetorim. Molecular docking and transcriptomic analyses indicated that and diflumetorim both might share the same mode of action, targeting NADH oxidoreductase. as a good fungicidal candidate against is worthy of further investigation.