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 T17-T24 showed high inhibitory activity against Rhizoctonia solani with an effective concentration (EC₅₀) value falling between 2.20 and 23.85 μg/mL, which were more active than or equivalent to the lead diflumetorim with its EC₅₀ of 19.80 μg/mL. In vivo Antifungal bioassays demonstrated that, at a concentration of 200 μg/mL, T7 and T21 showed higher inhibition against Pseudoperonospora cubensis than all Other compounds, while T23 exhibited the highest inhibition against Sphaerotheca fuliginea. T23 showed an approximately twofold lower inhibition potency against R. solani complex I NADH oxidoreductase than diflumetorim. Molecular docking and transcriptomic analyses indicated that T23 and diflumetorim both might share the same mode of action, targeting NADH oxidoreductase. T23 as a good fungicidal candidate against R. solani is worthy of further investigation.

6-isothiazol-5-ylpyrimidin-4-amine derivatives; Rhizoctonia solani; complex I NADH oxidoreductase; computer-aided pesticide design; fungicidal activity; natural product.