Design, Synthesis, and Antifungal Activities of 3-Acyl Thiotetronic Acid Derivatives: New Fatty Acid Synthase Inhibitors

Emerging fungal phytodiseases are increasingly becoming a food security threat. Twenty-six new 3-acylthiotetronic acid derivatives were designed, synthesized, characterized, and evaluated for activities against Valsa mali, Curvularia lunata, Fusarium graminearum, and Fusarium oxysporum f. sp. lycopersici . Among the 26 compounds, 6f was the most effective against V. mali, C. lunata, F. graminearum, and F. oxysporum f. sp. lycopersici with median effective concentrations (EC 50 ) of 4.1, 3.1, 3.6, and 4.1 μg/mL, respectively, while the corresponding EC 50 were 0.14, 6.7, 22.4, and 4.3 μg/mL of the fungicide azoxystrobin; 4.2, 41.7, 0.42, and 0.12 μg/mL of the fungicide carbendazim; and >50, 0.19, 0.43, and BS > 50 μg/mL of the fungicide fluopyram. The inhibitory potency against V. mali fatty acid synthase agreed well with the in vitro antifungal activity. The molecular docking suggested that the 3-acylthiotetronic acid derivatives targeted the C171Q KasA complex. The findings help understanding the mode of action and design and synthesis of novel potent fungicides.