Design, Synthesis, and Mechanistic Study of Benzoxazole Derivatives Targeting PMK1 to Inhibit Magnaporthe oryzae Pathogenicity

Rice blast disease, caused by Magnaporthe oryzae, is a major threat to global rice production. Motivated by the antifungal properties of benzoxazole scaffolds found in complex natural antibiotics, we designed and synthesized a series of benzoxazole-based, cost-effective derivatives with promising antifungal activity. Among these compounds, N-(benzo[d]oxazol-2-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide (H17) and N-(benzo[d]oxazol-2-yl)-5-(3-chloro-2-methylphenyl)nicotinamide (H23) showed superior inhibitory effects against M. oryzae, with IC₅₀ values of 0.42 and 0.50 μM, respectively. These values significantly higher than those of the positive control carbendazim (1.84 μM). In vivo experiments demonstrated that H17 and H23 exhibited curative effects similar to those of carbendazim. Mechanistic studies revealed that H17 and H23 target the M. oryzae pathogenicity mitogen-activated protein kinase 1 (MoPMK1), a key regulator of M. oryzae pathogenicity, thereby inhibiting spore germination and appressorium formation. Overall, this study highlights benzoxazole derivatives as promising candidates for novel fungicide development and proposes MoPMK1 inhibition as a novel strategy against rice blast, with the potential to bypass current resistance mechanisms in M. oryzae and other phytopathogenic fungi.