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

Rice blast disease, caused by <i>Magnaporthe oryzae</i>, 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, <i>N</i>-(benzo[<i>d</i>]oxazol-2-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamide (<b>H17</b>) and <i>N</i>-(benzo[<i>d</i>]oxazol-2-yl)-5-(3-chloro-2-methylphenyl)nicotinamide (<b>H23</b>) showed superior inhibitory effects against <i>M. oryzae</i>, 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). <i>In vivo</i> experiments demonstrated that <b>H17</b> and <b>H23</b> exhibited curative effects similar to those of carbendazim. Mechanistic studies revealed that <b>H17</b> and <b>H23</b> target the <i>M. oryzae</i> pathogenicity mitogen-activated protein kinase 1 (MoPMK1), a key regulator of <i>M. oryzae</i> 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 <i>M. oryzae</i> and other phytopathogenic fungi.