Synthesis, Antifungal Activity, and Potential Mechanism of Natural Product Pogostone Derivatives Containing an Acylhydrazone Scaffold

The current study designed and synthesized a series of acylhydrazone derivatives based on the natural product pogostone. Among them, compound <b>2a</b>_<b>15</b> exhibited potent fungicidal activity against <i>Valsa mali</i> (<i>V. mali</i>) (EC₅₀ = 0.34 μg/mL) and <i>Sclerotinia sclerotiorum</i> (<i>S. sclerotiorum</i>) (EC₅₀ = 0.45 μg/mL). At 200 μg/mL, <b>2a</b>_<b>15</b> exhibited 81.26 and 82.08% efficacies against <i>V. mali</i> and <i>S. sclerotiorum</i>, respectively. Qualitative structure-activity analysis showed that when the benzene ring was substituted by a bromine atom, chlorine atom, or electron-withdrawing group, compounds with the substituent group in the <i>para</i> position displayed the best activity. Compound <b>2a</b>_<b>15</b> treatment induced an explosion of ROS, unbalanced mitochondrial membrane potential, and declined activities of pectinase and SDH in <i>V. mali</i>. Moreover, the expression of the pectinase gene was significantly upregulated. Importantly, molecular docking revealed that <b>2a</b>_<b>15</b> had a strong affinity with SDH-B. According to density functional theory, more dispersed lowest unoccupied molecular orbital (LUMO) distribution and a low energy gap between the LUMO and HOMO were beneficial for activity improvement.