Discovery of the Chlorinated and Ammoniated Derivatives of Vanillin as Potential Insecticidal Candidates Targeting V-ATPase: Structure-Based Virtual Screening, Synthesis, and Bioassay

Vacuolar-type H⁺-ATPases (V-ATPases) play a crucial role in the life cycle of agricultural pests and represent a promising target for the development of novel insecticides. In this study, S18, a derivative of vanillin acquired from Specs database using a structure-based virtual screening methodology, was first identified as a V-ATPase inhibitor. It binds to subunit A of the Enzyme with a K_d of 1 nM and exhibits insecticidal activity against M. separata. Subsequently, using S18 as the lead compound, a new series of vanillin derivatives were rationally designed and efficiently synthesized. and their biological activities were assessed. Among them, compound 3b-03 showed the strongest insecticidal activity against M. separata by effectively targeting the V-ATPase subunit A with K_d of 0.803 μM. Isothermal titration calorimetric measurements and docking results provided insights into its interaction with subunit A of V-ATPase, which could facilitate future research aimed at the development of novel chemical insecticides.

V-ATPase; V-ATPase inhibitor; insecticidal activity; structure-based virtual screening; vanillin.