Novel Insecticidal Pyridylhydrazono Derivatives Identified via Scaffold Hopping and Conformation Regulation Strategies.

Abstract

Insect transient receptor potential vanilloid (TRPV) channels are critical targets for insecticides. In this study, various scaffold-hopping strategies were employed in the rational design of pyridylhydrazono derivatives as potential insect TRPV channels modulators. Insecticidal bioassay demonstrated that the initial target compounds exhibited lower insecticidal activity compared to pymetrozine, with the optimal compound B3 exhibiting a mortality rate of 53.3% against Aphis craccivora at 400 mg·L-1. Conformation analysis indicated that the high energy barrier required for the transition from the lowest-energy conformation to the active conformation may be a key factor contributing to the reduced insecticidal activities of the target compounds. Further structural optimizations aimed at reducing this energy barrier through binding mode-based conformation regulation led to the identification of optimal target 4-(3'-pyridylhydrazono)pyrazol-5-one derivatives C1 and C2. These compounds exhibited reduced transition energy barriers and improved insecticidal activity, with moderate mortality rate of 66.3% and 75.7% against A. craccivora at 400 mg·L-1, respectively. These findings provide valuable insights for future research on the discovery of insect TRPV modulators and have significant implications for the development of more effective agricultural insecticides.