Deuteration-Based Design, Green Synthesis, and Insecticidal Activity of Hexacyclic Pyrazol-3-amide Derivatives as Insect Growth Regulators
Shihui Luo, Bingbo Guo, Yan Liu, Yanjiao Feng, Congwang Cao, Jie An, Lei Chen, Li Zhang, Qing Yang, Xinling Yang
Abstract
The deuterium kinetic isotope effect (DKIE) underscores the stability of C–D bond, which can improve pharmacokinetic properties and reduce toxicity in compounds. Herein, the application of the deuteration strategy to improve the activity of insect growth regulators (IGRs) by replacing the C–H bond with a C–D bond at the benzylic position, known as the “soft spot”, is first investigated. The corresponding deuterated intermediates were obtained through a novel green and efficient method utilizing samarium diiodide (SmI 2 ) as a reductive deuterating agent and 2-methyltetrahydrofuran (2-MTHF) as a solvent to address environmental concerns. Subsequently, six deuterated compounds ( D-1 to D-6 ) of hexacyclic pyrazol-3-amide derivatives are synthesized and compared in terms of insecticidal activity against Plutella xylostella, revealing lower LC 50 values than nondeuterated compounds ( H-1 to H-6 ). Particularly, compound D-3 exhibited significantly better activity (LC 50: 11 mg/L) than H-3 (LC 50: 197 mg/L), even higher than commercial tebufenozide. Additionally, the inhibitory activities against ecdysone receptor/ultraspiracle protein (EcR/USP) and three chitinases─ Of ChtI, Of ChtII, and Of Chi-h─demonstrate that deuteration enhances binding affinity specifically to the Chitinase Of ChtI. After deuteration, the compounds exhibited a lower Clog P value and reduced energy gap, along with a slight reduction in lipophilicity and electrostatic potential, which together may contribute to improved activity. This work suggests that deuteration strategy is a promising approach to improve the compounds’ efficacy for pest control.