Deuteration-Based Design, Green Synthesis, and Insecticidal Activity of Hexacyclic Pyrazol-3-amide Derivatives as Insect Growth Regulators

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 (SmI2) 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 LC50 values than nondeuterated compounds (H-1 to H-6). Particularly, compound D-3 exhibited significantly better activity (LC50: 11 mg/L) than H-3 (LC50: 197 mg/L), even higher than commercial tebufenozide. Additionally, the inhibitory activities against ecdysone receptor/ultraspiracle protein (EcR/USP) and three chitinases─OfChtI, OfChtII, and OfChi-h─demonstrate that deuteration enhances binding affinity specifically to the Chitinase OfChtI. After deuteration, the compounds exhibited a lower ClogP 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.