Discovery of novel pyrazoline insecticides.

Background: The pyrazoline insecticides, invented by Philips Duphar in the 1970s, provide excellent control of lepidopterans and coleopterans and introduced a novel mode of action (MoA) as sodium-channel-blocking insecticides, but were not commercialized due to unacceptable persistence. This MoA is less explored, with only two successfully commercialized insecticides derived from the pyrazoline class - the oxadiazine indoxacarb from FMC (developed by DuPont) and the semicarbazone metaflumizone, co-developed by BASF and Nihon Nohyaku.

Results: The design and synthesis of novel pyrazoline insecticides with improved biological efficacy and favorable environmental fate profile are described. Their structures are confirmed by proton nuclear magnetic resonance (H-NMR) and liquid chromatography-mass spectrometry (LC-MS). Bioassay studies confirmed the insecticidal efficacy of the synthesized compounds against four key species: cotton boll weevil, tobacco budworm, diamondback moth and southern armyworm. Environmental fate profiles of a few representatives were evaluated, and MoA studies confirm that the MoA of these newly synthesized analogs (voltage-gated sodium channel block) is preserved.

Conclusion: We used a chemistry-driven approach to explore position 5 on the pyrazoline core and a computationally-driven approach for bio-isosteric replacement of the aryl amide, leading to two novel pyrazoline sub-classes with improved insecticidal activities and favorable environmental fate profiles compared to PH 60-41 (the Philips Duphar compound). The MoA of these novel sub-classes was also confirmed as block of voltage-dependent sodium channels. © 2024 Society of Chemical Industry.