AbstractBACKGROUNDThe 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.RESULTSThe 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 (1H‐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.CONCLUSIONWe 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.