The discovery of sulfoxaflor (Isoclast™ active) stemmed from a novel scaffold-based approach toward identifying bioactive molecules. It exhibits broad-spectrum control of many sap-feeding insect pests, including aphids, whiteflies, hoppers and Lygus. Systematic modifications of the substituents flanking each side of the sulfoximine moiety were carried out to determine whether these changes would improve potency.Structure-activity relationship (SAR) studies showed that, with respect to the methylene linker, both mono- and disubstitution with alkyl groups of varying sizes as well as cyclic analogs exhibited excellent control of cotton aphids. However, against green peach aphids a decrease in activity was observed with substituents larger than ethyl as well as larger cycloalkyl groups. At the terminal tail there appeared to be a narrow steric tolerance as well, with linear groups or small rings more active against green peach aphids than bulkier groups.A novel series of compounds exploring the substituents flanking the sulfoximine moiety of sulfoxaflor were prepared and tested for bioactivity against cotton aphids and green peach aphids. SAR studies indicated that a decrease in green peach aphid potency was observed at the methylene linker as well as at the terminal tail with bulkier substituents. A quantitative structure-activity relationship analysis of the compounds revealed significant correlation of activity with two molecular descriptors, vol (volume of a molecule) and GCUT_SMR_3 (molar refractivity). This predictive model helps to explain the observed activity with the various substituents. © 2016 Society of Chemical Industry.