Structural and electronic basis of stereoselectivity in isocycloseram: A DFT, spectroscopic, and docking study of its chiral isomers

Abstract

Chiral compounds have different physical and chemical properties and biological activities because of the structural difference, so it is important to characterize the relationship between the structure and property of chiral compounds. For the first time, this study systematically investigates the four chiral isomers of the new insecticide isocycloseram (cis-(+)-(5R,4S) ISR, cis-(−)-(5S,4R) ISM, trans-(+)-(5R,4R) ISO, trans-(−)-(5S,4S) ISS) using DFT, experimental spectroscopy (ECD/UV), and molecular docking. The results of the structural optimization at B3LYP/6–311G(d,p) and MP2/aug-cc-pVTZ calculations show that ISS is the most thermodynamically stable isomer. From surface electrostatic potential (ESP) and frontier molecular orbital (FMO) analysis, The results indicate that ISO has the largest ESP and the smallest energy gap (4.533 eV). Molecular docking indicates that ISM exhibits the most favorable binding energies toward the 2CBZ and 8HNC receptors (−8.57 and −9.37 kcal·mol⁻¹, respectively) and forms multiple hydrogen bonds with favorable geometries. Noncovalent interactions (NCI) analysis through interaction region indicator (IRI) method shows that ISR’s steric hindrance and ISO’s rigid intramolecular hydrogen bond prevent receptor binding. The experimental CD spectra and TDDFT-calculated ECD spectra display near mirror-image features for the enantiomeric pairs, providing a chiroptical fingerprint for absolute-configuration assignment. This study combines quantum chemistry, spectroscopy, and target modeling to provide the first molecular-level explanation of the stereoselective activity of this chiral pesticide, which can support the accurate design of pesticides and environmental monitoring.