In silico design of benzothiazole and phthalimide-derived hybrids as protoporphyrinogen IX oxidase inhibitors

Protoporphyrinogen IX oxidase (PPO) inhibition is a critical strategy for weed control in crop production. This study employed a computational approach integrating QSAR modelling, docking studies, and molecular dynamics to investigate the inhibitory activities of benzothiazole- and phthalimide-derived compounds against PPO. The MIA-QSAR method modelled p<i>K</i>i values for 52 compounds, complemented by docking and molecular dynamics to analyse ligand-enzyme interactions and identify potential agrochemical candidates. QSAR analysis yielded predictive models with <i>r</i>² = 0.77, <i>q</i>² = 0.55, and <i>r</i>² = 0.74. MIA plots guided the design of 12 derivatives, 5 of which showed promising p<i>K</i>i values (7.31-8.69). Docking and molecular dynamics revealed strong binding affinity and stability for these candidates. The presence of fluorine substituents and C=O and C=S bonds in tetrahydroisoindole moieties enhanced biological activity, leading to the proposition of effective PPO inhibitors. Synthetic routes for the top candidates were outlined for future development, aiming to improve agrochemical efficacy and address resistance issues in crop protection.