Positional Isomerism Tunes Molecular Reactivities and Mechanisms toward Pathological Targets in Dementia

Positional isomerism offers a powerful strategy to fine-tune molecular reactivity toward diverse pathogenic factors in complex diseases. Here, we show that positional isomerism in phenylene-based compact molecules bearing electron-donating groups at the para, ortho, or meta positions engineers distinct chemical reactivities with key pathological targets, including reactive oxygen species, metal-free amyloid-β (Aβ), and metal-bound Aβ, which are implicated in Alzheimer’s disease (AD). Comprehensive mechanistic analyses reveal that specific isomers drive covalent adduct formation, oxidation, and oxidative cleavage toward metal-free and metal-bound Aβ, with their chemical transformations governed by electronic and metal-binding properties dictated by the substitution pattern. In AD transgenic mice, para - and ortho -substituted analogs display markedly different efficacies in attenuating hippocampal oxidative stress, lowering amyloid plaque burden, and improving cognitive performance. Our findings establish a structure–property–reactivity framework in which subtle positional changes elicit divergent chemical and biological outcomes, providing a principle for rationally designing multi-target-directed chemical modulators to probe and control multifactorial networks underlying neurodegeneration.