Sustainably Synthesized Small Molecule Therapeutic Aggregates Attenuate Aβ-Induced ROS-Mitochondrial-Apoptotic Cascade in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, oxidative stress, mitochondrial dysfunction, and progressive neuronal loss, yet effective disease-modifying therapeutics remain limited. Herein, we report the sustainable synthesis of two triphenylamine-based donor-acceptor (D-A) scaffolds, TPA-IM (triphenylamine-indanonemalononitrile) and TPA-FM (triphenylamine-furanmalononitrile), via a catalyst-free ethanol-mediated Knoevenagel condensation under mild conditions, yielding high yields (>80%). Integrated photophysical, computational, biophysical, and cellular investigations revealed that acceptor engineering critically governs supramolecular assembly, amyloid-binding behavior, and neuroprotective efficacy. Among the two molecules, TPA-IM exhibited superior inhibition of Aβ40 fibrillogenesis and a stronger fibril-binding affinity, as evidenced by ThT kinetics, ITC, docking, and molecular dynamics simulations. Aggregate simulations and FETEM analyses further demonstrated distinct supramolecular assembly behavior associated with enhanced amyloid interactions. Importantly, TPA-IM effectively suppressed intracellular ROS generation, restored mitochondrial membrane potential, and attenuated Aβ-induced apoptosis in neuronal cells. Favorable BBB permeability and ADMET profiles further support its therapeutic potential. Collectively, this work establishes a mechanistic framework linking acceptor-controlled supramolecular organization with amyloid modulation and mitochondrial neuroprotection for AD therapeutics.