Multicomponent Synthesis of Multi-Target Quinazolines Modulating Cholinesterase, Oxidative Stress, and Amyloid Aggregation Activities for the Therapy of Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC50 = 6.67 μM, and 36.68% inhibition of Aβ1-42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD.