Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives

Alzheimer’s disease represents a major public health challenge facing aging population worldwide. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease modifying therapies. Following the MTDLs approach, a small library of coumarin-based derivatives was designed and synthesized, as a follow-up of our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern in position 6 or 7 was modified by introducing alkyl chains of variable lengths and carrying different terminal amino functions. Compound 13, bearing the bulkiest amine, emerged as a non-neurotoxic dual AChE/BuChE inhibitor, potentially suitable for the treatment of the middle stage of the disease. Besides, the introduction of a diethylamino spacer chain, as in compounds 4 and 10, led to nanomolar hAChE inhibitors endowed with significant inhibition of Aβ42 self-aggregation, while the reference compound was completely ineffective. Compound 10 also showed a promising neuroprotective behavior, which makes it a potential candidate to be developed into a disease-modifying agent.