Multitarget Biological Profiling of New Naphthoquinone and Anthraquinone-Based Derivatives for the Treatment of Alzheimer's Disease

Two series of naphthoquinone and anthraquinone derivatives decorated with an aromatic/heteroaromatic chain have been synthesized and evaluated as potential promiscuous agents capable of targeting different factors playing a key role in Alzheimer's disease (AD) pathogenesis. On the basis of the in vitro biological profiling, most of them exhibited a significant ability to inhibit amyloid aggregation, PHF6 tau sequence aggregation, acetylcholinesterase (AChE), and monoamine oxidase (MAO) B. In particular, naphthoquinone 2 resulted as one of the best performing multitarget-directed ligand (MTDL) experiencing a high potency profile in inhibiting beta-amyloid (A beta(40)) aggregation (IC50 = 3.2 mu M), PHF6 tau fragment (91% at 10 mu M), AChE enzyme (IC50 = 9.2 mu M) jointly with a remarkable inhibitory activity against MAO B (IC50 = 7.7 nM). Molecular modeling studies explained the structure-activity relationship (SAR) around the binding modes of representative compound 2 in complex with hMAO B and hAChE enzymes, revealing inhibitor/protein key contacts and the likely molecular rationale for enzyme selectivity. Compound 2 was also demonstrated to be a strong inhibitor of A beta(42) aggregation, with potency comparable to quercetin. Accordingly, atomic force microscopy (AFM) revealed that the most promising naphthoquinones 2 and 5 and anthraquinones 11 and 12 were able to impair A beta(42) fibrillation, deconstructing the morphologies of its fibrillar aggregates. Moreover, the same compounds exerted a moderate neuroprotective effect against A beta(42) toxicity in primary cultures of cerebellar granule cells. Therefore, our findings demonstrate that these molecules may represent valuable chemotypes toward the development of promising candidates for AD therapy.

Automated summary

Two series of naphthoquinone and anthraquinone derivatives have been synthesized and evaluated for their potential in targeting factors involved in Alzheimer's disease pathogenesis. Naphthoquinone 2 showed strong inhibitory activity against key enzymes and protein aggregation related to AD, making it a promising candidate for therapy.