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

Abstract

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 β-amyloid (Aβ 40 ) aggregation (IC 50 = 3.2 μM), PHF6 tau fragment (91% at 10 μM), AChE enzyme (IC 50 = 9.2 μM) jointly with a remarkable inhibitory activity against MAO B (IC 50 = 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 Aβ 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 Aβ 42 fibrillation, deconstructing the morphologies of its fibrillar aggregates. Moreover, the same compounds exerted a moderate neuroprotective effect against Aβ 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.

Structure-Property Relationship in Selected Naphtho- and Anthra-Quinone Derivatives on the Basis of Density Functional Theory and Car–Parrinello Molecular Dynamics

“…Naphtho-and anthra-quinone are parent compounds for 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone 1 [1] and 1,4-dihydroxy-anthraquinone 2 [2], which are the objects of the current study; see Figure 1. Naphtho-and anthra-quinone occur in many natural products, possessing diverse biological activity, being building blocks of many dyes; see for example [3][4][5][6][7][8][9][10][11][12][13]. They are also interesting classes of compounds from the materials science point of view.…”

A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE)

“…The lack of a protonatable moiety, a key feature for an efficient interaction at the catalytic anion site of cholinesterases, may explain the low activity measured. Even though it could be irrelevant to explain the AChE/BuChE selectivity, it is possible that BuChE is not able to tolerate the presence of an acidic group in the molecules [ 45 ]. After all, as far as we know, only a few examples of carboxylic acids endowed with cholinesterase inhibition activity have been reported in the literature [ 45 ].…”

“…Even though it could be irrelevant to explain the AChE/BuChE selectivity, it is possible that BuChE is not able to tolerate the presence of an acidic group in the molecules [ 45 ]. After all, as far as we know, only a few examples of carboxylic acids endowed with cholinesterase inhibition activity have been reported in the literature [ 45 ]. The restricted activity range towards AChE did not allow for the formulation of any comment about structure-activity relationships; however, as in FAAH inhibition, these preliminary experiments showed a low stereoselectivity of both enantiomers of 5 and 11 towards AChE.…”

“…The organic portion was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness, affording a solid crude, which was chromatographed on a silica gel column (using n-hexane/ethyl acetate, 80:20, as eluent), obtaining the title compound; yield 70%. 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 1.88 (s, 3H, CH 3 ), 3.73 (s, 3H, CH 3 ), 6.70-6.74 (m, 2H, aromatics), 7.28-7.41 (m, 5H, aromatic), 7.56-7.61 (m, 2H, aromatics); GC-MS m/z (%): 336 (1), 334 (1), 174 (45), 172 (45), 163 (79), 103 (100), 135 (72).…”

Synthesis, Biological Evaluation, and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

“…Besides the three major hypotheses, other features such as oxidative stress [ 8 ], biometal ions accumulation [ 9 ], and neuroinflammation [ 10 ] also participate in AD pathogenesis. Therefore, using an agent that can work simultaneously on several targets associated with AD pathogenesis—the multi-target-directed ligand (MTDL) has been suggested [ 11 , 12 , 13 ].…”