pharmaceuticals Review Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer’s Disease Marta Campora † , Valeria Francesconi †, Silvia Schenone, Bruno Tasso and Michele Tonelli * Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV, 3, 16132 Genova, Italy; [email protected] (M.C.); [email protected] (V.F.); [email protected] (S.S.); [email protected] (B.T.) * Correspondence: [email protected] † These authors equally contributed to the study and both should be considered as first author. Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by memory loss, cognitive impairment, and functional decline leading to dementia and death. AD imposes neuronal death by the intricate interplay of different neurochemical factors, which continue to inspire the medicinal chemist as molecular targets for the development of new agents for the treatment of AD with diverse mechanisms of action, but also depict a more complex AD scenario. Within the wide variety of reported molecules, this review summarizes and offers a global overview of recent advancements on naphthoquinone (NQ) and anthraquinone (AQ) derivatives whose more relevant chemical features and structure-activity relationship studies will be discussed with a view to providing the perspective for the design of viable drugs for the treatment of AD. In particular, cholinesterases (ChEs), β-amyloid (Aβ) and tau proteins have been identified as key targets of these classes of compounds, where the NQ or AQ scaffold may contribute to the biological effect against AD as main unit or significant substructure. The multitarget directed ligand (MTDL) strategy will be described, as a chance for these molecules to exhibit significant potential on the road to therapeutics for AD. Citation: Campora, M.; Francesconi, Keywords: naphthoquinone/anthraquinone derivatives; Alzheimer’s disease (AD); Aβ aggregation V.; Schenone, S.; Tasso, B.; Tonelli, M. inhibition; AChE and BChE inhibition; Tau inhibition; multitarget directed ligands Journey on Naphthoquinone and Anthraquinone Derivatives: New Insights in Alzheimer’s Disease. Pharmaceuticals 2021, 14, 33. 1. Introduction https://doi.org/10.3390/ph14010033 Alzheimer’s disease is deemed by World Health Organization as one of the most Received: 28 November 2020 common neurodegenerative diseases and more than 80% of total dementia cases in elderly Accepted: 30 December 2020 people. In 2019 World Alzheimer Report estimated over 50 million people living with Published: 5 January 2021 dementia globally, a figure set to increase to 152 million by 2050 [1]. The clinical manifesta- tions of AD are characterized by misfunctioning and gradual neuronal death, resulting in a Publisher’s Note: MDPI stays neu- progressive memory deterioration and cognitive decline, related to the loss of cholinergic tral with regard to jurisdictional clai- and glutamatergic function. The two distinctive hallmarks of AD are the presence of ms in published maps and institutio- extracellular accumulated Aβ plaques [2] and hyperphosphorylated tau protein in the nal affiliations. form of intracellular neurofibrillary tangles (NFT) [3]. AD pathogenesis is not yet fully understood, even if during the years different hypotheses have been formulated; currently it is usually described as a multifactorial disease caused by several factors which include: Copyright: © 2021 by the authors. Li- loss of cholinergic transmission, excessive protein misfolding and Aβ aggregation [4,5], censee MDPI, Basel, Switzerland. oxidative stress and free radical formation [6], metal dyshomeostasis [7], excitotoxicity, and This article is an open access article neuroinflammatory processes [6]. Moreover, the range of targets in AD is increasing, and distributed under the terms and con- for most part, enzymes have been recognized as crucial partners to AD onset and progres- ditions of the Creative Commons At- sion [8]. Hence, a number of molecules has entered clinical phase study with their targets, tribution (CC BY) license (https:// such as β-secretase (BACE1), phosphodiesterase, phospholipase A2, mitogen-activated creativecommons.org/licenses/by/ protein kinase (MAPK) and sirtuin 1 (SIRT1), as an example (clinicaltrials.gov). 4.0/). Pharmaceuticals 2021, 14, 33. https://doi.org/10.3390/ph14010033 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 34 Pharmaceuticals 2021, 14, 33 2 of 33 mitogen-activated protein kinase (MAPK) and sirtuin 1 (SIRT1), as an example (clinical- trials.gov). Bulk of of evidence evidence sheds sheds light light on on the the interconnected interconnected role role played played by bythese these factors factors in AD in ADpathogenesis pathogenesis and, and, consequently, consequently, on the on difficulties the difficulties of setting of setting up more up more effective effective drugs drugs over currentover current therapies. therapies. The marketed The marketed drugs drugsfor the for treatment the treatment of AD, of namely AD, namely the acetylcholin- the acetyl- esterasecholinesterase (AChE) (AChE) inhibitors inhibitors donepezil, donepezil, rivastigmine, rivastigmine, and andgalantamine galantamine and andthe theNMDA NMDA re- ceptorreceptor antagonist antagonist memantine, memantine, are are regarded regarded as as merely merely sympto symptomatic,matic, respectively respectively modu- lating thethe cholinergiccholinergic or or glutamatergic glutamatergic function function [9]. [9] However,. However, the synergisticthe synergistic effect effect between be- tweendonepezil donepezil and memantine and memantine in combination in combination regimen regimen is showing is showing ameliorated ameliorated outcomes out- for comecognition,s for cognition, global assessment, global assessment, daily activities, daily andactivities, neuropsychiatric and neuropsychiatric symptoms, symptoms, but lower butacceptability lower acceptability than monotherapy than monotherapy [10]. [10]. In this scenario,scenario, thethe medicinal medicinal chemistry chemistry efforts efforts have have been been paid paid with with a view a view to disclos-to dis- closinging novel novel chemotypes chemotypes which which could could include include in their in their structures structures the required the required pharmacophoric pharmaco- phoricfeatures features to target to one target or moreone or of more these of factors these implicatedfactors implicated in AD. Many in AD. examples Many examples of NQ and of AQNQ compoundsand AQ compounds from natural from sources natural or sources synthetic or havesynthetic emerged have in emerged virtue of in their virtue promising of their propertiespromising againstproperties AD. against In the presentAD. In the review present we willreview focus we our will survey focus our on cholinesterases,survey on cho- Alinesterases,β and tau proteins Aβ and astau main proteins targets as ofmain NQ targets and AQ of compounds, NQ and AQ whose compounds, networked whose roles net- in ADworked etiology roles are in AD detailed etiology as follows are detailed (Figure as1 ).follows (Figure 1). Figure 1.1. SchematicSchematic representation of somesome biochemicalbiochemical pathwayspathways implicatedimplicated inin ADAD pathogenesis:pathogenesis: thethe interconnectioninterconnection between main targets of NQ and AQ derivatives. Each letter refers to a key event that signs AD etiology, as detailed in the following paragraphs (Sections 1.1–1.3). following paragraphs (Sections 1.1–1.3). 1.1. Role of Aβ in AD 1.1. Roleβ-amyloid of Ab in is AD a protein consisting in 40–42 amino acids, formed by proteolytic cleav- age ofβ -amyloida 695 amino is a acids protein long consisting type I transmembrane in 40–42 amino protein, acids, formed known by as proteolytic amyloid precursor cleavage proteinof a 695 (APP) amino [11] acids. This long proteolytic type I transmembrane cleavage can take protein, two different known aspathways. amyloid In precursor physio- proteinlogical conditions, (APP) [11]. it This occurs proteolytic via the major cleavage non can amyloidogenic take two different pathway pathways. involving In phys-an α- secretaseiological conditions,that cleaves itAPP occurs to form via thesoluble major α-APP, non amyloidogenicwhich is removed pathway from the involving brain, and an aα -secretasemembrane that-tethered cleaves intracellular APP to form C soluble-terminalα-APP, fragment, which called is removed CTFα fromor C83 the [12]. brain, A andsec- onda membrane-tethered enzyme, γ-secretase, intracellular located within C-terminal the transmembrane fragment, called zone, CTFα thenor C83 cleaves [12]. the A second mem- braneenzyme, peptideγ-secretase, into two located small withinpeptides, the p3 transmembrane and APP intracellular zone, then domains cleaves (AICDs), the membrane which peptideare not “amyloidogenic” into two small peptides, [12,13] Th p3e andprocess APP of intracellular APP cleavage domains has been (AICDs), shown which to be im- are pairednot “amyloidogenic” in genetically determined [12,13] The forms process of of AD APP [14,15] cleavage. The amyloidogenic has been shown pathway to be impaired begins within genetically the cleavage determined of the extracellular forms of AD part [14, 15of]. APP The amyloidogenicby β-secretase, pathwaywhich forms begins soluble with the cleavage of the extracellular part of APP by β-secretase, which forms soluble APPβ fragment (sAPPβ) and a C-terminal fragment CTFβ or