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Development of 2-Methoxyhuprine As Novel Lead for Alzheimer's Disease

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Development of 2-Methoxyhuprine As Novel Lead for Alzheimer's Disease molecules Article Development of 2-Methoxyhuprine as Novel Lead for Alzheimer’s Disease Therapy Eva Mezeiova 1,2, Jan Korabecny 1,2 ID , Vendula Sepsova 1,3 ID , Martina Hrabinova 1,3, Petr Jost 1,3, Lubica Muckova 3, Tomas Kucera 3, Rafael Dolezal 1, Jan Misik 1,3, Katarina Spilovska 1,2, Ngoc Lam Pham 1,3, Lucia Pokrievkova 4, Jaroslav Roh 4, Daniel Jun 1,3, Ondrej Soukup 1,2, Daniel Kaping 2 and Kamil Kuca 1,5,* ID 1 Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; [email protected] (E.M.); [email protected] (J.K.); [email protected] (V.S.); [email protected] (M.H.); [email protected] (P.J.); [email protected] (R.D.); [email protected] (J.M.); [email protected] (K.S.); [email protected] (N.L.P.); [email protected] (D.J.); [email protected] (O.S.) 2 National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic; [email protected] 3 Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; [email protected] (L.M.); [email protected] (T.K.) 4 Department of Organic and Biorganic Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic; [email protected] (L.P.); [email protected] (J.R.) 5 Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic * Correspondence: [email protected]; Tel.: +420-495-833-447 Received: 3 July 2017; Accepted: 22 July 2017; Published: 28 July 2017 Abstract: Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer’s disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors—THA and (−)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule. Keywords: acetylcholinesterase; Alzheimer’s disease; butyrylcholinesterase; tacrine; 7-MEOTA; huprine Y; 2-methoxyhuprine 1. Introduction Alzheimer’s disease (AD) is neurodegenerative disorder which manifests itself in neurocognitive dysfunction (e.g., memory loss, behavioral abnormalities, depression, hallucinations, delusion, and agitation). The neuropathological changes associated with AD ultimately lead to consistent irreversible loss of neurons and synapses throughout the brain. This consequently results in the aggravation of AD symptoms and finally in patient’s death [1]. AD is considered one of the major public health issues due to the lack of effective treatment and demographic aging, which will increase the number of people suffering from AD in the future. The economic impact of AD is another important fact to consider [2,3]. Molecules 2017, 22, 1265; doi:10.3390/molecules22081265 www.mdpi.com/journal/molecules Molecules 2017, 22, 1265 2 of 19 Molecules 2017, 22, 1265 2 of 19 The development of effective AD drug treatment builds upon pathomechanism understanding. Onethe lack of the of effective oldest hypothesistreatment and describing demographic mechanisms aging, which ofwill AD increase development the number support of people cholinergic suffering dysfunctionfrom AD in the [1]. future. Accordingly, The economic the alterationsimpact of AD in is cholinergicanother important system fact (such to consider as reduction [2,3]. of activity The development of effective AD drug treatment builds upon pathomechanism understanding. One of different enzymes that are responsible for the synthesis end release of neurotransmitter of the oldest hypothesis describing mechanisms of AD development support cholinergic dysfunction [1]. acetylcholineAccordingly, (ACh))the alterations lead to in degeneration cholinergic system of cholinergic (such as reduction neurons of and activity the of disruption different enzymes of cholinergic that neurotransmission.are responsible for the Currently synthesis end approved release of compoundsneurotransmitter for acetylcholine the treatment (ACh)) of mildlead to to degeneration moderate of AD stages—donepezil,cholinergic neurons rivastigmine,and the disruption and of galantamine cholinergic neurotransmission. provide symptomatic Currently treatment approved by compounds improving cholinergicfor the treatment neurotransmission of mild to moderate via inhibition AD stages of acetylcholinesterase—donepezil, rivastigmine, (AChE, and E.C. galantamine 3.1.1.7.) to provide improve thesymptomatic quality of lifetreatment of AD by patients improving [1,4 ]cholinergic (Figure1). neurotransmission via inhibition of acetylcholinesterase (AChE,Besides E.C. AChE3.1.1.7.)inhibitors to improve (AChEIs),the quality memantineof life of AD patients (Figure [1,4]1) has (Figure been 1). approved for moderate to severeBesides stages AChE of AD inhibitors treatment. (AChEIs), Memantine memantine acts (Figur as ane 1)N has-methyl- been approvedD-aspartate for moderate receptor to (NMDAr) severe antagoniststages of AD protecting treatment. against Memantine glutamate acts as an mediated N-methyl- excitotoxicityD-aspartate receptor [1,4– (NMDAr)6]. Also otherantagonist approaches protecting are against glutamate mediated excitotoxicity [1,4–6]. Also other approaches are currently extensively pursued; currently extensively pursued; among others inhibitors of beta-secretase [7–9], direct inhibition of among others inhibitors of beta-secretase [7–9], direct inhibition of amyloid beta (Aβ) overproduction [10], β amyloidor their betacombination (A ) overproduction into one entity [11,12]. [10], or their combination into one entity [11,12]. FigureFigure 1.1. Structures of of currently currently available available drugs drugs for thefor treatment the treatment of AD—donepezil, of AD—donepezil, rivastigmine, rivastigmine, memantine, and galantamine, and structures of THA and its methoxy derivative 7-MEOTA. memantine, and galantamine, and structures of THA and its methoxy derivative 7-MEOTA. Other neuropathological changes associated with AD are intracellular neurofibrillary lesions composed of hyperphosphorylatedOther neuropathological tau protein changes and extracellular associated accumulation with ADof Aβ are plagues intracellular [1,13–15]. Despite neurofibrillary research lesionsefforts composedto develop novel of hyperphosphorylated therapeutics addressing tauAβ overload protein or and tau extracellular hyperphosphorylation, accumulation it still lacks of A β plagueseffectiveness [1,13– resulting15]. Despite in AChEIs research and effortsmemantin to to develop remain the novel only therapeutics approved AD addressing drugs [16]. Aβ overload or tauThe hyperphosphorylation, first clinically used drug it still for lacksthe treatment effectiveness of AD, resulting THA (1,2,3,4-tetrahydro-9-aminoacridine), in AChEIs and memantin to remain is centrally active, reversible AChEI. It was withdrawn from the market due to its poor oral bioavailability, the only approved AD drugs [16]. the necessity of multiple day-doses, and a number of serious side effects such as hepatotoxicity, nausea, The first clinically used drug for the treatment of AD, THA (1,2,3,4-tetrahydro-9-aminoacridine), is diarrhea, urinary incontinence, and potential carcinogenicity [17]. However, THA remains interesting for centrallymedicinal active, chemists reversible involved AChEI. in AD It research was withdrawn as a scaffold from for the the market development due to itsof poornovel oral lead bioavailability, compounds thewith necessity better toxicological of multiple profile day-doses, than andthe parent a number mole ofcule. serious With this side in effects mind, sucha THA as derivative, hepatotoxicity, 7-MEOTA, nausea, diarrhea,was developed urinary [18,19]. incontinence, 7-MEOTA and retained potential the carcinogenicitypharmacological [profile17]. However, of THA with THA lower remains occurrence interesting of forside medicinal effects. This chemists lower toxicity involved can be in ascribed AD research to having as a different scaffold metabolic for the developmentpathway [17,20]. of novel lead compounds with better toxicological profile than the parent molecule. With this in mind, a THA derivative,2. Design 7-MEOTA, was developed [18,19]. 7-MEOTA retained the pharmacological profile of THA with lowerThe essential occurrence idea of behind side effects. the design This of lower huprines toxicity was to can find be a ascribed lead molecule to having that awill different be able metabolicto span pathwaythe active [17 side,20]. of AChE as much as possible [21]. To achieve this aim, two known AChEIs were chosen. Indeed, huprines amalgamate structural motifs of THA (4-aminoquinoline system) and (−)-huperzine A 2.(carbobicyclic Design bridged moiety). The development of huprines has
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