Tacrine hybrids as multi-target-directed ligands in Alzheimer’s disease: influence of chemical structures on biological activities
- 252 Downloads
Alzheimer’s disease is a neurological disorder, which is the most common form of dementia affecting mostly elderly people. The number of patients is still rapidly increasing which results in negative impacts on population. The loss of cholinergic transmission is one of the signs of Alzheimer’s disease; it is connected with cognition impairment and memory loss. Therefore, some drug therapies are based on restoring the cholinergic function. Therefore, drug therapies are based on the cholinergic hypothesis. Acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine are nowadays in medical use. Tacrine possesses a simple structure and strong activity, but despite these features, it was withdrawn from the market due to its side effects. Due to the multifactorial etiology of Alzheimer’s disease, researchers have investigated multi-target-directed ligands based on tacrine structure to achieve better treatment efficacy. To broaden the therapeutic profile of the ligands, tacrine is bound to numerous moieties with various applications. The hybrids can be obtained in three ways: first, by conjugating; second, by fusing; third, by merging single molecules. The hybrids can target numerous disease pathways simultaneously. This is a promising concept, which will create multiple drugs that will minimize the symptoms of diseases in elderly populations. In this review, we will be describing differently synthesized series of tacrine compounds which were divided based on their biological activities.
KeywordsTacrine Multifunctional drugs Alzheimer’s disease Acetylcholinesterase Hybrids
Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder which is characterized at the beginning by episodic and semantic memory loss and cognitive impairment. As the disease progresses, one may experience a decline in language functions, depression, apathy, and anxiety. In later stages, psychotic features and personality changes may develop (Hugo and Ganguli 2014; Lehrner et al. 2017). It is expected that, by 2030, 65.7 million, and, by 2050, 115.4 million people will be affected by this disease (Prince et al. 2013). Despite many years of research, the main cause of the disease is unknown and only symptomatic treatment is used. Pathological changes result in a loss of cholinergic neurons, decreased level of neurotransmitter acetylcholine (ACh), increased β-amyloid (Aβ) and tau-protein deposition, and dyshomeostasis of bio-metals and oxidative stress (Mullan 1993; Querfurth and LaFerla 2010). There are a few hypotheses, which could explain the AD pathophysiology (such as the cholinergic, Aβ, or tau cascade hypotheses). Nowadays, Aβ and tau cascade hypotheses are considered as more important than the cholinergic one. The cholinergic hypothesis was defined over 30 years ago as the first AD hypothesis. The damage of the cholinergic neurons is observed in the hippocampus, amygdala, frontal cortex, and other structures responsible for learning, memory, or conscious awareness. The main changes observed in cholinergic neurons are choline uptake, impaired acetylcholine release, and deficits in the expression of nicotinic and muscarinic receptors (Bartus et al. 1982; Terry and Buccafusco 2003). The second hypothesis is the Aβ one. The basis to this hypothesis was given by Glenner and Wong 1984. They investigated the cerebrovascular amyloid derived from patients with Down syndrome (Glenner and Wong 1984). Aβ is a peptide consisting of 37–43 amino acids in which isoforms 1–40 and 1–42 are the most common. The Aβ1–42 is considered as the one with the highest toxicity to neurons. Aβ derives from the amyloid precursor protein which is cleaved by several enzymes—beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), a β-secretase, and γ-secretase. The imbalance in production and Aβ aggregation and its accumulation in the brain may be one of the factors that causes AD (Grøntvedt et al. 2018; Haass and Selkoe 2007; Sanabria-Castro et al. 2017; Tanzi and Bertram 2005). Next hypothesis regards neurofibrillary tangles which occur during AD. The tangles are mostly consisted of hyper-phosphorylated and aggregated form of tau. Tangles may also occur as soluble protein in axons and do not cause any toxicity. Their main role is to stabilize microtubules. However, hyper-phosphorylated tau is insoluble, makes aggregates, and causes neurotoxicity. This results in cognition impairment (Khlistunova et al. 2006; Oddo et al. 2006; Querfurth and LaFerla 2010). The oxidative stress is mostly caused by Aβ, which is a generator of reactive oxygen species by causing mitochondria damaged (Good et al. 1996; Hensley et al. 1994). Aβ blocks mitochondrial enzymes (Reddy and Beal 2008). In results, electron transport, ATP production and mitochondrial membrane potential are being impaired and damaged mitochondria easily release free radicals (Good et al. 1996). In addition, higher levels of metal ions (iron, copper, and zinc) are associated with reactive oxygen species (ROS) damage and neurodegeneration. Iron ions increase tau phosphorylation and aggregation (Lovell et al. 1998; Yamamoto et al. 2004). The calcium regulation is in imbalanced in neurodegenerative disorders. The higher concentration of intracellular calcium leads to Aβ formation, its aggregation, and induction of apoptosis. Aβ by itself also increases calcium imbalance (Isaacs et al. 2006; Mullan 1993; Small 2009).
The most important risk factor is old age where AD is mostly diagnosed in people above 65. Comorbidities such as stroke, hypertension, heart diseases, hypercholesterolemia, smoking, and genetic factors have also their impacts (Alves et al. 2010; Cataldo et al. 2010; Hugo and Ganguli 2014). Currently, the most popular treatment is the inhibition of acetylcholinesterase (AChE)—which hydrolyzes the ACh to choline and acetate. The low levels of ACh result in the cognitive impairment and memory problems that occur decades after the beginning of the neurodegenerative process (Francis et al. 1999; Siegfried 1993). Treatment only alleviates the symptoms and barely stops the progression of disease. AChE inhibitors (AChEI) are donepezil, rivastigmine and galanthamine, which are used to treat mild-to-moderate AD. The N-methyl-d-aspartate (NMDA) receptor antagonist—memantine—is also used in symptomatic treatment.
The AChE possesses at least two substrate-binding sites: based on the bottom of the gorge, the active site; located at the entry of the gorge, the peripheral anionic site (PAS). The active site is built of two subsides: the catalytic anionic site (CAS) where the ACh moiety is stabilized by Trp84, Glu199, and Phe330 (Sussman et al. 1991); by the second subside, the catalytic triad which is made of Ser200–His440–Glu327 which hydrolyzes ACh. The carbonyl oxygen of ACh is stabilized by oxyanion hole (made of peptic NH groups from Gly118, Gly119, and Ala201), whereas the acetyl group of ACh is connected with acyl-pocket (Trp233, Phe288, Phe290, and Phe331) of AChE (Harel et al. 1993). PAS influences on the catalytic activity and is made of the three principal amino acids—Trp279, Tyr70, and Asp72. In the surface of the gorge, the rings of 14 aromatic residues (Tyr70, Trp84, Trp114, Tyr121, Tyr130, Trp233, Trp279, Phe288, Phe290, Phe330, Phe331, Tyr334, Trp432, and Tyr442) are located (Colletier et al. 2006; Sussman et al. 1993). ACh is hydrolyzed by cholinesterases—AChE and butyrylcholinesterase (BChE). During the progression of AD, AChE level decreases, whereas BChE increases (Perry et al. 1978). The PAS of the AChE is responsible not only for hydrolyzing ACh, but also for aggregation of Aβ protein, its stabilization, and deposition. Accumulation of Aβ aggregates leads to calcium dysregulation, formation of reactive oxygen species, and neuronal cell membrane damage (Cai et al. 2011; Green and LaFerla 2008; Hardy and Selkoe 2002).
Drugs, which can act on various stages of the neurotoxic cascades, have been investigated and are called multi-target-directed ligands (MTDLs). MTDLs can target numerous pathways involved in the AD development. The hybrid comprises two or more molecules; each molecule belongs to different pharmacological and chemical classes. Single molecules are connected in three ways to obtain novel hybrids (Morphy et al. 2004; Morphy and Rankovic 2005). First, “conjugates” are MTDLs, which have two frameworks (each one possessing pharmacophore elements) and are connected by a linker group (no part of the linker should be found in the ligands). This method of obtaining MTDLs is very common and is described in detail in this review. The linker between two moieties impacts on hybrid’s inhibitory activity. In the second method, the size of the linker between frameworks decreases and ligands touch themselves by the same group in the linker. This type of strategy described and evaluated by Jerábek et al. (2017) fuses tacrine (THA) with resveratrol. In the third method, MTDLs are synthesized by merging both frameworks, where common structures combine together (Morphy et al. 2004; Morphy and Rankovic 2005). Fusing and merging strategies are recently regarded as better than conjugating, due to the fact that they receive lower molecular weight and decrease in structural complexity. These features should help hybrids in crossing the blood–brain barrier (BBB) (Rankovic 2015). Hybrids represent a new strategy to treat AD, enhancing efficacy and improving safety in regards to drugs that have only a single target. AChEI is bound to another moiety to synthesize a multifunctional hybrid, which interacts with the AChE and provides additional properties. It can result in the increase of potency (Cavalli et al. 2008; Singh et al. 2016).
In our review, we focused on THA hybrids, which were synthesized in the last years. All hybrids were divided into five groups on the basis on their biological activities: THA derivatives with cholinesterase inhibition; with cholinesterase inhibition and Aβ antiaggregation properties; with cholinesterase inhibition and antioxidant properties; with cholinesterase inhibition, antiaggregation, and antioxidant properties; with cholinesterase inhibition, antioxidant, and non-hepatotoxicity properties. We provided detailed description of IC50 values toward AChE and BChE, as well as information about type of inhibition, % inhibition of Aβ aggregation, impact of length of the linker on hybrids activities, or antioxidant assay results toward the most promising hybrid of each group. Moreover, we presented chemical structures with their modifications for all hybrids, which make easier to understand the connection between structure and activity.
Tacrine derivatives with cholinesterase inhibition
Elsinghorst et al. investigated novel gallamine–THA hybrids 4a–b, 5a–b, and 6a–b (Fig. 3) as two binding site inhibitors. THA bound to the CAS and gallamine to the PAS of the AChE according to the molecular modeling study. Almost all the compounds showed lower IC50 values toward AChE and BChE than THA and gallamine. The compound 4a presented the best results towards eeAChE [IC50 0.467 nM, THA IC50 300 nM, and human BChE (hBChE) IC50 1.50 nM], while the compound 4b showed the highest inhibitory activity towards hAChE (IC50 5.44 nM, THA hAChE IC50 926 nM, hBChE IC50 1.42 nM). The 6-chloro substitution in the THA moiety did not increase the inhibitory activity of the hybrids as it was observed for other hybrids. Increasing substitution of the gallamine-derived moiety diminished the inhibitory potency. The allosteric potency of hybrids was higher than the one observed for gallamine or THA. Novel compounds bound to the core and peripheral region of the allosteric site (Elsinghorst et al. 2007).
Spilovska et al. evaluated novel heterodimers of 7-MEOTA-adamantylamine thioureas with different linker lengths 9a–g (Fig. 4). 7-MEOTA and amantadine were less potent inhibitors than THA and novel heterodimers. There was no significant difference between compounds with a longer or shorter linking chain. The best inhibitory activity toward hAChE and hBChE was demonstrated by compound 9d (IC50 value of 0.47 μM for hAChE and IC50 value of 0.11 μM for hBChE) which possessed five carbon atoms in the linker and whose potency was similar to the one presented by THA (AChE IC50 0.5 µM, BChE IC50 0.023 µM). Based on molecular modeling, this compound bound itself to the CAS and PAS of AChE (Spilovska et al. 2013).
Tacrine derivatives with cholinesterase inhibition and Aβ antiaggregation properties
Camps et al. evaluated novel donepezil–THA hybrids 12a–h (Fig. 6). According to the molecular modeling study, they bound to the PAS (donepezil moiety), CAS (THA or 6-chlorotacrine moiety), and mid-gorge-binding sites of AChE. The length of the linker between moieties has an impact on the arrangement of the hybrids inside the gorge of the enzyme. All of the novel hybrids were very potent inhibitors of human erythrocytes AChE and human serum BChE with IC50 values in the sub and nanomolar range. The most active inhibitors of human erythrocytes, AChE, were those with the indanone system, a chlorine atom on the THA moiety, and a three-methylene linker, especially the compound 12d (IC50 0.27 nM, hBChE IC50 66.3 nM, THA hAChE IC50 205 nM, and donepezil hAChE IC50 11.6 nM). Novel hybrids were less potent toward hBChE than hAChE. All of them showed higher potency than THA. Moreover, the compounds 12c–h (at the concentration of 100 µM) presented their ability to inhibit AChE-Aβ1–40 aggregation. All the hybrids showed significant Aβ antiaggregation properties, and were more potent than THA or donepezil. The most potent toward hAChE, 12d, showed 46.1% inhibition of Aβ antiaggregation. The strongest was 12f, which inhibited Aβ antiaggregation in 65.9% (THA—only 7% inhibition) (Camps et al. 2008).
Camps et al. synthesized and tested novel pyrano(3,2-c)quinoline–6-chlorotacrine hybrids 14a–j (Fig. 7) as potent dual-binding site AChEI connected through an amido-containing oligomethylene linker. Being a dual-binding inhibitor, 6-chlorotacrine interacted with the CAS and pyrano(3,2-c)quinoline moiety with the PAS of AChE which was evaluated in the molecular modeling study. Novel compounds exhibited inhibition potency toward hAChE (14c IC50 7.03 nM) and hBChE (14c IC50 331 nM), although their inhibitory activities (except 14c) were slightly lower than that of 6-chlorotacrine (hAChE IC50 8.32 nM and hBChE IC50 916 nM). The length of the linker and the position of the amino group had an impact on potency. Due to the inhibition of the PAS of AChE, inhibitors diminished the AChE-induced Aβ-40 aggregation (14i, 6-chlorotacrine—45.9% and 8.5% of inhibition, respectively, at the concentration of 100 µM). They might inhibit self-induced Aβ aggregation (14i, 6-chlorotacrine—49.1%, 7.1% of inhibition, respectively, at the concentration of 50 µM) and β-secretase activity (14j, 6-chlorotacrine—77.8%, not active, respectively, at the concentration of 2.5 µM) (Camps et al. 2009).
Chen et al. synthesized a series of THA–flurbiprofen hybrids 17a–e (Fig. 9) connected by the alkylenediamine linker. Among all hybrids, 17d, the longest linker chain, presented the best inhibitory activity toward eeAChE (IC50 19.3 nM, IC50 BChE 3.7 nM). Its result was better than those of THA (AChE IC50 61.7 nM and BChE IC50 9.0 nM). 17d demonstrated its binding to the CAS through THA moiety and interaction with the PAS of AChE through the benzene ring of flurbiprofen. Moreover, 17d was tested in the Aβ inhibition assay (31% reduction of Aβ formation at the concentration of 0.25 µM) and could inhibit the formation of Aβ due to its ability to inhibit presenilin (Chen et al. 2013).
Sola et al. synthesized heptamethylene-linked levetiracetam–huprine and levetiracetam–6-chlorotacrine hybrids 19a–b, 20 (Fig. 10). The hybrids showed inhibitory potency against human recombinant AChE in nanomolar range (19a IC50 3.1 nM, 19a hBChE IC50 135 nM, THA hAChE IC50 317 nM, and 6-chlorotacrine hAChE IC50 5.9 nM). Inhibition of Aβ42 was tested in the inhibition assay at the concentration of 20 μM. 20 had the best inhibition—36.4%, where THA was below 10%. The C57BL6J mice that were treated with 20, a dose of 5 mg/kg, provide (based on results from acute toxicity study) a 43% inhibition of mouse brain AChE after 10 min of administration. Aβ burden was reduced in APP/PS1 mice’s brains which treated with 20 (Aβ burden—below 0.6% area; THA—0.8% area) (Sola et al. 2015).
Tacrine–fluorobenzoic acid hybrids
Tacrine derivatives with cholinesterase inhibition and antioxidant properties
Rodriguez-Franco et al. evaluated novel melatonin–THA hybrids 25a–m (Fig. 13). Hybrids presented inhibitory activity of IC50 from subnanomolar to picomolar range. The addition of chlorine atom into the position 6 of the THA moiety improved the inhibitory activity. The most potent compound toward hAChE was 25g (IC50 of 8 pM, hBChE IC50 7.8 nM, THA hAChE IC50 350 nM, and hBChE IC50 40 nM). Their oxygen radical absorbance capacity was higher than that of melatonin. 25e was four times, when 25g was 2.5 times more active than trolox (Rodriguez-Franco et al. 2006).
Tacrine–mefenamic acid hybrids
Bornstein et al. evaluated novel series of THA and 6-chlorotacrine–mefenamic acid hybrids 27a–t, 28a–t, 29a–f, 30a–f (Fig. 14). Hybrids were non-competitive or mixed-type inhibitors of AChE. Hybrids interacted with AChE by PAS (mefenamic acid), CAS (THA moiety), and spanning the active-site gorge through a methylene-based linker according to the molecular modeling study. Most of the hybrids presented higher inhibitory activity toward eeAChE AChE than THA (IC50 52.4 nM). Among the series of compounds (29a–f, 30a–f), hybrid 30c (IC50 AChE 0.495 nM) possessed the highest inhibitory activity towards AChE. Among the series of compounds 27a–t, 28a–t, the hybrids with 6-chlorotacrine moieties showed higher inhibitory activity than non-halogen counterparts (28m IC50 AChE 0.418 nM). Due to the fact that mefenamic acid has antiinflammatory activity, the ROS inhibition assay was performed. All compounds presented good inhibitory activity, where hybrid 28m had the best inhibition toward ROS (IC50 0.009 nM and THA IC50 183 nM) (Bornstein et al. 2011).
Tacrine derivatives with cholinesterase inhibition, antiaggregation, and antioxidant properties
Rosini et al. designed and investigated novel carvedilol–THA hybrids 34a–d (Fig. 17). Compounds presented their inhibitory activity toward hAChE in the nanomolar range (compound 34c IC50 1.54 nM and hBChE IC50 189 nM) and their potency was higher than that of THA (hAChE IC50 424 nM). Hybrids were able to bind to the CAS of AChE by tetrahydroacridine moiety and PAS through carbazole moiety as to the molecular modeling study. The compounds were also able to inhibit Aβ self- and AChE aggregation (34c, THA 63.2% and 7% at 100 µM concentration; 25.5% and 5% at 10 µM concentration, respectively) and antagonized NMDA receptors. The compound 34a was capable of neuronal cell protection against ROS (IC50 23 µM; trolox IC50 49.55 µM) caused by oxidative stress (Rosini et al. 2008).
Marco-Contelles et al. evaluated novel hybrids based on THA and nimodipine called tacripyrines 36a–n (Fig. 18). Compounds possessed inhibitory activity toward hAChE and hBChE. Half of them presented higher potency toward AChE than THA, although their inhibitory activity for BChE was rather weak. The best inhibitors were 36h (hAChE IC50 71 nM; hBChE IC50 > 100,000 nM), 36j,l (hAChE IC50 58 nM and 45 nM, respectively, both hBChE IC50 > 100,000 nM) compounds (THA hAChE IC50 147 nM and hBChE IC50 36 nM). Hybrids showed their potency to inhibit pro-aggregating action of AChE and self-aggregation of Aβ (the best was compound 36k—30.7% of inhibition of hAChE-induced aggregation and 34.9% of inhibition of self-aggregation at the concentration of 50 µM). This compound was also investigated in molecular modeling tests. It showed binding to the PAS, but not to the CAS of AChE. Hybrids also showed higher efficiency against free radicals than THA and nimodipine (36k—55.78% of protection; nimodypine—36.03%; THA—0%) (Marco-Contelles et al. 2009).
Tacrine–o-hydroxy- or o-aminobenzylamine hybrids
The 2-aminobenzothiazole moiety appears in many biomolecules. Its derivatives strongly interact with Aβ and inhibit the peptide aggregation (Soto-Ortega et al. 2011). They play neuroprotective roles and may be used as brain-imaging agents in Alzheimer’s disease (Alagille et al. 2011).
β-Carbolines are derived from the biogenic amines tryptamine and serotonin by condensation with aldehydes or R-ketoacids. They are potent and specific inhibitors of dual-specificity tyrosine phosphorylation-regulated kinase 1A; moreover, they are proved to inhibit AChE and the phosphorylation of tau protein on multiple sites associated with tau pathology in AD (Adayev et al. 2011; Frost et al. 2011).
Tacrine hybrids with natural-based cysteine
Tacrine derivatives with cholinesterase inhibition, and antioxidant and non-hepatotoxicity properties
Mao et al. evaluated novel THA–ebselenium hybrids 43a–i (Fig. 23). Compound 43i (AChE IC50 2.55 nM and BChE IC50 2.80 nM) with 5-carbon linker presented the highest inhibitory activity toward eeAChE and esBChE when THA IC50 was 109 nM and 15.8 nM. Hybrids with shorter carbon spacer were less potent AChE and BChE inhibitors. Hybrid 43i was a mixed-type inhibitor of AChE. It interacted with the both CAS and PAS of AChE regarding to the molecular modeling study. Compounds were evaluated for their antioxidant activity. Compound 43e and 43i possessed similar hydrogen peroxide scavenging activity as ebselen (about 75%) at the concentration of 100 µM when THA had almost no activity at this concentration. In the hepatotoxicity assay (on human hepatic stellate cells), hybrid 43i at the concentration of 10 and 5 µM provided higher cell viability than THA (110–100%; THA—90%) (Mao et al. 2013).
Nepovimova et al. synthesized novel THA–trolox hybrids 45a–u (Fig. 24). Hybrids were tested for their inhibitory activity towards human recombinant AChE. The inhibitors block enzyme in micro and submicromolar ranges (from hAChE IC50 13.29 to 0.08 μM, from hBChE IC50 1.30 to 0.02 µM, THA hAChE IC50 0.32 µM, hBChE IC50 0.08 µM, and trolox did not inhibit AChE). 45p, 45t, and 45u presented the best inhibitory activity (hAChE IC50 0.08 µM, hBChE IC50 0.77, 0.70, 0.54 µM, respectively). Hybrids were divided into three groups, differing in the substitution on THA heterocycle. For the 7-methoxytacrine derivatives (45a–g), the IC50 values ranged in micromolar scale and were more potent (except 45d) than prototype, 7-methoxytacrine. Non-substituted hybrids provided better results than the first group. In the third group, the addition of chlorine atom into tetrahydroacridine scaffold led to increased inhibitory activity. None of novel inhibitors showed a better potency than 6-chlorotacrine. The best inhibitor, 45u (with 6-chlorotacrine, 8-carbon linker, and trolox moiety), presented the mixed-type inhibition and bound to the AChE in inverse way in comparison with the other dual-binding-site inhibitors of AChE—the trolox moiety interacted with the CAS, whereas THA binds to the PAS of the enzyme. In DDPH, 45u displayed good antioxidant activity (EC50 44.09 µM), however, slightly lower than trolox (EC50 16.20). Only compounds 45h and 45u showed Pe values above the limits (Pe 4.4 × 10−6 cm s−1, 5 × 10−6 cm s−1, respectively), which indicated that they could cross the BBB. The cytotoxicity effect on HepG2 cell line was investigated. Derivative 45u showed nontoxic properties at concentration 0.5 µM, when IC50 of THA was 19.37 µM and that of 6-chlorotacrine—7.13 µM. The metabolic assay was carried out to explain the missing in vitro hepatotoxic effect of 45u. This compound did not convert into toxic hydroxylated derivative of THA; more than 85% remained unchanged after 1 h of incubation in human liver microsomes system. In the in vivo study, 45u was evaluated for its potential acute toxicity properties and LD50 value. Conversely to the in vitro study, 45u had LD50 value above 500 mg/kg when 6-chlorotacrine only 7.5 mg/kg. It can be caused due to the differences in metabolism and pharmacokinetics in animal body in comparison only to one type of cells in the in vitro studies (Nepovimova et al. 2015).
Xie et al. synthesized novel series of THA–trolox hybrids 46a–g (Fig. 24). All compounds showed AChE inhibitory activity in nanomolar range. Compound 46d possesses the highest inhibitory activity towards hAChE (IC50 23.5 nM and THA IC50 435.1 nM) and hBChE (IC50 20.5 nM and THA IC50 23.2 nM). In the DDPH assay, hybrids showed that they were strong antioxidants (46d IC50 48.7 µM), similar to trolox (IC50 35.6 µM). Kinetic studies and molecular modeling provided information about the mixed-type inhibition by 46d. It was proved that 46d could easily cross the BBB (8.87 × 10−6 cm s−1). The hepatotoxicity test was performed in rats. Animals were treated with the highest tolerated dose of THA or equimolar dose of 46d. 46d did not change the level of liver enzymes (ALAT and ASPAT) and was comparable to control; in result, it had a little hepatotoxicity and was less toxic than THA (Xie et al. 2015).
The research for an effective drug against AD is still ongoing. The current treatment is only symptomatic and cannot stop the progression of disease. The promising way concerns MTDLs based on THA moiety. The THA modification leads to improve its chemical properties. In our comprehensive review, compounds are divided into the groups: THA derivatives with cholinesterase inhibition; with cholinesterase inhibition and Aβ antiaggregation properties; with cholinesterase inhibition and antioxidant properties; with cholinesterase inhibition, antiaggregation, and antioxidant properties; with cholinesterase inhibition, annd antioxidant and non-hepatotoxicity, properties; with cholinesterase inhibition, Aβ antiaggregation, and non-hepatotoxicity properties. To summarize: (1) THA moiety is important structure in MTDLs’ development. It mostly binds to CAS; however, for example in THA–trolox hybrids, THA moiety can bind also to PAS. It is possible to obtain dual-binding site hybrids, which can have good inhibitory activity. (2) The length of the spacer influences the inhibitory activity. The highest inhibition is found for hybrids with 5–9-carbon linker. (3) The substitution at 6 or 6 and 8 positions of THA ring by chlorine leads to increase inhibitory activity towards AChE. (4) The most effective inhibitors were: THA–mefenamic acid hybrid (IC50 0.495 nM with 8-carbon linker and 6-chlorotacrine moiety); THA–gallamine hybrids (IC50 0.467 nM with 5-carbon linker and THA moiety); THA–donepezil hybrids (IC50 0.27 nM with 3-carbon linker and 6-chlorotacrine moiety); THA–indole heterodimers (IC50 0.02 nM with 6-carbon linker and 6-chlorotacrine moiety); THA–o-aminobenzylamine hybrids (IC50 0.55 nM with 9-carbon linker and THA moiety); THA–benzofuran hybrids (IC50 0.86 nM with 7-carbon linker and THA moiety); THA–melatonin hybrids (IC50 8 pM with 6-carbon linker and 6,8-dichlorotacrine moiety). (5) Linking many activities of drugs together has led to the development of MTDLs. Novel hybrids possessed many properties such as: inhibition of Aβ aggregation, low cytotoxicity effect on different cell lines, low hepatotoxic properties, reduction of oxidative stress, and increase in the BBB permeability.
While talking only about advantages of MTDLs therapy, it also faces some problems. Novel hybrids might possess too high-molecular-weight mass due to two or three connected smaller moieties. Therefore, hybrids may violate Lipinski’s rule of 5 and present low CNS penetration. For novel compounds, it is always crucial to obtain good results in ADMET calculations and later in the in vivo pharmacokinetic studies. It is also important to notice the reason for the different concentrations of inhibitor in in vitro assay. In the AChE-Aβ inhibitions assays, researchers use higher concentrations of AChE, Aβ, and inhibitor than those present in human brain. The high level of AChE concentration is essential to accelerate the aggregation process of Aβ. It is important for analytical purposes. The inhibitor/AChE concentration ratio from AChE inhibition assay and from Aβ-inhibition test should be compared. The obtained values should be of the same magnitude, which can indicate that high (in µM) and low (in nM) concentrations of inhibitor give both inhibitory activities (Marco-Contelles et al. 2009). Similar situation is observed in comparison between in vivo and in vitro tests. Both assays may differ due to the differences in pharmacokinetics and metabolism, where also biotransformation is an important process, for example, in toxicity assays. Therefore, concentration of drugs used in in vitro and in vivo assays may vary—for example, like for 7-MEOTA 7, which has some toxicity for the cell in the in vitro assays, but does not show acute or chronic hepatotoxicity in the in vivo assays (Nepovimova et al. 2015). Moreover, in the in vivo assays, it is important to assess LD50 values of novel inhibitors before performing another test. It is crucial to obtain concentration that is general not toxic for animals and will enable to perform in vivo tests.
The last drug against AD, which was approved by the FDA in 2003, was memantine. Since 2003, over 200 compounds reached Phase II, but only 50 went to the Phase III. However, none of them have passed so far Phase III. It might be caused by wrong strategy, inadequate doses of novel drugs, lack of therapeutic efficacy, the serious side effects or just lack of diagnostic criteria, and markers of the disease which could set the clinical endpoints and efficacy standards. Clinical trials are conducted at late stages of AD, when therapeutic drugs are aimed at the early pathological processes. For example, antiAβ agents should be tested at first stages of disease. Moreover, the dosing needs to be more aggressive due to the large burden of pathological changes in the brain even in mild stage of AD. Some clinical trials failures have proper explanations. For example, solanezumab slowing (in around 15%) of cognitive decline, but more likely binds to monomers than to Aβ oligomers (more toxic). It caused a small yield of clinical benefit. Dimebon and R-flurbiprofen did not provide good pharmacokinetics and convincing efficacy. Currently, in III Phase are a few types of novel drugs: amyloid antibodies (antiAβ oligomers agents)—crenezumab, aducanumab and gantenerumab, acetylcholinesterase inhibitor—octohydroaminoacridine succinate, the combination of donepezil and choline alphoscerate, and the MTDLs, such as AVP-786 (NMDA antagonist and P-glycoprotein inhibitor) and TRx-00237 (inhibitor of monoamine oxidase, nitroxide production, and Tau aggregation) (Bachurin et al. 2017; Hung and Fu 2017; Stower 2018). Many novel compounds have being excessively tested in clinical trials (in 2016, antiAβ drugs were investigated in the largest number). So far, Aβ is considered as the best target for AD treatment. The Aβ hypothesis is acknowledged and inspires researchers to develop new drugs. Numerous compounds affect Aβ pathology pathway and might reduce effects (such as oxidative stress) which is caused by Aβ. These compounds focus on reducing production of Aβ (beta and gamma secretase inhibitors), increasing clearance (monoclonal antibodies, which bind to soluble Aβ or senile plaques) and preventing Aβ aggregation. Among described hybrids, almost all were tested against Aβ aggregation and showed their inhibitory properties. Therefore, MTDLs are highly promising compounds for treating AD. They might act against Aβ and toxicity which Aβ caused. Nevertheless, better understanding the pathophysiology of AD will be important to obtain compounds with advantageous properties and finally to combat the disease.
Original research on novel tacrine derivatives has been still carrying out. Since the original drafting of our review, a few important publications have appeared: Cen et al. 2018; Chioua et al. 2018; Hamulakova et al. 2018; Hepnarova et al. 2018; Hiremathad et al. 2018; Jiang et al. 2018; Li et al. 2018; Liu et al. 2018; Skibiński et al. 2017; Wu et al. 2018.
Financial support by Grant (503/3-015-01/503-31-002) from the Medical University of Lodz and grant from the National Science Centre in Poland (Project number: 2015/19/B/NZ7/02847) is gratefully acknowledged.
- Camps P, Formosa X, Galdeano C, Gómez T, Muñoz-Torrero D, Scarpellini M, Viayna E, Badia A, Clos MV, Camins A, Pallàs M, Bartolini M, Mancini F, Andrisano V, Estelrich J, Lizondo M, Bidon-Chanal A, Luque FJ (2008) Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation. J Med Chem 51:3588–3598. https://doi.org/10.1021/jm8001313 Google Scholar
- Camps P, Formosa X, Galdeano C, Muñoz-Torrero D, Ramírez L, Gómez E, Isambert N, Lavilla R, Badia A, Clos MV, Bartolini M, Mancini F, Andrisano V, Arce MP, Rodríguez-Franco MI, Huertas O, Dafni T, Luque FJ (2009) Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and β-amyloid-directed anti-alzheimer compounds. J Med Chem 52:5365–5379. https://doi.org/10.1021/jm900859q Google Scholar
- Chand K, Alsoghier HM, Chaves S, Santos MA (2016) Tacrine-(hydroxybenzoyl-pyridone) hybrids as potential multifunctional anti-Alzheimer’s agents: AChE inhibition, antioxidant activity and metal chelating capacity. J Inorg Biochem 163:266–277. https://doi.org/10.1016/j.jinorgbio.2016.05.005 Google Scholar
- Chioua M, Buzzi E, Moraleda I, Iriepa I, Maj M, Wnorowski A, Giovannini C, Tramarin A, Portali F, Ismaili L, López-Alvarado P, Bolognesi ML, Jóźwiak K, Menéndez JC, Marco-Contelles J, Bartolini M (2018) Tacripyrimidines, the first tacrine-dihydropyrimidine hybrids, as multi-target-directed ligands for Alzheimer’s disease. Eur J Med Chem 155:839–846. https://doi.org/10.1016/j.ejmech.2018.06.044 Google Scholar
- Clark AL, Mitchelson F (1976) The inhibitory effect of gallamine on muscarinic receptors. Br J Pharmacol 58:323–331. https://doi.org/10.1111/j.1476-5381.1976.tb07708.x Google Scholar
- Czarnecka K, Szymański P, Girek M, Mikiciuk-Olasik E, Skibiński R, Kabziński J, Majsterek I, Malawska B, Jończyk J, Bajda M (2017) Tetrahydroacridine derivatives with fluorobenzoic acid moiety as multifunctional agents for Alzheimer’s disease treatment. Bioorg Chem 72:315–322. https://doi.org/10.1016/j.bioorg.2017.05.003 Google Scholar
- Gazova Z, Soukup O, Sepsova V, Siposova K, Drtinova L, Jost P, Spilovska K, Korabecny J, Nepovimova E, Fedunova D, Horak M, Kaniakova M, Wang ZJ, Hamouda AK, Kuca K (2017) Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer’s disease treatment. Biochim Biophys Acta Mol Basis Dis 1863:607–619. https://doi.org/10.1016/j.bbadis.2016.11.020 Google Scholar
- Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence of neuronal oxidative damage in Alzheimer’s disease. Am J Pathol 149:21–28Google Scholar
- Hamulakova S, Janovec L, Soukup O, Jun D, Janockova J, Hrabinova M, Sepsova V, Kuca K (2018) Tacrine-coumarin and tacrine-7-chloroquinoline hybrids with thiourea linkers: cholinesterase inhibition properties, kinetic study, molecular docking and permeability assay for blood-brain barrier. Curr Alzheimer Res Press. https://doi.org/10.2174/1567205015666180711110750 Google Scholar
- Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, Butterfield DA (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91:3270–3274Google Scholar
- Hepnarova V, Korabecny J, Matouskova L, Jost P, Muckova L, Hrabinova M, Vykoukalova N, Kerhartova M, Kucera T, Dolezal R, Nepovimova E, Spilovska K, Mezeiova E, Pham NL, Jun D, Staud F, Kaping D, Kuca K, Soukup O (2018) The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer’s disease. Eur J Med Chem 150:292–306. https://doi.org/10.1016/j.ejmech.2018.02.083 Google Scholar
- Jeřábek J, Uliassi E, Guidotti L, Korábečný J, Soukup O, Sepsova V, Hrabinova M, Kuča K, Bartolini M, Peña-Altamira LE, Petralla S, Monti B, Roberti M, Bolognesi ML (2017) Tacrine-resveratrol fused hybrids as multi-target-directed ligands against Alzheimer’s disease. Eur J Med Chem 127:250–262. https://doi.org/10.1016/j.ejmech.2016.12.048 Google Scholar
- Keri RS, Quintanova C, Marques SM, Esteves AR, Cardoso SM, Santos MA (2013) Design, synthesis and neuroprotective evaluation of novel tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease. Bioorg Med Chem 21:4559–4569. https://doi.org/10.1016/j.bmc.2013.05.028 Google Scholar
- Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM (2006) Inducible expression of tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem 281:1205–1214. https://doi.org/10.1074/jbc Google Scholar
- Korabecny J, Musilek K, Zemek F, Horova A, Holas O, Nepovimova E, Opletalova V, Hroudova J, Fisar Z, Jung YS, Kuca K (2011) Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties. Bioorg Med Chem Lett 21:6563–6566. https://doi.org/10.1016/j.bmcl.2011.08.042 Google Scholar
- Kruman I, Guo Q, Mattson Mark P (1998) Calcium and reactive oxygen species mediate staurosporine-induced mitochondrial dysfunction and apoptosis in PC12 cells. J Neurosci Res 51:293–308. https://doi.org/10.1002/(SICI)1097-4547(19980201)51:3%3c293:AID-JNR3%3e3.0.CO;2-B Google Scholar
- Lehrner J, Coutinho G, Mattos P, Moser D, Pflüger M, Gleiss A, Auff E, Dal-Bianco P, Pusswald G, Stögmann E (2017) Semantic memory and depressive symptoms in patients with subjective cognitive decline, mild cognitive impairment, and Alzheimer’s disease. Int Psychogeriatr 29:1123–1135. https://doi.org/10.1017/S1041610217000394 Google Scholar
- Liu W, Wang H, Li X, Xu Y, Zhang J, Wang W, Gong Q, Qiu X, Zhu J, Mao F, Zhang H, Li J (2018) Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment. Bioorg Med Chem 26:3117–3125. https://doi.org/10.1016/j.bmc.2018.04.037 Google Scholar
- Mao F, Huang L, Luo Z, Liu A, Lu C, Xie Z, Li X (2012) O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation. Bioorg Med Chem 20:5884–5892. https://doi.org/10.1016/j.bmc.2012.07.045 Google Scholar
- Marco-Contelles J, León R, de los Ríos C, Samadi A, Bartolini M, Andrisano V, Huertas O, Barril X, Luque FJ, Rodríguez-Franco MI, López B, López MG, García AG, Carreiras Mdo C, Villarroya M (2009) Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease. J Med Chem 52:2724–2732. https://doi.org/10.1021/jm801292b Google Scholar
- Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) Beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12:376. https://doi.org/10.1523/JNEUROSCI.12-02-00376.1992 Google Scholar
- Muñoz-Ruiz P, Rubio L, García-Palomero E, Dorronsoro I, del Monte-Millán M, Valenzuela R, Usán P, de Austria C, Bartolini M, Andrisano V, Bidon-Chanal A, Orozco M, Luque FJ, Medina M, Martínez A (2005) Design, synthesis, and biological evaluation of dual binding site acetylcholinesterase inhibitors: new disease-modifying agents for Alzheimer’s disease. J Med Chem 48:7223–7233. https://doi.org/10.1021/jm0503289 Google Scholar
- Najafi Z, Mahdavi M, Saeedi M, Karimpour-Razkenari E, Asatouri R, Vafadarnejad F, Moghadam FH, Khanavi M, Sharifzadeh M, Akbarzadeh T (2017) Novel tacrine-1,2,3-triazole hybrids: in vitro, in vivo biological evaluation and docking study of cholinesterase inhibitors. Eur J Med Chem 125:1200–1212. https://doi.org/10.1016/j.ejmech.2016.11.008 Google Scholar
- Nepovimova E, Korabecny J, Dolezal R, Babkova K, Ondrejicek A, Jun D, Sepsova V, Horova A, Hrabinova M, Soukup O, Bukum N, Jost P, Muckova L, Kassa J, Malinak D, Andrs M, Kuca K (2015) Tacrine-trolox hybrids: a novel class of centrally active, nonhepatotoxic multi-target-directed ligands exerting anticholinesterase and antioxidant activities with low in vivo toxicity. J Med Chem 58:8985–9003. https://doi.org/10.1021/acs.jmedchem.5b01325 Google Scholar
- Perry EK, Perry RH, Blessed G, Tomlinson BE (1978) Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol Appl Neurobiol 4:273–277. https://doi.org/10.1111/j.1365-2990.1978.tb00545.x Google Scholar
- Quintanilla RA, Muñoz FJ, Metcalfe MJ, Hitschfeld M, Olivares G, Godoy JA, Inestrosa NC (2005) Trolox and 17β-estradiol protect against amyloid β-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway. J Biol Chem 280:11615–11625. https://doi.org/10.1074/jbc.M411936200 Google Scholar
- Rodriguez-Franco MI, Fernandez-Bachiller MI, Perez C, Hernandez-Ledesma B, Bartolome B (2006) Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J Med Chem 49:459–462. https://doi.org/10.1021/jm050746d Google Scholar
- Rosini M, Simoni E, Bartolini M, Cavalli A, Ceccarini L, Pascu N, McClymont DW, Tarozzi A, Bolognesi ML, Minarini A, Tumiatti V, Andrisano V, Mellor IR, Melchiorre C (2008) Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: a promising direction for the multi-target-directed ligands gold rush. J Med Chem 51:4381–4384. https://doi.org/10.1021/jm800577j Google Scholar
- Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci USA 109:E2895–E2903. https://doi.org/10.1073/pnas.1121081109 Google Scholar
- Sola I, Aso E, Frattini D, López-González I, Espargaró A, Sabaté R, Di Pietro O, Luque FJ, Clos MV, Ferrer I, Muñoz-Torrero D (2015) Novel levetiracetam derivatives that are effective against the Alzheimer-like phenotype in mice: synthesis, in vitro, ex vivo, and in vivo efficacy studies. J Med Chem 58:6018–6032. https://doi.org/10.1021/acs.jmedchem.5b00624 Google Scholar
- Spilovska K, Korabecny J, Kral J, Horova A, Musilek K, Soukup O, Drtinova L, Gazova Z, Siposova K, Kuca K (2013) 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer’s disease treatment—synthesis, biological evaluation and molecular modeling studies. Molecules 18:2397–2418. https://doi.org/10.3390/molecules18022397 Google Scholar
- Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P, Tohda M, Boonyarat C (2014) Synthesis, biological evaluation and molecular modeling study of novel tacrine–carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease. Eur J Med Chem 75:21–30. https://doi.org/10.1016/j.ejmech.2014.01.020 Google Scholar
- Xie SS, Lan JS, Wang XB, Jiang N, Dong G, Li ZR, Wang KD, Guo PP, Kong LY (2015) Multifunctional tacrine–trolox hybrids for the treatment of Alzheimer’s disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties. Eur J Med Chem 93:42–50. https://doi.org/10.1016/j.ejmech.2015.01.058 Google Scholar
- Yamagata K, Ichinose S, Miyashita A, Tagami M (2008) Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat. Neuroscience 153:428–435. https://doi.org/10.1016/j.neuroscience.2008.02.028 Google Scholar
- Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F, Kitamoto T (2004) Iron (III) induces aggregation of hyperphosphorylated τ and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem 82:1137–1147. https://doi.org/10.1046/j.1471-4159.2002.t01-1-01061.x Google Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.