Coumarin Derivatives in Pharmacotherapy of ...

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REVIEW ARTICLE

Coumarin Derivatives in Pharmacotherapy of Alzheimer´s Disease Slavka Hamulakovaa, Maria Kourkováb,c and Kamil Kucac,d* a Department of Organic Chemistry, Institute of Chemical Sciences, Faculty of Science, P. J. Safarik University, Moyzesova 11, SK041 67 Kosice, Slovak Republic; bDepartment of Biochemistry, Institute of Chemical Sciences, Faculty of Science, P. J. Safarik University, Moyzesova 11, SK-041 67 Kosice, Slovak Republic; cBiomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, CzechRepublic; dDepartment of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanského 62, 500 03 Hradec Kralove, Czech Repulic

ARTICLE HISTORY Received: March 12, 2016 Revised: May 15, 2016 Accepted: May 29, 2016 DOI: 10.2174/1385272820666160601155 411

Abstract: Coumarins are naturally occurring phytochemicals with heterocyclic structures which display a wide range of biological activities against neurological diseases such as Alzheimer´s disease (AD). This study reviews recent research into the design, synthesis and pharmacological profile of several series of synthetic coumarin ligands with clearcholinesterase, and assesses the monoamino oxidases (MAO-A and MAO-B) inhibitory activity, A anti-aggregation potency and antioxidant properties reported for these novel derivatives. Our attention is focused on a comparison of the neuroprotective effects of these coumarin derivatives in terms of their potential as mono-, homo- and heterodimers as agents in the treatment of AD. The monocoumarin derivatives 13a & 13b with benzyl pyridinium group showed outstanding levels of acetylcholinesterase inhibitory activity (IC50 = 0.11, 0.16 nM). Bis-coumarin ligands showed high levels of inhibitory activity and selectivity for MAO-A. Tacrinecoumarin heterodimer 21b was the most active inhibitor of hBChE (IC50 = 38 pM).

Keywords: Coumarin, Alzheimer´s Disease, acetylcholinesterase inhibitor, A aggregation, bis-coumarin dimers, tacrine-coumarin heterodimers, monoamine oxidases. 1. INTRODUCTION The neurodegenerative disorder Alzheimer´s disease (AD) is one of the most common causes of dementia and is typically characterized by the apparent loss of cognitive function including thinking and memorisation. These losses result in language difficulties, limited ability to perform everyday activities and other neuropsychiatric symptoms [1]. The main origins of AD are amyloid plaques (A-amyloid) and their aggregates, neurofibrillary tangles (NFT) consisting of hyperphosphorylated tau protein and the degeneration of the basal forebrain cholinergic neurons [2]. Studies of pathological lesions have led researchers to propose several hypotheses concerning the origins of AD which include the cholinergic hypothesis [3-5], the amyloid cascade hypothesis [6], hyperphosphorylation [7], the cell cycle hypothesis [8] and the brain derived neurotrophic factor hypothesis [9]. Several active players in AD pathology have been identified to date, including oxidative stress, free radical formation [10, 11], metal dyshomeostasis [12, 13], mytochondrial disfunction [14, 15], inflammation [16, 17], and cholesterol raft and vascular factor [18, 19]. Three palliative approaches have met with some success in limiting the development of AD, namely anti-amyloid, neuroprotective and strengthening approaches. The main aim of these therapeutic strategies is to prevent or inhibit the formation and aggregation of A amyloid, or to reduce the soluble levels of the amyloid [20]. Other disease modifying strategies are currently under active evaluation which target abnormal tau protein by reducing its phosphorylation and/or aggregation in addition to offering neuroprotec

*Address correspondence to this author at the Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, CzechRepublic; Tel: +420 603 289 166; E-mail: [email protected]

1385-2728/17 $58.00+.00

tive effects [21]. The only two classes of drugs for AD treatment which are currently approved by the Food and Drug Administration (FDA) for mild to medium forms of AD are acetylcholinesterase inhibitors (AChEIs) and, for medium to serious AD, the N-methylD-aspartate receptor (NMDAR) antagonist memantine, both of which are known to possess neuroprotective qualities [22]. Several studies have shown that AChEIs (tacrine, donepezil, galantamine, rivastigmine) not only offer symptomatic benefits, but also affect the underlying processes of AD through their neuroprotective and disease-modifying properties [23-27]. Recent research has also suggested that that the NMDAR antagonist memantine acts may also act as an inhibitor of the internal ribosome entry site, thereby reducing the expression of APP and thus ameliorating the symptoms of AD [28]. Multi-target-directed ligands (MTDLs) which interact with different targets peculiar to multifactorial pathologies have also been applied against neurodegeneration [29].

O Fig. (1). Coumarin.

O

Coumarin (1,2-benzopyrone, 2H-1-benzopyran-2-one) 1 (Fig. 1) forms the core of a large class of phenole derived compounds isolated from plants which display a wide range of biological activities [30-36]. Recent studies have revealed that coumarine derivatives are potential inhibitors of monoamine oxidases (MAO-A and MAO-B) [37], cholinesterases (AChE/BChE), A aggregation [3842] and that they may also protect against oxidative stress [43, 44]. These findings suggest that coumarin derivatives should be considered as potential future therapeutic agents for the effective treatment of AD. © 2017 Bentham Science Publishers

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Current Organic Chemistry, 2017, Vol. 21, No. 00

MeO

O

Hamulakova et al.

O

MeO

MeO

O

O

MeO N

N

2, IC50 = 44.5 nMa, 48.9 nMd MeO

O

3a, IC50 = 62.1 nMa MeO

O

O

OMe

O

MeO

MeO

N

N I

3b, IC50 = 10.5 nMa

3c, IC50 = 18.3 nMa Me O O

N

N

MeO

N H

N

N

MeO

Me

Me

O

O

O

7a, IC50 = 4.5 μMb

9a, IC50 = 21 nMb

O

N

H N

MeO

O MeO

MeO

O

O

8a, IC50 = 5.3 μMb

O MeO

O

4N

O

O

O

N H O

11, IC50 = 7.6 nMc

9b, IC50 = 14 nMc O

N MeO

Br

O

MeO

O

F

O

O

N

O

13a, IC50 = 0.11 nMb

12a, IC50 = 21 nMc O F

O Br

O

O

N

O

OMe

13c, SI = 4468

O

O

N

O 13b, IC50 = 0.16 nMb

O

O

CH2OH

O

O

N 14, Ki = 3.40 μMe Cl a

15, IC50 = 15.8 μMf, 0.010 μMg, 0.12 μMb

Human recombinant AChE, b Electrophorus electricus AChE, c Bovine erythrocytes AChE, d BChE from human serum, e Torpedo marmorata AChE, f rMAO-A from rat brain, rMAO-B from electric eel.

g

Fig. (2). Chemical structures of the most effective coumarin inhibitors [45-50].

2. MONOCOUMARIN CHOLINESTERASE INHIBITORS Many compounds which contain a coumarin skeleton have been studied in their capacity as AChEIs. Coumarin derivative AP2238 2 was the first coumarin compound to be studied in depth and was found to possess the ability to interact simultaneously with both the catalytic active site (CAS) and the peripheral active site (PAS) of AChE [45]. The chemical structures of the most effective monocoumarin ligands are shown in Figure 2.

Piazzi et al. proposed and synthesized a series of 6,7disubstituted-2H-2-chromenone derivatives (derivatives 3) and examined the inhibitory effect of these compounds on hAChE and hBChE (Table 1) [45]. The inhibitory ability of new compounds was measured by IC50 compared and was examined in comparison to the control, derivative 2. Structure-activity relationship (SAR) analysis of the position of benzylalkylamino moiety and substituents on the heteroaromatic

Coumarin Derivatives in Pharmacotherapy of Alzheimer´s Disease


comparison to the control, derivative 2. The reported inhibitory activity (IC50 = 18.3 nM) was approximately twice as high as that of the control compound and, in addition this, coumarin derivative 3c was also shown to inhibit 38% of A amyloid aggregation [45]. Three types of coumarin derivatives (series A-C) with phenylpiperazine functions on the coumarin ring (derivatives 4-8) were synthesized and their anticholinesterase activities examined (Table 1) [46]. The A-series (derivatives 4) consists of coumarin derivatives with a phenylpiperazine function at position 6, the B-series (derivatives 5, 6) at position 3 and the C-series (derivatives 7, 8) at position 4 (Table 1).

nucleus revealed that the N-benzyl-N-methyl group in p-position (Table 1) and 6,7-dimethoxy coumarin displayed the highest anticholinesterase activity recorded to date. Analysis of function groups linked to phenyl suggests that only the o-methoxy group in the terminal phenyl ring of derivative 3a showed inhibition activity (IC50 = 62.1 nM) of the same order of magnitude as the key compound 2 [45]. The results also confirmed the significance of the positive charge of the methyl ammonium analogue 3b (Fig. 2) which showed the lowest IC50 of the series (IC50 = 10.5 nM). The replacement of the methyl substituent of the amino group for the ethyl group resulted in a higher level of potency for derivative 3c in Table 1.

Synthesized monocoumarine compounds.

Compound

Coumarin skeleton

Linker (X)

Substituents (Y)

X R1

3

R2

O

O

R3

N Y p-H, m-H, o-NO2, p-NO2, m-NO2 , o-Me, m-Me, p-Me, o-OMe, m-OMe

3 [45] R1, R2 = OMe, R1 = H, R2 = OMe,

R3 = Me, Et, EtOH

R1 = OMe, R2 = H, R1 = H, R2 = NO2 , R1 = H, R2 = NH2

4 [46]

X

R1 4

6

Y N

(series A)

O

o-Me, p-Me, p-OMe, H, p-Cl, o-OMe, p-OEt

N

O

R1= OMe, Cl

O

Y

3

5 [46]

X O

H, o-Me, p-OMe, o-OMe, p-Cl, p-Me, o, m-diCl

N

(series B)

N

O

O 6 [46] p-Me, H, p-Cl, o-Cl, p-NO2

N

Y

(series B)

N

X 7 [46]

4

Me

Y o-OMe, p-OMe, p-Me, o-Me, H

N

(series C)

O

N

O

O 8 [46]

N (series C)

N

3

p-Me, H, p-Cl, o-Cl

Y

4


Hamulakova et al.

Table 1. contd….

Compound

Coumarin Skeleton

Linker (X)

Substituents (Y)

NH(CH2)2N(CH3) NH(CH2)3N(CH3) NH(CH2)4N(CH3) O(CH2)3N(CH3)

N N O 9 [47]

HN

3

MeO

X N

MeO

O

O

O N O N

3 H N

R1

X

10 [47]

R2

O

O

n

O

R1, R2 = OMe R1, R2 = H

N

n = 1-3

3 H N

MeO

X

H N

11[47]

MeO

O

3 O

R1

12 [47]

R2

O

O

O

X N

O

R1, R2 = H R1, R2 = OMe, H R1, R2 = OMe R1, R2 = H, OMe

3 13 [48]

X

H, o-F, p-F, m-F, o-F, o-NO2, o-Cl, m-Cl, o,m-diCl, m,p-diCl, o-Me, m-Me, p-Me, m-CN, p-CH2-Cl, p-OMe

O

R O

O

N

R = H, 8-OMe, 6-Br

Y

Most of the proposed hybrids displayed only a modest inhibitory effect on AChE. The compounds with phenylpiperazine functions at positions 3 and/or 4 of the coumarin skeleton (series B & C) were found to be more potent AChE inhibitors than the coumarins substituted at position 6 (series A). The AChE inhibitory activity of

the synthesized monocoumarin compounds of the B-series are in the IC50 range of 6.7 M to 34 M [46], results which are comparable to those of the C-series, which range from 4.5 M to 61 M. The compounds with a smaller substitution on the phenylpiperazine showed stronger inhibitory activity, a finding which suggests that


the spacing among the carbonyl group and the nitrogen of piperazine are crucial for the inhibitory effect of the compounds. Significant levels of AChE inhibition were also recorded for the Cseries compounds substituted with piperazine rings at position 4, derivatives 7a and 8a, (IC50 = 4.5 M and 5.3 M) (Fig. 2) [46]. Catto et al. reported the synthesis of a new series of 6,7dimethoxy-3-substituted coumarins (derivitives 9-12, Table 1) linked to a benzylamino group placed at an appropriate distance from the 3-position of the coumarin ring [47]. A substantial increase in inhibitory activities against AChE and BChE was recorded in the amides with elongated linkers. Amide 9a (Fig. 2) with four methylene groups in the linker showed high levels of inhibitory potency (IC50 = 21 nM) and the replacement of the amide group with the ester group decreased the IC50 of derivative 9b even further to 14 nM. The Acis-3-amino-cyclohexanecarboxylic acid derivative, amide 11 (Fig. 2), exhibited the highest activity (IC50= 7.6 nM) and selectivity of the whole series of 6,7-dimethoxy-3substituted coumarins against AChE showing a level of potency similar to the control substance donepezil. Interestingly, the extension of the spacer between coumarin and the N-benzyl function with a methylene group resulted in increased inhibitory activity of compound 12a (IC50 = 21 nM) with BChE/AChE selectivity by a factor of 186 [47]. Alipour et al. described the most potent inhibitors of AChE reported to date, a novel family of coumarin analogues (compounds 13) connected to the benzyl pyridinium function (Table 1) [48]. The most active compounds of this family, derivatives 13a and 13b (Fig. 2) displayed higher levels of inhibitory activity towards AChE (IC50 = 0.11 nM and 0.16 nM) than was recorded for the control, donepezil (IC50= 14 nM). Compound 13c exhibited the highest selectivity for AChE with a selectivity index (SI) of 4468 (SI is determined as the ratio of IC50 (BChE)/ IC50 (AChE)). Indeed, the AChEI activity of these hybrids were found to be largely dependant on the steric and electronic properties of both benzyl and coumarine moiety [48]. A substantial four-fold decline in activity was observed following the introduction of fluorine at position 4 of benzyl, and a similar change was observed upon the introduction of bromine to the coumarin moiety. Bulky substituents at position 4 of benzyl therefore displayed weaker activity compared to those with smaller substituents (CH3 > Cl > F). The addition of an electronwithdrawing substituent on position 3 of the benzyl function increased the activity of the coumarin derivatives, and the presence of a second substituent introduced to the benzyl ring was found to lead to a considerable reduction in the activity of the coumarin compounds [48]. MAO-A and MAO-B inhibitors, analogues of 7hydroxycoumarin, were tested as acetylcholinesterase inhibitors. The best performing MAO-B inhibitor was 7-[3-chlorobenzyl)oxy]3,4-dimethylcoumarin (derivative 14, Fig. 2), which exhibited the strongest inhibition of AChE with Ki= 3.40 μM [49]. From the newly synthesized series of 2H-chromen-2-one derivatives, 7-(4(N-benzyl-N-methylaminomethyl)benzyloxy)-4-(hydroxymethyl)2H-chromen-2-one hydrochloride (derivative 15, Fig. 2) was the most interesting on account of its excellent dual AChE and MAO B inhibitory activity; also noteworthy was the ability of the compound to permeate through the blood-brain barrier (BBB) and in vitro neuroprotective activity by passive diffusion [50]. 3. BIS-COUMARIN MAO-A AND MAO-B INHIBITORS The series of cumarine derivatives including Esuprone; LU 53439; 7-benzylossi derivatives 15 or 3-acyl coumarins 16 (Fig. 3) have also been reported as a MAO inhibitors [51-53]. MAOs exist


5

in two isoenzyme forms, MAO-A and MAO-B [54], and both show high substrate selectivity and inhibitor sensitivity [55]. MAO-A is more selective for the oxidation of serotonin, noradrenaline and adrenaline, whereas MAO-B preferably oxidizes phenylethylamine and benzylamine. In tests conducted on rat brains, dopamine, tyramine, and tryptamine were preferably oxidized by MAO-A, while studies on the human brain revealed that the same amines are deaminated by MAO-B [56]. Normal brain development and neurotransmition is directly dependant on the activity of the enzymes. Recent research indicates that their level is genetically determined and that the presence of the enzymes can influence some aspects of personality or addictive behaviours [57]. There is some evidence that a combined treatment with inhibitory activity against two different enzymes, e.g. physostigmine with a MAO-B inhibitor and a cholinesterase inhibitor, might prove to be an effective form of treatment [58, 59]. MAOIs directly influence the level of neurotransmitters and they have proved their efficiency through their widespread use as antidepressant and antianxiety drugs. Recent studies have also demonstrated the potential application of these agents in the treatment of neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease [60]. Chimenti et al. [60] designed and synthesized a novel series of bis-coumarin hybrids, derivatives 16a-g (Fig. 3), which were intended to act as MAO-A/B inhibitors. Most of the compounds displayed inhibitory activity in the nanomolar range, and showed a selectivity against MAO-A and MAO-B. From all of the studied compounds, derivatives 16b and 16d showed the highest levels of MAO-A inhibitory activity (pKi (MAO-A) = 9.0 and 8.4, respectively) and also displayed the highest selectivity (pSI = pKi (MAO-A) - pK i (MAO-B) = 3.0 and 2.66, respectively). The measured inhibitory activity of bis-coumarin-3-carboxamides 16a-g against MAO-A demonstrated that derivative 16e (with phenyl ring linked to the carboxamide groups in the 1,2 positions) showed the most potent activity (pKi (MAO-A) = 7.79) in comparison with the other compounds containing a phenyl or cyclohexyl linker between two coumarin-3carboxamide moieties. 4. MULTIFUNCTIONAL TACRINE-COUMARIN LIGANDS In the last few years, several studies have reported the design, synthesis and pharmacological evaluation of a series of heterodimers containing tacrine units combined with other units of AChEIs. These added units include tacrine-ferulic acid heterodimers [61], tacrine-melatonin heterodimers [62], tacrinecarvedilol heterodimers [63], tacrine-NO donor heterodimers [64], tacrine-gallamine heterodimers [65], tacrine-donepezil heterodimers [66], tacrine-propidium heterodimers [67]. These combinations are intended to allow simultaneous interaction with both the active and the peripheral binding sites of AChE. Tacrine is known to inhibit both forms of ChE by binding to the CAS, and has an IC50 value in the nanomolar range. The compound also benefits from a relatively low molecular weight which is suitable for modification. Tacrine also prevents A- aggregation and the deposit of A-amyloid plaques due to its interaction with the PAS of AChE [68]. Several tacrine heterodimers MTDLs have been designed and synthesized in the aim of improving the biological activity of the agent and also of extending its capabilities beyond its initial role as an AChE inhibitor. This latter approach allows the compounds to interact with more than one specific AD target and represents an innovative strategy for AD treatment [69]. The chemical structures of the most effective tacrine-coumarin heterodimers are shown in Figure 4.

6


Hamulakova et al.

N

O

N EtO3S

O

O

O

Esuprone

LU 53439 R

O

O

COR´

O

O

14

O

15 O

O N H

R

O

S

O

X

N H

O

O

O

R

16a-g R=

H

H, OCH3

H

X=

- (CH2)2

- (CH2)4

- (CH2)6

a

b, c

H

d

H

e

H

f

g

Fig. (3). Chemical structures of bis-coumarin MAO-A and MAO-B inhibitors.

Elsinghorst et al. [70] developed a new series of dual binding site AChE inhibitors containing a 7-dietylaminocoumarin unit, a 9hydrazidotacrine unit and a spacer bearing enamine function (derivatives 18) (Fig. 4). This derivative was found to be a potent inhibitor of both hAChE and hBChE in vitro, although while the level of inhibition against hAChE was at the picomolar level (IC50 = 280 ± 10 pM), the inhibition activity against hBChE was many times lower (IC50 = 16 ± 1 nM). The presence of a fluorophore in the compound’s structure indicates the potential of this agent for further histochemical applications. Xie et al. [40] synthesized a series of multifunctional hybrids (derivatives 19) combining tacrine and coumarin scaffolds into a single molecule (Table 2). A piperazine side-armed-alkane spacer was used to connect the coumarin and tacrine fragments. The compounds were tested to establish the efficiency of their simultaneous inhibition of both ChEs and A aggregation, and the agent’s additional ability to chelate metal ions was also examined. Compound 19a displayed the highest level of inhibitory activity against AChE (IC50 = 0.092 μM) and its potency was 3 and 29 times stronger than that of tacrine and galantamine, respectively (Fig. 4). Compound 19b exhibited the highest inhibition against BChE with a IC50 value measured at 0.099 μM, a level of inhibition which was 128-times more efficient than that of galantamine (Fig. 4). The results indicate that the lengthening of the alkyl chain spacer from two to six carbon atoms lead to a decrease in AChE inhibitory activity. The studies also reveal that the prolongation of the alkyl chainspacer from five to six carbon atoms resulted in the highest level of BChE inhibitory activity, ranging from 0.099 M to1.27 M (Fig. 4). The metyl substitution at position 4 of the coumarin moiety increased

the inhibitory activity against both AChE and BChE in comparison to the non-substituted compounds. All of the tested compounds, either with or without methyl substituent at position 4 of coumarin were more active inhibitors of A aggregation than curcumin. Compound 19a also displayed metal-chelating capabilities and low cell toxicity. Sun et al. [41] evaluated the SAR in a series of tacrinecoumarin hybrids with an ,-Alkyl diamine chain linker added at position 3 of coumarin (derivatives 20) (Table 2). The highest AChE inhibition activity was measured on the Compound 20a, containing 6 methylenes, was found to be the most efficient inhibitor of AChE, while the other compounds in the series featuring either shorter (5 methylenes) or longer (7 methylenes) alkyl chain linkers displayed lower levels of inhibition activity. Similarly, the inhibitory activity of these compounds was affected by the presence of the substitution at position 6 and 7 of a condensed benzene ring of coumarin. Compound 20a was identified as the most potent candidate with a potency against both hAChE and BChE (Ki = 16.7 nM and Ki = 16.1 nM respectively) which was almost double that of the control tacrine (Fig. 4). Derivative 20b (K i = 8.1 nM) (Fig. 4) was found to be the most potent inhibitor of hBChE, while compound 20c displayed almost equivalent levels of activity against both hAChE and hBChE (Ki = 24.3 nM, 23.7 nM). These tacrine-coumarin hybrids were also screened for their inhibitory activity against A-aggregation and -secretase, using curcumin as a control; compounds 20d and 20e were found to be the best inhibitors of A-aggregation, recording IC50 values of ~ 5.0 μM and ~ 6.1 μM, respectively.



N

O N H N

( ) nO

N

Me

HN N H

O

O

O N H N

O

19a, n = 2, IC50 = 0.092 μMc 19b, n = 6, IC50 = 0.099 μMd

O

O

1 R

( ) N N nH H

2 R

N

1 R O

( ) N nH

N

O

( )

H N

H N

N

22b, IC50 = 38,29 nMa

N H N

N

n

N H

N H

O O 22a, n = 4, IC50 = 0.0154 μMe, 0.328 μMf

N

H N

R2 21a, n = 8, R1 = 5-OH-7-OMe, R2 = 6-Cl, IC50 = 35pMe 21b, n = 8, R1 = 6-OMe, R2 = H, IC50 = 38 pMb 21c, n = 8, R1= 5,7-diOMe, R2 = H, IC50 = 2.1 μMg 21d, n = 8, R1= 6-OH, R2 = H, IC50 = 2.8 μMg

O N H

( )

O

20a, n = 6, R1, R2 = H, Ki = 16.7 nMa, Ki = 16.1 nMb 20b, n = 5, R1, R2 = OMe, Ki = 8.1 nMb 20c, n = 6, R1= OMe, R2 = H, Ki = 24.3 nMa, Ki = 23.7 nMb

HO

H N

O

O

O

N

18: IC50 = 280 ± 10 pMa, 16 ± 1 nMb

O

7

N m

O

O

HO

( ) nO

2 R O

1 R

O 25b, n = 3, m = 2, R1, R2 = H, IC50 = 16.12 nMd 25f, n = 2, m = 3, R1, R2 = H, IC50 = 17.70 nMc 26c, n = 2, m = 3, R1, R2 = Me, IC50 = 16.11 nMa a

Human recombinant AChE, b Human serum BChE, c Electrophorus electricus AChE, d Equine serum BChE, e Human erythrocytal AChE, f Human plasmatic BChE, g hBACE-1

Fig. (4). Chemical structures of tacrine-coumarin hybrids [40-42, 70-73]. Table 2.

Chemical structures of tacrine-coumarin hybrids.

Comp.

Coumarin skeleton

Linker (X)

R1

O O

O

O

N HN

n

Substituents (R)

R1: H, Me, Ome, Ph

N

4

19 [40]

Tacrine skeleton

X

X n = 2-6

N X

O 20 [41]

3

6 R1

X O

O

7 R2

HN

n = 5-7

NH n

R1: H, Ome, Me, OCF3 R2: H, Ome

N

8


Hamulakova et al.

Table 2. contd…

Comp.

Coumarin skeleton

Linker (X)

Tacrine skeleton

X

O HN

21 [42]

n

R1

2

X

NH

R1: H, 6-OMe, 5,7-diOMe, 6,7-diOMe, 6-OH, 5-OH, 7-OMe, 5,7-diOH

R2

n = 5-8, 10

O

Substituents (R)

N

R2: H, 6-Cl, 6,8- diCl

O

O 22-24 [71, 72]

X

NH n

HN

X 4

O

O

n = 2-4, 6-9

N

OH S HN

N H

NH

S H N

N

R2 25, 26 [73]

X

N

R1

O

O O

O N

X

N n

n = 2-6 m = 2, 3

Fernández-Bachiller [42] has recently reported the synthesis of a large series of tacrine-4-oxo-4H-chromene hybrids, derivatives 21 (Table 2). The compounds were screened for their potential cholinergic; antioxidant and A-lowering activities. The tacrine fragment was substituted with either one or two chlorine atoms while the 4-oxo-4H-chromene fragment carried either one or two phenol groups, and the fragments were connected by alkylenediamine linkers of different lengths. The compounds were evaluated for their inhibitory activity against human recombinant BACE-1 protein, human AChE and human BChE. Tacrine-4-oxo-4H-chromene hybrid 21a produced from 6-chlorotacrine and 5-hydroxy-7-methoxy-4-oxo-4Hchromene was found to be the most efficient hAChE inhibitor of this series (IC50 = 35 pM), displaying a level of inhibition 10 000times higher than the parent tacrine fragment (Fig. 4). Compound 21b, derived from tacrine and 6-methoxy-4-oxo-4H-chromene was the most active inhibitor of hBChE with an IC50 value 1052-times higher than tacrine (IC50 = 38 pM), while derivative 21c was found to be the strongest inhibitor of hBACE-1 (IC50 = 2.1 μM) (Fig. 4). Compound 21d composed of unsubstituted tacrine combined with 6-hydroxy-4-oxo-4H-chromene through a 10 methylene spacer showed high levels of simultaneous inhibition of hBACE-1 and ChEs, with a level of antioxidant activity 1.3-fold higher than vitamin E and the addition on CNS-permeability (Fig. 4).

NH m

R1: H, Me, Cl R2: H, Me, OMe, OEt, CF3, Ph, NH2

N

Hamulakova et al. [71, 72] synthesized a wide range of different compounds based on the addition of different tethers of different lengths to connected tacrine and coumarin fragments; derivatives 22 contained different alkylenediamine tethers, derivatives 23 contained different thiosemicarbazides tethers and derivatives 24 contained linkers with thiazolidinone heterocycles (Table 2). It was suggested that the structure of the linkers could match with narrow enzymatic cavities, thereby resulting in simultaneous interaction between the heteroaromatic fragments and both the CAS and PAS of AChE. The length of the linker connecting the coumarin moiety and tetrahydroacridine skeleton was found to play a significant role in determining the affinity for AChE. Increasing levels of AChE inhibitory activity (IC50 = 3 μM - 0.00154 μM) were recorded for compounds with alkyl chains lengthened from two to four carbon atoms, while this tendency was reversed for compounds with alkyl chain spacers lengthened by six to nine methylenes (IC50 = 65 nM 120 nM) [72]. Tacrine-coumarin hybrids with increasing numbers of amino groups showed correspondingly increasing levels of AChE inhibitory activity. Among these compounds, tacrinecoumarin heterodimer 22a with four methylene groups between the tacrine and amide group displayed excellent inhibition of hAChE with an IC50 value measured at 0.0154 μM, a value approximately 32 times higher than that of tacrine and 974 times higher than that of 7-MEOTA [71]. Compound 22a also exhibited the best selectivity for hAChE (SI = 21.30). The Ki1 value of 0.0041 μM for ligand


22a indicates that this compound demonstrates the strongest affinity towards hAChE, (55 times higher than that of tacrine and 510 times higher than that of 7-MEOTA). Lineweaver-Burk plot analysis revealed a non-competitive inhibition of hAChE by ligand 22a. Compound 22b with a fourteen-atom linker and four amino groups (IC50 = 38.29 nM) showed the highest inhibitory activity against AChE, demonstrating a level of potency 13- and 392-times stronger than that of the controls tacrine (IC50 = 500 nM) and 7-MEOTA (IC50 = 15 000 nM), respectively (Fig. 4). The replacement of the alkyl chain with a thiosemicarbazide linker or thiazolidinone moiety led to a dramatic decrease in AChE inhibitory activity (IC50 = 8.17, 15.7 μM). Xie et al. developed a series of new tacrine-coumarin hybrids, derivatives 25a-j & 26a-j, with both ChE and MAO-B inhibitory activity and the ability to penetrate the blood-brain barrier (BBB) [73]. They are based the conjugation of tacrine with a set of coumarin derivatives connected with piperazine side-armed alkane spacers of different lengths. Compound 25f with a three-carbon linker between the tacrine and piperazine moiety and a two-carbon linker between the piperazine and coumarin skeleton displayed an IC50 value of 17.70 nM, a potency which can be attributed to the ability of the compound to bind to both the PAS and CAS of AChE. The most potent inhibitory activity against BChE was measured for compound 25b (IC50 = 16, 12 nM). The introduction of substituents to the 3- and/or 4-positions of the coumarin moiety did not have any significant effect on the inhibitory activity of the compounds against either ChEs or MAOs.Compound 26c displayed the highest level of MAO-B inhibition and also showed high levels of inhibition of eeAChE, eqBChE and hAChE/hBChE; the compound also showed good permeability of the BBB [73]. CONCLUSION Coumarin derivatives have emerged as a very promising class of anti-Alzheimer agents whoch possess the ability to interact with different targets at different levels of the neurotoxic cascade of AD. The coumarin ring, which seems to be essential for the optimal inhibition of AChE, was selected as the basis for the synthesis of a wide range of derivatives which were intended to inhibit ChEs through the inhibition of self-induced A aggregation via primary interaction with the PAS of AChE. The monocoumarin derivatives with a coumarin skeleton linked to the benzyl pyridinium group, compounds 13a & 13b, showed outstanding levels of acetylcholinesterase inhibitory activity (IC50 = 0.11, 0.16 nM). N, N´-bis[2oxo-2H-benzopyran]-3-carboxamides showed high levels of inhibitory activity and selectivity for MAO-A. The most interesting inhibitor, compound 17e with a phenyl ring linked to the carboxamide groups in the 1 & 2 positions, showed the most potent inhibition activity (pKi (MAO-A) = 7.79). Heterocoumarin dimers which are able to bind simultaneously to both the catalytic and peripheral dualsites of AChE were also found to exhibit other pharmacological characteristics including anti-aggregating activities, significant inhibition of MAO & BACE, metal-chelating and antioxidant activities. The nature and the length of the linkers connecting tacrine and coumarin fragments were found to play a significant role in determining the level of AChE inhibition, in addition to the size and position of the substituents of the coumarin and tacrine moiety. Tacrine-6-methoxy-4-oxo-4H-chromene heterodimer 21b was the most active inhibitor of hBChE (IC50 = 38 pM) being 1052-times more potent than the control tacrine.


9

CONFLICT OF INTEREST The authors confirm that the content of this article contains no conflict of interest. ACKNOWLEDGEMENTS The work was supported by Slovak Grant Agency VEGA (Grant 1/0001/13) and project NV15-30954A, MH CZ DRO (UHHK, 00179906) and Long-term development project UHK. LIST OF ABBREVIATIONS AChE AD A NFT AChEIs CAS CNS hBACE-1 BBB NMDAR APP ee AChE

= = = = = = = = = = = =

FDA hAChE hBChE 7-MEOTA Me M MTDLs MAO-A MAO-B nM pM SAR SI NO PAS

= = = = = = = = = = = = = = =

Acetylcholinesterase Alzheimer´s disease -amyloid peptide Neurofibrillary tangles Acetylcholinesterase inhibitors Catalytic anionic site Central nervous system Human -Secretase Blood-brain-barrier N-methyl-D-aspartate receptor Amyloid precursor protein Electrophorus electricusacetylcholinesterase Food and Drug Administration Human acetylcholinesterase Human butyrylcholinesterase 7-Hydroxy-1,2,3,4-tetrahydroacridine Methyl Micromolar Multi-target-directed ligands Monoamine oxidase A Monoamine oxidase B Nanomolar Picomolar Structure and activity relationships Selectivity index Nitric oxide Peripheral anionic site

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