Synthesis and biological evaluation of new tacrine analogues under microwave irradiation

Article abstract of DOI:10.1248/cpb.c17-00113

Efficient routes to various kinds of heterocycles incorporating the p-halophenyl moiety have been synthesized. Different pyrrole derivatives have been synthesized, as well, by Thorpe–Ziegler cyclization. Therefore, we synthesized different analogues of tacrine by Friedl?nder reaction of o-amino nitriles (pyrazolo, furano and pyrrolo) with different cycloalkanones. The use of microwave irradiation leads to shorter production times and high product conversion. These synthesized compounds were biologically evaluated by Ellman’s test on acetylcholinesterase inhibition.

Full text of DOI:10.1248/cpb.c17-00113

732
Chem. Pharm. Bull. 65, 732–738 (2017)
Vol. 65, No. 8
Regular Article
Synthesis and Biological Evaluation of New Tacrine Analogues under
Microwave Irradiation
,a,b
Hossa Fahad Alshareef,a Heba Abd El Hady Mohamed,* and Abdellatif Mohamed Salaheldinc
a Chemistry Department, Faculty of Applied Science, Umm Alqura University; P.O. Box 13401, Makkah 21955, KSA:
b Department of Chemistry, Faculty of Science (Girl’s), Al-Azhar University; P.O. Box 11754, Nasr City, Egypt: and
c Department of Chemistry, Faculty of Science, Cairo University; Giza 12613, A. R. Egypt.
Received February 7, 2017; accepted April 25, 2017
Efficient routes to various kinds of heterocycles incorporating the p-halophenyl moiety have been synthe-
sized. Different pyrrole derivatives have been synthesized, as well, by Thorpe–Ziegler cyclization. Therefore,
we synthesized different analogues of tacrine by Friedländer reaction of o-amino nitriles (pyrazolo, furano
and pyrrolo) with different cycloalkanones. The use of microwave irradiation leads to shorter production
times and high product conversion. These synthesized compounds were biologically evaluated by Ellman’s
test on acetylcholinesterase inhibition.
Key words tacrine; Friedländer reaction; enaminone; Alzheimer’s disease; acetylcholinesterase; microwave
irradiation
Alzheimer’s disease (AD) is recognized as one of the most in the search for more powerful, safer tacrine derivatives.6)
common diseases to affect the elderly, and its effect on this set
Attempts to modify the structure of tacrine have been
of population is serious. It is characterized by neuronal loss, achieved either by changing the ring size, increasing the num-
synaptic damage, a deficit in neurotransmitter acetylcholine ber of rings, or by introducing heteroatoms.7–16) One study
and vascular plaques. Unfortunately, the occurrence of AD is found that tacrine is more active against AChE than other
now rising exponentially in both genders as the general popu- compounds that contain four rings. But these compounds have
lation ages. Until recently an exact scientific description of shown potential activity against β-amyloid protein aggregation
the cause of this disease had not been defined. And despite an in the brain and they are more selective.7) Five membered ring
impressive amount of development in understanding the mo- tacrine analogues have been identified for a long period.8)
lecular mechanisms behind AD, an effective therapeutic drug
Recently, Kirsch and colleagues synthesized velnacrine and
is still not obtainable. The inhibition of acetylcholinesterase tacrine anlogues that contain thiazole, thiophene, selenophene
(AChE) to increase the acetylcholine (ACh) level in synapses or 4-azaisoindole heterocycles.9–12) New analogues of tacrine
is the most recent method for the treatment of AD.1–3)
have been developed by replacing the primary amino group
At this time there are four AChE inhibitor (AChEI) drugs with the azetidine moiety.13) Analogues of tacrine that contain
accepted by the U.S. Food and Drug Administration (FDA) heterocyclic rings as pyridine, oxazole and pyran have been
for the treatment of AD: tacrine, rivastigmine, donepezil and developed by a Spanish–Portuguese group and the inhibi-
galantamine (Fig. 1). Tacrine, the first AChEI generally pre- tory effects of these on butyryl cholinesterase and AChE have
sented in therapy, under the trade name Cognex® since 1993 been reported.14) Barreiro et al. synthesized tacrine analogues
has low selectivity for AChE leading to side effects, it is now containing pyrazolonaphthyridine or pyrazolopyridine systems
infrequently used due to its hepatotoxicity (in ca. 50% of pa- and concluded that these compounds were the good inhibitors
tients), which does not happen with the other three drugs.4,5) of AChE.15) It has also been reported that the attendance of
Nevertheless, studies using tacrine analogues have continued halogen atoms in tacrine derivatives advances the activity.16)
Fig. 1. Structures of the Four Acetylcholinesterase Inhibitors (AChEIs)
*To whom correspondence should be addressed. e-mail: hebaa_elhady@yahoo.com; habasuny@uqu.edu.sa
© 2017 The Pharmaceutical Society of Japan

Vol. 65, No. 8 (2017)
Chem. Pharm. Bull.
733
Here, the synthesis and biological evaluation of fused five- well as the nonappearance of a CN absorption band in the IR
membered aromatic ring analogues of tacrine containing spectrum. The structures of the synthesized compounds are
halogens such as the pyrrolotacrines, pyrazolotacrines and in covenant with their spectroscopic and analytical data (see
furanotacrines heterocyclic ring systems are reported (Charts Experimental).
1–3). We designed new tacrine analogues from heterocyclic
Pyrazolo[3,4-b]pyridines are significant compounds due to
system containing an enaminonitrile moiety by reaction of a their structural relationship to azaindoles and their biological
cyclic ketone with an ortho-aminonitrile in the attendance of a activity. A number of these are potentially biologically ac-
Lewis acid, according to the Friedländer reaction.
tive compounds as new inhibitors of xantine oxidase.23,24)
Due to their variety of activities, we have been extended our
work on ortho-aminocyanopyrazoles24,25) and their deriva-
Results and Discussion
Chemistry As an extension of our interest on the chemis- tives as inhibitors of xanthine oxidase,26) For this purpose we
try of β,β-enaminonitriles, we report here the results aimed at started from the key intermediates (N1-substituted-5-amino-
exploring the possible utility of 3-anilino-2-cyanoacrylonitrile 4-cyanopyrazoles) 8a–d17) (Chart 2). The introduction of a CF3
in the synthesis of heterocyclic compounds. We converted group provided compounds with increased lipophilicity and
the β,β-enaminonitriles 3 which were prepared by recognized activity when compared to their non-fluorinated analogues.
procedures17) into the corresponding 3-aminopyrrole deriva- The trifluoromethyl substituted compounds, in particular, have
tives 4 through reaction with chloroacetonitrile in presence of been reported to possess such biological activity as herbicidal,
a base, a Thorpe–Ziegler cyclization18–22) (Chart 1).
The new pyrrolotacrines 5 and 6 were synthesized, as il- gregation.27)
fungicidal, analgesic, antipyretic, and inhibitors of platelet ag-
lustrated in Chart 1, from the readily available N1-aryl-3-ami-
The 5-amino-1-substituted pyrazole-4-carbonitriles 8 were
nopyrrolocarbonitrile derivatives 4 according to Friedländer used as starting materials as they contain a cyano group ad-
reaction (FR). Under thermal conditions the reaction time jacent to an amino group which is necessary to synthesize the
was 8–10h, which was reduced to about 30min, under mi- condensed rings of the fused heterocycles via reactions of het-
crowave irradiation and compound 5 was obtained in good erocyclic enaminonitrile derivatives via FR under thermal and
yields (75–87%); see Table 1. Using cyclopentanone or cyclo- microwave heating to produce the pyarazolotacrine derivatives
hexanone, we obtain the expected target molecules in good
yield. However, when Y was an ester or ketone group (4f, g)
regioisomers 6 were formed. The cyclization happened wholly
in the direction of the nitrile in position 4 of the pyrrole, so
Table 1. Friedländer Cyclization Reaction under Classical Heating and
Microwave Irradiation
regioisomers 6 were formed. The structures of these novel
Classical heating
Time (h) Yield %
67
MW irradiation
1
Compounds
compounds were evaluated by mass spectrometry, and by H-
Time (min)
Yield %a)
and 13C-NMR spectroscopy. For example in compound 6a the
1H-NMR spectrum showed the presence of a quartet signal at
4.22ppm and a triplet signal at 1.14ppm of the ester group, as
5a
5b
5c
5d
5e
5f
9
2×15
2×15
2×12
2×12
2×16
2×16
2×15
2×15
2×15
2×16
2×16
2×16
2×15
2×15
2×15
85
80
78
86
72
78
79
76
87
62
69
45
66
65
70
9
7
60
64
66
55
48
64
62
62
44
48
30
42
50
52
7
10
10
8
5g
6a
6b
9a
9b
9c
9d
9e
14
8
8
9
9
10
10
9
10
a) Yield of pure compounds.
Chart 1. Syntheses of Compounds 4a–g, 5a–g, 6a and b
Chart 2. Synthesis of Compounds 8a–d and 9a–e

734
Chem. Pharm. Bull.
Table 2. Anti-Alzheimer’s Activity
Vol. 65, No. 8 (2017)
%
(Anticholinesterase Inhibitory
Activity) of Different Concentrations of Organic Compounds Compared
with Donepezil
Concentration
Donepezil
Compounds
25µmol/mL 50µmol/mL 100µmol/mL 100µmol/mL
5a
5b
5c
5e
5f
28.47
36.53
26.24
25.48
28.00
33.00
29.87
27.56
37.36
31.89
28.36
30.34
33.40
44.69
30.25
32.40
31.00
35.12
33.69
29.89
44.60
38.90
31.54
33.00
58.35
63.35
41.46
40.10
41.10
49.34
41.60
46.00
51.30
50.50
37.40
42.00
66.67
64.54
53.81
56.44
61.56
59.50
62.74
56.40
53.40
57.56
58.40
49.00
5g
6a
6b
9a
9b
9e
14
Chart 3. Synthesis of Compound 14
9a–e. The structures of these compounds were established and
determined by their spectroscopic and analytical data.
Reaction of 4-bromophenacyl bromide 11 with malononi-
trile 10 in ethanol and KOH yielded phenacyl malononitrile
derivative 12, which underwent cyclization into furan deriva-
tive 13 under basic conditions28) (Chart 3).
Data represented as the mean of three replicates in each group. Statistical analysis
was carried out using an SPSS computer program, (one way ANOVA), coupled with
a co-state computer program, where the unshared letter is significant at p≤0.01.
The synthesis of the new furanotacrine 14 was achieved
as shown in Chart 3, starting from previously synthesized
2-amino-5-arylfuran-3-carbonitriles 13 according to FR under
thermal and microwave heating.
Table 3. IC50 Results of the Different Organic Compounds Compared
with Donepezil on AChE in Vitro
Compounds
IC50 (nM)
Biology The inhibitory activities of the synthesized com-
pounds against AChE were studied in comparison with the
reference compound donepezil using the method of Ellman
et al.29) The results are recorded in Tables 2 and 3.
5a
6.32
6.87
4.50
4.35
4.45
5.35
4.51
4.99
5.56
5.48
4.06
4.55
7.23
5b
5c
5e
Cholinesterase is a family of enzymes that catalyzes the
hydrolysis of the neurotransmitter acetylcholine (ACh) into
choline and acetic acid, a reaction necessary to allow a cho-
linergic neuron to return to its resting state after activation.
AChE used in the present study (E.C. 3.1.1.7) is found in
motor neurons of the mammalian brain; the majority of AChE
occurs in a tetrameric, G4 form, wihile much smaller amounts
are present in a monomeric G1 (4S) form. According to our
data, all compounds inhibited AChE, with donepezil used as
reference compound.
5f
5g
6a
6b
9a
9b
9e
14
Donepezil
IC50: The dose of the compounds that inhibit 50% of the AChE.
From these results, and for the pyrrolotacrines 5 and 6a, b
we conclude that: (a) all synthesized tacrine compounds have
the potent to moderate activity; (b) compound 5b is the most and e regarding the type of substituent at the C-4 in the aro-
potent inhibitor; (c) the substiution of a fused cyclohexane ring matic ring and the effect of the size of the fused cycloalkane
with fused cyclopentane ring [compare 5a with 5b] improved ring, the same structure–activity relationships (SARs) could
the anti-AChE activity of the tacrine derivatives; (d) regarding also be determined. The most potent inhibitor was compound
the type of substituent at C-4 in the aromatic ring in com- 9a while 9e showed lower activity.
pounds that bear the same cycloalkane fused ring system the
The furanotacrine analogue 14 showed reactivity of 85%
inhibitory potency followed this order: either H
≫4-OMe>4-F compared with the donepezil reference compound. Overall,
[compare 5b with e and f (cyclohexane)] or H>naphthyl>4- compounds 5b (98%) and 9a (96%) demonstrated the most
Cl [compare 5a with c and g (cyclopentane); (e) introducing a potent inhibition of AChE compared with the donepezil refer-
methoxy group at para position of the phenyl led us to the less ence compound.
active 5e (around 37% less active than 5b). Some authors have
reported that the presence of halogen atoms in tacrine deriva-
tives, especially the chlorine atom, improved anti-AChE activ-
Conclusion
Three heterocyclic compounds, pyrrole, pyrazole and furan
ity, but this was not observed in our study.16) Compounds 6a derivatives were prepared as starting materials for the synthe-
and b with a different annelations between the pyridine and sis of tacrin analogues, according to typical FR under ther-
pyrrolo rings, when compared with all the others presented mal and microwave heating. The inhibition of AChE by the
lower activity than 5b (6a was lower by 32% and 6b by 27%). synthesized tacrine analogues was evaluated. Compounds 5b
Once again, the five membered saturated ring doesn’t amelio- (98%) and 9a (96%) were the most potent for the inhibition of
rate the anti-AChE activity.
AChE compared with the donepezil itself.
From the data in Table 2 and for the pyrazolotacrines 9a, b

Vol. 65, No. 8 (2017)
Chem. Pharm. Bull.
735
H, 3.87; N, 26.91. Found: C, 69.12; H, 4.07; N, 26.81.
Experimental
Materials and Methods Melting points were measured
in open capillaries (uncorrected) on a Gallenkamp melting 4b
point apparatus. IR spectra were verified using a Shimadzu
3-Amino-1-(4-chlorophenyl)-1H-pyrrole-2,4-dicarbonitrile
Yellowish white solid, in 85% yield, mp 243–245°C
FT IR 8101 PC spectrometer using KBr technique. A Var- (EtOH). 1H-NMR (CDCl3) δ: 7.19 (s, 1H, H-C(5)), 4.30 (s,
ian Mercury VXR-300 NMR spectrometer was used for re- 2H, NH2), 7.51 (d, 2H, J=9.0Hz, H-C(3′), H-C(5′)), 7.35 (d,
1
cording NMR spectra. 13C-NMR (75.46MHz) and H-NMR 2H, J=9.0Hz, H-C(2′), H-C(6′)). IR (KBr): 2232, 2200 (CN),
(300MHz)) were verified in deuterated chloroform (CDCl3) or 3468, 3363 (NH2) cm−1. MS (EI)=242 (77%). Anal. Calcd for
dimethyl sulfoxide (DMSO-d6). Tetramethylsilane (TMS) was C12H7ClN4 (242.66): C, 59.39; H, 2.91; N, 23.09. Found: C,
used as an internal reference. Whenever possible the complete 59.33; H, 2.90; N, 23.11.
1
assignment of H and 13C in the NMR spectra was carried out
by heteronuclear multiple quantum coherence (HMQC) and 4c
heteronuclear multiple bond correlation (HMBC) double reso-
3-Amino-1-(4-methoxyphenyl)-1H-pyrrole-2,4-dicarbonitrile
1
Beige solid, in 91% yield, mp 186–188°C (EtOH). H-NMR
nance experiments. Electron impact (EI) mass spectra were (DMSO-d6) δ: 6.11 (s, 2H, NH2), 3.80 (s, 3H, OCH3), 7.84 (s,
recorded on a Shimadzu GCMS-QP-2010 plus mass spectrom- 1H, H-5), 7.07 (d, 2H, J=8.8Hz, Ar-H, 3′, 5′), 7.41 (d, 2H,
eter at 70eV. Microwave irradiation was performed using a J=8.8Hz, Ar-H, 2′, 6′); 13C-NMR (DMSO-d6) δ: 83.23 (C-4),
CEM MARS oven. Elemental analyses were carried out at the 88.18 (C-2), 55.56 (OCH3), 113.38 (CN), 114.71 (C-3′,5′), 114.23
Micro-Analytical Centre of Cairo University, Giza, Egypt and (CN), 125.44 (C-2′,6′), 130.12 (C-1′), 132.52 (C-5), 148.32
recorded on an Elementar-Vario EL automatic analyzer. Bio- (C-3), 159.21 (C-4′). IR (KBr): ν=2227, 2205 (CN), 3437, 3349
logical evaluations were carried out at the Animal Reproduc- (NH2) cm−1.
tion Research Institute (ARRI) at the, Ministry of Agriculture,
Dokki, Cairo, Egypt. Compounds 3 were prepared as in the 4d
literature.18,20)
3-Amino-1-(4-fluorophenyl)-1H-pyrrole-2,4-dicarbonitrile
Yellowish white solid, in 82% yield, mp 186–188°C (EtOH).
General Procedure for the Preparation of 2-((Aryl- 1H-NMR (CDCl3) δ: 6.15 (s, 2H, NH2), 7.32 (s, 1H, H-C(5)),
amino)methylene) Malononitrile Derivatives 3a–e To a 7.25–7.28 (d, 2H, Ar-H, J=9.0Hz), 7.85–7.88 (d, 2H, Ar-H,
solution of the aromatic amine derivatives 2a–e (0.1mol) in J=9.0Hz). IR (KBr): 3445, 3348 (NH2), 2222 (CN) cm−1. MS
ethanol (100mL) ethoxymethylene malononitrile (EMMN) 1 (EI)=226 (80%). Anal. Calcd for C12H7FN4 (226.21): C, 63.71;
(0.1mol) was added slowly (only half the total quantity); when H, 3.12; N, 24.77. Found: C, 63.60; H, 3.25; N, 24.66.
the solution began to boil the other half was added and stirred
for 30min. On cooling the precipitate formed was filtered off 4e
and recrystallized from ethanol. Compounds 3a–c were pre-
pared according to the literature.19,21)
3-Amino-1-(naphthalen-1-yl)-1H-pyrrole-2,4-dicarbonitrile
1
Pink solid in 63% yield, mp 206–208°C (EtOH). H-NMR
(DMSO-d6) δ: 6.20 (brs, 2H, NH2), 7.30–7.40 (m, 1H, Ar-H),
2-((4-Fluorophenylamino)methylene)malononitrile 3d
7.62–7.68 (m, 3H, Ar-H), 7.97 (s, 1H, H-5), 8.10–8.18 (m, 3H,
Yellow solid in 84% yield, mp 250–252°C (EtOH-DMF). Ar-H). IR (KBr): 3410–3337 (NH2), 2221 (CN) cm−1. MS
1H-NMR (DMSO-d6) δ: 6.91–6.94 (d, 2H, Ar-H, J=0, (EI)=258 (100%). Anal. Calcd for C16H10N4 (258.28): C, 74.40;
9.0Hz), 7.30–7.33 (d, 2H, Ar-H, J=9.0Hz), 8.37 (s, 1H), 11.02 H, 3.90; N, 21.69. Found: C, 74.66; H, 3.85; N, 21.60.
(brs, 1H, NH). IR (KBr): 3301 (NH), 2216 (CN) cm−1. MS
Ethyl
3-Amino-4-cyano-1-(4-fluorophenyl)-1H-pyrrole-2-
(EI)=187 (84%). Anal. Calcd for C10H6FN3 (187.17): C, 64.17; carboxylate 4f
1
H, 3.23; N, 22.45. Found: C, 64.35; H, 3.48; N, 22.40.
White solid in 74% yield, mp 128–130°C (EtOH). H-NMR
2-((Naphthalen-1-ylamino)methylene)malononitrile 3e
(CDCl3) δ: 1.05 (t, 3H, J=7.2Hz, CH3), 4.11 (q, 2H, J=7.2Hz,
1
Pink solid in 84%yield, mp 123–125°C (EtOH). H-NMR CH2), 6.14 (s, 2H, NH2), 7.38–7. 41 (d, 2H, Ar-H, J=9.0Hz),
(DMSO-d6) δ: 7.10–7.18 (m, 1H, Ar-H), 7.50–7.61 (m, 3H, 7.55–7.58 (d, 2H, Ar-H, J=9.0Hz), 7.92 (s, 1H, H-5). IR (KBr):
Ar-H), 7.85 (s, 1H), 8.05–8.12 (m, 3H, Ar-H). IR (KBr): 3425 3455, 3340 (NH2), 2224 (CN), 1656 (CO) cm−1. MS (EI)=273
(NH), 2216 (CN) cm−1. MS (EI)=219 (100%). Anal. Calcd for (67%). Anal. Calcd for C14H12FN3O2 (273.26): C, 61.53; H,
C14H9N3 (219.24): C, 76.70; H, 4.14; N, 19.17. Found: C, 76.85; 4.43; N, 15.38. Found: C, 61.64; H, 4.31; N, 15.50.
H, 4.25; N, 19.36. 4-Amino-5-(4-bromobenzoyl)-1-(4-fluorophenyl)-1H-
General Procedure for the Preparation of 3-Aminopyr- pyrrole-3-carbonitrile 4g
role Derivatives 4a–g To a solution of the intermediate
Pale yellow solid, in 80% yield, mp 220–222°C (EtOH).
3a–e (0.01mol) the α-halo compound (chloroacetonitrile, 1H-NMR (DMSO-d6) δ: 6.58 (s, 2H, NH2), 7.41–7.44 (d, 2H,
4-bromophenacylbromide and ethyl bromoacetate) (0.01mol) J=9Hz, Ar-H), 7.57–7.60 (d, 2H, J=9Hz, Ar-H), 7.65–7.68
and triethylamine (TEA, 5mL) were added, with cooling. (d, 2H, J=9Hz, Ar-H), 8.05 (s, 1H, H-5), 7.92–7.95 (d, 2H,
The reaction mixture was then refluxed for 15–30min, cooled J=9Hz, Ar-H); IR (KBr): 1678 (CO), 3423, 3318 (NH2), 2220
30mL of water was added. The precipitate formed was filtered (CN) cm−1. MS (EI)=384 (15%), 383 (M+, 79Br, 95), 385 (M+,
off, washed several times with water and recrystallized from a 81Br, 87); Anal. Calcd for C18H11BrFN3O (384.20): C, 56.27; H,
proper solvent.22)
2.89; N, 10.94. Found: C, 56.45; H, 3.04; N, 11.15.
3-Amino-1-phenyl-1H-pyrrole-2,4-dicarbonitrile 4a
General Procedure to Prepare Analogues of Tacrine (via
White solid, in 88% yield, mp 204–206°C (EtOH) (lit.21), Friedländer Reaction) 5a–g, 6a and b
1
187–188°C). H-NMR (CDCl3) δ: 7.22 (s, 1H, H-C(5)), 4.29 (s,
Thermal Method
2H, NH2), 7.47–7.56 (m, 3H, Ar-H), 7.39–7.42 (m, 2H, Ar-H).
A mixture of cyclopentanone or cyclohexanone (3.1mmol),
IR (KBr): 2205, 2227 (CN), 3456, 3360 (NH2) cm−1. MS 2-substituted-3-aminopyrrole-4-carbonitrile 4 (0.3mmol), and
(EI)=208 (64%). Anal. Calcd for C12H8N4 (208.22): C, 69.22; anhydrous AlCl3 (3.1mmol) in distilled 1,2-dichloroethane

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Chem. Pharm. Bull.
Vol. 65, No. 8 (2017)
(15mL), was refluxed for 8–10h controlled by TLC, then MS (EI)=(35Cl) 309 (88%), (37Cl) 311 (30%). Anal. Calcd for
cooled to room temperature. After cooling a mixture of tet- C17H13ClN4 (308.76): C, 66.13; H, 4.24; N, 18.15. Found: C,
rahydrofurane and water (1:1, 20mL) was added, then NaOH 66.10; H, 4.19; N, 17.96.
(aq. solution 10%) drop wise until the solution was basic.
After stirring for 30min, the mixture was extracted with di- cyclopenta[e]pyrrolo[3,2-b]pyridine-3-carbonitrile 5d
chloromethane (3×20mL). The joint extracts were washed by
Yellow solid, in 86% yield, mp 220–222°C. 1H-NMR
8-Amino-1-(4-methoxyphenyl)-1,5,6,7-tetrahydro-
saline (20mL) and dehydrated over MgSO4, then filtered, and (CDCl3) δ: 2.74 (t, 2H, J=7.8Hz, H-7), 2.15–2.23 (m, 2H,
evaporated to obtain a solid followed by purification by pre- H-6), 3.01 (t, 2H, J=7.8Hz, H-5), 3.90 (s, 3H, OCH3), 3.78 (s,
parative layer chromatography (PLC) (CH2Cl2–MeOH, 9:1) or 2H, NH2), 7.07 (d, 2H, J=9.2Hz, H-3′,5′), 7.55 (s, 1H, H-2),
recrystallization from EtOH.
Microwave Irradiation Method
7.38 (d, 2H, J=9.2Hz, H-2′,6′). 13C-NMR (CDCl3) δ: 114.70
(CN), 55.71 (OCH3), 23.26 (C-6), 26.97 (C-7), 34.50 (C-5),
In a round bottomed flask of 100mL equipped with a con- 88.30 (C-3), 114.82 (C-3′,5′), 116.26 (C-7a), 117.29 (C-8a),
denser we added a solution of 2-substituted-3-aminopyrrole- 125.05 (C-3a), 128.05 (C-2′,6′), 131.14 (C-1′), 136.15 (C-2),
4-carbonitrile 4 (1mmol) with either cyclopentanone or cyclo- 145.93 (C-8), 160.32 (C-4′), 163.49 (C-4a). IR (KBr): ν=2218
hexanone (1.4mmol) in 30mL of distilled 1,2-dichloroethane. (CN), 3393, 3299 (NH2) cm−1. MS (EI)=304 (71%). Anal.
Anhydrous AlCl3 (4mmol) was then added, and the mixture Calcd for C18H16N4O (304.35): C, 71.04; H, 5.30; N, 18.41.
was refluxed for 30 and 32min, respectively, under microwave Found: C, 71.09; H, 5.25; N, 18.30.
irradiation (at a constant power of 400W). The mixture was
9-Amino-1-(4-methoxyphenyl)-5,6,7,8-tetrahydro-1H-
then cooled to room temperature. After cooling a mixture of pyrrolo[3,2-b]quinoline-3-carbonitrile 5e
tetrahydrofurane and water (1:1, 20mL) was added, followed
Yellow solid, in 72% yield, mp 213–215°C. 1H-NMR
by the drop wise addition of NaOH (aq. solution 10%) until (DMSO-d6) δ: 6.34 (brs, 2H, NH2), 7.53 (s, 1H, H-2),
the solution was basic. After this, the mixture was stirred for 1.85–1.88 (m, 4H, H-6,7), 2.43–2.47 (m, 2H, H-8), 2.98–3.02
30min, and extracted with dichloromethane (3×20mL). The (m, 2H, H-5), 7.03 (d, 2H, J=8.8Hz, H-3′,5′), 7.38 (d, 2H,
combined extracts were washed with saline (20mL), dried J=8.8Hz, H-2′,6′). 13C-NMR (DMSO-d6) δ: 22.69 (C-6), 22.80
over MgSO4, filtered, and the solvent evaporated to obtain a (C-7), 23.19 (C-8), 33.48 (C-5), 87.88 (C-3), 110.97 (C-9a),
solid, which was identical in all respects with that obtained 114.78 (C-3′,5′), 114.84 (CN), 116.80 (C-3a), 128.08 (C-2′,6′),
from the thermal method (mp, TLC, NMR).
131.02 (C-1′), 136.76 (C-2), 137.81 (C-7a), 143.53 (C-9), 154.70
8-Amino-1-phenyl-1,5,6,7-tetrahydrocyclopenta[e]pyrrolo- (C-4a), 160.27 (C-4′). IR (KBr): 2223 (CN), 3485, 3360
[3,2-b]pyridine-3-carbonitrile 5a
(NH2) cm−1. MS (EI)=318 (68%). Anal. Calcd for C19H18N4O
Yellow solid, in 85% yeild, mp 242–244°C. 1H-NMR (318.37): C, 71.68; H, 5.70; N, 17.60. Found: C, 71.62; H, 5.79;
(DMSO-d6) δ: 2.71 (t, 2H, J=7.7Hz, H-C(7)), 2.16–2.26 (m, N, 17.41.
2H, H-C(6)), 4.85 (s, 2H, NH2), 2.91 (t, 2H, J=7.8Hz, H-C(5)),
7.55–7.66 (m, 5H, Ar-H), 8.28 (s, 1H, H-C(2)). 13C-NMR pyrrolo[3,2-b]quinoline-3-carbonitrile 5f
(DMSO-d6) δ: 22.82 (C(6)), 27.30 (C(7)), 86.75 (C(3)), 34.18 Pale yellow solid, in 78% yield, mp. 252–254°C. H-NMR
9-Amino-1-(4-f luorophenyl)-5,6,7,8-tetrahydro-1H-
1
(C(5)), 115.46 (CN), 116.15 (C(8a)), 119.23 (C(3a)), 124.54 (CDCl3) δ: 3.86 (s, 2H, NH2), 1.85–1.92 (m, 4H, H-6,7),
(C(4′)), 126.52 (C(2′), C(6′)), C(5′)), 129.97 (C(7a)), 129.61 2.49 (m, 2H, H-8), 3.03 (m, 2H, H-5), 7.42 (d, 2H, J=9.0Hz,
(C(3′), 138.21 (C(1′)), 137.17 (C(2)), 145.76 (C(8)), 162.19 H-2′,6′), 7.57 (d, 2H, J=9.0Hz, H-3′,5′), 7.54 (s, 1H, H-2).
(C(4a)). IR (KBr): 2224 (CN), 3465, 3360 (NH2) cm−1. MS 13C-NMR (CDCl3) δ: 114.42 (CN), 23.29 (C-6), 22.70 (C-7),
(EI)=274 (63%). Anal. Calcd for C17H14N4 (274.32): C, 74.43; 26.81 (C-8), 33.59 (C-5), 89.41 (C-3), 111.45 (C-8a), 116.39
H, 5.14; N, 20.42. Found: C, 74.39; H, 5.10; N, 20.45.
9-Amino-1-phenyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]- (C-3a), 136.92 (C-2), 137.49 (C-1′), 143.93 (C-9), 155.19 (C-4a).
quinoline-3-carbonitrile 5b
IR (KBr): 2229 (CN) 3412, 3335 (NH2) cm−1. MS (EI)=306
(C-9a), 127.79 (C-2′,6′), 130.02 (C-3′,5′), 135.49 (C-4′), 136.46
Yellowish white solid, in 80% yield, mp 223–224°C. (58%). Anal. Calcd for C18H15FN4 (306.34): C, 70.56; H, 4.95;
1H-NMR (DMSO-d6) δ: 2.40–2.52 (m, 2H, H-C(8)), 1.70–1.84 N, 18.28. Found: C, 70.81; H, 4.84; N, 18.35.
(m, 4H, H-C(6), H-C(7)), 2.74–2.86 (m, 2H, H-C(5)), 7.53–7.65
(m, 5H, Ar-H), 4.74 (s, 2H, NH2), 8.29 (s, 1H, H-C(2)). [e]pyrrolo[2,3-b]pyridine-3-carbonitrile 5g
13C-NMR (DMSO-d6) δ: 115.75 (CN), 23.28 (C(8)), 22.61
Dark pink solid, in 79% yield. mp 289–292°C. H-NMR
4-Amino-1-(naphthalen-1-yl)-1,5,6,7-tetrahydrocyclopenta-
1
(C(7)), 22.40 (C(6)), 33.06 (C(5)), 86.52 (C(3)), 110.56 (C(9a)), (DMSO-d6) δ: 2.14–2.25 (m, 2H, H-6), 2.73 (t, 2H, J=7.7Hz,
118.48 (C(3a)), 124.49 (C(4′)), 129.64 (C(3′), 126.62 (C(2′), H-7), 2.99 (t, 2H, J=7.8Hz, H-5), 4.88 (s, 2H, NH2), 7.49–7.54
C(6′), C(5′)), 138.28 (C(2)), 138.69 (C(1′)), 143.49 (C(8a)), (m, 4H, Ar-H), 8.25 (s, 1H, H-2). 13C-NMR (DMSO-d6) δ:
145.93 (C(9)), 153.41 (C(4a)). IR (KBr): 2219 (CN), 3467, 3356 22.42 (C-6), 27.98 (C-7), 34.59 (C-5), 86.45 (C-3), 116.436
(NH2) cm−1. MS (EI)=288 (49%). Anal. Calcd for C18H16N4 (CN), 117.95 (C-8a), 120.83 (C-3a), 123.54, 124.27, 125.15,
(288.35): C, 74.98; H, 5.59; N, 19.43. Found: C, 74.95; H, 5.56; 126.17, 126.99, 127.58, 128.65, 129.23, 133.15 (Ar-C), 130.84
N, 19.40.
8-Amino-1-(4-chlorophenyl)-1,5,6,7-tetrahydrocyclopenta[e]- (C(4a)). IR (KBr): 3458, 3365 (NH2), 2219 (CN) cm−1. MS
pyrrolo[3,2-b]pyridine-3-carbonitrile 5c (EI)=324 (88%). Anal. Calcd for C21H16N4 (324.36): C, 77.75;
Yellow solid, in 78% yield, mp 304–306°C. 1H-NMR H, 4.98; N, 17.26. Found: C, 77.89; H, 5.12; N, 17.35.
(DMSO-d6) δ: 2.14–2.24 (m, 2H, H-6), 2.81 (t, 2H, J=7.7Hz, Ethyl 8-Amino-2-(4-fluorophenyl)-2,5,6,7-tetrahydrocyclo-
H-7), 3.11 (t, 2H, J=7.7Hz, H-5), 6.75 (brs, 2H, NH2), 7.59 (d, penta[e]pyrrolo[3,4-b]pyridine-3-carboxylate 6a
(C-7a), 135.14 (C-2), 136.48 (C-1′), 149.66 (C(8)), 162.19
2H, J=9.0Hz, H-2′,6′), 7.71 (d, 2H, J=9.0Hz, H-3′,5′), 8.64
Yellow solid, in 76% yield, mp 208–210°C. 1H-NMR
(s, 1H, H-2). IR (KBr): 2226 (CN), 3446, 3325 (NH2) cm−1. (CDCl3) δ: 1.14 (t, 3H, J=7.5Hz, CH3), 2.04–2.14 (m, 2H,

Vol. 65, No. 8 (2017)
Chem. Pharm. Bull.
737
H-6), 2.78 (t, 2H, J=8.0Hz, H-7), 3.03 (t, 2H, J=8.1Hz, H-5), J=6.0Hz, H-8), 2.54 (t, 2H, J=6.0Hz, H-5), 2.0–1.80 (m, 4H,
4.21 (q, 2H, J=7.5Hz, CH2), 6.31 (s, 2H, NH2), 7.12 (d, 2H, H-7, H-6); δC (CDCl3): 55.51 (OMe), 158.51 (C-8a), 157.40
J=9.0Hz, H-3′,5′), 7.40 (d, 2H, J=9.0Hz, H-2′,6′), 7.83 (s, 1H, (C-4′), 149.76 (C-4), 144.85 (C-9a), 133.46 (C-1′), 129.78
H-1). 13C-NMR (CDCl3) δ: 14.25 (CH3), 22.71 (C-6), 26.94 (C-3), 122.72 (C-2′,6′), 114.12 (C-3′,5′), 105.23 (C-3a), 107.40
(C-7), 34.35 (C-5), 60.12 (CH2), 109.59 (C-8a), 110.04 (C-3a), (C-4a), 34.16 (C-8), 22.93 (C-5), 22.88 and 22.87 (C-7, C-6);
111.48 (C-7a), 113.61 (C-3′,5′), 124.47 (C-1), 125.15 (C-2′,6′), MS (EI)=294 (93%). Anal. Calcd for C17H18N4O; (294.15): C,
133.39 (C-1′), 138.39 (C-3), 145.94 (C-8), 159.44 (C-4′), 161.48 68.37; H, 6.20; N, 18.54. Found: C, 68.38; H, 6.26; N, 18.58.
(CO), 165.68 (C-4a). IR (KBr): 3477, 3339 (NH2), 1712 (CO)
1-(4-Trifluoromethylphenyl)-1,5,6,7-tetrahydrocyclopenta[e]-
cm−1. MS (EI)=351 (81%). Anal. Calcd for C19H18FN3O2 pyrazolo[3,4-b]pyridin-4-amine 9d
(351.40): C, 67.24; H, 5.35; N, 12.38. Found: C, 67.41; H, 5.45;
N, 12.29.
A brown solid, in 66% yield, mp 266–268°C. δH (DMSO-
d6): 6.84 (brs, 2H, NH2), 8.37 (s, 1H, H-C3), 8.62 (d, 2H,
(9-Amino-2-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H- J=8.7Hz, H-2′,6′), 7.85 (d, 2H, J=8.4Hz, H-3′,5′), 2.90 (t,
pyrrolo[3,4-b]quinolin-3-yl)(4-bromophenyl)methanone 6b 2H, J=7.5Hz, H-7), 2.07 (m, 2H, H-6), 2.73 (t, 2H, J=7.5Hz,
1
Pale yellow solid, in 87% yield, mp 263–265°C. H-NMR H-5); δC (DMSO-d6): 166.33 (C-7a), 152.89 (C-8a), 145.01
(DMSO-d6) δ: 1.77–1.82 (m, 4H, H-6,7), 2.44 (m, 2H, H-8), (C-4), 143.21 (C-1′), 134.41 (C-3), 126.18 (C-3′,5′), 124.50 (q,
2.81 (m, 2H, H-5), 6.42 (s, 2H, NH2), 7.31–7.35 (d, 2H, Ar-H, 2J=31.8Hz, C-4′), 122.58, 126.18, 129.89 (the other peak of
H-3′,5′), 7.41–7.46 (d, 2H, Ar-H, H-2″,6″), 7.52–7.53 (d, 2H, the q is hidden under C2′, C-6′, 1J=274.5Hz, CF3), 119.19
Ar-H, H-2′,6′), 7.63–7.66 (d, 2H, Ar-H, H-3″,5″), 7.85 (s, 1H, (C-2′,6′), 112.05 (C-4a), 105.82 (C-3a), 34.57 (C-7), 26.70 (C-5),
H-1). 13C-NMR (DMSO-d6) δ: 22.67 (C-7), 22.91 (C-6), 26.17 22.52 (C-6); MS (EI)=318 (55)%. Anal. Cald for C16H13F3N4.
(C-8), 34.59 (C-5), 104.63 (C-8a), 112.97 (C-9a), 119.47 (C-3), (318.11): C, 59.65; H, 4.20; N, 17.17. Found: C, 59.42; H, 4.54;
122.37 (C-1), 125.78 (C-2′,6′), 128.53 (C-3′,5′), 129.30 (C-4″), N, 16.98.
130.25 (C-3″,5″), 131.30 (C-2″,6″), 131.42 (C-3a), 141.66 (C-1′),
1-(4-Trif luoromethylphenyl)-5,6,7,8-tetrahydro-1H-
145.81 (C-9), 157.41 (C-4a), 159.92 (C-4′), 175.56 (CO). IR pyrazolo[3,4-b]quinolin-4-amine 9e
(KBr): 3458, 3342 (NH2), 1657 (CO) cm−1. MS (EI)=463
Light brown solid, in 56% yield, mp 115–118°C; δH (DMSO-
(M+, 79Br, 64%), 465 (M+, 81Br, 61%). Anal. Calcd for d6): 6.78 (brs, 2H, NH2), 8.65 (d, 2H, J=8.4Hz, H-2′,6′), 8.40
C24H19BrFN3O (464.33): C, 62.08; H, 4.12; N, 9.05. Found: C, (s, 3H, H-3), 7.85 (d, 2H, J=8.7Hz, H-3′,5′), 2.52–2.42 (m, 2H,
62.15; H, 4.22; N, 9.27.
H-5), 2.88–2.78 (m, 2H, H-8), 1.86–1.74 (m, 4H, H-7, H-6); δC
5-Amino-4-cyano-1-substituted Pyrazoles 8a–d Were (DMSO-d6): 157.35 (C-8a), 150.55 (C-4), 147.28 (C-9a), 143.30
Previously Prepared by Us22) Preparation of Pyrazolo- (C1′), 134.45 (C-3), 126.21 (C-3′,5′), 122.61, 126.17, 129.80 (the
1
tacrine 9a–e
other peak of the q is hidden under C-2′, C-6′, J=272.9Hz,
1-Phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4- CF3), 124.32 (q, 2J=31.9Hz, C-4′), 118.92 (C-2′,6′), 107.59
amine 9a
(C-4a), 105.21 (C-3a), 33.75 (C-8), 22.91 (C-6 or C-7), 22.63
A yellowish white solid, in 62% yield, mp 195–197°C. δH (C-5), 22.43 (C-6 or C-7). MS (EI)=332 (45%). Anal. Calcd
(DMSO-d6): 6.68 (brs, 2H, NH2), 8.40–8.29 (m, 2H, H-2′,6′), for C17H15F3N4 : C, 61.44; H, 4.51; N 16.86. Found C, 61.02; H,
7.47 (t, 2H, J=7.2Hz, H-3′,5′), 8.33 (s, 3H, H-3), 7.21 (t, 1H, 5.21; N, 16.57.
J=7.5Hz, H-4′), 2.85–2.74 (m, 2H, H-8), 2.52–2.40 (m, 2H,
Preparation of 2-(2-(4-Bromophenyl)-2-oxoethyl)malo-
H-5), 1.85–1.71 (m, 4H, H-7, H-6); δC (DMSO-d6): 22.72 nonitrile 12 To a solution of 4-bromophenacyl bromide 11
and 22.53 (C-7, C-6), 22.92 (C-5), 33.78 (C-8), 105.05 (C-3a), (0.01mol) the malononitrile (0.01mol) and KOH 10% (5mL)
106.83 (C-4a), 119.45 (C-2′,6′), 124.53 (C-4′), 128.84 (C-3′,5′), were added with cooling. The reaction mixture was stirred
132.94 (C-3), 140.28 (C-1′), 146.99 (C-9a), 150.07 (C-4), 157.05 for 30min, after cooling ice-water (50mL) was added, the
(C-8a). IR (KBr): 3415, 3330 (NH2) cm−1. MS (EI)=264(44%). solid product was filtered off washed thoroughly with cold
Anal. Calcd for C16H16N4: C, 72.70; H, 6.10; N, 21.20. Found: water and crystallized from ethanol. Pale white solid, in 80%
1
C, 72.97; H, 6.09; N, 20.93.
yield, mp 116–118°C (EtOH). H-NMR (CDCl3) δ: 3.61–3.65
1-(4-Chlorophenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]- (d, 2H,CH2), 4.10–4.14 (t, 1H, CH), 7.61–7.64 (d, 2H, Ar-H,
quinolin-4-amine 9b
J=9.0Hz), 8.10–8.13 (d, 2H, Ar-H, J=9.0Hz). IR (KBr): 2216,
Yellowish white solid, in 69% yield, mp 151–152°C; δH 2224 (CN), 1630 (CO) cm−1. MS (EI)=263 (80%). Anal. Calcd
(DMSO-d6): 6.72 (brs, 2H, NH2), 7.52 (d, 2H, J=7.0Hz, for C11H7BrN2O (263.09): C, 50.21; H, 2.68; N, 10.65. Found:
H-3′,5′),8.41 (d, 2H, J=7.0Hz, H-2′,6′), 8.34 (s, 1H, H-3), C, 50.32; H, 2.89; N,10.70.
2.52–2.42 (m, 2H, H-5), 2.85–2.74 (m, 2H, H-8), 1.86–1.70 (m,
To a Preparation of 2-Amino-5-(4-bromophenyl)furan-
4H, H-7, H-6). δC (DMSO-d6): 150.09 (C-4), 157.15 (C-8a), 3-carbonitrile 13 The intermediate 12 (0.01mol) in ethanol
147.11 (C-9a), 133.45 (C-3), 139.12 (C-1′), 128.79 (C-3′,5′), (40mL) and TEA (2mL) was added. The reaction mixture was
128.34 (C-4′), 120.61 (C-2′,6′), 105.05 (C-3a), 107.08 (C-4a), refluxed for 2h. After cooling overnight, the solid product
33.73 (C-8), 22.89 (C-5), 22.65 and 22.45 (C-7, C-6). MS was filtered off, washed thoroughly with cold ethanol–water
(EI)=297 (44%), 300 (M+, 37Cl, 23), 299 (19%), 298 (M+, and crystallized from ethanol. Brown solid, in 67% yield, mp
1
35Cl, 100%). Anal. Calcd for C16H15N4Cl: C, 64.32; H, 5.06; N, 148–150°C (EtOH). H-NMR (CDCl3) δ: 5.15 (brs, 2H, NH2),
18.75. Found: C, 63.89; H, 4.97; N, 18.54.
1-(4-Methoxyphenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]- (d, 2H, Ar-H, J=9.0Hz). IR (KBr): 3340–3180 (NH2), 2210
quinolin-4-amine 9c
(CN) cm−1. MS (EI)=263 (65%). Anal. Calcd for C11H7BrN2O
7.31–7.34 (d, 2H, Ar-H, J=9.0Hz), 7.45 (s, 1H, H-4), 8.01–8.04
Beige solid, in 45% yield, mp 107–108°C. δH (400MHz, (263.09): C, 50.22; H, 2.68; N, 10.65. Found: C, 50.29; H, 2.62;
CDCl3): 4.61 (brs, 2H, NH2), 8.12 (d, 2H, J=7.0Hz, H-2′,6′), N, 10.72.
7.97 (s, 1H, H-3), 7.01 (d, 2H, J=6.8Hz, H-3′,5′), 2.98 (t, 2H,
2-(4-Bromophenyl)-6,7-dihydro-5H-cyclopenta[e]furo-

738
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Vol. 65, No. 8 (2017)
Lett., 5, 1495–1500 (1995).
[2,3-b]pyridin-4-amine 14 Light brown solid, in 70%
yield, mp 283–285°C. H-NMR (DMSO-d6) δ: 2.05–2.14 (m,
1
6) Fernández-Bachiller M. I., Pérez C., Monjas L., Rademann J.,
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dron, 64, 9309–9314 (2008).
2H, H-6), 2.75 (t, 2H, J=8.1Hz, H-7), 3.05 (t, 2H, J=8.0Hz,
H-5), 6.14 (brs, 2H, NH2), 6.95 (s, 1H, H-3), 7.62–7.65 (d, 2H,
J=9.2Hz, H-3′,5′), 8.14–8.17 (d, 2H, J=9.2Hz, H-2′,6′). IR
(KBr): 3465, 3358 (NH2) cm−1. MS (EI)=328 (M+, 79Br, 91%),
330 (M+, 81Br, 85%). Anal. Calcd for C16H13BrN2O (329.19): C,
58.38; H, 3.98; Br, 24.27; N, 8.51. Found: C, 58.52; H, 4.14; Br,
24.35; N, 8.64.
Anti-Alzheimer’s Activity of Various Extracts of Tao-
nia (T.) atomaria Using a Cholinesterase Inhibitory Assay
The inhibition of cholinesterase various extracts of T. at-
omaria was assessed by a colorimetric method performed in
flat-bottom 96-well microtitre plates. A typical study involved
the use of 5µL of AChE solution, at a final assay concentra-
tion of 0.08U/mL; 200µL of 0.1M phosphate buffer pH 8;
5µL of 5,5′-dithiobis-(2-nitrobenzoic acid) (DTNB) at a final
concentration of 0.5mM prepared in 0.1M phosphate buffer
pH 7 containing 0.12M of sodium bicarbonate; and 5µL of
the test extract. The reactants were mixed and pre-incubated
for 15min at 30°C. The reaction was initiated by adding 5µL
of acetylthiocholine iodide (ATCI) at a final concentration of
0.5mM. As a control the inhibitor solution was replaced with
buffer. The change in absorbance at 412nm was measured on
a spectrophotometer (Ellman et al.).29) Donepezil was used
as a standard. Statistical analysis was carried out using an
SPSS computer program, (one way ANOVA), coupled with a
co-state computer program, where the unshared letter is sig-
nificant at p≤0.01.
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K., Synthesis, 11, 1578–1591 (2002).
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(1981).
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491–496 (1992).
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Acknowledgments The authors would like to thank the
Institute of Scientific Research and Revival of Islamic Heri-
tage at Umm Al-Qura University (Project ID.43405019) for
financial support.
25) Campos A. M., Salaheldin A. M., Rodrigues L. M., ARKIVOC, xvi,
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Conflict of Interest The authors declare no conflict of
interest.
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