close

Вход

Забыли?

вход по аккаунту

?

Design Synthesis and Molecular-modeling Study of Aminothienopyridine Analogues of Tacrine for Alzheimer's Disease.

код для вставкиСкачать
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
590
Full Paper
Design, Synthesis, and Molecular-modeling Study of
Aminothienopyridine Analogues of Tacrine for Alzheimer’s
Disease
Mohga M. Badran1, Maha Abdel Hakeem1, Suzan M. Abuel-Maaty1, Afaf El-Malah1,
and Rania M. Abdel Salam2
1
2
Cairo University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Cairo, Egypt
Cairo University, Faculty of Pharmacy, Pharmacology and Toxicology Department, Cairo, Egypt
2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford
tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds
have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as
standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison
with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore,
molecular-modeling studies were performed in order to rationalize the obtained biological results.
Keywords: AChE (Acetylcholine esterase) / Alzheimer’s disease / Docking / Tacrine analogues / Thienopyridines
Received: September 17, 2009; Revised: November 25, 2009
DOI 10.1002/ardp.200900226
Introduction
Alzheimeŕs disease is a degenerative disorder of the central
nervous system and is the common cause of dementia among
the elderly. Neuropathological evidence has demonstrated
that cholinergic functions decline in the basal forebrain and
cortex in the senile dementia of Alzheimer type [1–3].
Accordingly, enhancement of cholinergic neurotransmission
[4] has been considered as one potential therapeutic
approach against Alzheimeŕs disease. One treatment strategy
to enhance cholinergic function is the use of acetylcholine
esterase (AChE) inhibitors to increase the amount of acetylcholine in order to maintain as long as possible the neurotransmission by acetylcholine which was hindered by the
formation of b-amyloid plaques (Fig. 1).
The first AChE inhibitor used in this context was tacrine
[5, 6] 1 sold under the name Cognex1. It became the subject of
intense pharmacological scrutiny for its efficacy in
alleviating the symptoms of Alzheimeŕs disease. In addition,
Correspondence: Maha Abdel Hakeem, Cairo University, Faculty of
Pharmacy, Pharmaceutical Organic Chemistry Department, Kaser el-Aini
street, P. O. 11562, Cairo, Egypt.
E-mail: mahaabdelhakim_12@hotmail.com
Fax: þ20 2 532-0005
Abbreviation: Acetylcholine esterase (AChE).
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
donepezil [7, 8] (Aricept1) 2, huperzine 3, and tacrine-huperzine A hybrid [9] 4 were also effective AChE inhibitors for the
treatment of Alzheimeŕs disease. The aim of this study was to
develop novel tacrine analogues namely aminothienopyridines for pharmacological evaluation against cholinesterase
activity and comparing their action with tacrine.
Results and discussion
Chemistry
The synthesis started from substituted 2-amino-3-cyanothiophenes 2–4, which were prepared from the corresponding
cycloalkanones 1a–c adopting conditions employed by
Gewald et al. [10] (Scheme 1).
The first approach to the tacrine derivatives was achieved
through lewis-acid-mediated cyclodehydration reaction
between the aminocyanothiophenes 2–4 and the appropriate
cycloalkanones in toluene using boron trifluoride diethyl
etherate [11] to afford the following compounds (Schemes 2–6).
In a second approach to obtain the tacrine analogues
(Schemes 2–6), the thiophenes 2–4 were either heated under
reflux in an excess of the desired liquid cycloalkanones or
fused with the solid ones using anhydrous zinc chloride as
lewis acid.
The use of anhydrous zinc chloride [12] allowed rapid
access to the target molecules with good yield when the
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Aminothienopyridine Analogues of Tacrine
591
Scheme 3. Synthesis of compounds 9–11.
Figure 1. Representative examples of some AChE inhibitors.
cycloalkanones were liquid, while boron trifluoride diethyl
etherate was the reagent of choice with the solid ones. All the
new compounds have been fully characterized through their
spectroscopic data.
Biological evaluation
Scheme 4. Synthesis of compound 13.
The preliminary anti-acetylcholine esterase activity for
the synthesized thienopyridines derivatives was assessed
Scheme 5. Synthesis of compound 15.
Scheme 1. Synthesis of compounds 2–4.
Scheme 6. Synthesis o compound 17.
Scheme 2. Synthesis of compounds 5–7.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
according to Elman’s method [13] using tacrine as reference
compound. AChE was obtained from homogenates of rat
brain. Results of anti-acetylcholine esterase activity of the
tested compounds as well as tacrine are shown in Table 1. The
screening results showed that compounds 10b, 11a, b, 13, 15,
17 have no inhibitory activity, while compounds, 5–7, 9a, b,
10a exhibited significant (p < 0.05) inhibition against AChE,
compared with tacrine. From the biological activity studies,
www.archpharm.com
592
M. M. Badran et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Table 1. Inhibition of AChE activity of tacrine and some of the
synthesized thienopyridines.
Inhibition
(%)
Choline esterase content
(U/g wet weight)
Compound
(10 mg/kg)
0
60.16
35.86
32.84
53.13
39.84
15.62
32.87
31.17
34.38
21.86
375.36 26.23
149.55 12.49§
241.3 17.52C,#
252.09 21.54§,#
175.95 18.8§
225.8 20.77§,#
316.71 30.72#
251.98 22.36§,#
258.06 10.86§,#
246.33 13.3§,#
293.25 16.59§,#
Control (saline)
Tacrine
5a
5b
6a
6b
7a
7b
9a
9b
10a
Statistical analysis was carried out by one-way ANOVA test followed by Tukey–Kramer multiple comparisons test to compare
the means of the different groups.
Each value represents the mean S.E. (n ¼ 6–8 rats).
§
Significantly different from the normal control group at
p < 0.05.
#
Significantly different from the tacrine group at p < 0.05.
we could conclude that compound 6a is the most active one,
it demonstrated inhibitory activity nearly similar to tacrine
(53.13%), while 6b showed moderate activity 39.84%. Their
structures are shown in Fig. 2. Compound 7a showed the
lowest activity 15.61%.
Moreover, compound 6a with a thienopyridine ring system
fused to two cyclopentane rings displayed highest inhibitory
activity among all the tested compounds. The lack of inhibitory activity of compounds, 10b, 11a, b, 13, 15, 17, may be
attributed to the bulkiness of these compounds which might
hinder their proper fitting to the active site of the acetylcholine esterase enzyme. Unfortunately, there is no obvious
correlation to distinguish between structure and biological
activity.
Figure 3. Proposed binding model of tacrine with the main amino
acid residue of AChE.
the various interactions between ligands and the enzyme’s
active site in detail. Docking studies of inhibitors were performed by MOE-2008 (Molecular Operating Enviroment) on
the basis of the existing X-ray crystal structure of tacrineAChE complex [14] (Code: 1ACJ). We performed 100 docking
iteration for each ligand, and thge top-scoring configuration
of each of the ligand-enzyme complexes was selected on
energetic grounds.
The binding model suggests that tacrine is sandwiched
between the rings of Phe-330 and Try-84, its aromatic phenyl
and pyridine rings showed parallel p-p interaction with the
phenyl ring of Phe-330 with average distances of 3.4 and
3.6 Å, respectively. In addition, both of the two rings showed
interaction with the five-membered ring of indole of Try-84
with average distances of 3.5 and 3.55 Å, respectively. The
aromatic nitrogen of tacrine is hydrogen-bonded to the mainchain carbonyl oxygen of His-440 (average N O distance:
Molecular modeling study
Molecular docking as well as conformational alignment studies of the synthesized compounds were performed in order to
gain an insight into the mechanism of enzyme inhibition.
Besides, molecular docking studies helped understanding
Figure 2. Structures of compounds 6a and 6b.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 4. Interaction between ligand tacrine and the aromatic residues in the active-site gorge of AChE.
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Figure 5. Proposed binding model of compounds 5a, 5b, and
tacrine with AChE.
3.4 Å), while the amino group is bonded to a water molecule
bonded to Ser-81.
The proposed binding model of tacrine with amino acid
residue of AChE is shown in Fig. 3. Moreover, the tacrine
Aminothienopyridine Analogues of Tacrine
593
docking conformation within AChE demonstrating its interaction with the aromatic residue in the active-site gorge of
AChE is shown in Fig. 4.
Docking of compound 5a (Fig. 5) showed p-p interaction
of its thiophene and pyridine rings with the phenyl ring of
Phe-330 with average distances of 3.5 Å. In addition, both of
the two rings showed interaction with the five-membered
ring of indole of Try-84 with average distances of 3.51 and
3.52 Å, respectively. The aromatic nitrogen of the pyridine
ring is hydrogen-bonded to the main-chain carbonyl oxygen
of His-440 (average N O distance: 3.46 Å), while the amino
group is bonded to a water molecule bonded to Ser-81.
Compound 5b showed the same interactions as 5a with small
differences in distances.
Conformational superposition of tacrine (from the X-ray
crystal structure of tacrine-AChE complex) with compounds
5a and 5b (from the docking simulation) are also shown in
Fig. 5. The superposition shows that their hydrophilic and
hydrophobic groups overlapp with each other.
Moreover, 5a, b docking conformation within AChE demonstrating their interaction with the aromatic residue in the
active-site gorge of AChE is shown in Fig. 6.
Nevertheless, the superpositions of either 5a or 5b and
tacrine in the active site of the AChE pocket (from surface
and maps) are shown in Fig. 7.
From the above-mentioned data, the molecular modeling
studies of the examined compounds 5a, b showed that they
are bound to the active-site gorge of AChE with position and
orientation very close to that seen from the X-ray crystal
structure of the tacrine-AChE complex [14].
On the other hand, docking of compounds 6a, b into the
AchE-active site (Fig. 8) showed almost the same contacts as 5a,
b, yet, there were some different features: the phenyl ring of
Phe-330 only interacted with the pyridine ring in 6a at average distances of 3.7 Å and the thiophene ring in 6b at average
distance of 3.75 Å. In addition, 6a interacted with its pyridine
ring to the five-membered ring of indole of Tyr-84 at an
average distance of 3.5 Å while its thiophene ring interacted
Figure 6. Interaction between the ligands 5a,
b and the aromatic residues in the active-site
gorge of AChE.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
594
M. M. Badran et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Figure 7. The superposition of compounds
5a, b (red) and tacrine (grey) in the active site
of the AChE pocket.
Figure 8. Proposed binding model of compounds 6a, 6b and tacrine with AChE.
with the six-membered ring of the Tyr-84 indole at an average
distance of 3.7 Å. Compound 6b showed interaction between
the pyridine and thiophene rings with the five-membered
indole ring of Tyr-84 at average distances 3.5 and 3.6 Å,
respectively. The average N O distances between the
main-chain carbonyl oxygen of His-440 and pyridine nitrogen
of 6a and 6b are 3.53 and 5.45 Å, respectively. Conformational
superposition of tacrine (from the X-ray crystal structure of
the tacrine-AChE complex) with compounds 6a and 6b (from
the docking simulation) are shown in Fig. 8.
Figure 9. Interaction between ligands 6a, b
and the aromatic residues in the active-site
gorge of AChE.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Aminothienopyridine Analogues of Tacrine
595
Figure 10. The superposition of compounds
6a, b (red) and tacrine (grey) in the active site
of the AChE pocket.
Figure 11. Proposed binding model of compounds 7a, b and tacrine with AChE.
Furthermore, 6a, b docking conformation within AChE
demonstrating their interaction to the aromatic residue
in the active-site gorge of AChE is shown in Fig. 9.
The superpositions of either 6a or 6b and tacrine in the active
site of AChE pocket (from surface and maps) are shown in
Fig. 10.
Regarding compounds 7a and b, their dockings in the
AChE-active site (Fig. 11) demonstrated p-p interaction
between the phenyl ring of Phe-330 with their pyridine rings
only at average distances of 3.7 and 3.6 Å, while their thiophene rings interacted with the six-membered ring of the Tyr84 indole at average distances of 3.77 and 3.9 Å, respectively.
Figure 12. Interaction between ligands 7a, b
and the aromatic residues in the active-site
gorge of AChE.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
596
M. M. Badran et al.
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Figure 13. The superposition of compounds
7a, b (red) and tacrine (grey) in the active site
of the AChE pocket.
Figure 14. Proposed binding model of compounds 9a, b and tacrine with AChE.
Additionally, their pyridine rings interacted with the fivemembered ring of Tyr-84 indole at average distances of 3.55
and 3.59 Å. The average N O distance between the mainchain carbonyl oxygen of His-440 and their pyridine nitrogen
is 3.71 and 3.78 Å, respectively. Conformational superpositions of tacrine (from the X-ray crystal structure of the
tacrine-AChE complex) with compounds 7a and 7b (from
the docking simulation) are shown in Fig. 11.
Furthermore, 7a, b docking conformation within AChE
demonstrating their interaction to the aromatic residue
in the active-site gorge of AChE is shown in Fig. 12.
The superpositions of either 7a or 7b and tacrine in the active
Figure 15. Interaction between ligands 9a, b
and the aromatic residues in the active-site
gorge of AChE.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
Aminothienopyridine Analogues of Tacrine
597
Figure 16. The superposition of compounds
9a, b (red) and tacrine (grey) in the active site
of the AChE pocket.
site of the AChE pocket (from surface and maps) are shown in
Fig. 13.
Compounds 9a and b, their docking in the AChE-active site
(Fig. 14) revealed p-p interaction between the phenyl ring of
Phe-330 with their thiophenes at average distances of 3.4 Å,
and also demonstrated p-p interaction between the phenyl
ring of Phe-330 with their pyridine rings at average distances
of 4.01 and 3.6 Å, respectively. On the other hand, their
thiophene rings interacted with the five-membered ring of
Tyr-84 indole at average distances of 3.95 and 3.82 Å, respectively. Additionally, their pyridine rings interacted with the
five-membered ring of the indole of Tyr-84 at an average
distance of 3.85 Å. The average N O distances between
the main-chain carbonyl oxygen of His-440 and their pyridine
nitrogen are 4.61 and 4.33 Å, respectively. Conformational
superpositions of tacrine (from the X-ray crystal structure of
Figure 18. Interaction between ligand 10a and the aromatic
residues in the active-site gorge of AChE.
Figure 17. Proposed binding model of compound 10a and tacrine
with AChE.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 19. The superposition of compound 10a (red) and tacrine
(grey) in the active site of the AChE pocket.
www.archpharm.com
598
M. M. Badran et al.
tacrine-AChE complex) with compounds 9a and 9b (from the
docking simulation) are shown in Fig. 14.
9a, b docking conformation within AChE demonstrating
their interaction to the aromatic residue in the active-site
gorge of AChE is shown in Fig. 15. The superpositions of
either 9a or 9b and tacrine in the active site of the AChE
pocket (from surface and maps) are shown in Fig. 16.
Docking of compound 10a in the AchE-active site (Fig. 17)
showed only p-p interaction between the phenyl ring of Phe330 with its phenyl ring at an average distances 3.65 Å, as
well as p-p interaction between the five-membered ring of
indole of Tyr-84 and its pyridine at an average distances of
3.72 Å. The average N O distances between the mainchain carbonyl oxygen of His-440 and their pyridine nitrogen
are 6.5 Å. Conformational superpositions of tacrine (from the
X-ray crystal structure of tacrine-AChE complex) with compound 10a (from the docking simulation) are shown in
Fig. 17.
Docking conformation of 10a within AChE demonstrating
their interaction to the aromatic residue in the active-site
gorge of AChE is shown in Fig. 18. The superpositions of
either 10a and tacrine in the active site of the AChE pocket
(from surface and maps) are shown in Fig. 19.
Overall, the main common feature is the sandwiching of
the aromatic portions of tacrine and the newly synthesized
compounds between the phenyl ring of Phe-330 and the
indole of-Tyr 84, with small differences in the rings in contact
and the distances between them.
On the other hand, docking of compounds 10b, 11a, b, 13,
15, 17 showed very poor interaction with the active-site gorge
of AChE. Conformational superpositions of tacrine (from the
X-ray crystal structure of the acrine-AChE complex) with
these compounds revealed that there was nearly no overlap
between them and tacrine (data not shown).
Conclusion
We reported here the synthesis of various thienopyridines as
tacrine analogues. The synthesized compounds were tested
for their anti-acetylcholine esterase activity. Results showed
that nine of the compounds demonstrated significant
activity in comparison with tacrine, they are more or less
similar to each other and showed moderate inhibitory
activity. In addition, their docking results revealed that they
also have nearly comparable fitting scores. It is worth to
mention that, although compound 6a has similar docking
results, it demonstrated the highest biological activity which
was very close to that of tacrine. Unfortunately, 7a afforded
the lowest inhibitory activity without finding any reasonable
explanation. In addition, compound 10a which had a low fit
score among the tested compounds, showed also a low
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
biological activity. Interestingly, compounds 10b, 11a, b,
13, 15, 17, which had a very poor fit score, had no inhibitory
activity.
Experimental
Chemistry
Melting points are obtained on Griffin apparatus and the values
given are uncorrected, IR spectra were recorded on a Shimadzu
435 spectrometer (Shimadzu, Japan), using KBr disks. 1H-NMR
spectra were recorded on a Mercury-300BB 300 MHz and a Varian
Gemini 200 MHz spectrometer (both, Varian, USA) using TMS as
internal standard. Mass spectra were recorded on a Jeol JMS-AX
500 mass spectrometer (Jeol, Japan). Elemental analyses for C, H,
and N were within 0.4% of the theoretical values and were
performed at the Microanalytical Center, Cairo University.
Progress of the reaction was monitored by TLC using precoated
aluminium sheets silica gel Merck 60 F 254 (Merck, Germany)
and was visualized by UV lamp.
General method for the cyclodehydration reaction
Method A: 2-Amino-3-cyanothiophenes, suitable ketone (1.1
eq.), and sodium-dried toluene (120 mL) were placed in a
three-necked round-bottom flask fitted with an overhead
stirrer. Boron trifluoride diethyl etherate (1.1 eq.) was added
slowly via syringe, and the reaction mixture was heated at
reflux for 24 h. On cooling, the toluene was decanted and, to
liberate the product, the remaining solids were treated with
sodium hydroxide (2 M, 120 mL) and heated at reflux for
24 h. After cooling, the organic components were extracted
with chloroform, the organic layers were combined, dried,
and the solvent was evaporated in vacuo and crystallized from
ethanol to give the desired product.
Method B: To a solution of the corresponding thiophenes
(0.01 mol) in the appropriate ketone (10 mL) was added
anhydrous zinc chloride (0.01 mol) and the mixture was
heated under reflux for 4 h. The separated solid was filtered,
washed with water, dried, and crystallized from petroleum ether
to afford the desired thienopyridine derivatives.
Method C: A mixture of 2-amino-3-cyanothiophenes (0.01 mol),
the corresponding ketone (0.01 mol), and anhydrous zinc
chloride (0.01 mol) was fused at 140–1608C for 4–6 h. The
solid obtained was collected by filtration, washed with water,
and crystallized from ethanol to give thienopyridines.
4-Amino-2,3-dimethyl-6,7-dihydro-5H-thieno[2,3-b]
cyclopenta[e]pyridine 5a
The title compound was prepared from the reaction of 2-amino-3cyano-4,5-dimethylthiophene 2 and cyclopentanone 1b adopting
method B to give 5a. Yield: 60%; m. p.: >2808C; IR (KBr) cm1:
3400, 3300, 3200 (NH2), 2950–2850 (CH aliphatic), 1630 (C –
– N);
1
H-NMR (DMSO-d6) d: 2.05 (m, 2H, CH2), 2.74 (s, 3H, CH3), 2.89 (m,
5H, CH3, CH2), 3.08 (m, 2H, CH2), 5.87 (s, 2H, NH2, D2O, exchangeable); MS m/z (% abundance): 218 [Mþ] (1.19). Anal. calcd.
for C12H14N2S: C, 66.02; H, 6.46; N, 12.83. Found: C, 66.22; H,
6.36; N, 12.90.
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
4-Amino-2,3-dimethyl-5,6,7,8-tetrahydrothieno[2,3-b]
quinoline 5b
The title compound was prepared from the reaction of 2 and
cyclohexanone 1c adopting method B to give 5b. Yield: 92%
(reported yield: 95% [15]).
9-Amino-1,2,3,6,7,8-hexahydrocyclopenta[4,5]thieno[2,3-b]
cyclopenta[e]pyridine 6a
The title compound was prepared from the reaction of 2-amino-3cyano-5,6-dihydro-4H-cyclopenta[b]thiophene 3 and 1b adopting
method B to give 6a. Yield: 72%; m. p.: >2808C; IR (KBr) cm1:
1
3405, 3339, 3306 (NH2), 2928, 2854 (CH aliphatic), 1651(C –
– N); HNMR (DMSO-d6) d: 1.86 (m, 2H, CH2), 2.11 (m, 2H, CH2), 2.43 (m,
2H, CH2), 2.77–2.92 (m, 4H, 2CH2), 3.09 (m, 2H, CH2), 6.40, 7.06
(2s, 2H, NH2, D2O exchangeable); MS m/z (% abundance): 230 [Mþ]
(8.44). Anal. calcd. for C13H14N2S: C, 67.79; H, 6.13; N, 12.17.
Found: C, 67.60; H, 6.35; N, 12.00.
10-Amino-2,3,6,7,8,9-hexahydro-1H-cyclopenta[4,5]
thieno[2,3-b]quinoline 6b
The title compound was prepared from the reaction of 3 and 1c
adopting method B to give 6b. Yield: 80%; m. p.: >2808C; IR (KBr)
cm1: 3400, 3300, 3200 (NH2), 2950–2900 (CH aliphatic), 1625
(C –– N); 1H-NMR (DMSO-d6) d: 1.85 (m, 6H, 3 CH2), 2.85–2.96 (m, 4H,
2 CH2), 3.16 (m, 4H, 2 CH2), 6.41–6.42 (br.s, 2H, NH2, D2O
exchangeable); MS m/z (% abundance): 244 [Mþ] (55.74). Anal.
calcd. for C14H16N2S: C, 68.81; H, 6.60; N, 11.47. Found: C,
68.65; H, 6.50; N, 11.64.
10-Amino-2,3,6,7,8,9-hexahydro-1H-[1]benzothieno[2,3-b]
cyclopenta[e]pyridine 7a
The title compound was prepared from the reaction of 2-amino-3cyano-4,5,6,7-tetrahydro[1]benzothiophene 4 and 1b adopting
methods A or B to give 7a. Yield: 40% (method A), 60% (method
B); m. p.: 246–2488C; IR (KBr) cm1: 3425, 3325, 3221 (NH2), 2934,
1
2860 (CH aliphatic), 1632 (C –
– N); H-NMR (DMSO-d6) d: 1.76–1.80
(m, 6H, 3 CH2), 2.42–2.46 (m, 2H, CH2), 2.71–2.75 (m, 4H, 2 CH2),
2.77–2.98 (m, 2H, CH2), 6.03 (s, 2H, NH2, D2O exchangeable); MS
m/z (% abundance): 244 [Mþ] (100). Anal. calcd. for C14H16N2S: C,
68.81; H, 6.60; N, 11.47. Found: C, 68.96; H, 6.45; N, 11.65.
11-Amino-1,2,3,4,7,8,9,10-octahydro[1]benzothieno[2,3-b]
quinoline 7b
The title compound was prepared from the reaction of 4 and 1c
adopting methods A or B to give 7b. Yield: 38% (method A), 90%
(method B); m. p.: 2608C (reported yield: 92%; m. p.: 2188C [15]);
1
H-NMR (DMSO-d6) d: 1.80–1.84 (m, 4H, 2 CH2), 2.03–2.13 (m, 2H,
CH2), 2.49–2.50 (m, 2H, CH2), 2.71–2.76 (m, 4H, 2 CH2), 2.88–2.97
(m, 4H, 2 CH2), 6.283 (s, 2H, NH2, D2O exchangeable).
4-Amino-2,3-dimethyl-5H-thieno[2,3-b]indeno[2 0 ,10 -e]
pyridine 9a
The title compound was prepared from the reaction of 2 and 2,3dihydroindan-1-one 8a adopting method A to give 9a. Yield:
40%; m. p.: >2808C; IR (KBr) cm1: 3420, 3320, 3227 (NH2),
3051 (CH aromatic), 2940, 2888, 2862 (CH aliphatic), 1632
(C –– N); 1H-NMR (DMSO-d6, TFAA-H) d: 2.27, 2.35 (2s, 6H, 2 CH3),
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Aminothienopyridine Analogues of Tacrine
599
3.68 (s, 2H, CH2), 3.91 (s, 2H, NH2, D2O exchangeable), 7.41–7.54,
7.69–7.84 (2m, 4H, aromatic H); MS m/z (% abundance): 266 [Mþ]
(6). Anal. calcd. for C16H14N2S: C, 72.14; H, 5.30; N, 10.52. Found:
C, 72.39; H, 5.15; N, 10.40.
4-Amino-2,3-dimethyl-5,10-dihydrothieno[2,3-b]
benzo[g]quinoline 9b
The title compound was prepared from the reaction of 2 and 1tetralone 8b adopting method B to give 9b. Yield: 59%; m. p.:
>2808C; IR (KBr) cm1: 3411, 3327, 3219 (NH2), 3048 (CH aro1
matic), 2938, 2854 (CH aliphatic), 1632 (C –
– N); H-NMR (DMSO-d6)
d: 2.42–2.53 (2br.s, 6H, 2 CH3), 2.79–2.83 (m, 2H, CH2), 2.92–2.94
(m, 2H, CH2), 7.13 (br.s, 2H, NH2, D2O exchangeable), 7.42–7.46,
8.11–8.13 (2m, 4H, aromatic H); MS m/z (% abundance): 280 [Mþ]
(9). Anal. calcd. for C17H16N2S: C, 72.82; H, 5.75; N, 9.99. Found: C,
72.64; H, 5.90; N, 10.10.
11-Amino-1,2,3,10-tetrahydrocyclopenta[4,5]thieno[2,3-b]
indeno[2 0 ,10 -e]pyridine 10a
The title compound was prepared from the reaction of 3 and 8a
adopting method A to give 10a. Yield: 58%; m. p.: 2308C; IR (KBr)
cm1: 3410, 3327, 3220 (NH2), 3048 (CH aromatic), 2937, 2853
1
(CH aliphatic), 1629 (C –
– N); H-NMR (DMSO-d6) d: 1.88–1.91 (m, 2H,
CH2), 2.29–2.49 (m, 2H, CH2), 2.88–3.14 (m, 2H, CH2), 3.81 (s, 2H,
indeno CH2), 7.24–7.98 (m, 4H, aromatic H), 8.80 (s, 2H,
NH2, D2O exchangeable); MS m/z (% abundance): 278 [Mþ] (40).
Anal. calcd. for C17H14N2S: C, 73.35; H, 5.07; N, 10.07. Found: C,
73.55; H, 5.15; N, 10.24.
12-Amino-2,3,6,11-tetrahydro-1H-cyclopenta[4,5]
thieno[2,3-b]benzo[g]quinoline 10b
The title compound was prepared from the reaction of 3 and 8b
adopting method B to give 10b. Yield: 60%; m. p.: >2808C; IR (KBr)
cm1: 3404, 3302, 3228 (NH2), 3078 (CH aromatic), 2981–2858
1
(CH aliphatic), 1647 (C –
– N); H-NMR (DMSO-d6) d: 1.69–1.79 (m, 4H,
2 CH2), 2.58–2.70 (m, 2H, CH2), 2.91–2.93 (m, 2H, CH2), 3.19–3.31
(m, 2H, CH2), 6.92 (s, 2H, NH2, D2O exchangeable), 7.38–7.54,
7.80–7.82 (2m, 4H, aromatic H); MS m/z (% abundance) 292 [Mþ]
(100). Anal. calcd. for C18H16N2S: C, 73.93; H, 5.52; N, 9.58. Found:
C, 73.88; H, 5.32; N, 9.70.
12-Amino-2,3,4,11-tetrahydro-1H-[1]benzothieno[2,3-b]
indeno[2 0 ,10 -e]pyridine 11a
The title compound was prepared from the reaction of 4 and 8a
adopting method A to give 11a. Yield: 58%; m. p.: >2808C; IR (KBr)
cm1: 3350, 3200 (NH2), 3050 (CH aromatic), 2950–2900 (CH
1
aliphatic), 1620 (C –
– N); H-NMR (DMSO-d6) d: 1.84 (s, 4H, 2 CH2),
2.80, 3.04 (2br.s, 4H, 2 CH2), 3.43 (br.s, 2H, NH2, D2O exchangeable), 3.86 (s, 2H, indeno CH2,), 7.55–7.58 (m, 2H, aromatic H),
7.72, 8.00 (2m, 2H, aromatic H); MS m/z (% abundance): 292 [Mþ]
(100). Anal. calcd. for C18H16N2S: C, 73.93; H, 5.52; N, 9.58. Found:
C, 73.70; H, 5.65; N, 9.40.
13-Amino-1,2,3,4,7,12-hexahydro[1]benzothieno[2,3-b]
benzo[g]quinoline 11b
The title compound was prepared from the reaction of 4 and
8b adopting method B to give 11b. Yield: 90%; m. p.: >2808C; IR
(KBr) cm1: 3450, 3330, 3200 (NH2), 3100–3050 (CH aromatic),
www.archpharm.com
600
M. M. Badran et al.
1
2950–2900 (CH aliphatic), 1650 (C –
– N); H-NMR (DMSO-d6) d: 1.82
(m, 4H, 2 CH2), 2.03–2.09 (m, 2H, CH2), 2.56–2.62 (m, 2H, CH2),
2.75–3.03 (m, 4H, 2 CH2), 5.77 (s, 2H, NH2, D2O exchangeable),
7.32–8.15 (m, 4H, aromatic H); MS m/z (% abundance): 306 [Mþ]
(100). Anal. calcd. for C19H18N2S: C, 74.47; H, 5.92; N, 9.14. Found:
C, 74.70; H, 6.10; N, 9.35.
11-Amino-7,12,12-trimethyl-7,10-methano-1,2,3,4,7,8,9,10octahydro[1]benzo-thieno[2,3-b]quinoline 13
The title compound was prepared from the reaction of 4 and
camphor 12 adopting methods A or C to give 13. Yield: 65%
(method A), 60% (method C); m. p.: >2808C; 1H-NMR (DMSO-d6)
d: 1.03–1.10 (m, 9H, 3 CH3), 1.23 (m, 4H, 2 CH2), 1.79 (s, 2H,
NH2, D2O exchangeable), 2.74–2.90 (m, 5H, camphor H),
3.42–3.45 (m, 8H, 4 CH2); IR (KBr) cm1: 3450, 3350, 3200
(NH2), 2900–2850 (CH aliphatic), 1620 (C –
– N); MS m/z (% abundance): 308 [Mþ – 4] (49.79), 278 [308 – 2 CH3] (73.36). Anal. calcd.
for C19H24N2S: C, 73.03; H, 7.74; N, 8.97. Found: C, 73.20; H, 7.55;
N, 8.75.
11-Amino-2-methyl-1,2,3,4,7,8,9,10-octahydro[1]
benzothieno[2,3-b][1,6]naphtha-pyridine 15
The title compound was prepared from the reaction of 4 and Nmethylpiperidin-4-one 14 adopting method B to give 15. Yield:
62%; m. p.: >2808C; IR (KBr) cm1: 3300, 3200 (NH2), 2950, 2900
1
(CH aliphatic), 1630 (C –
– N); H-NMR (DMSO-d6) d: 1.71 (m, 6H, 3
CH2), 2.34–2.41 (m, 8H, 4 CH2), 2.61 (s, 3H, CH3), 6.96 (s, 2H,
NH2, D2O exchangeable); MS m/z (% abundance): 274 [M þ 1]
(2.04). Anal. calcd. for C15H19N3S: C, 65.90; H, 7.01; N, 15.37.
Found: C, 65.70; H, 7.25; N, 15.50.
13-Amino-1,2,3,4,7,12-hexahydro[1]benzothieno
[3 0 ,2 0 :5,6]pyrido[2,3-b]quinoline 17
The title compound was prepared from the reaction of 4 and
1,2,3,4-tetrahydro-quinolin-2-one 16 adopting method A to give
17. Yield: 29%; m. p.: 1008C; IR (KBr) cm1: 3442, 3317, 3220 (NH2,
NH), 3032 (CH aromatic), 2937, 2864 (CH aliphatic), 1632 (C –
– N);
1
H-NMR (DMSO-d6) d: 1.70–1.80 (m, 4H, 2 CH2), 2.30 (s, 2H, quinoline CH2), 2.40–2.48 (m, 2H, CH2), 2.83–2.90 (m, 2H, CH2), 5.00
(br.s, 2H, NH2, D2O exchangeable); 6.83–6.94 (m, 2H, aromatic H),
7.10–7.18 (m, 2H, aromatic H), 10.08 (s, 1H, NH, D2O exchangeable); MS m/z (% abundance): 307 [Mþ] (2.03). Anal. calcd.
for C18H17N3S: C, 70.32; H, 5.58; N, 13.67. Found: C, 70.55; H,
5.78; N, 13.80.
Materials and methods
Animals
Adult male albino Wister rats weighing 180–200 g were used in
the present study. Rats were purchased from the animal house of
El-Nile Company (Cairo, Egypt). Rats were kept under constant
laboratory conditions and were allowed free access to food and
water throughout the period of investigation. The test compounds were orally administered once. After 30 min, rats were
killed, decapitated, then, the brains were carefully removed and
homogenized in normal saline (pH ¼ 7.4).
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
concentration of the assay solution containing the test compound consisted of 0.1 M sodium phosphate buffer (pH ¼ 8.0),
0.3 mM 5,50 -dithiobis-2-nitrobenzoic acid (DTNB, Ellman’
reagent), 0.02 U of AChE from Electrophorus electricus and
0.5 mM acetylthiocholine iodide as substrate of the enzymatic
reaction. The assay solutions without the substrate were preincubated with enzyme for 10 min at 378C. After preincubation,
the substrate was added. The absorbance changes at 405 nm
were recorded for 5 min with a microplate reader GENios
FI29004 (Tecan Ltd, Austria). The AChE inhibition was determined for each compound. Each assay was run in triplicate
and each reaction was repeated at least three times.
The study was carried out according to international guidelines
and approved by the ethical committee for animal experimentation at the Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Statistical analysis
Statistical analysis was carried out by one-way ANOVA followed
by Tukey–Kramer multiple comparisons test for comparison of
means of different groups. Each value represents mean S.E.
(n ¼ 6–8 rats).
Molecular docking
All the molecular-modeling studies were carried out on an Intel
Pentium 1.6 GHz processor, 512 MB memory with Windows XP
operating system using Molecular Operating Environment
(MOE 2008.10; Chemical Computing Group, Canada)
(Molecular Operating Environment (MOE 2008.10); C.C.G., Inc.,
1255 University St., Suite 1600, Montreal, Quebec, Canada H3B
3X3. 2005. www.chemcomp.com) as the computational software.
All the minimizations were performed with MOE until a RMSD
gradient of 0.05 kcal mol1 A1 with MMFF94x force-field and
the partial charges were automatically calculated.
The X-ray crystallographic structure of acetylcholine esterase
complexed with tacrine (PDB ID: 1ACJ) was obtained from the
protein data bank available at the RCSB Protein Data Bank,
www.rcsb.org) with a 2.80 – A resolution:
Enzyme structures were checked for missing atoms, bonds and
contacts; hydrogens and partial charges were added to the system using Protonate 3D application; water molecules were manually deleted; the active site was generated using the residues
close to the tacrine atoms; the ligand molecules were constructed using the builder module and were energy-minimized;
all antagonist structures were docked into the active site by using
the MOE Dock tool.
This method is divided into a number of stages: (a)
Conformational analysis of ligands. The algorithm-generated conformations from a single 3D conformation by conducting a systematic search. In this way, all combinations of angles were created for
each ligand. (b) Placement. A collection of poses was generated from
the pool of ligand conformations using the Triangle Matcher
placement method. Poses were generated by superposition of
ligand atom triplets and triplets of points in the receptor binding
site in a systematic way. (c) Scoring. Poses generated by the placement methodology were scored using the London dG scoring
function implemented in MOE, which estimates the free energy
of binding of the ligand from a given pose. The top ten poses for
each ligand were the output in a MOE database. Each resulting
ligand pose was then subjected to MMFF94x energy minimization.
AchE-inhibition assay in vitro
Inhibitory activity against AChE was evaluated at 378C by
the colorimetric method reported by Ellman [13]. The final
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
The authors have declared no conflict of interest.
www.archpharm.com
Arch. Pharm. Chem. Life Sci. 2010, 10, 590–601
References
[1] R. T. Bartus, R. L. Dean, B. Beer, A. S. Lippa, Science 1982, 217,
408–414.
[2] K. L. Davis, P. Powchik, Lancet 1995, 345, 625–630.
[3] M. Rainer, CNS Drugs 1997, 7, 89–97.
[4] P. N. Tariot, H. J. Federoff, Alzheimer Dis. Assoc. Disord. 2003, 17,
105–113.
[5] M. Johansson, A. Hellstrom, E. Lindahl, A. Nordberg,
Dementia 1996, 7, 111–117.
[6] A. Kurz, J. Neural Transm. Suppl. 1998, 54, 295–299.
[7] A. J. Wagstaff, D. McTavish, Drugs Aging 1994, 4, 510–540.
[8] H. Sugimoto, Chem. Rec. 2001, 1, 63–73.
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Aminothienopyridine Analogues of Tacrine
601
[9] P. R. Carlier, D.-M. Du, Y. Han, J. Liu, Y.-P. Pang, Bioorg. Med.
Chem. Lett. 1999, 9, 2335–2338.
[10] K. Gewald, E. Schinke, H. Bottcher, Chem. Ber. 1966, 99, 94–
100.
[11] M. T. McKenna, G. R. Proctor, L. C. Young, A. L. Harvey, J. Med.
Chem. 1997, 40, 3516–3523.
[12] J. A. Moore, L. D. Kornreich, Tetrahedron Lett. 1963, 20, 1277–
1281.
[13] G. L. Ellman, K. D. Courtnry, V. Andres, R. M. Featherstone,
Biochem. Pharmacol. 1961, 7, 88–95.
[14] M. Harel, I. Schalk, L. Ehret-Sabatier, F. Bouet, et al., Proc. Natl.
Acad. Sci. U. S. A. 1993, 90, 9031–9035.
[15] P. Seck, D. Thomas, G. Kirsch, J. Heterocycl. Chem. 2008, 45, 853.
www.archpharm.com
Документ
Категория
Без категории
Просмотров
0
Размер файла
820 Кб
Теги
tacrine, synthesis, design, molecular, stud, modeling, disease, aminothienopyridine, alzheimers, analogues
1/--страниц
Пожаловаться на содержимое документа