Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido[2,3-b]pyrazine Derivatives

Article abstract of DOI:10.1111/cbdd.12579

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3′-nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC₅₀ values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3-(3′-methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3′-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be selective inhibition for BChE with IC₅₀ values of 0.583 ± 0.052 μm and AChE with IC₅₀ value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors. A series of pyrido[2,3-b]pyrazine (6a-6q) derivatives has been synthesized and evaluated for inhibitory activities against cholinesterases; acetylcholinesterase, and butyrylcholinesterase. Molecular docking of active compounds was also performed to suggest the putative binding modes with cholinesterases.

Full text of DOI:10.1111/cbdd.12579

Received Date : 01-Mar-2015
Revised Date : 17-Apr-2015
Accepted Date : 27-Apr-2015
Article type : Research Article
Syntheses, Cholinesterases Inhibition and Molecular Docking Studies of Pyrido[2,3-b]pyrazine
Derivatives
Abdul Hameed,*a Syeda Tazeen Zehra,a Syed Jawad Ali Shah,b Khalid Mohammed Khan,a Rima
D. Alharthy,c Norbert Furtmann,d,e Jürgen Bajorath,d Muhammad Nawaz Tahir,f Jamshed Iqbal,*b
a
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological
Sciences, University of Karachi, Karachi-75270, Pakistan
b Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060,
Pakistan
c Department of Chemistry, King Abdulaziz University, Jeddah, Saudi Arabia
d Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal
Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmann Str. 2, D-53113 Bonn, Germany
e Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
f Department of Physics, University of Sargodha, Sargodha
*Corresponding Authors:
Abdul Hameed, abdul.hameed@iccs.edu
Jamshed Iqbal, drjamshed@ciit.net.pk
Address correspondence to:
Prof. Dr. Jamshed Iqbal
Centre for Advanced Drug Research,
COMSATS Institute of Information Technology,
Abbottabad, Postal Code 22060, Pakistan
Telephone: +92-992-383591-96
Fax: +92-992-383441
E-Mail: drjamshed@ciit.net.pk
Running Title:
Pyrido[2,3-b]pyrazine derivatives as Cholinesterases Inhibitors
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Abstract
Cholinesterases, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), have a role in
cholinergic deficit which evidently leads to Alzheimer’s disease (AD). Inhibition of cholinesterases with
small molecules is an attractive strategy in AD therapy. The present study demonstrates synthesis of
pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and
BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3′-
nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both, AChE and
BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μM, respectively. The analogues, 3-(3′-
methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3′-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be
selective inhibitors for BChE with IC50 value of 0.583 ± 0.052 μM and AChE with IC50 value of 0.899 ± 0.10
μM, respectively. Molecule docking studies of the active compounds suggested the putative binding
modes with cholinesterases. The potent compounds among the series could potentially serves as good
leads for the development of new cholinesterase inhibitors.
Keywords: Acetophenone derivatives, diaminopyridine, pyrido[2,3-b]pyrazines, cholinesterases,
acetylcholinesterase (AChE), butyrylcholinesterase (BChE)
1. Introduction
Alzheimer’s disease (AD) is recognized as most common cause of dementia which affects 36 million
people worldwide. According to a world Alzheimer’s report 2012, the data could projected to 115
million patients with dementia by 2050, unless an effective treatment is developed to reverse the AD
symptoms (1). The severity of the AD complications put it into the loop of top ten leading causes of
death and makes it imperious for chemists and pharmacists to develop efficacious drugs. The symptoms
associated with AD are gradual decline in memory, weakening in language skills and other cognitive
dysfunctions (2-4). Evidence showed a significant role of cholinesterases, acetylcholinesterase (AChE, EC
3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8), in cognitive dysfunctions (5). These enzymes
predominantly effect the hydrolysis of acetylcholine neurotransmitters at synaptic cleft which lead to
severe loss of cholinergic neurons in AD patients (6). The major hallmarks associated with this
neurodegenerative disorder are including; 1) deposition of γ-amyloid peptides due to excessive cleavage
of amyloid proteins and 2) development of neurofibrillary tangles from aggregated tau protein, both
together lead to degeneration of cholinergic neurons. The current available therapeutics to reduce AD
symptoms are including the AChE inhibitors donepezil, galantamine, neostigmine and dual inhibitor
rivastigmine to improve cognitive impairments in AD patients (7-9). The available remedies prove to be
effective only in the early stages of disease, impels to develop new inhibitors for the management of AD
(10-12).
Both cholinesterases, AChE, and BChE, differ in their distribution pattern and activities in a healthy
individual and AD patient (13). The AChE is distributed in multiple cells, but mainly concentrated in
cholinergic nervous system while BChE, constituted in liver, distribute in the body via blood plasma.
Previous studies demonstrate that in AD brain the activity of AChE reduces to almost its half while the
activity of BChE elevates in later stages of AD complications to compensate the hydrolysis of AChE (9,
14). The role of BChE in the deposition of β-amyloid (Aβ) has also been reported in AD brain (15). A
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general comparison of both enzymes showed a 20 Aº long narrow gorge deep in the protein which ends
to a bottom catalytic triad where the hydrolysis of acetylcholine takes place to choline and acetic acid.
The size of AChE active site gorge is relatively small (302 Aº), due to 14 bulky aromatic amino acids
residues, as compared to BChE gorge (502 Aº) which is comprised of 8 aryl amino acids residues (16, 17).
The difference in gorge size and aryl residues pattern in both cholinesterases provides a mean of
selectivity for inhibitors.
The approaches utilized to counter AD symptoms via cholinesterases inhibition, AChE and BChE, are
either selective or non-selective. Various types of molecules such as carbamates (phenothiazine
derivatives, neostigmine etc.), tacrine, piperidines (donepezil) organophosphates, [1,6] or [1,8]-
naphthyridine derivatives (12, 18, 19), Schiff bases (20) and purine nuelcoside (21) etc. have been
reported as cholinesterases inhibitors. In the present study, we have synthesized a series of pyrido[2,3-
b]pyrazines (6a-6q) due to their close resemblance with [1,8]-naphthyridine derivative 2 and tacrine 3
with an extra nitrogen atom at C-4 or C-5/9 position which may also participate in π-π interactions of
inhibitors with the active site of enzyme during inhibition (Figure-1). Literature showed varied
applications of pyrido[2,3-b]pyrazine type compounds in pharmaceutical field such as antituberculosis,
(22) antitumor, (23, 24) antiallergic agents (25) etc. The synthesized pyrido[2,3-b]pyrazines (6a-6q) were
evaluated as cholinesterases inhibitors against both electric eel AChE and equine serum BChE by using
the standard Ellman's colorimetric assay (26).
Figure-1: Structure of pyrido[2,3-b]pyrazines 1, [1,8]-naphthyridine derivative 2 and tacrine 3
2. Results and discussion
2.1. Chemistry
To synthesize desired pyrido[2,3-b]pyrazines (6a-6q), a concise synthetic route was adopted. The layout
of the synthetic route has been presented in the Scheme-1. The α-methyl group of the corresponding
acetophenone 4 was oxidized with selenium oxide to dicarbonyl intermediate 4A (27). In the next step,
the corresponding dicarbonyl intermediate 4A was coupled with pyridine-2,3-diamine 5 at room
temperature furnishing the pyridopyrazine ring system (28). The method proved to be consistent and
straight forward to assemble the pyrido[2,3-b]pyrazine core. The optimized reaction conditions were
then deployed on other acetophenone derivatives as well as cyclohexanone 7 to afford the
corresponding pyrido[2,3-b]pyrazines in 50-90% yield in a regioselective way. (29) The regioselectivity
was observed due to difference in reactivity of the aldehyde and ketone moieties within a same
molecule i.e. intermediate 4A. The structures of pyrido[2,3-b]pyrazines (6a-6q) were confirmed with
different spectroscopic techniques including 1H and 13C NMR spectroscopy, mass spectrometry (EI+, ESI+
and HRMS), IR spectroscopy (30, 31). The X-ray crystal structures of compounds 6c and 6f further
confirm the structure and regioselectivity in the pyridopyrazine analogues (Figure-2)..
Scheme-1: Synthesis of pyrido[2,3-b]pyrazine derivatives (6a-6q)
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Figure-2. X-ray crystal structures of 3′-methyl 6c and 3′-fluoro 6f pyrido[2,3-b]pyrazines
2.2. In vitro inhibitory activity of pyridopyrazine analogues against AChE and BChE
The synthetic pyrido[2,3-b]pyrazines (6a-6q) were evaluated as inhibitors against electric eel AChE and
equine BChE by following the Ellman’s procedure (26). Bioactivities results showed that most of the
compounds in the series have significant activity against both cholinesterases; AChE and BChE (Table-1).
Neostigmine (IC50 = 22.2 ± 3.2 μM for AChE and IC50 = 49.6 ± 6.11 μM for BChE) and donepezil (IC50 =
0.032 ± 0.003 μM for AChE and IC50 = 6.41 ± 0.34 μM for BChE) has been used as standard
cholinesterases inhibitors. For AChE, compound 6a without any substituents showed the least inhibitory
activity with an IC50 value of 9.65 ± 0.324 μM, while 3′-fluorophenyl 6f and 3′-nitrophenyl 6n
pyridopyrazine analogues bearing electron withdrawing substituents displayed highest inhibitory
activities among the series with an IC50 values of 0.899 ± 0.10 and 0.466 ± 0.121 μM, respectively.
Substitution of 3′-fluoro group with chloro group slightly reduced the activity of 6h to IC50 values of 1.26
± 0.022 μM. The 4′-nitrophenyl 6m derivatives also showed significant activity with IC50 values of 1.97 ±
0.02 μM. Further compounds in the series showed inhibitory activities with IC50 values ranging between
2.45 ± 0.31 μM – 5.88 ± 0.1.21 μM (Table-1).
For BChE, the 3′-methylphenyl derivative 6c bearing electron denoting substituent displayed potent
inhibitory activity with IC50 values of 0.583 ± 0.052 μM. Whereas, substituting 3′-methyl group with
electron withdrawing nitro group makes a slight decline in the activity of 6n to IC50 value of 1.89 ± 0.05
μM. The 4′-chlorophenyl 6g also displayed significant inhibitory activities with IC50 values of 2.63 ± 0.312
μM while the other chloro (6h, 6i) or fluoro 6f derivatives in the series showed weak or poor activities
against BChE. Since the compound 6n demonstrated good inhibitory activity for AChE with IC50 values of
0.466 ± 0.121 μM. So, it is consider as dual inhibitor for cholinesterases. The compound with bulky
substituent, 4′-piperidine 6p was found less active against AChE with an IC50 value 4.75 ± 0.521 μM,
while moderately active against BChE with an IC50 value 3.91±0.621 μM. This may be due to bulky
piperidine residue to accommodate at the bottom of gorge of both enzymes. A tacrine 3 (12) like
compound 6q also displayed moderate inhibitory activity against both cholinesterases (Table-1).
Summatively, the inhibitory data of synthetic compounds demonstrate that the positions, electronic
effect and size of the corresponding substituents influence the binding and π-π interaction of
pyridopyrazine derivatives (6a-6q) with targeted enzymes. The active compound 6f displayed 88 times
more selectivity for AChE inhibition. Conversely, the compound 6c showed 10 times more for BChE
inhibition (32). The selectivity of the compounds towards targeted cholinesterases inhibition added an
advantage to regulate the activity of AChE or BChE in AD therapy.
Table-1: In Vitro AChE and BChE inhibitory activities of pyrido[2,3-b]pyrazines (6a-6q).
3. Computational Studies
In the RCSB Protein Bank, X-rays structures of equine BChE are currently not available and for electric
eel AChE only low crystallographic resolution (>4 Å) structures are available (33). Therefore, X-ray
structures of human AChE (PDB ID 4BDT) and human BChE (PDB ID 4BDS) were used as template
structures for docking. The active site gorge of AChE is considerably smaller than the gorge of BChE (16,
17). For dual AChE/BChE inhibitors, this might lead to different binding characteristics. The analysis of
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AChE X-ray structures revealed multiple side chain orientations of Tyr337 depending on the co-
crystallized ligands. Accordingly, in our docking study, the side chain of Tyr337 in AChE was treated
flexibly. In BChE the corresponding residue Ala328 has no side chain flexibility and hence the entire
active site was kept rigid.
Figure-3 (left side) showed an overlay of the best AChE inhibitor 6n and the crystallographic inhibitor
huprine W. In its preferred docking pose, compound 6n is located at the bottom of the active site gorge
and almost coplanar with residues Trp86 and Tyr337, which enables of π-π-interactions. The nitro
substituent is in hydrogen bonding distance to the residue Tyr341. Two additional hydrogen bonds
might be formed between two nitrogen atoms of the pyridopyrazine ring and the hydroxyl group of
Tyr337. Although the large gorge area of AChE might also accept different binding conformations, the
predicted binding mode resembles the co-crystallized inhibitor huprine W and is further stabilized by
several well defined short range interactions.
The putative binding mode of the most potent BChE inhibitor 6c (Figure-3, right side) in the active site of
BChE differs from the pose of compound 6n in the active site of AChE. The exchange of residue Pro446
in AChE with the larger residue Met437 in BChE prevents a coplanar orientation of the pyridopyrazine
compounds in the active site of BChE. Instead, the methyl substituted phenyl substructure is directed
into a lipophilic pocket formed by residues Phe329, Leu286, Val288, Trp231, and Phe398. The
pyridopyrazine core fragment is in π-interaction distance to residues Trp82 and His438. The gorge area
of BChE is even larger than in AChE and therefore accommodates other plausible binding conformations.
However, after detailed analysis of potential short range interactions, the presented binding pose was
preferred.
With the exception of inhibitor 6p, all other pyridopyrazine derivatives presented herein are expected to
display similar binding modes as the compound 6n in AChE and 6c in BChE. In compound 6p, the
piperidine substituent is too large to be accommodated at the bottom of the gorge of both enzymes and
therefore most likely binds to the mid gorge area.
Figure-3: On the left, an overlay of the predicted binding mode of inhibitor 6n (carbon atoms colored
magenta) and the crystallographic inhibitor huprine W (carbon atoms colored yellow) in the active site
of AChE (cyan) is shown. On the right, the putative binding conformation of inhibitor 6c (carbon atoms
colored green) in the active site of BChE (orange) is shown.
4. Conclusion:
The bioactivity data of pyrido[2,3-b]pyrazines 6a-6q and molecular docking concluded that some of
these derivatives exhibited good inhibitory activity against AChE and BChE. Compound 6n with an IC50
value of 0.466 ± 0.121 μM for AChE and 1.89 ± 0.05 μM for BChE may serve as dual inhibitor. Compound
6f showed selective inhibition for AChE with an IC50 value of 0.899 ± 0.10 μM and compounds 6c
displayed selective inhibition for BChE with an IC50 value of 0.583 ± 0.052 μM. The potential leads found
in anticholinesterase assay can be used to develop new therapeutic agents for AD therapy.
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Conflict of Interest
The authors have declared no conflict of interest.
Acknowledgement:
We are thankful to Higher Education Commission (HEC), Pakistan (Project No. 20-1910 under NRPU).
N.F. is supported by a fellowship from the Jürgen Manchot Foundation, Düsseldorf, Germany.
Supplementary Information
The supplementary information has the scanned copies of 1H NMR spectra and X-ray crystallographic
data of crystal structures 6c and 6f. CCDC number of 6c 1033368 and 6f 1033369, respectively, contains
these supplementary crystallographic data. The data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by e‐mailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(0)1223‐336033.
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