Synthesis and biological evaluation of ranitidine analogs as multiple-target-directed cognitive enhancers for the treatment of Alzheimer's disease

Article abstract of DOI:10.1016/j.bmcl.2016.09.072

Using molecular modeling and rationally designed structural modifications, the multi-target structure–activity relationship for a series of ranitidine analogs has been investigated. Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties provide optimal interactions with the hydrophobic and π–π interactions with the peripheral anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives were the most potent analogs and other key determinants were revealed. In addition to improving AChE activity and chemical stability, structural modifications allowed determination of binding affinities and selectivities for M1–M4 receptors and butyrylcholinesterase (BuChE). These results as a whole indicate that the 4-nitropyridazine moiety of the JWS-USC-75IX parent ranitidine compound (JWS) can be replaced with other chemotypes while retaining effective AChE inhibition. These studies allowed investigation into multitargeted binding to key receptors and warrant further investigation into 1,8-naphthalimide ranitidine derivatives for the treatment of Alzheimer's disease.

Full text of DOI:10.1016/j.bmcl.2016.09.072

Accepted Manuscript
Synthesis and Biological Evaluation of Ranitidine Analogs as Multiple-target-
directed Cognitive Enhancers for the Treatment of Alzheimer’s Disease
Jie Gao, Narasimha Midde, Jun Zhu, Alvin Terry, Campbell McInnes, James
Chapman
PII:
S0960-894X(16)31021-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.09.072
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Bioorganic & Medicinal Chemistry Letters
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2 September 2016
28 September 2016
Please cite this article as: Gao, J., Midde, N., Zhu, J., Terry, A., McInnes, C., Chapman, J., Synthesis and Biological
Evaluation of Ranitidine Analogs as Multiple-target-directed Cognitive Enhancers for the Treatment of
Alzheimer’s Disease, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.
2016.09.072
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Bioorganic & Medicinal Chemistry Letters
Synthesis and Biological Evaluation of Ranitidine Analogs as Multiple-target-
directed Cognitive Enhancers for the Treatment of Alzheimer’s Disease
Jie Gao1, 2, Narasimha Midde1, Jun Zhu1, Alvin Terry2, Campbell McInnes1, James Chapman1.
1 Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
2Department of Pharmacology and Toxicology, Augusta University, Health Sciences Campus, CB-3530, 1459 Laney Walker Blvd., Augusta, GA 30912
Corresponding Author: Campbell McInnes: E-mail: mcinnes@sccp.sc.edu; Phone: (803) 576-5684
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Using molecular modeling and rationally designed structural modifications, the multi-target
structure-activity relationship for a series of ranitidine analogs has been investigated.
Incorporation of a variety of isosteric groups indicated that appropriate aromatic moieties
provide optimal interactions with the hydrophobic and π-π interactions with the peripheral
anionic site of the AChE active site. The SAR of a series of cyclic imides demonstrated that
AChE inhibition is increased by additional aromatic rings, where 1,8-naphthalimide derivatives
were the most potent analogs and other key determinants were revealed. In addition to
improving AChE activity and chemical stability, structural modifications allowed determination
of binding affinities and selectivities for M1-M4 receptors and butyrylcholinesterase (BuChE).
These results as a whole indicate that the 4-nitropyridazine moiety of the JWS-USC-75IX parent
ranitidine compound (JWS) can be replaced with other chemotypes while retaining effective
AChE inhibition. These studies allowed investigation into multitargeted binding to key receptors
and warrant further investigation into 1,8-naphthalimide ranatidine derivatives for the treatment
of Alzheimer’s disease.
Keywords:
cyclin dependent kinase
protein-protein interaction
cyclin groove
REPLACE
inhibitor
2009 Elsevier Ltd. All rights reserved
Alzheimer’s disease (AD) is the most common type of dementia
in the elderly and currently there is no preventive or curative
treatment available for the disease1. A major symptom of AD is
cognitive dysfunction with the pathological decline of
AChEIs) could have pro-cognitive effects as well disease-
modifying properties by inhibiting A aggregation in AD17.
Moreover, during the progression of AD, cortical levels of
BuChE are significantly increased and found within lesions that
contain amyloid plaques and neurofibrillary tangles, suggesting
that the enzyme might participate in the formation of these
cholinergic neurotransmission2.
Most of the current
pharmaceutical treatments for AD are AChE inhibitors with
donepezil (Figure 1) being the only treatment approved by the
FDA for all stages of Alzheimer’s disease.3,4 Unfortunately,
currently approved drugs have been found to benefit only about
half the individuals who take them and to only temporarily
decrease symptoms4. It has been gradually unveiled that
cognitive dysfunction is multifactorial in nature5-6 and that in
addition to AChE, other cholinergic targets such as
butyrylcholinesterase (BuChE)7-8, muscarinic (M1-M4)9-10 and
several nicotinic acetylcholine receptors11-12 are simultaneously
involved in cognitive functioning. Targeting BuChE (in addition
to AChE) should be advantageous in the context of AD since
AChE levels go down while BuChE levels go up as the disease
progresses8. Furthermore, in the AD brain, increasing levels of
lesions.
These observations indicate a potential disease
modifying effect of compounds that inhibit BuChE18.The
muscarinic receptors are likely also significant as M2 selective
antagonists have been hypothesized to be useful when given in
conjunction with an AChE inhibitor to ameliorate the cognitive
and psychotic symptoms inherent in the disease19, an important
observation since more than half of patients with AD also suffer
from psychotic symptoms in addition to severe cognitive
deficits20. Targeting the M2 receptor in particular is desirable
since it is an autoreceptor that functions to diminish ACh
release9-10. In addition some studies suggest that the M1 and M3
rceptors are desirable AD targets and recently their cysrtal
structures have been solved21.
AChE and BuChE correlate with the development of amyloid
Cavalli A et al22 presented the terminology “multi-target-directed
ligands” (MTDLs) to describe single compounds “that are
effective in treating complex diseases through their ability to
interact with the multiple targets thought to be responsible for
disease pathogenesis”, an important concept considering the
multiple AD drug targets outlined above. The potential
advantages of MTDLs relative to multiple single target
13-14
plaques and neurofibrillary tangles8,
.
It has been
hypothesized that AChE binds through its peripheral site to the
nonamyloidogenic form of A and acts as a pathological
chaperone inducing
a
conformational transition to the
amyloidogenic form 15-16. Accordingly, compounds that have the
ability to bind and inhibit both the catalytic anionic site (CAS)
and peripheral anionic site (PAS) of AChE (dual binding site

formulations are that they avoid possible drug interactions with
other active components and also offer a single and therefore less
complex pharmacokinetic and ADMET profile during clinical
development23. In addition, MTDLs could also simplify
therapeutic regimens and improve compliance, an important
consideration, especially for cognitively impaired patients. Thus,
MTDLs might present an effective avenue to provide optimal
therapeutic effects for the treatment of cognitive and behavioral
dysfunction in AD23.
nonpolar amino acid residues: 2) cation-π interactions between
the dimethylammonium group and Trp 86 at the CAS, 3) π-π
interactions between rings at both ends of the molecules in this
series and aromatic residues located at the PAS; 4) hydrogen
bonds between key substituents (eg. N(CH3)2, NO2) and polar
residues at the PAS.
Since plausible binding modes were generated for JWS and
donepezil in complex with AChE, these were further
superimposed and a comparison of non-bonded interactions made
(Figure 1 bottom panel). JWS was found to have a pattern of
binding to AChE similar to that of donepezil, which suggests that
it may have similar pharmacological function to one of the most
potent AChE inhibitors and widely used agents among the few
approved pharmaceutical treatments for AD.
Previous studies reported that JWS (Figure 1) targets both AChE
(IC50 = 470 nM) and M2 receptors (IC50 = 60 nM) concurrently24-
26. This compound has been also shown to improve information
processing, attention, and memory in rodents and nonhuman
primate models and therefore could potentially treat the cognitive
and behavioral symptoms of AD26. These data support JWS as a
prototypical representative of a novel class of MTDLs for the
therapy of cognitive dysfunction. The objective of this study is to
explore structure-activity relationship of the JWS core structure
and to further modify and optimize this series as a MTDL.
Synthesis
and
evaluation
of
N-(2-(((5-
ethyl)-4-
((dimethylamino)methyl)furan-2-yl)methyl)thio)
nitropyridazin-3-amine (JWS) and analogs:
Previous studies have demonstrated that the 4-nitropyridazine
moiety of JWS is critical to both its AChE inhibitory activity and
also for its selectivity for muscarinic receptors24. As a result of
this observation, this group was selected for optimization to
obtain more potent MTDLs. As shown in Figure 2, docking
studies strongly suggest that the 4-nitropyridazine moiety binds
to the PAS of AChE and that favorable van der Waals and π-π
stacking interactions between the pyridazine ring and Trp286
and/or Tyr72 contribute to binding of JWS and AChE.
Docking of JWS into AChE
In order to guide the structural modification of ranitidine analogs,
molecular docking protocols were utilized to predict binding
interactions of this series and use this information to discover
new chemical entities with an optimal multifunctional activity
profile. Since JWS was initially synthesized as an AChE inhibitor
and as crystal structures for this drug target are widely available,
a protocol for docking ligands into the AChE crystal structure
(PDB: 2H9Y)27 was validated and conformations for JWS and
donepezil bound to the active site generated (Figure 1).
Figure 2. Left Panel: The interactions (green lines) between the pyridazine
group of JWS and the PAS of AChE. Right Panel: The binding conformation
of compound 10 (R1 is methyl, R2 is phenyl) illustrating additional
complementarity with Trp286.
Therefore, in order to further enhance the van der Waals contacts
between the pyridazine ring and the PAS, it was reasoned that
substitution of the ring with alkyl or aromatic groups might be
effective. In addition, replacement of the pyridazine with
isosteric ring systems was evaluated in order to explore structural
variability and impact on π-π stacking interactions with the PAS.
The synthesis and in vitro evaluation of such JWS analogs as
potential cholinesterase inhibitors and muscarinic antagonists is
reported to explore progress towards next generation MTDL as
AD therapeutics.
Figure 1. Chemical structures (top panel) and predicted binding modes of
donepezil (left) and JWS (right) generated by molecular docking. The bottom
panel illustrates superposition of the binding modes of both compounds.
The docking results obtained for JWS reveal that the
dimethylamino group binds to the CAS, a key site of interaction
previously observed to be necessary for potent AChE inhibition
(Figure 1).
Since this group would be protonated at
physiological pH it would therefore mimic the binding of the
quaternary amine group in AChE with the CAS. The binding
mode generated illustrates a variety of non-bonded interactions
involved in the inhibition of ranitidine analogs to AChE, and in
particular, emphasize the importance of the following: 1) van der
Waals interactions between hydrophobic components and

further potential of these compounds as AD therapeutics, blood
brain barrier penetration prediction was undertaken for each of
the lead series. Of the most active compounds in Table 1, JWS
and compound 10 were both predicted to have good BBB
permeability (AdaBoost_MACCSFP BBB score of 0.558 and
0.934 respectively; See the supplementary information for more
details).
Synthesis and evaluation of JWS analogs containing
pyridazine isosteres. An interesting observation from this study
was that 4-nitropyridazine analogs, including JWS, undergo a
The procedure used for the synthesis of JWS analogs was
adapted from that previously described24 and is shown in Scheme
1. In all cases, the formation of the 2-((5-
((dimethylamino)methyl)furan-2-yl)methylthio)ethanamine
backbone was accomplished through a Mannich reaction to
generate intermediate 1 prior to substitution of the hydroxyl
group with 2-thioethanolamine in concentrated hydrochloric acid
to yield 2. Substitution of the two thiomethyl groups of 1,1-
bis(methylthio)-2-nitroethylene was accomplished by reaction
with compound 2 to generate intermediate 3, followed by
reaction with hydrazine, to provide compound 4. A set of
pyridazine analogs (compound 5-13) were synthesized utilizing
the cyclization of the resulting hydrazine derivative, 4 with
various diones. The activities of these 4-nitropyridazine analogs
of JWS are summarized in Table 1. Compounds were evaluated
in AChE25, 28, BuChe25, 28 and M1 – M4 assays 29-30 (For Tables 1-
3, 1 M compound was tested) as previously described. JWS
analogs 5-7 possess small aliphatic groups at R1 and R2 and
these were found to decrease activity. Compounds 8-13 contain
phenyl substituted pyridazines and possess similar or better
degree of chemical decomposition (estimated at about 10% after
6 months) as evidenced by the appearance of a new H-NMR
1
peak and a color change. Further analysis using HPLC-MS and
followed by NMR, determined the primary impurity to be the
product of replacement of the nitro with a hydroxyl group.
Pharmacological testing of the purified hydroxyl compound
revealed no AChE or M2 antagonist activities and therefore,
nitropyridazine derivatives were tested for other activities
immediately following synthesis. This observation led to the
synthesis of compounds 14-18 (Scheme 2) which incorporate
pyridazine isosteres in order to improve chemical stability.
AChE inhibition than JWS, in particular compounds 10 (IC50
=
0.16µM) and 12 (IC50 = 0.19 µM) which increase the AChE
inhibition almost 3-fold relative to the unsubstituted
nitropyridazine. Comparison of the combination of the single
phenyl ring with either a hydrogen or small alkyl substituent at
the two positions vs. those with a phenyl ring at R1 and R2
produced consistent SAR data. The R1 phenyl was tolerated in
each case without significantly affecting activity (JWS vs. 9) and
the phenyl ring at R2 in both cases resulted in more effective
AChE inhibition (compare 7 and 8; 11 and 12). The predicted
binding mode of 10 (Figure 2), the most potent AChE inhibitor,
indicates that the phenyl ring at R2 increases the π-π stacking
interactions with Tyr72 and Trp286 at the PAS of AChE
resulting in improved inhibitory activity. Addition of thiophene
groups at both R1 and R2 led to a slight increase in AChE
activity compared to JWS however to a lesser degree than the
corresponding phenyl substitutions. None of the pyridazine
substitutions however, provide improvements in antagonist
activity for the muscarinic M2 receptor relative to the JWS
parent compound. Respectable levels of activity were observed
however for compounds 5, 7 and 10. The higher levels of M2
activity are favored by a methyl group at R1 or R2 as seen in
these compounds. Generally speaking, a bulky substituent at R1
leads to decreased potency on M2. Interestingly the presence of
two phenyl substituents led to increased M3 activity and slightly
decreased M2 activity (compare 12 vs. 10). In order to assess the

Table 2. JWS analogs with different aromatic groups at site A and their multiple activities
AChE
(IC50µM) (IC50µM)
BuChE
M1(%)a
56.2
Compound
R
M2(%)
50.8
M3(%)
24.3
M4(%)
24.9
14
16.18
5.34
10.41
>50
7.65
8.36
>50
15
16
17
18
19
n.t.
25.2
69.9
57.4
72.1
n.t.
9.8
n.t.
2.3
n.t.
7.7
>50
72.8
71.3
54
49.8
30.1
41.5
42.7
43.6
47.7
>50
>50
4.04
21.18
20
1.18
2.96
88.5
67
66.6
62.3
21
22
23
1.65
>50
>50
7.1
>50
88.8
37.5
n.t.
81
-19
n.t.
90.4
18.5
n.t.
92.1
4.2
47.21
n.t.
24
>50
>50
n.t.
n.t.
n.t.
n.t.
25
26
>50
>50
77.4
60.1
50.8
27.4
69.6
43.5
33.8
47.3
5.01
7.65

inhibAs shown in Table 2, the AChE inhibitory activities of
compound 14-18 decreased (IC50 > 5µM) compared to the
activity of JWS, suggesting that the nitropyridazine group is a
critical binding determinant. Compound 16 (chloropyridazine)
possessed an IC50 value of 10.41µM for AChE, which is similar
to that of the pyrimidine containing compound 14. These results
indicate that functional groups with hydrogen bond acceptors
might be favorable for effective AChE inhibitory activity since
the nitro group appears to be a critical determinant. This
prediction was further corroborated by docking results (Figure 3
left panel). One of the oxygen atoms in the NO2 group interacts
with Arg296 via a hydrogen bond contributing to its ligand-
enzyme binding at the PAS of AChE. Therefore, compounds 19-
26 with different hydrogen bond acceptor groups were
synthesized using routes described in Schemes 2 and 3.
none of the analogs had activity for the muscarinic acetylcholine
receptors (data not shown). According to its predicted AChE
binding mode (Figure 3, right panel), the 3-nitro-1,8-
naphthalimide group binds to the PAS through various
interactions including two hydrogen bonds, (NO2 interaction with
Tyr72 and one of the imide carbonyl groups has contacts with
Arg296) while the napthyl ring system provides π-π stacking
interactions with Trp286.
The model structures generated through docking indicate that
these structural characteristics contribute to the potent AChE
inhibitory activity and moderate BuChE inhibition of the
napthalimide series and as before an aromatic nitro group is a key
binding determinant. Compared to donepezil (IC50 = 0.050 M),
compound 33 is only 3 fold less active and is the most potent
compound in the entire series of JWS analogues. While these
compounds possess improved AChE inhibitory activities, the
napthalimide modification results in diminished binding affinities
for M1-M4 receptors compared to JWS. These results also
indicate that while the 5,6 position on the 4-nitropyridazine
moiety of JWS may not be necessary for AChE inhibition, it is a
critical determinant for potent and selective binding to the M2
Table 3. JWS analogs containing cyclic imide groups
Figure 3. Left Panel: The interactions of the 4-nitropyridazine group of JWS
showing the hydrogen bond interaction of the critical nitro group. Right
Panel: The binding mode of the 1,8-napthamimide derivative 33 illustrating
the pi-pi interactions with Trp 286 and the hydrogen bonds of the nitro group.
AChE
(IC50µM)
Compound
R
BuChE (IC50µM)
>50
The resulting structural modifications of the JWS parent led to
more stable chemical entities and produced varying effects on
AChE inhibition. Of this series, compounds 19-21 had the
highest levels of AChE inhibition as indicated by low
micromolar IC50 values. These derivatives all contain a nitro
group again pointing to its critical role in binding to the PAS. A
significant observation resulted from the testing of compounds 20
and 21 which possessed respectable M1-M4 activity and in
particular 21 had almost complete inhibition of all of these at 1
M. This demonstrated that compound 21 would be a useful tool
compound for probing the effects of inhibiting M1-M4 and
AChE simultaneously. Compound 20, the most potent AChE
inhibitor was not predicted to have efficient penetration of the
BBB however (AdaBoost_MACCSFP BBB score of -3.906).
27
11.82
>50
14.46
>50
28
29
30
31
32
33.39
3.57
3.34
46
Synthesis and evaluation of JWS analogs containing cyclic
imide isosteres.
Further to the synthesis and testing of the pyridazine isosteres
shown in Table 2, a series of cyclic imide groups were
incorporated onto the amine of compound 2 (Scheme 3, Table 3).
These include N-substituted succinimides (27, 28), pthalimides
(one phenyl ring; 29, 30, 31), and also 1,8-naphthalimides (two
fused phenyl rings; 31, 32). There is a general trend among these
analogs for potency enhancement as the size of the pyrimidine
replacement increases. The succinimide analogs are 5 to 10 fold
less potent than the larger pthalimides with the 4-nitro (30) and
the unsubstituted (29) pthalimides being the most active with low
micromolar IC50 s. The 5-nitro (31) however was considerably
less active having a 46 M inhibition constant. As mentioned
above, the 1,8-naphthalimides were the most potent of the cyclic
imide series with the 3-nitro derivative, 33 delivering the most
effective AChE inhibition (IC50 = 0.15 M) while also possessing
good levels of BuChE inhibition (IC50 = 8.01 M). Surprisingly
>50
7.21
1.27
33
0.15
8.01

6.
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Of particular note, replacement of the 4-nitropyridazine moiety
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Acknowledgments
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We thank Drs. Michael Walla and William Cotham in the
Department of Chemistry and Biochemistry at the University of
South Carolina for assistance with Mass Spectrometry and Helga
Cohen and Dr. Perry Pellechia for NMR spectrometry. This work
was supported by the NIH grant RO1DA035714.
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Supplementary Material
Supporting Information consists of full synthetic procedures
used, characterization data for compounds made and further
details on the computational experiments that were carried out.

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Synthesis and Biological Evaluation of Ranitidine
Analogs as Multiple-target-directed Cognitive
Enhancers for the Treatment of Alzheimer’s Disease
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Jie Gao, Narasimha Midde, Jun Zhu, Alvin Terry, Campbell McInnes, James Chapman.
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