The structural simplification of lysergic acid as a natural lead for synthesizing novel anti-Alzheimer agents

Article abstract of DOI:10.1016/j.bmcl.2021.128205

Alzheimer's disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation of damaged proteins β-amyloid (Aβ) and hyperphosphorylated tau outside and inside neurons, respectively. Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study, sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the synthesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was ULK-1 which has a significant role in autophagy.

Full text of DOI:10.1016/j.bmcl.2021.128205

Bioorg. Med. Chem. Lett. 47 (2021) 128205
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The structural simplification of lysergic acid as a natural lead for
synthesizing novel anti-Alzheimer agents
a
b
b
b
Muhammed Alzweiri , Amsha A. Alsegiani , Endri Karaj , Daniyah A. Almarghalani ,
a
b
b,*
Yahia Tabaza , Zahoor A. Shah , L.M. Viranga Tillekeratne
a
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
b
Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43606, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
Alzheimer’s disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality
by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to
carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other
mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation
of damaged proteins β-amyloid (Aβ) and hyperphosphorylated tau outside and inside neurons, respectively.
Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid
structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study,
sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were
carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently
cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and
anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the syn-
thesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed
with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling
were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was
ULK-1 which has a significant role in autophagy.
Alzheimer
Structural simplification
Lysergic acid
Neuroprotection
Alzheimer’s (AD) is a neurodegenerative disease, considered to be
the most prevalent form of dementia.1 It affects mostly elderly people,
ages 65 years and over, in sporadic type of AD. The number of people
expected to show AD manifestations is speculated to exceed 130 million
by 2050. In 2015, the health care cost of AD was approximated to be
phosphorylated tau, synaptic dysfunction, hormonal imbalance and a
2
cascade of inflammatory responses. Oxidative stress is also a possible
etiological factor of AD.1 In 2000, it was noticed that people who
consumed nonsteroidal anti-inflammatory drugs for various inflamma-
5
tory diseases had less incidence and prevalence of AD. Therefore,
$
818 billion.2 Moreover, by 2040 neurodegenerative diseases are sup-
blocking inflammatory signaling was cited as a therapeutic strategy
3
6,7
posed to be the second leading cause of mortality. With the increase in
life expectancy, the world is very prone to encounter a dementia
against AD. Microglia play an essential role in regulating the plasticity
of the synapse, surveying the neurons from pathogen intrusions, clean-
ing the damaged cells by phagocytosis and facilitating remodeling of
neuronal circuits. However, the excessive activity of microglia might
idiosyncratically lead to neuronal loss due to aberrant induction of
inflammation.4 Activated microglia release nitric oxide (NO), tumor
3
epidemic in the near future. The most recognizable features of AD are
accumulations of amyloid plaques consisting of β-amyloid (Aβ peptide)
outside neurons and aggregates of neurofibrillary tangles resulting from
hyper-phosphorylation of tau protein inside the neurons.1 Histological
examination of autopsy brain specimens revealed that the amyloid
plaques not only consisted of proteins, but also glial cells such as
microglia.4
The exact mechanism of AD is still ambiguous.3 Pathology of AD is
attributed to mitochondrial damage, accumulation of Aβ,
necrosis factor-alpha (TNF ) and other pro-inflammatory cytokines
α
8
causing a disruption of mitochondria and inducing apoptosis. Inflam-
mation is a key factor for several CNS diseases such as stroke, multiple
sclerosis, Parkinson and AD.8
One of the newly introduced mechanism of neuroinflammation is
*
Corresponding author.
E-mail address: ltillek@utnet.utoledo.edu (L.M.V. Tillekeratne).
https://doi.org/10.1016/j.bmcl.2021.128205
Received 30 March 2021; Received in revised form 6 June 2021; Accepted 11 June 2021
Available online 15 June 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

M. Alzweiri et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128205
Fig. 1. Structural simplification of lysergic acid to guide the synthesis of
simpler anti-Alzheimer agents.
endoplasmic reticulum (ER) stress, which might prove to be a potential
target in treating neurodegenerative diseases.9,10 ER is responsible for
Fig. 2. The synthesized compounds.
secretory and membrane protein modifications including folding and
post-translational alterations.1
1,12
A change in the lumen of ER
including the level of calcium and folding capacity of chaperone proteins
may trigger protein misfolding, which could be solved by unfolding
1
3,14
protein response (UPR).
If UPR does not work properly then
apoptosis commence through a cascade of inflammatory responses
attributed to ER stress.1 Chemicals that induce ER stress include;
tunicamycin which interferes with protein glycation during the post-
translational modification and thapsigargin which disrupts ER calcium
5
1
6,17
levels.
Lipopolysaccharide (LPS) as a flammogen triggers ER stress
and also induces cellular pro-inflammatory cascade after binding to a
1
8
membrane receptor called TLR4.
One of the promising lead compounds in the treatment of AD is
lysergic acid. It is an ergot alkaloid extracted from rye fungus Claviceps
purpurea.19 Ergot alkaloids are used in improving mental recognition
and other symptoms related to AD.2 For example, the FDA-approved
0
ergot derived drug, ergoloid mesylates (Hydergine®), bestows small
measurable improvements in the treatment of AD.2
1,22
Nicergoline
(
Sermion®) is another ergoline alkaloid that is currently used for senile
2
3
dementia. Ergot alkaloids are assumed to enhance the blood flow to
the brain and modulate the neurotransmitter function.23 However, there
is still a lack of effective AD medications and therefore, developing more
efficacious and safe candidates is crucial.2
4,25
Several analogues of lysergic acid were synthesized by adopting a
structural simplification strategy. Their neuroprotection and anti-
inflammatory properties as well as their potential in inhibiting acetyl-
cholinesterase were evaluated. Moreover, the neuroprotective efficacy
of the compounds was assessed in silico against known molecular targets
involved in AD and then compared using in vitro assays.
Scheme 1. Synthesis of compounds using methyl acrylate in Heck coupling.
acceptor such as carbonyl group and an ammonium head for steering the
compound towards its receptor, connected by a spacer such as a benzoid
nucleus. Using lysergic acid as a model of ergot-derived compounds,
carbonyl group containing moieties such as ester were incorporated into
some analogues and an amide group was introduced in others to
improve the drugability of the compounds. Analogues lacking ammo-
nium head were also tested to obtain a better insight of the role of basic
nitrogen on activity as the loss of ionization may enhance some kinetic
properties such as penetration of blood–brain barrier (BBB). Moreover,
compounds without basic functionality may lead to activity against
targets other than acetylcholinesterase. While some of the analogues
preserved the ergoline ring system, structure simplification also
involved trimming down the fused tetracyclic ring of ergoline to simpler
bicyclic indole system in some of the synthesized analogues. Addition-
ally, shortening the distance between the basic nitrogen and the indole
ring may affect activity; Castle and Whittle found that increasing the
distance between the basic nitrogen and the indole ring failed to produce
Since lysergic acid derivatives are well known as anti-AD agents (e.g.
FDA approved drug Hydergin®), they were adopted here as lead com-
pounds for designing new potential anti-AD agents. Structural simplifi-
cation as a drug design approach was used to rationalize the synthetic
targets. Structural simplification is generally used to reduce the molec-
ular complexity of natural products. Additionally, simplifying chemical
structure may enhance both efficacy and pharmacokinetic properties of
compounds, and may lead to analogues with reduced undesirable side
effects as exemplified by morphine analogues methadone and pethidine
that are derived by the simplification of morphine structure. The pro-
posed analogues were designed by the simplification of lysergic acid
skeleton while preserving some components of acetylcholine esterase
inhibitor pharmacophore (Fig. 1). The synthetic intermediates as well as
synthesis byproducts were also subjected to biological testing to expand
the structure–activity relationship profile.
2
6,27
SAR of acetylcholine esterase inhibitors revealed a hydrogen bond
biologically active compounds in derivatives of lysergic acid,
2

M. Alzweiri et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128205
Scheme 2. Synthesis of compounds using acrylamide in Heck.
Scheme 3. Synthesis of non-carbonyl containing compounds.
100
*
*
50
0
Fig. 3. Proposed catalytic cycle mediated by an anionic Pd(0) complex formed
from palladium (0) and palladium (II). The anionic form of the complex may
enhance the stability and the nucleophilicity of the catalyst towards the aryl
halide reactant in the oxidative addition step. The rest of the cycle includes
other elements of catalytic cycle; migratory insertion and reductive elimination.
Fig. 4. Percentage viability of PC12 cells under oxygen and glucose deprived
(OGD) conditions and treated with varying concentrations of donepezil. Con-
centrations which caused significant differences at a p-value ≤ 0.05 compared
with the reference (OGD/R) are marked with (*).
whereas reducing this distance to one carbon length depicted strong
biological activity and toxicity.28 Another example is gramine, which
has one carbon atom distance between its basic nitrogen and indole ring
and possesses activity against AD.2 It is conceivable that activity of
gramine derivatives may be due to generation of a reactive electrophilic
species upon loss of amine function.
1
00
*
ns
9
5
0
*
Altogether, sixteen analogues were synthesized of which six; namely
M5, M8, M11, M12, M14 and M16 (Fig. 2) are novel compounds and a
few; M2, M9 and M13 are commercially available. The analogues M3
and M5 were designed by dissecting the alicyclic rings of lysergic acid
and reducing the distance between the basic amine and indole by one
carbon atom. It has been reported that amide and ester modification of
carboxylic acid in other lysergic acid analogues affords CNS activity.3
Therefore, carboxylic acid conversion to simple ester or amide led to M1,
M3, M4, M5, M6, M7, M8 and M15. The analogues without a basic
functional group were designed to prepare a diverse set of compounds
for a comprehensive understanding of SAR. The synthesis involved as
key reactions Heck coupling used to introduce the hydrogen bond
acceptor such as ester or amide group and Mannich reaction to introduce
the basic amine fragment (Scheme 1). Michael addition of
nitromethane-derived carbanion was employed to build the precursor
for cyclisation. Potentially toxic nitro was reduced to amine using zinc
dust in acidic medium.
0
0,31
Fig. 5. Percentage viability of PC12 cells grown in oxygen and glucose (OGD)
deprived conditions and treated with 1 µM of test compounds. Compounds that
showed significant differences compared to donepezil (DPZ) at a p-value ≤ 0.05
are asterisked.
enormously (>90%) when a mixture of Pd(II) and Pd(0) catalysts was
used (Fig. 3). This remarkable reactivity when a combination of Pd(0)
and Pd(II) catalysts was used maybe explained as due to rate enhance-
32
ment through the generation of an anionic Pd(0) intermediate (Fig. 3)
.
Heck reaction was carried out by heating the reaction mixture in a
microwave synthesizer and gave 85% yield when methyl acrylate was
used as olefin coupling partner (Scheme 1). Heck reaction with acryl-
amide gave low yields (<30%, Scheme 2) when several Pd(II) and Pd(0)
catalysts were used individually. Interestingly, the yields increased
The anionic Pd(0) complex formed is more nucleophilic and drastically
enhances the rate of the oxidative addition step in the catalytic cycle.
Moreover, the generated ionic Pd(0) complex increases the stability of
the catalytically active Pd(0) state. Eventually, the introduction of
nitromethane anion, followed by reduction of the nitro group with zinc
3

M. Alzweiri et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128205
#
#*
#
*
100
100
*
*
*
*
*
*
*
50
50
0
#*
0
LPS+1µM each compound
LPS+1µM
Fig. 6. Percentage of cell viability after inducing inflammation in SIM-A9 cell
line with lipopolysaccharides (LPS) and treating with 1 µM concentration of
each compound. (#) denotes significant difference between each group and LPS
group, and (*) refers to a significant difference in comparison with donepezil
Fig. 8. Nitric oxide (NO) release from microglial SIM-A9 cell line after treat-
ment with LPS and 1 µM from each compound. (#) denotes significant differ-
ence between each group and LPS whereas asterisked groups are significantly
different than Donepezil (DPZ).
(
DPZ). P-Value ≤ 0.05.
1
500
000
*
#*
*
100
#
1
*
50
500
0
0
TCN+1µM
Fig. 9. Acetylcholinesterase inhibition activity compared to Donepezil (DPZ).
M3, M5 and M15 are not significantly different than donepezil (DPZ) at p-value
Fig. 7. Percentage of cell viability after exposing PC12 cells to tunicamycin
≤
0.05 at a concentration of 1 µM for each.
(
TCN) and treating cells with 1 µM of tested compounds. (#) denotes significant
difference between each group and TCN group, whereas (*) refers to a signif-
icant difference of each group in comparison with Donepezil (DPZ). P-Value
nitro containing compound M11. Interestingly, it has been reported that
≤
0.05.
some nitro compounds acted as neuroprotective agents in ischæmic
animal models due to the lowering of NO levels.3
3,34
On the other hand,
dust and acid were carried out (Scheme 3).
the nitro group has an intrinsic inflammatory effect through the gener-
ation of reactive oxygen species.35 The neuroprotective activity and the
lack of anti-inflammatory effect of M11 are consistent with these
findings.
The neuroprotective properties of synthesized compounds were
assessed using cellular assays and anti-AD drug donepezil (DPZ) was
used as the positive control. In an initial screening to determine a suit-
able concentration for testing, the lowest concentration at which DPZ
exhibited significant neuroprotection in neuronal cell line under oxygen
Interestingly, M5 and M8 are significantly potent than DPZ. In order
to gain a deeper insight into the anti-inflammatory mechanisms, the
compounds were further tested in two other assays, one using the
neuronal cell line (PC12), and the other using the microglial cell line
(SIM-A9). ER stress was used to determine the anti-inflammation effects
of the compounds (Fig. 7).
and glucose-deprived conditions (OGD) was 0.1
the compounds were initially screened for neuroprotective activity at a
0-fold higher concentration of 1 M with DPZ as the positive control
Fig. 5). All compounds were screened in each assay, but only the most
μM (Fig. 4). Therefore,
1
μ
(
active ones were included in the plots for clarity. Six analogues; M3, M5,
M6, M8, M9 and M11showed neuroprotective activity comparable with
that of DPZ. The analogues M3, M5, M9 have basic amine group, while
the analogues M3, M5, M6 and M8 are structurally similar. Interestingly,
the analogues M3, M5 and M8 share common structural features with
lysergic acid. Some of nitro/bromine containing compounds, M6, M9
and M11 show neuroprotective effects as well. To further evaluate their
biological activity, the compounds were tested for anti-inflammatory
properties.
The neuronal PC12 cell line was challenged with tunicamycin (TCN)
to induce ER stress and treated with 1
μM of each compound. A
remarkable activity in increasing cell viability was observed. More
interestingly, the analogues M3, M5, M6, M8, M9 and M11 were more
potent than DPZ. Microglia have a significant role in the induction of
neuroinflammation with a mechanism related to increasing oxidative
stress. Microglial cells first challenged with LPS, release NO, which leads
to inflammation. As shown in Fig. 8, the tested compounds showed
significant differences in the ability to reduce NO release from the cells,
compared to the untreated group. Once more, the analogues structurally
related to lysergic acid, namely M3, M5, M8 and M9, were more potent
than DPZ in reducing NO release from microglia.
Interestingly, the cell line, which was first challenged with LPS,
significantly recovered after treatment with compounds M3, M5 and
M8, which have close structural resemblance to lysergic acid (Fig. 6). As
seen in the Fig. 6, all of the tested compounds were effective except the
Most of the analogues possessed structural components required for
4

M. Alzweiri et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128205
Acknowledgments
This study was supported by NIH grants R15CA213185 to L.M.V.T
and R01NS112642 to ZAS, and the American Heart As-sociation grant
0.5
1
7AIREA33700076/ZAS/2017 to ZAS. The authors thank the Fulbright
0
Program for a Visiting Scholar Award to MHA.
-0.5
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128205.
-1
-1.5
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