Ugi Reaction Synthesis of Oxindole-Lactam Hybrids as Selective Butyrylcholinesterase Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.1c00344

Molecular hybridization is a valuable approach in drug discovery. Combining it with multicomponent reactions is highly desirable, since structurally diverse libraries can be attained efficiently in an eco-friendly manner. In this work, isatin is used as the key building block for the Ugi 4-center 3-component reaction synthesis of oxindole-lactam hybrids, under catalyst-free conditions. The resulting oxindole-β-lactam and oxindole-γ-lactam hybrids were evaluated for their potential to inhibit relevant central nervous system targets, namely cholinesterases and monoamine oxidases. Druglikeness evaluation was also performed, and compounds 4eca and 5dab exhibited great potential as selective butyrylcholinesterase inhibitors, at the low micromolar range, with an interesting predictive pharmacokinetic profile. Our findings herein reported suggest oxindole-lactam hybrids as new potential agents for the treatment of Alzheimer's disease.

Full text of DOI:10.1021/acsmedchemlett.1c00344

pubs.acs.org/acsmedchemlett
Letter
Ugi Reaction Synthesis of Oxindole−Lactam Hybrids as Selective
Butyrylcholinesterase Inhibitors
́
̃
̃
Pedro Brandao, Oscar López, Luisa Leitzbach, Holger Stark, José G. Fernández-Bolanos,
Anthony J. Burke, and Marta Pineiro*
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ABSTRACT: Molecular hybridization is a valuable approach in
drug discovery. Combining it with multicomponent reactions is
highly desirable, since structurally diverse libraries can be attained
efficiently in an eco-friendly manner. In this work, isatin is used as
the key building block for the Ugi 4-center 3-component reaction
synthesis of oxindole−lactam hybrids, under catalyst-free con-
ditions. The resulting oxindole−β-lactam and oxindole−γ-lactam
hybrids were evaluated for their potential to inhibit relevant central
nervous system targets, namely cholinesterases and monoamine
oxidases. Druglikeness evaluation was also performed, and
compounds 4eca and 5dab exhibited great potential as selective
butyrylcholinesterase inhibitors, at the low micromolar range, with
an interesting predictive pharmacokinetic profile. Our findings
herein reported suggest oxindole−lactam hybrids as new potential agents for the treatment of Alzheimer’s disease.
KEYWORDS: Isatin, multicomponent reactions, Ugi reaction, Alzheimer’s disease, oxindole−lactam hybrids
compounds in drug discovery, for their potential interaction
ulticomponent reactions (MCRs) emerged as a key tool
Mfor diversity-oriented synthesis in medicinal chemistry. with multiple targets, in a polypharmacology context.13,14
Another important concept in the realm of polypharmacol-
ogy is molecular hybridization. By incorporating different
pharmacophoric moieties in a single chemical framework,
namely the so-called privileged structures, a synergetic effect
on the therapeutic potential of new drug candidates is
frequently observed, often due to multitarget interaction
activity.15−20 Several research groups focused their attention
on the application of isatin as an outstanding feedstock for the
generation of libraries via MCRs.21,22 Oxindoles, often
obtained from reactions using isatin as starting material,23−25
and lactams, namely β- and γ-lactams,26,27 are well-known
privileged structures present in a wide diversity of scaffolds,
with a plethora of biological activities reported (Figure 1).28−30
Herein we have explored the 4-center 3-component Ugi
reaction (U4c3CR) involving isatin to prepare a library of
oxindole-β-lactams for developing druglike hybrid molecules,
increasing the scope of N-unsubstituted isatins used as starting
materials and, most importantly, accessing new libraries of
The opportunity to integrate in a one-step approach three or
more reactants in a single chemical framework not only allows
the quick preparation of highly substituted libraries, with
different substitution patterns, but also contributes to faster
identification of hit compounds, and even in the hit-to-lead
optimization process. In recent years, several efforts have been
made in order to integrate MCRs in drug discovery programs,
and the number of publications reporting the application of
these reactions in the synthesis of biologically active
compounds have soared.1−4 One more advantage of MCRs
is their inherent sustainability, as they usually allow high atom
economy, decreasing the number of required synthetic steps.
These incredible chemical transformations are excellent tools
for the successful implementation of the 12 principles of green
chemistry.5,6
Among the wide diversity of MCRs, the Ugi reaction,
established by the Estonian-born German chemist Ivar Karl
Ugi in 1959,7 is one of the most relevant reactions for drug
discovery settings, as it integrates the structural features of,
classically, an aldehyde, a carboxylic acid, an amine, and an
isocyanide in a single product.8,9 This allows the generation of
two new amide bonds, and it is well established that amides are
the most commonly occurring functional group in bioactive
molecules.10−12 As many biological targets are proteins,
peptidomimetics emerged as a very relevant class of
Special Issue: Medicinal Chemistry in Portugal and
Spain: A Strong Iberian Alliance
Received: June 18, 2021
Accepted: July 20, 2021
https://doi.org/10.1021/acsmedchemlett.1c00344
© XXXX American Chemical Society
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Figure 1. Examples of drugs bearing the oxindole and β- and γ-lactam heterocycles.
Figure 2. Isatin, isocyanide, and amino acid components scope for the U4c3CR.
oxindole-γ-lactam hybrids. The potential of these molecules on
cholinesterase (ChE) inhibition has also been evaluated,
showing promising results for further development of
therapeutic drug candidates against Alzheimer’s disease,
especially as selective butyrylcholinesterase (BuChE) inhib-
itors. Selected compounds were also evaluated as potential
inhibitors of monoamine oxidase (MAO A and MAO B).
Using the best reaction conditions reported by Rainoldi et
al.,31 two libraries were effectively generated, using the reagent
scope depicted in Figure 2. A wide variety of isatins were
suitable to perform the U4c3CR, as well as isocyanides, with
the exception of 2-morpholinoethyl isocyanide (2e), which did
not lead to the formation of the desired product. Four different
amino acids were screened, with 3-aminopropanoic acid (or β-
alanine (3a)) and 4-aminobutanoic acid (or γ-aminobutyric
acid (3b)) affording the corresponding β- and γ-lactam
derivatives, respectively. 5-Aminopentanoic acid (or 5-amino-
valeric acid (3c)) and 6-aminohexanoic acid (or ε-amino-
caproic acid (3d)) were also evaluated; however, the
corresponding δ- and ε-lactam derivatives were not formed,
indicating that increasing the chain size of the amino acid
derivative prevents the intramolecular cyclization and therefore
the formation of larger lactam rings under the reaction
conditions tested, which included performing the reaction in
the presence of an excess of amino acid and isocyanide
components and known catalysts of the Ugi reaction, InCl3
and ZnCl2.
The overall synthetic approach is depicted in Scheme 1. This
approach, promoted using acidic and protic 2,2,2-trifluoroe-
thanol (TFE) as reaction media,32 proved to be an efficient
one-step methodology for synthesis of several β- and γ-lactam-
oxindole hybrids (see Supporting Information for experimental
details). The generated library as well as the respective isolated
yields are shown in Figure 3.
It is noticeable that increasing the size of the lactam ring
leads to an overall decrease of the yields. The reaction yield is
mostly influenced by the substituents at the aromatic ring of
isatin, while N-substituted isatins allow similar yields
comparatively to the ones obtained using N-unsubstituted
isatin. The different alkyl isocyanides tested did not lead to
significant differences in the yields, although aliphatic
isocyanides tend to display higher ones. The structural
characterization of the 31 oxindole−lactam hybrids reported,
including the four previously reported, is given in the
Supporting Information.31
Druglike properties of the synthesized compounds, as well as
some of their most relevant physicochemical properties for a
good pharmacokinetic profile assessment, were evaluated in
silico. We selected SwissADME to perform this evaluation, as
this easy-to-use, free web tool is very versatile and provides a
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Scheme 1. Synthetic Approach for U4c3CR
wide diversity of information in a very efficient way.33 The
other advantage of this suite is the availability of five key
druglikeness filtersLipinski (Pfizer) rule of five,34,35 Ghose
(Amgen) filter,36 Veber (GSK) filter,37 Egan (Pharmacopeia)
filter,38 and Muegge (Bayer) filter.39
Three important descriptors of the druglikeness compliance
of new drug candidates are the number of hydrogen bond
acceptors and receptors, as well as the number of rotatable
bonds. The results obtained for all the new compounds are
depicted in Figure 4. Gratifyingly, the key parameters (referred
to above) for our library of β- and γ-lactam−oxindole
derivatives fell within the specifications established for three
of the key druglikeness filters, namely the Lipinski, Muegge,
and Veber filters.
Molecular weight (MW) is another important property
evaluated by several filters, including the Lipinski filter (MW ≤
500 Da), the Ghose rule (160 ≤ MW ≤ 480 Da), and the
Muegge filter (200 ≤ MW ≤ 600 Da). All the compounds
reported present MWs within the established intervals.
Furthermore, and considering the central nervous system
(CNS) distribution of the biological targets evaluated in this
work, it is important to take into account that CNS drugs
usually exhibit reduced MWs, usually in or below a 400−600
Da range. Marketed CNS-acting drugs display a MW mean
value of 310 Da.40 The lipophilicity (evaluated according to
the calculated partition coefficient, CLogP) is another
important feature to consider in the drug discovery process.
Its value is evidenced by being one of the properties taken into
account in four out of the five main filtersLipinski filter
(CLogP ≤ 5), Ghose filter (−0.4 ≤ CLogP ≤ 5.6), Egan filter
(CLogP ≤ 5.88), and Muegge filter (−2 ≤ CLogP ≤ 5).
Optimal blood−brain barrier (BBB) permeation is attained by
compounds displaying a CLogP ranging between 1.5 and 2.7,
with a mean value of 2.1, with marketed CNS-acting drugs
possessing a CLogP mean value of 2.5.40 Figure 5 correlates
these two features for the synthesized library, with all of them
falling within the established parameters for all the filters.
A BOILED-Egg (Brain Or IntestinaL EstimateD permeation
method) model can also be assessed using SwissADME. This
model predicts the behavior of the synthesized molecules in
what concerns their ability to cross the gastrointestinal barrier
via passive diffusion (white area), making them suitable
candidates for oral administration, and also their ability to
reach the central nervous system targets, by crossing the BBB
(yolk/yellow area).41 These calculations take into consid-
eration two important propertiesthe lipophilicity (in this
case, WLogP, calculated according to the Wildman and
Crippen method42) and the topological polar surface area
(TPSA), a property which is considered in three out of five
filters (Veber filter, TPSA ≤ 140 Å2; Egan filter, TPSA ≤ 131.6
Å2; and Muegge filter, TPSA ≤ 150 Å2). As depicted in Figure
6, all the synthesized compounds exhibit good predictive
gastrointestinal absorption, making them suitable candidates
for oral administration. However, BBB permeation, as
expected, is exclusively exhibited by some N-substituted
oxindoles, including N-phenyl (4daa, 5dab) and N-benzyl-
oxindole (4eaa, 4eca, 5eab) derivatives. Those compounds
with very greasy amide side-chains, like 4bca and 5bcb, were
predicted to easily cross the BBB.
SwissADME also evaluates the presence of Pan-Assay
Interference Compounds (PAINS), which possess the ability
to interact with multiple targets and therefore can be wrongly
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Figure 3. Library of oxindole−β-lactam and oxindole−γ-lactam hybrids.
identified as hit compounds in one specific screening; however,
further development of such compounds is undesirable due to
their off-target effects.43,44 None of our compounds were red-
flagged in this regard. Furthermore, all the compounds comply
with the five druglikeness filters, which makes them promising
drug candidates for further development (see Supporting
Information for experimental details).
The ChE inhibition potential of the synthesized compounds
was evaluated using model cholinesterases, namely AChE
(Electrophorus electricus) and BuChE (equine serum) (Table 1)
(see the Supporting Information for experimental details).
Concerning AChE inhibition, only one compound, 5hab,
showed moderate inhibitory activity (IC50 = 45 μM).
However, more promising results were achieved against
BuChE, indicating a great potential for these oxindole−lactam
hybrids to act as selective BuChE inhibitors.
The title compounds can be categorized in three different
groups according to their potency toward BuChE: inactive
(IC50 > 100 μM), moderate inhibitors (18 μM < IC50 < 94
μM), or strong inhibitors (IC50 < 10 μM). The latter group of
compounds (4eca, 5dab, 5acb) are the most promising ones,
with all of them behaving as mixed inhibitors; that is, they can
bind both the free enzyme and the E−S complex. Moreover,
compound 4eca was slightly more potent than galantamine
(IC50 = 3.9 μM), one of the current cholinesterase inhibitors in
clinical use against Alzheimer’s disease and used herein as a
positive control.
D
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Figure 4. Calculated hydrogen bond acceptors, hydrogen bond donors, and rotatable bonds for the synthesized library of oxindole−lactam hybrids.
name a few). We could also verify that oxindoles bearing
substituents in the aromatic ring exhibit weak to no activity
and that alkyl isocyanides, in particular t-octyl isocyanide, tend
to achieve more active compounds, while benzyl isocyanide
leads to weak inhibitors or inactive compounds. The
substitution at position 1 of the oxindole core also plays a
role in the bioactivity shown by these derivatives. Propargyl
and methyl derivatives lead to inactive compounds (except in
the case of 5bcb, which possesses good BuChE inhibition
activity probably due to the combination of t-octyl and γ-
lactam ring), whereas N-phenyl or N-benzyl oxindoles tend to
exhibit promising activity. Integrating these results with the
BOILED-Egg model, we verify that out of the three most
active compounds, the two more active (4eca and 5dab)
predictably possess activity to cross the BBB, which is of great
importance for the treatment of Alzheimer’s disease. This is of
major interest, as it can open the door for the development of
new selective BuChE inhibitors with potential therapeutic
Figure 5. Relation between MW and CLogP of the synthesized
application. Indeed, several efforts are being undertaken in
compounds.
recent years to achieve selective BuChE inhibitors, as such
therapeutic option is still not available in clinical practice.45−47
The BuChE role in the pathophysiology of Alzheimer’s disease
is also gaining attention, as recent evidence indicates this
enzyme is present in high concentration in severe/late stages of
Alzheimer’s disease, whereas AChE depletes with disease
evolution.48−50
In order to further study the potential of this library, selected
compounds were evaluated against MAO A and MAO B
enzymes, as these targets are involved in several pathologies
affecting the CNS, including neurodegenerative diseases. As
the propargyl moiety is present in many MAO inhibitors, we
selected the compounds bearing this chain to perform this
screening (4caa, 4cda, and 5cdb) (see the Supporting
Information for experimental details). The results are
summarized in Table 2.
Unfortunately, no relevant MAO inhibition was observed,
with the best result being achieved by compound 5cdb,
displaying a 13.2% inhibition of MAO A at a concentration of
1 μM.
Figure 6. BOILED-Egg model for the oxindole−lactam hybrids
synthesized via U4c3CR.
In conclusion, a series of β- and γ-lactam−oxindole hybrids
were successfully synthesized using the versatile U4c3CR. ChE
inhibition activity screening showed great potential for some of
these compounds, in particular the γ-lactam−oxindole hybrid
4eca and β-lactam−oxindole hybrids 5dab and 5acb, to inhibit
selectively BuChE in the low micromolar range, and therefore
Taking a closer look at the structures of the synthesized
compounds and the exhibited activity, a pattern can be
observed. The γ-lactam derivative is always more active than
the β-lactam counterpart, which is either less active or inactive
(e.g., 5dab versus 4daa, 5acb versus 4aca, 5eab versus 4eaa, to
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more studies are currently being undertaken to further explore
the potential of these compounds for the treatment of
Alzheimer’s disease. The hybrids exhibit great potential as
new drug candidates, due to their predicted physicochemical
properties and excellent druglikeness profiles. Further studies
are currently underway to explore the potential of these
compounds as multitarget drug candidates.
Table 1. ChE Inhibition Results (IC50 and Ki for the Most
Promising Compounds)
a b
Inhibition of cholinesterases (IC50, μM) .
AChE
(Electrophorus
electricus)
BuChE
(equine
serum)
Compound
Ki (μM)
4aaa
4baa
4caa
4daa
4eaa
4faa
4gaa
4haa
4iaa
>100
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00344.
■
sı
22
51
>100
80
>100
57
1
2
1
5
Experimental procedures for biological activity evalua-
tion assays, as well as the general procedure for the
synthesis of the described compounds, and respective
1
characterization (including H and 13C NMR, ATR-
4jaa
>100
4aba
4aca
4ada
FTIR, melting points, HRMS, as well as SwissADME
evaluation reports). (PDF)
42
>100
5
>100
Kia = 1.8 0.1
Kib = 4.8 0.6
(Mixed inhibition)
AUTHOR INFORMATION
Corresponding Author
■
4eca
1.8 0.2
>100
Marta Pineiro − University of Coimbra, CQC and
Department of Chemistry, 3004-535 Coimbra, Portugal;
orcid.org/0000-0002-7460-3758; Email: mpineiro@
qui.uc.pt
4cda
4bba
4bca
5aab
5bab
54
>100
7
Authors
Kia = 6.1 1.1
Kib = 18 6 (Mixed
inhibition)
Pedro Branda
Department of Chemistry, 3004-535 Coimbra, Portugal;
LAQV-REQUIMTE, Rua Romao Ramalho, 59, University of
̃
o − University of Coimbra, CQC and
5dab
6.2 0.3
̃
5eab
5fab
5gab
5hab
5iab
5jab
5abb
32
>100
68 13
94
3
́
́
Evora, 7000 Evora, Portugal; orcid.org/0000-0002-
1455-7470
́
Oscar López − Departamento de Química Orgánica, Facultad
de Química, Universidad de Sevilla, E-41071 Seville, Spain
Luisa Leitzbach − Institute of Pharmaceutical and Medicinal
45
5
3
>100
Chemistry, Heinrich Heine University Du
Duesseldorf, NRW, Germany
Holger Stark − Institute of Pharmaceutical and Medicinal
Chemistry, Heinrich Heine University Dusseldorf, 40225
̈
sseldorf, 40225
44
2
Kia = 7.4 1.8
Kib = 15 1 (Mixed
inhibition)
5acb
>100
8.4 0.1
̈
5adb
5bcb
5cdb
Galantamine
71
18
>100
3.9 0.3
3
1
-
Duesseldorf, NRW, Germany; orcid.org/0000-0003-
3336-1710
José G. Fernández-Bolanos − Departamento de Química
̃
2.7 0.2
-
Orgánica, Facultad de Química, Universidad de Sevilla, E-
41071 Seville, Spain; orcid.org/0000-0003-1499-0650
a
b
[S] = 112 μM. A set of 5−6 different inhibitor concentrations was
used, and the data were obtained in duplicate and expressed as the
mean SD.
Anthony J. Burke − LAQV-REQUIMTE, Rua Romao
̃
́
́
Ramalho, 59, University of Evora, 7000 Evora, Portugal;
́
University of Evora, Department of Chemistry, 7000 Evora,
Table 2. MAO A and MAO B One-Point Screening for
Compounds Bearing the N-Propargyl Moiety (n = 4)
Portugal; orcid.org/0000-0001-8248-1116
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00344
MAO A
MAO B
a
a
Compounds
Inhibition SD [%]
Inhibition SD [%]
Notes
Control
Clorgyline
Safinamide
4caa
4cda
5cdb
0.0 0.8
100.4 0.9
−1.6 3.3
5.9 7.1
8.9 0.7
13.2 3.8
0.0 2.9
28.2 14.0
97.0 0.4
7.4 1.5
7.6 4.7
6.1 7.0
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P. Brandao
̃
acknowledges FCT for the PhD grant PD/BD/
128490/2017-CATSUS FCT-PhD Program. Coimbra Chem-
istry Centre (CQC) is supported by the Portuguese Agency for
a
MAO inhibition was calculated as percentages related to control at a
test concentration of 1 μM and given as mean
independent experiments in duplicate.
̂
Scientific Research, “Fundaca̧ o para a Ciencia e a Tecnologia”
̃
(FCT) through project UIDB/00313/2020 and UIDP/00313/
2020, cofunded by COMPETE2020-UE. We also acknowledge
the UC-NMR facility for obtaining the NMR data (www.
SD of two
F
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Letter
(19) Stark, H. The chemical probe - scopes, limitations and
challenges. Expert Opin. Drug Discovery 2020, 15 (12), 1365−1367.
(20) Proschak, E.; Stark, H.; Merk, D. Polypharmacology by Design:
A Medicinal Chemist’s Perspective on Multitargeting Compounds. J.
Med. Chem. 2019, 62 (2), 420−444.
nmrccc.uc.pt). This work was also financed by the FEDER
Funds through the Operational Competitiveness Factors
ProgramCOMPETEand by National Funds through
FCTFoundation for Science and Technologywithin the
́
scope of the project UIDB/50006/2020. O. López would also
(21) Liu, Y. Y.; Wang, H.; Wan, J. P. Recent Advances in Diversity
Oriented Synthesis through Isatin-based Multicomponent Reactions.
Asian J. Org. Chem. 2013, 2 (5), 374−386.
like to thank the Dirección General de Investigación of Spain
(CTQ2016-78703-P), Junta de Andalucía (FQM134), and
FEDER (501100008530) for financial support. Partial support
from the EU COST Actions CA15135 (to HS and AJB),
CA18133 (to HS), and CA18240 (to HS) is also acknowl-
edged.
(22) Brandao, P.; Marques, C. S.; Carreiro, E. P.; Pineiro, M.; Burke,
̃
A. J. Engaging Isatins in Multicomponent Reactions (MCRs) - Easy
Access to Structural Diversity. Chem. Rec. 2021, 21 (4), 924−1037.
(23) Bogdanov, A. V.; Mironov, V. F. Advances in the Synthesis of
Isatins: A Survey of the Last Decade. Synthesis 2018, 50 (8), 1601−
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