Synthesis of large Stokes shift and narrow emission indole-triazole-carboxamide peptidomimetics via MCR-click strategy

Article abstract of DOI:10.1016/j.tetlet.2016.04.040

A series of indole peptidomimetics with potential for the future emergence as efficient therapeutic agents for stage 2 Human African Trypanosomiasis (HAT) is described. The peptidomimetics are constructed based on a build-pair concept using green chemistry models like multicomponent coupling strategy and click chemistry. The photophysical properties of the molecules are promising and point to the added possibilities of these molecules for the development of optical imaging agents.

Full text of DOI:10.1016/j.tetlet.2016.04.040

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of large Stokes shift and narrow emission indole–triazole–
carboxamide peptidomimetics via MCR-click strategy
⇑
Rajeena Pathoor, D. Bahulayan
Department of Chemistry, University of Calicut, Malappuram 673635, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of indole peptidomimetics with potential for the future emergence as efficient therapeutic agents
for stage 2 Human African Trypanosomiasis (HAT) is described. The peptidomimetics are constructed
based on a build-pair concept using green chemistry models like multicomponent coupling strategy
and click chemistry. The photophysical properties of the molecules are promising and point to the added
possibilities of these molecules for the development of optical imaging agents.
Received 7 March 2016
Revised 8 April 2016
Accepted 12 April 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Carboxamide
Stokes shift
Human African Trypanosomiasis
Click chemistry
A newly emerging strategy for the diversity-oriented synthesis
of functional organic molecules is the use of privileged scaffolds.1 A
privileged scaffold is a key structural entity present in a biologi-
cally active molecule from which the biological activity is mainly
originating. Among the various privileged scaffolds, indoles, tria-
zoles, and carboxamides are the three potential structural scaffolds
frequently occurring in natural as well as synthetic therapeutics.
For example, 3-substituted indole derivatives are reported to be
useful for the development of enzyme inhibitors,2 bioreceptormod-
ulators,3 cannabinoid receptors4 etc. N-acyl or N-alkyl indole
derivatives are also present in numerous biologically active
molecules.5 Carboxamides are another interesting moiety present
in many drug molecules.6 Telaprevir, used for the treatment of
hepatitis C, bortezomib, a threonine protease inhibitor and prazi-
quantel used for the treatment of schistosomiasis are some of the
examples of this category. Similarly, triazole derivatives also pos-
sess valuable clinical profiles like anti-HIV,7 anti-allergic,8 anti-
fungal,9 or anti-viral properties.10 Figure 1 shows selected drug
molecules with one of these moieties as privileged scaffold.
Recently, indoline-2-carboxamide derivative A (Fig. 2a) was
reported as a therapeutic agent for stage 1 Human African
Trypanosomiasis (HAT).11
blood–brain barrier and attack the central nervous system leading
to medical conditions such as confusion, sleep disorders, coma or
even death. No effective vaccine is available till date for the treat-
ment of stage 2 HAT and therefore it is important to develop more
bio-compatible molecules that can cross the blood–brain barrier to
provide better bioavailability at the HAT infected sites.
The failure of A to produce better results for type 2 HAT may be
the poor stability of the molecule due to the vulnerability of the
indole amide moiety and the ether oxygen toward protease action.
Similarly, lipophilicity affects both blood–brain barrier permeation
and brain distribution. It has been recognized that lipophilic mole-
cules have greater access to the brain than hydrophilic molecules.
Lipophilicity could bring the inhibitor into closer proximity with a
brain target and exists in a highly lipophilic environment.12 One of
the methods to improve the stability, lipophilicity and bioavailabil-
ity of a peptide like drug molecule is the creation of its pep-
tidomimetic version by substituting its protease unstable amide
bonds with more stable isosteres.13 Many functionalities like
1,2,3-triazole, ACH2AOA, ACH2ACOA, and ACH@CHA are identi-
fied as amide bond isosteres.14 Among the various amide bond iso-
steres, 1,2,3-triazole is the more prominent one due to its close
similarity with amide bonds in terms of physiochemical properties
However, it fails to produce positive results for the treatment of
stage 2 HAT due to lack of tolerability in biological environment.
Stage 2 is more fatal because at this stage the parasites cross the
such as planarity, dipole moment, Ca distance, and number of
H-bonding sites.15 A 1,2,3-triazole can be easily linked between
two subunits of a single drug via copper (I) catalyzed [3+2]
azide-alkyne click cycloaddition (CuAAC)16 which is now emerged
as a waste-free and chemoselective ligation tool for the fragment
coupling of small molecule segments to produce conformationally
⇑
Corresponding author. Tel.: +91 9995538062; fax: +91 494 2400269.
E-mail address: bahulayan@yahoo.com (D. Bahulayan).
http://dx.doi.org/10.1016/j.tetlet.2016.04.040
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pathoor, R.; Bahulayan, D. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.040

2
R. Pathoor, D. Bahulayan / Tetrahedron Letters xxx (2016) xxx–xxx
HOOC
HOOC
F
O
OH
B
H3CO
H
N
CH3
N
N
CH3
N
H
OH
N
N
O
(b)
O
S
O
O
(c) Bortezomib
N
N
O
H3C
NMe2
Cl
TBSO
H2N
N
(a) Indomethacin
(b) Sulindac
O
OTBS
H3C
O
O
O
N
N
S
NH
N
N
O
O
H2N
H2N
N
(f) TSAO
O
Cl
O
O
NH
O
NH
O
H
N
H
(e) CAI
O
Cl
H
(d) Telaprevir
Cl
a-acylaminoamide as a core structure, (e, f): 1,2,3-triazole as
Figure 1. Representative examples of commercial drug molecules with: (a, b): indole as a structural part, (c, d):
core structure.
The studies were started with the synthesis of the starting alky-
nes and azides. The alkynes 1a–c were obtained via the base cat-
alyzed propargylation of corresponding 3-substituted indole with
propargyl bromide in DMF as shown in Scheme 1. The carboxamide
fragments were synthesized in the form of azides (Fig. 4 and
Table 1) via the post reaction modification of the corresponding
H
N
(a)
O
Previus work
This work
N
O
Cl
O
A
R1
N
carboxamide chlorides obtained from an Ugi
4 component
R2
N
O
reaction.18
(b)
N
N
N
The carboxamide scaffolds as shown in Figure 4 are selected due
to their unique structural features comprising of at least four sub-
stitutable diversity points. Since large number of aldehydes, ami-
nes, carboxylic acids, and isonitriles are available, it is possible to
construct large collections of carboxamides via solid phase or solu-
tion phase combinatorial synthesis.
As shown in Table 1, the carboxamide chloride intermediates
were obtained by mixing equimolar amount of aldehyde, amine,
chloroacetic acid, and tert-butylisonitrile in methanol at room tem-
perature by following Ugi 4 component reaction protocol. These
scaffolds were subsequently converted to the corresponding azides
by treating with sodium azide in presence of potassium carbonate
in DMF at room temperature (see Supplementary information for
detailed procedure).
H
O
R3
N
ITC
Figure 2. (a) Recently reported indoline-2-carboxamide derivative as potential
curing agent for stage Human African Trypanosomiasis (HAT). (b) General
structure of the indole triazole carboxamide (ITC) obtained via isosteric
substitution.
1
restricted drug-like molecules.17 In continuation of our ongoing
research on peptidomimetic small molecules,18 we decided to
investigate the possibility of designing new peptidomimetic ver-
sions of A via structural as well as isosteric modification to create
indole–triazole–carboxamide derivatives (ITC) as shown in
Figure 2b.
Having synthesized the indole alkynes and carboxamide azides,
we proceed to the synthesis of indole peptidomimetics by CuAAC
ligation between these two entities. Eight peptidomimetics were
prepared from each category of alkynes with selected azides from
Table 1. For example, for the synthesis of ICT-1 series, we reacted
A build/pair strategy19 based on multicomponent reactions
(MCRs)20 and click chemistry was used for the synthesis of the
indole peptidomimetics ITC-1, ITC-2, and ITC-3 (Fig. 2) (Fig. 3).
X
X
O
O
HN
O
HN
H
N
H
N
O
O
O
N
O
N
O
N
N
N
O
N
N
O
N
N
N
N
X
N
N
ICT-1
ICT-2
ICT-3
N
H
Figure 3. Representative structures of the indole peptidomimetics ICT-1, ICT-2 and ICT-3.
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R. Pathoor, D. Bahulayan / Tetrahedron Letters xxx (2016) xxx–xxx
3
The subsequent aqueous work-up followed by solvent wash
afforded the peptidomimetics in pure form. The peptidomimetics
and their starting scaffolds were thoroughly characterized by 1H
NMR, 13C NMR, FT-IR, and mass spectral studies (see Supplemen-
tary data for experimental and compound characterization). The
structure of various peptidomimetics belong to the ICT-1 series
are presented in Table 2. The synthesis of the peptidomimetics in
the ICT-2 series and ICT-3 series were also done in the same way
and the details are presented in Tables 3 and 4. Irrespective of
the nature of the skeletal substitution patterns, all the pep-
tidomimetics were formed in good to excellent yield with a maxi-
mum of 92% for 3a (Table 2, entry 1).
R1
R1
Br
+
N
N
DMF, K2CO3
H
CHO
O
O
O
N
N
N
H
1a
1b
1c
Scheme 1. List of alkyne functionalized indole scaffolds synthesized.
We then moved on to the computation of the drug property
descriptors of all the three series of peptidomimetics using molin-
spiration property calculation service.21 Drug-likeness of the mole-
cules mainly depends on their molecular size, lipophilicity, polarity
(accessed by the polar surface area, tPSA) and the presence of opti-
mal number of rotatable bonds.22 Drug like molecules usually have
logP values in between À0.4 and 5.6.23 The calculated drug-prop-
erty descriptors are presented in Table S1 in the Supplementary
information. These peptidomimetics have logP values in between
4.25 and 5.28 and are in the preferred range of antipsychotic
(CNS) drugs. The enhanced logP values of the new peptidomimet-
ics compared to A point to the potential of these molecules for
improved blood–brain barrier (BBB) permeation and brain distri-
bution and the possibilities for further studies focused to stage 2
HAT inhibition.
Diversity point 2
Diversity point 1
O
N
Large possibilites
for diversity
N3
N
H
O
multiplication
Diversity point 4
Diversity point 3
Figure 4. General structure of the carboxamide scaffolds in the azideform.
alkyne 1a with azides 2c–f, 2h, 2j, 2k, and 2l to obtain 3a–h. In a
representative reaction an equimolar mixture of alkyne functional-
ized indole and the carboxamideazide were mixed with 0.2 equiv
of sodium ascorbate in a mixed solvent system containing tert-
butanol, water, and DMSO (4:2:1) at room temperature for 48 h.
It has been reported that indole or triazole based molecules are
also useful for optical imaging of cellular targets.24 Much attention
has been given to the development of NIR dyes due to their good
tissue permeability and low autofluoresence.25 However, the use
Table 1
List of carboxamide azides 2a–l synthesized for the ligation reaction with indole alkynes 1a–c
R
R
R
CHO
O
H
O
O
H
N3
N
Methanol
rt, 72h
Cl
N
NaN3, K2CO3
N
+
NC
N
OH
O
O
Cl
DMF
NH2
R
R
R
F
Cl
NO2
Cl
O
H
O
O
H
N
O
H
N
H
N
N3
N
N3
N3
N
N3
N
N
N
O
O
O
O
F
2a
2c
2b
2d
Cl
F
N
O
O
O
H
H
NO2
H
O
H
N
N3
N
N3
O
N
N
N3
N3
N
N
O
O
N
O
O
2f
2h
2gO
2e
Br
Br
NO2
Cl
H
H
N
O
H
N
O
N3
H
N
N3
N
N3
N
N
N3
N
N
O
O
O
2j
2k
2i
2l O
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R. Pathoor, D. Bahulayan / Tetrahedron Letters xxx (2016) xxx–xxx
Table 2
List of ICT-1 series 1,4-substituted triazolyl-3-formyl indole scaffolds substituted with carboxamide residues
X
O
H
O
HN
H
DMSO
O
O
N
O
t-BuOH, H2O
CuSO4
+
N3
N
O
N
N
H
N
N
Na Ascorbate
X
N
N
Entry
ICT-1 series
Yield (%)
Entry
ICT-1 series
Yield (%)
NO2
HN
F
O
HN
O
H
O
H
O
O
N
O
N
N
1
92
5
90
N
N
3b
N
N
N
3a
N
N
Abs/Em(nm)
296/364
Abs/Em(nm)
296/364
F
H
Cl
H
O
O
HN
HN
O
O
O
O
N
N
2
N
90
6
N
3d
89
N
N
3c
N
N
N
N
Abs/Em(nm)
Abs/Em(nm)
297/376
295/394
Br
H
F
HN
O
HN
O
H
O
O
O
N
O
N
N
3f
3
N
3e
90
7
91
N
N
N
N
N
N
Abs/Em(nm)
297/360
Abs/Em(nm)
294/404
NO2
HN
Br
H
O
HN
O
H
O
O
O
N
O
N
N
4
90
8
91
N
N
3h
3f
N
N
N
N
N
Abs/Em(nm)
298/375
Abs/Em(nm)
297/402
Table 3
List of ICT-2 series 1,4-substituted triazolyl-3-acetyl indole scaffolds substituted with carboxamide residues
O
X
O
HN
O
DMSO
+
N3
O
X
N
N
t-BuOH, H2O
CuSO4
Na Ascorbate
N
H
O
N
O
N
N
N
N
Entry
ICT-2 series
Yield (%)
Entry
ICT-2 series
Yield (%)
Cl
O
F
O
HN
HN
O
O
O
O
N
N
N
N
1
83
5
83
N
N
4b
4a
N
N
N
N
Abs/Em(nm)
308/402
Abs/Em(nm)
304/414
F
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R. Pathoor, D. Bahulayan / Tetrahedron Letters xxx (2016) xxx–xxx
5
Table 3 (continued)
Entry
ICT-2 series
Yield (%)
Entry
ICT-2 series
Yield (%)
F
O
HN
O
HN
O
O
O
N
O
N
N
2
87
6
86
N
4d
N
N
4c
N
N
N
N
Abs/Em(nm)
308/385
Abs/Em(nm)
309/394
Br
O
Br
O
HN
HN
O
O
O
N
O
N
N
N
N
3
87
7
85
N
4e
4f
N
N
Abs/Em(nm)
N
N
Abs/Em(nm)
309/434
308/404
NO2
HN
NO2
HN
O
O
O
O
O
O
N
N
4
87
8
86
N
N
4g
N
N
4h
N
N
N
N
Abs/Em(nm)
305/386
Abs/Em(nm)
308/394
Table 4
List of ICT-3 series indole peptidomimetics
O
N
O
N
O
H
O
N
DMSO
O
N
O
N
N
+
N3
N
t-BuOH, H2O
CuSO4
Na Ascorbate
O
X
H
N
O
H
N
X
H
Entry
ICT-3 series
Yield (%)
Entry
ICT-3 series
Yield (%)
O
O
N
H
N
H
N
N
O
O
Cl
O
O
O
O
1
88
6
82
N
N
N
N
N
N
Cl
Abs/Em(nm)
5b
Abs/Em(nm)
286/356
5a
N
H
N
H
284/386
O
O
N
N
N
H
N
H
O
N
O
F
O
O
2
84
7
85
N
N
O
O
N
N
N
F
Abs/Em(nm)
Abs/Em(nm)
283/335
5c
5d
N
H
N
H
286/332
O
O
N
N
N
N
H
O
H
O
F
O
O
3
83
8
82
N
N
O
O
N
N
N
N
Cl
Abs/Em(nm)
5e
5f
Abs/Em(nm)
282/354
N
H
281/330
N
H
(continued on next page)
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R. Pathoor, D. Bahulayan / Tetrahedron Letters xxx (2016) xxx–xxx
Table 4 (continued)
Entry
ICT-3 series
Yield (%)
Entry
ICT-3 series
Yield (%)
O
O
N
H
N
H
N
N
O
N
O
Cl
O
O
O
O
N
N
4
90
9
91
N
N
N
F
Abs/Em(nm)
285/334
5g
N
N
H
H
5h
Abs/Em(nm)
275/332
features is inappropriate at this stage. Interestingly, the pep-
tidomimetics were found to be intact to the changes in pH. This
is important because the sensitivity toward pH and other reactive
species like singlet oxygen affect the performance of the probe dur-
ing in vivo imaging.26 A normalized absorption–emission spectra
of the peptidomimetics showing high Stokes shift is given in
Figure 5.
In summary we have developed a convenient methodology for
the synthesis of
a series of indole based bifunctional pep-
tidomimetics using a build-pair concept. The structural scaffolds
are derived from readily available building blocks based on multi-
component coupling strategy and the fragments thus generated
were assembled by copper (I) catalyzed [3+2] azide-alkyne
cycloaddition.
The drug property descriptors of the molecules points to the
possibilities of these new peptidomimetics as efficient therapeutic
agents for stage 2-HAT infection whereas the photophysical prop-
erties indicates their potential as efficient fluorescent probes for
optical imaging especially were tryptophan is used as probe. We
hope this work will certainly open the way for an effective inhibi-
tor for stage 2 Human African Trypanosomiasis (HAT).
Figure 5. The normalized absorption and emission spectra of indole peptidomimet-
ics 3h, 4a, 4e, and 5h in DMSO at room temperature (Stokes shift. 100 nm).
of these dyes can lead to tissue heating and it also requires the
assistance of a night vision camera as the emitting light is not vis-
ible to naked eyes.26 In this regard, lower wavelength emitting
dyes with high quantum efficiency and less autofluorescence are
expected to produce better results than NIR dyes for the naked
eye detection of tumors and other malignant cell lines during
in vivo imaging. Tryptophan is one such indole based probe used
for the imaging of biological proteins.27 Tryptophan absorbs light
at 290 nm and emit light between 320 and 400 nm. However, the
major drawback here also is the autofluorescence and the protease
instability in biological conditions. One of the methods to over-
come the issue of autofluorescence is the design of probes with
high Stokes shift which is the asymmetry between the excitation
and emission wavelengths.28 Based on the stability providing
structural features present in the new ICT series peptidomimetics
and their promising drug property descriptor values, we decided
to examine the photophysical properties our molecules to bring
out their possibilities as optical imaging agents.
Acknowledgments
R.P. thanks council of scientific and Industrial research (CSIR),
New Delhi for senior research fellowship (SRF).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.
040.
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Please cite this article in press as: Pathoor, R.; Bahulayan, D. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.04.040