Synthesis of bicyclic 1,4-thiazepines as novel anti-: Trypanosoma brucei brucei agents

Article abstract of DOI:10.1039/c9md00064j

1,4-Thiazepines derivatives are pharmacologically important heterocycles with different applications in medicinal chemistry. In the present work, we describe the preparation of new bicyclic thiazolidinyl-1,4-thiazepines 3 by reaction between azadithiane c

Full text of DOI:10.1039/c9md00064j

View Article Online
View Journal
MedChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: F. Vairoletti, A.
Medeiros, P. Fontán, J. Meléndrez, C. Tabárez, G. Salinas, J. Franco, M. Comini, J. Saldaña, V. Jancik, G.
Mahler and C. Saiz, Med. Chem. Commun., 2019, DOI: 10.1039/C9MD00064J.
This is an Accepted Manuscript, which has been through the
Volume 7 Number 1 January 2016 Pages 1–204
Royal Society of Chemistry peer review process and has been
accepted for publication.
MedChemComm
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Broadening the field of opportunity for medicinal chemists
www.rsc.org/medchemcomm
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
Themed issue: Antibiotic Resistance
ISSN 2040-2503
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
rsc.li/medchemcomm

Please do not adjust margins
Page 1 of 8
MedChemComm
View Article Online
DOI: 10.1039/C9MD00064J
ARTICLE
Synthesis of bicyclic 1,4-thiazepines as novel anti-Trypanosoma
brucei brucei agents.
Franco Vairolettia, Andrea Medeirosb,c, Pablo Fontána, Jennifer Meléndreza, Carlos Tabáreza,
Gustavo Salinasd, Jaime Francob, Marcelo A. Cominib, Jenny Saldañae, Vojtech Jancikf, Graciela
Mahlera* and Cecilia Saiz a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
1,4-Thiazepines derivatives are pharmacologically important heterocycles with different applications in medicinal
chemistry. In the present work, we describe the preparation of new bicyclic thiazolidinyl-1,4-thiazepines 3 by reaction
between azadithiane compounds and Michael acceptors. The reaction scope was explored and the yields were optimized.
The activity of new compounds was evaluated against Nippostrongylus brasiliensis and Caenorhabditis elegans as
anthelmintic models and Trypanosoma brucei brucei. The most active compound was 3l, showing an EC50 = 2.8 ± 0.7 μM
against T. b. brucei and a selectivity index >71.
chemists.7 In this context, our group has previously prepared
small libraries containing N, O- and S-fused heterocycles.3,8 In
an earlier approach, we synthesized a novel bicyclic scaffold:
Introduction
Parasitic diseases affect hundreds of millions of people
worldwide and result in significant mortality and devastating
social and economic consequences.1 However, most of the
drugs available are decades old and have several limitations,
such as poor efficacy, toxicity and the emergence and spread
of drug resistance. The scientific community is concerned
about this problem and fortunately has showed an increasing
interest in this field, including efforts to identify new targets
leading to the development of potential drug candidates.2 In
this context, our recent research is focused on the preparation
of discrete libraries designed against specific key targets of
parasites and bacteria. These include the essential redox
enzymes thioredoxin glutathione reductase (TGR) of
platyhelminths,3 the cysteine protease expressed by
Trypanosoma cruzi cruzipain,4 and the metallo-β-lactamase
enzymes of bacteria.5
thiazolidinyl-2,3,4,5-tetrahydro-1,4-thiazepine
3a.
The
compound was prepared by condensation of azadithiane 1a
and dimethylacetylene-dicarboxylate 2a through a domino
process (see Scheme 1).9,10
Scheme 1. Previously prepared thiazolidinyl-thiazepine 3, 3a: R1 = n-Bu.
Thiazepinone and thiazepine derivatives are pharmacologically
important compounds with potential applications in the
treatment of cancer and inflammatory diseases.11,12
Benzothiazepines (A) are privileged scaffolds that exhibit
interesting biological activities,13 thiazolothiazepines (B) and
1,3-thiazepine derivatives (C) have shown antiviral activity,14
see Figure 1.
Over the past decade, the design and preparation of new
libraries of compounds has been directed to increasing
molecular diversity,6 representing a challenge for organic
a. Laboratorio de Química Farmacéutica, Departamento de Química Orgánica,
Facultad de Química, Universidad de la República, Montevideo, Uruguay.
b. Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo,
Montevideo, Uruguay.
c. Departamento de Bioquímica, Facultad de Medicina, Universidad de la República,
Montevideo, Uruguay.
Figure 1. Representative structures of 1,4 and 1,3-thiazepines with biological
d. Worm Biology Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay.
e. Laboratorio de Experimentación Animal, Depto de Ciencias Farmacéuticas,
Facultad de Química, Universidad de la República, Montevideo, Uruguay.
f. Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Toluca,
México.
interest.
Thus, the thiazolinindyl-2,3,4,5-tetrahydro-1,4-thiazepines 3
are new and therefore unexplored bicycles that represent a
promising scaffold for medicinal chemistry. Hence we designed
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
and synthesized
a library of bicyclic thiazolidinyl-1,4-
Please do not adjust margins

Please do not adjust margins
MedChemComm
Page 2 of 8
ARTICLE
Journal Name
Table 2. Solvent and temperature optimization for 3b preparatioVni.ew Article Online
thiazepines, introducing different functional groups at the N-
moiety and/or at the ring substituents. A primary screening of
compounds as potential antiparasitic agents against helminths
and protozoa was undertaken.
DOI: 10.1039/C9MD00064J
Results and discussion
In order to determine the best conditions for the preparation
of thiazolidinyl-1,4-thiazepines 3 (Scheme 1), we prepared five
azadithianes 1 to be used as starting materials. We selected
primary amines bearing benzyl groups with EWG or EDG and
aliphatic amines. The condensation of 1,4-dithiane-2,5-diol
with primary amines in p-TsOH/EtOH at reflux gave the
corresponding azadithianes 1 as a single product. Compounds
1b-f were obtained in high to very high yields (64 to 93 %), see
Table 1.
Entry
Solvent
CH2Cl2
CH2Cl2
Conditions
Overnight, rt
4h, reflux
30’, 78°C, MW
30’, 78°C, MW
30’, 68°C, MW
30’, 110°C, MW
3b Yield (%)a
1
2
3
4
5
6
35
40
47
27
5
MeCN
ClCH2CH2Cl
CF3CH2OH
BuOH
29
a Isolated yield.
Once we selected the best solvent, we explored the influence
of the catalyst in the reaction; results are shown in Table 3.
Based on previous reports, we used a Lewis acid (CF3SO3Ag),
different bases (DABCO and DMAP),PPh3 and NH4OAc as
possible catalysts for the thia-Michael addition.15
Table 1. Synthesis of 2,5-dithio-7-azabicyclo[2.2.1]heptane 1.
Entry
R
Bn
p-OMe Bn
p-Cl Bn
p-F Bn
Product
1b
1c
1d
1e
Yield %
76
64
85
93
Table 3. Catalyst optimization for 3b preparation.
1
2
3
4
5
6
CH2CH2OH
CH2CH2CH2COOH
1f
1g
86
13
Entry
Catalyst
No catalyst
CF3SO3Ag (0.04 eq)
NH4OAc (0.1 eq)
PPh3 (0.2 eq)
3b Yield (%)*
1
2
3
4
5
6
36
29
47
42
56
67
Azadithianes 1b-f were used as nucleophiles with different
Michael acceptors in order to prepare thiazepines 3.
DMAP (0.1 eq)
DABCO (0.1 eq)
Optimization of thiazepine 3 formation
The optimization was performed studying different reaction
conditions. Variables included the catalyst, the solvent, the
heating source and the temperature. To determine the optimal
reaction conditions, benzyl-azadithiane 1b and the
commercially available diethylacetylene-dicarboxylate 2b were
used as starting materials, see Table 2.
* Yields were determined after column purification.
We first assayed the reaction with no catalyst, obtaining 3b in
36% yield (entry 1). While the use of CF3SO3Ag did not improve
the yield of the reaction, NH4OAc slightly increased the yield to
47%, see entry 3. The reaction in presence of catalytic PPh3
gave 42% yield. The best results were obtained when using
bases like DMAP or DABCO (0.1 eq), leading to thiazepine 3b in
57 and 67% yields respectively; see entries 5 and 6.
The reaction was firstly performed in CH2Cl2 at room
temperature and at reflux under conventional thermal heating
(Table 2, entries 1 and 2). We then explored the use of
microwave as a source of heating and MeCN as solvent,
affording better yields (entry 3) compared to conventional
heating. Finally a preliminary solvent screening was performed
using microwave heating (Table 2, entry 4 to 6).
Taking these results together, it seems that nucleophilic
assistance, in particular by basic-like catalysts (i.e. DABCO or
DMAP) improve the addition reaction (see entries 3-6).
The polar nature of the solvent suggests the formation of
charged species during the course of the reaction. As depicted
in Scheme 2, we propose a mechanism based on a thiolate-
iminium I formation via azadithiane ring opening. Polar aprotic
solvents and temperature could favour the thiolate I formation
see Scheme 2(a). The base could participate reacting with
Solvent optimization included the use of halogenated solvents
(ClCH2CH2Cl and CH2Cl2), polar protic solvents (CF3CH2OH,
BuOH) and a polar aprotic solvent (MeCN). The best results
were obtained using MeCN, a solvent with high dielectric
constant and dipolar moment, affording 3b in 47% yield.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
MedChemComm
Please do not adjust margins
Journal Name
ARTICLE
Study of the reaction scope
Michael acceptor 2, affording intermediate II, see Scheme 2
(b).15 Thiolate
would attack intermediate II affording
View Article Online
DOI: 10.1039/C9MD00064J
I
zwitterion III, which could then be trapped through a 7-endo-
trig cyclization to afford the bicyclic product 3 after elimination
of the base. This cyclization is favoured according to Baldwin’s
rules.16
To study the scope and versatility of the reaction, we used
different Michael acceptors 2, prepared by addition of lithium
acetylenes to different aldehydes, followed by MnO2 alcohol
oxidation, see Scheme 3.17
Scheme 3. Synthesis of Michael acceptors 2.
We therefore proceed to study the reaction scope between
different primary amines 1 (described in Table 1) and the
prepared alkynes 2 as Michael acceptors, see Table 4.
Table 4. Study of the reaction scope using different Michael acceptors.
Scheme 2. Proposed mechanism for the formation of thiazolidinylthiazepine 3.
We had previously proposed the structure of thiazolidinyl-
thiazepine 3 based on the long-range W coupling between Ha
and Hb (4J = 0.8 to 1.0 Hz). In this paper we report the
confirmation of the molecular structure of 3d by single crystal
X-ray diffraction (Figure 2).
Entry
R1
R2
R3
Prod Yield
(%)a
1
2
3
4
5
6
7
8
9
1b (R1 = Bn)
1c (R1 = p-OMeBn)
1d (R1 = p-Cl Bn)
1e (R1 = p-F Bn)
1f (R1=(CH2)2OH)
1c (R1 = p-OMeBn)
1b (R1 = Bn)
-OEt
-OEt
-OEt
-CO2Et
-CO2Et
-CO2Et
-CO2Et
-CO2Me
-CO2Me
-CO2Me
-CO2Me
-2-Py
3b
3c
3d
3e
3f
67
72
75
61
41
-OEt
-PhpCl
-PhpCl
-PhpCl
(CH2)2Ph
-PhpCl
3g
3h
3i
83
34b
65b
NRc
1b (R1 = Bn)
1b (R1 = Bn)
3j
a
b
Yields were calculated after purification. Reaction conditions were CH2Cl2/p-
Figure 2. ORTEP diagram of compound 3d.
TsOH, reflux. c NR = no reaction was observed.
As we can observe in Table 4, the reaction is versatile and
occurs in presence of different Michael acceptors 2. When we
used the symmetric diethylacetylene-dicarboxylate 2b (entries
1 to 4), the reaction occurred as expected, affording the
corresponding thiazolidinyl-thiazepines 3 in high to very high
yields. When we set up the reaction with alkynyl ketone 2c
Single crystals of compound 3d were obtained from
saturated CH2Cl2 solution. Compound 3d crystallized in the
centrosymmetric monoclinic P21/n space group with one
molecule of 3d in the asymmetric unit. Table S1 in the
Supporting Information contains selected bond distances and
angles while Table S2 contains the data collection and (see Scheme 3), containing an ester moiety and a ketone, we
observed thiazepines 3g and 3i in better yields (entries 6 and
8). This result was expected because the ketone has a more
electrophilic centre that favours product formation. The best
yield is observed in entry 6, using Michael acceptor 2c. No
reaction was observed with 2e, probably due to the absence of
a di-carbonyl system (entry 9).
refinement details. The molecular structure confirms the
insertion of C=C fragment into one of the two S–C(N) bonds
and therefore the formation of the seven-membered 1,4-
thiazepine ring. Furthermore, as can be expected from the
proposed mechanism, both enantiomers of 3d are observed in
the crystal.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
MedChemComm
Page 4 of 8
ARTICLE
Journal Name
Hybrids design and synthesis
an in vitro spectrophotometric assay. Tested at 50 μM, none of
the thiazepines and furoxan-hybridDsOI:s1h0.o10w3s9/C9sMigDn0if0ic0a64nJt
inhibitory activity of the enzyme (Table 5).
View Article Online
Once we prepared the library of thiazepines 3b-i, we designed
and synthesized hybrid compounds, which combine the
thiazepine scaffold with a furoxan ring (Figure 3). We selected
furoxans as they are extremely valuable frameworks with
interestingly biological properties to target the library against
trypanosomatids and helminths. Recently Salinas and co-
workers have reported furoxan-containing compounds that
inhibit TGRs from Fasciola hepatica and Echinococcus
granulosus, both classes of parasitic flatworms: trematoda and
cestoda respectively.18 With respect to trypanosomatids, the
furoxan scaffold is also present in compounds with activity
against T. cruzi19 and T. b. brucei.20
Complementary, we also screened the prepared compounds
against the nematodes Nippostrongylus brasiliensis and
Caenorhabditis elegans as models for anthelmintic discovery.
Both species are close relatives to hookworms and to H.
contortus, one of the most pathogenic nematodes of
ruminants23 since all of them belong to nematode clade V.
2. N. brasiliensis L4. We assayed the library of thiazepines at 20
μM, results are shown in Table 5. Compounds display only
modest activity, the best performance was observed for
thiazepine 3e, bearing a p-F benzyl group in R1 (N. brasiliensis
death of 47%).
3. C. elegans as a model for anthelmintic screening. Traditional
screens that rely on parasitic worms are costly and labor
intensive. Recently, P. Roy and co-workers established C.
elegans, a free-living nematode, as an effective and cost-
efficient model system for anthelmintic discovery.24
Compounds were screened at 100 μM, using a sensitive
motility assay. The results are shown in Table 5. The library
compounds did not show remarkable activity on this model.
Figure 3. Designed furoxan-thiazepine hybrids 3l, 3m and 3o.
Table 5. Anthelmintic evaluation of thiazepines 3b-h and hybrids 3l, 3m and 3o.
Entry
Cmp
N. brasiliensis
% TGR
inhibition
[50 μM]b
% C. elegans
Furoxan 4 was prepared according to the general procedure
described by Maloney group.21 Hybrid compounds were
prepared according to Scheme 4.
death %
[20μM]a
5.9
13.8
17.1
47.6
20.6
27.6
20.5
-
motility inhibition
[100 μM]c
1
2
3
4
5
6
7
8
9
10
11
12
13
3b
3c
3d
3e
3f
3g
0
36
0
41
0
29
0
0
0
-
N/A
N/A
100
20
50
37
26
18
3
51
22
-
3h
3l
3m
3o
Abz
Iver
Aur
-
-
-
100
N/A
N/A
N/A
100
N/A
a
Death percentage of Nippostrongylus brasiliensis [L4] at [inh]
= 20 μM.
Albendazole EC50 = 0.34 μM). b Percentage of thiorredoxin glutathione reductase
(TGR) inhibition (%) was measured at [inh] = 50 μM. Auranofin was used as
reference, showing 85% inhibition at 30nM. C. elegans motility inhibition assay
c
was performed at [inh] = 100 μM. Reference was performed with 2% DMSO,
Scheme 4. Preparation of hybrids 3l, 3m and 3o.
corresponding to 0% motility inhibition. N/A not assayed.
Anthelmintic activity
In summary, we explored the anthelmintic activity of the
library through three different model assays, but neither the
thiazepine nor the hybrids were active.
1. Thioredoxin glutathione reductase (TGR) inhibition. The
selenoenzyme TGR was selected as molecular target because it
is ubiquitous and indispensable for flatworm parasites,22 and
because the furoxan moiety of our hybrid compounds had
previously shown activity as TGR inhibitor.18 Prepared
compounds were screened as potential inhibitors of TGR using
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
MedChemComm
Please do not adjust margins
Journal Name
ARTICLE
9-fold more active than the second when assayedVaietw5ArµticMle .OTnlhinee
introduction of furoxan rings in R or R is beneficial for the
anti-trypanosomal activity. In contrast, compound 3o bearing
two furoxan rings at R2 and R3 is inactive, which suggests that
introducing a furoxan at position R3 is detrimental for activity.
The hybrids 3l and 3m were selected to determine EC50 in T. b.
brucei (EC50 = 2.8 ± 0.7 μM and EC50 = 2.5 ± 0.2 μM
respectively), see Table 6.
Anti- Trypanosoma activity
1
2
DOI: 10.1039/C9MD00064J
The anti-trypanosomal activity of the thiazepines library was
evaluated against the bloodstream form of T. brucei brucei,
causative agent of Nagana disease of cattle and suitable model
of T. b. rhodesiense, which causes acute Human African
trypanosomiasis. The compounds were screened at 30 μM and
5 μM and the % of parasite death determined by flow
cytometry (Table 6). Compounds showing T. brucei death at 30
µM > 90% were selected for EC50 determination against
parasites and murine macrophages. The selectivity index was
calculated as EC50 macrophage/EC50 T. b. brucei. Trypanosoma
brucei brucei strain 427, cell line 449 (a kind gift of Dr. R. Luise
Krauth-Siegel, Heildeberg University, Germany) and mouse
macrophages from the cell line J774 (purchased from the
American Type Culture Collection, ATCC® code TIB-67™) were
used in the experiments.
Strikingly, while 3l lacked cytotoxicity at 200 μM, 3m resulted
highly toxic to macrophages (EC50 = 3.1 µM). Compound 3l
displayed the highest selectivity against T. brucei (SI>71).
Drug-like properties
Finally, we calculated Lipinski parameters25 to analyse the
chemical and physical properties of the thiazepine library and
evaluate its druglikeness (Table 7).
Thiazepines 3b-h follow the rule of 5: log P under 5, MW under
500 dalton, HBA<10 and HBD<5. This suggests that bicyclic
scaffolds would have good bioavailability when administered
orally, which could encourage the exploration of other
relevant biological activities for these compounds.
Thiazepine scaffolds 3b-h evaluation
With the exception of 3f, all thiazepines exerted more than
50% parasite death when tested at 30 μM. Thiazepine 3f was
the less active compound; the structural feature is the
presence of a hydroxyethyl group instead of the benzyl group
in the N bridge. This points out the importance of R1
substituent for the activity, feature that could guide further
exploration at this level. EC50 of thiazepines 3b-e and 3g were
determined, data shown in Table 6. The anti-trypanosomal
activity of all the selected compounds is of the same order
than that of the reference drug Nfx. Thiazepine 3d (R1 = p-
ClBn) was the best compound displaying an EC50 = 8 M.
Thiazepines 3e and 3g were toxic for macrophages with SI =
3.6 and 0.6 respectively. Interestingly, at 200 M our best
compound 3d lacked toxicity against macrophages (SI > 25).
Table 7. Lipinski’s parametersa for thiazepines 3 and % T. b. brucei death at 30 M.
Entry
Com
p
log P
MW
HBD
HBA
% Death [30 µM]
1
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3f
3g
3h
3l
3m
3o
2.8
393
423
427
411
399
475
445
563
605
685
0
0
0
0
1
0
0
0
0
0
5
6
5
5
6
6
5
10
7
11
98.8 ± 0.3
97.7 ± 0.3
97.3 ± 0.4
99.4 ± 0.1
3.6± 1.2
95.9± 0.6
57.5 ± 2.2
97.8 ± 0.5
97.7 ± 0.1
76.7 ± 1.1
2.68
3.36
2.96
1.82
3.95
4.07
3.57
5.48
4.93
10
aCalculated according to the method of Ghose, Pritchett and Crippen in Spartan
10.
Table 6. Anti-T. b. brucei activity of thiazolidinyl-thiazepines 3b-h and furoxan-
thiazepine hybrids 3l, 3m and 3o. Values represent the mean ± SD (n = 3).
M
EC50 (µM)
Comp
death at 30
µM
death at 5
µM
EC50 (µM)
SIa
The compound with the best inhibition profile 3l breaks one of
the rules (MW). Nonetheless, there is a significant number of
drugs in the 500 < MW < 600 range; molecules are still
considered drug-like despite breaking one of the rules.
According to Roughley’s analyses, 36% of drugs break at least
one rule.26
3b
3c
3d
3e
3f
3g
3h
3l
3m
3o
Nfx
98.8 ± 0.3
97.7 ± 0.3
97.3 ± 0.4
99.4 ± 0.1
3.6± 1.2
95.9± 0.6
57.5 ± 2.2
97.8 ± 0.5
97.7 ± 0.1
23.3 ± 1.1
-
3.5 ± 3.7
3.0 ± 0.5
2.4 ± 1.2
12.7 ± 1.7
1.8± 5.7
0 ± 5.0
3.4 ± 13.4
60.4 ± 1.2
89.4 ± 2.1
12.2 ± 2.2
-
18.9 ± 2.6
18.0 ± 2.0
8.0 ± 0.4
17.8 ± 3.7
-
16.4 ± 1.5
-
2.8 ± 0.7
2.5 ± 0.2
-
200 ± 11
>200
> 200
64.4 ± 3.5
-
9.7 ± 0.6
-
> 200
3.1 ± 0.5
-
10
> 11
> 25
3.6
-
0.6
-
> 71
1.2
-
Conclusions
In conclusion, we optimized the synthesis of thiazepines 3,
using DABCO as catalyst and microwave heating. X-Ray single-
crystal diffraction confirmed the bicyclic structure of
compound 3b and a mechanism for the base catalysis was
proposed.
15 ± 3
150 ± 5
10
a Selectivity index = EC50 macrophage/EC50 T. b. brucei.
Furoxan-hybrids 3l-o evaluation
Hybrids containing one furoxan ring 3l and 3m are both more
active than Nfx and also more active than thiazepine 3d. If we
compare hybrid 3m with its precursor thiazepine 3h, the first is
We were able to prepare a small library of thiazolidinyl-
thiazepines 3b-h and furoxan-hybrids 3l, 3m and 3o, whose
antiparasitic activity was evaluated against four different
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
MedChemComm
Page 6 of 8
ARTICLE
Journal Name
Spencer J and Vila A. Bisthiazolidines: A SubsVtrieawteA-rMticilme Oicnkliinneg
targets. Thiazepine scaffolds 3b-d show good activity against
the infective form of T. b. brucei and low cytotoxicity against
murine macrophages, the best compound was 3d (EC50 = 8.0 ±
0.4 and SI > 25). Hybrids 3l and 3m bearing one furoxan ring in
different position, present the highest potency (EC50 = 2.8 ± 0.7
and 2.5 ± 0.2 µM respectively). Taking into account the
cytotoxicity against a mammalian cell model, the most
selective compound is 3l with an excellent SI (>71).
Scaffold as an Inhibitor of the NDM-1 Carbapenemase. ACS
DOI: 10.1039/C9MD00064J
Infect. Dis. 2015;1:544–554.
6. a) Lovering F, Bikker J and Humblet C. Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical
Success. J. Med. Chem. 2009;52:6752. b) Lovering F. Escape from
Flatland 2: complexity and promiscuity. Med. Chem. Commun.
2013;4:515-519.
7. Galloway W, Isidro-Llobet A and Spring D. Diversity-oriented
synthesis as a tool for the discovery of novel biologically active
small molecules. Nat. Commun. 2010;1:80:1-13.
8. Saiz C, Villamil V, González M, Rossi M, Martínez L, Suescun L,
Vila A, Mahler G. Enantioselective synthesis of new
oxazolidinylthiazolidines as enzyme inhibitors. Tetrahedron:
Asymmetry, 2017;28:110–117.
These results are encouraging due to the good anti-T. b. brucei
activity and the novelty of the thiazepine scaffold. Compound
3d and derivatives could be used as leaders for further studies
against trypanosomatids.
9. Saiz C, Castillo
V and Mahler G. Imine Domino Reactions
Generate Novel Scaffolds: Fused Bisthiazolidines or Bisthiiranes.
Synlett. 2012;7:1090-1094.
10. Ramsaywack S, Martić S, Milton S, Gates L, Grant A, Labib M,
Decken A and Kraatz H. Synthesis and Surface Investigations of N-
Substituted 2,5-Dithio-7-azabicyclo[2.2.1]heptanes on Gold
Surfaces. J. Phys. Chem. C. 2012;116:7886−7896.
11. Van den Hoven B and Alper H. Remarkable Synthesis of 2-(Z)-6-
(E)-4H-[1,4]-Thiazepin-5-ones by Zwitterionic Rhodium-Catalyzed
Chemo- and Regioselective Cyclohydrocarbonylative Ring
Supplementary data
Supplementary data to this article can be found online at…
CCDC-1885443 contains the supplementary crystallographic
data for this paper. Copies of the data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/const/retrieving.html
or from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: (+44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
Expansion of Acetylenic Thiazoles.
2001;123:1017-1022.
J. Am. Chem. Soc.
12. Robl J, Sun CQ, Stevenson J, Ryono D, Simpkins L, Cimarusti M,
Dejneka T, Slusarchyk W, Chao S, Stratton L, Misra R, Bednarz M,
Asaad M, Cheung H, Abboa-Offei B, Smith P, Mathers P, Fox M,
Schaeffer T, Seymour A and Trippodo N. Dual metalloprotease
inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide
mimetics as inhibitors of angiotensin-converting enzyme and
neutral endopeptidase. J. Med. Chem. 1997;40:1570-1577.
13. Saha D, Jaina G and Sharma A. Benzothiazepines: chemistry of a
privileged scaffold. RSC Adv. 2015;5:70619-70639.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
14. a) Struga M, Kossakowski J, Koziol A, Kedzierska E, Fidecka S, La
Colla P, Ibba C, Collu G, Sanna G, Secci B, Loddo R. Synthesis,
pharmacological and antiviral activity of 1,3-thiazepine
derivatives. Eur J Med Chem. 2009;44:4960–4969. b) Neamati N,
Turpin J, Winslow H, Christensen J, Williamson K, Orr A, Rice W,
Pommier Y, Garofalo A, Brizzi A, Campiani G, Fiorini I and Nacci V.
Thiazolothiazepine Inhibitors of HIV-1 Integrase. J. Med. Chem.
1999;42:3334-3341.
This work was supported by grants from the Programa de
Desarrollo de Ciencias Básicas (PEDECIBA, Uruguay), ANII-FCE
3_2016_1_126500 (Agencia Nacional de Investigación
e
Innovación, Uruguay), and CSIC Grupos (Comisión Sectorial de
Investigación Científica, Uruguay). We would like to
acknowledge Prof. Leopoldo Suescun for his helpful advice to
resolve the crystal structure of 3d. MC acknowledges the
support of FOCEM-MERCOSUR, COF 03/11.
15. Sharma A, Wadhwa P and Kharbanda A. Thia-Michael addition:
An emerging strategy in organic synthesis. Asian J. Org. Chem.
2018; 10.1002/ajoc.201700609.
16. Baldwin JE. Rules for Ring Closure. J Chem Soc, Chem. Commun.
1976;0:734-736.
17. Wipf P, Aoyama Y and Benedum T. A Practical Method for
Oxazole Synthesis by Cycloisomerization of Propargyl Amides.
Org. Lett. 2004;6:3593-3595.
Notes and references
1. Goupil L and McKerrow J. Introduction: Drug Discovery and
Development
for
Neglected
Diseases.
Chem.
Rev.
2014;114:11131.
18. Ross F, Hernández P, Porcal W, López G, Cerecetto H, González
M, Basika T, Carmona C, Fló M, Maggioli G, Bonilla M, Gladyshev
2. Renslo A and McKerrow J. Drug discovery and development for
neglected parasitic diseases. Nature Chemical Biology.
2006;2:701-710.
3. Saiz C, Castillo V, Fontán P, Bonilla M, Salinas G, Rodríguez A,
Mahler G. Discovering Echinococcus granulosus thioredoxin
glutathione reductase inhibitors through site-specific dynamic
combinatorial chemistry. Mol. Div. 2014;18:1-14.
4. a) Pizzo C, Faral-Tello, G. Yaluff, E. Serna, S. Torres, N. Vera, C.
Saiz, C. Robello, G. Mahler. New approach towards the synthesis
of selenosemicarbazones, useful compounds for Chagas' disease.
Eur. J. Med. Chem. 2016;109:107-113. b) Pizzo C, Faral-Tello P,
V, Boiani
M and Salinas G. Identification of Thioredoxin
Glutathione Reductase Inhibitors That Kill Cestode and
Trematode Parasites. PLoS ONE. 2012;7(4):e35033.
19. a) Hernández P, Rojas R, Gilman RH, Sauvain M, Lima LM,
Barreiro EJ, González M, Cerecetto H. Hybrid furoxanyl N-
acylhydrazone derivatives as hits for the development of
neglected diseases drug candidates. Eur. J. Med. Chem.
2013;59:64-74. b) Massarico Serafim RA, Gonçalves JE, Pereira de
Souza F, de Melo Loureiro AP, Storpirtis S, Krogh R, Defini
Andricopulo A, Dias LC, Igne Ferreira E. Design, synthesis and
biological evaluation of hybrid bioisoster derivatives of N-
acylhydrazone and furoxan groups with potential and selective
anti-Trypanosoma cruzi activity. Eur. J. Med. Chem. 2014;82:418-
425
Salinas G, Fló M, Robello C, Wipf
P and Mahler G.
Selenosemicarbazones as potent cruzipain inhibitors and their
antiparasitic properties against Trypanosoma cruzi. Med. Chem.
Commun. 2012;3:362-368.
5. González M, Kosmopoulou M, Mojica M, Castillo V, Hinchliffe P,
Pettinati I, Brem J, Schofield C, Mahler G, Bonomo R, Llarrull L,
20. Florence GJ, Fraser AL, Gould ER, King EF, Menzies SK, Morris JC,
Thomson MI, Tulloch LB, Zacharova MK and Smith TK.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
MedChemComm
Please do not adjust margins
Journal Name
ARTICLE
Development of simplified heterocyclic acetogenin analogues as
View Article Online
potent and selective Trypanosoma brucei Inhibitors.
ChemMedChem. 2016;11:1503– 1506.
DOI: 10.1039/C9MD00064J
21. Rai G, Thomas CJ, Leister W, Maloney DJ. Synthesis of oxadiazole-
2-oxide analogues as potential antischistosomal agents.
Tetrahedron Lett. 2009;50:1710–1713.
22. a) Kuntz AN, Davioud-Charvet E, Sayed AA, Califf LL, Dessolin J, et
al. (2007) Thioredoxin glutathione reductase from Schistosoma
mansoni: An essential parasite enzyme and a key drug target.
PLoS Med. 2007;4(6):e206. b) Song L, Li J, Xie S, Qian C, Wang J,
Zhang W, Yin X, Hua Z, Yu C. Thioredoxin Glutathione Reductase
as a Novel Drug Target: Evidence from Schistosoma japonicum.
PLoS ONE. 2012;7(2): e31456.
23. a) Gordon S, Costa L, Incerti M, Manta E, Saldaña JC, Domínguez
L, Mariezcurrena R, Suescun L. Synthesis and in vitro anthelmintic
activity against Nippostrongylus brasiliensis of new 2-amino-4-
hydroxy-d-valerolactam derivatives. Il Farmaco. 1997;52:603-
608. b) Domínguez L, Saldaña J, Chernin J. Use of L4 larvae of
Nippostrongylus brasiliensis for the in vivo screening of
anthelmintic drugs. Canad. J. Vet. Res. 2000;64:160-163.
24. a) Burns R, Luciani G, Musso G, Bagg R, Yeo M, Zhang Y,
Rajendran L, Glavin J, Hunter R, Redman E, Stasiuk S, Schertzberg
M, McQuibban GA, Caffrey CR, Cutler SR, Tyers M, Giaever G,
Nislow C, Fraser AG, MacRae CA, Gilleard
J and Roy PJ.
Caenorhabditis elegans is useful model for anthelmintic
a
discovery. Nat. Commun. 2015;6:7485, 1-11. b) Mathew M,
Mathew N, Miller A, Simpson M, Au V, Garland S, Gestin M,
Edgley ML, Flibotte S, Balgi A, Chiang J, Giaever G, Dean P, Tung
A, Roberge M, Roskelley C, Forge T, Nislow C and Moerman D.
Using C. elegans forward and reverse genetics to identify new
compounds with anthelmintic activity. PLoS Negl Trop Dis.
2016;10(10):e0005058.
25. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental
and computational approaches to estimate solubility and
permeability in drug discovery and development settings. Adv.
Drug Delivery Rev. 2001;46:3 –26.
26. Roughley SD and Jordan AM. The Medicinal Chemist’s Toolbox:
An Analysis of Reactions Used in the Pursuit of Drug Candidates.
J. Med. Chem. 2011;54:3451–3479.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

MedChemComm
Page 8 of 8
View Article Online
DOI: 10.1039/C9MD00064J
423x81mm (144 x 144 DPI)