Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as antikinetoplastid agents

Article abstract of DOI:10.1016/j.ejmech.2020.112146

In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC₅₀ > 10 μM (vs 0.18 μM and 2.31 μM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 μM ≤ IC₅₀ ≤ 2.18 μM vs IC₅₀ = 2.31 μM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC₅₀ > 10 μM).

Full text of DOI:10.1016/j.ejmech.2020.112146

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Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as
antikinetoplastid agents
Fanny Mathias, Anita Cohen, Youssef Kabri, Núria Waddington Negrão, Maxime D.
Crozet, Roberto Docampo, Nadine Azas, Patrice Vanelle
PII:
S0223-5234(20)30113-6
DOI:
https://doi.org/10.1016/j.ejmech.2020.112146
EJMECH 112146
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 3 December 2019
Revised Date: 12 February 2020
Accepted Date: 12 February 2020
Please cite this article as: F. Mathias, A. Cohen, Y. Kabri, Nú.Waddington. Negrão, M.D. Crozet,
R. Docampo, N. Azas, P. Vanelle, Synthesis and in vitro evaluation of new 5-substituted 6-
nitroimidazooxazoles as antikinetoplastid agents, European Journal of Medicinal Chemistry (2020), doi:
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Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as
antikinetoplastid agents†
Fanny Mathiasa, Anita Cohenb, Youssef Kabria, Núria Waddington Negrãoc, Maxime D. Crozeta,
Roberto Docampoc,d, Nadine Azasb, Patrice Vanellea*.
a
Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de
Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385, Marseille Cedex 05, France.
b Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France.
c Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602, U.S.A.
d Department of Cellular Biology, University of Georgia, Athens, GA 30602, U.S.A.
†This paper is dedicated to the late Professor Alain Gueiffier.

Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as
antikinetoplastid agents†
Fanny Mathiasa, Anita Cohenb, Youssef Kabria, Núria Waddington Negrãoc, Maxime D. Crozeta, Roberto Docampoc,d,
Nadine Azasb, Patrice Vanellea*.
a
Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard
Jean Moulin, CS30064, 13385, Marseille Cedex 05, France.
b Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France.
c Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602, U.S.A.
d Department of Cellular Biology, University of Georgia, Athens, GA 30602, U.S.A.
†This paper is dedicated to the late Professor Alain Gueiffier.
Abstract
the Trypanosomatidæ, including Leishmania genus and
Trypanosoma genus, are the cause of several human
diseases classified as neglected tropical diseases. [1], [2], [3]
The most widespread neglected tropical diseases with
the highest death rates are visceral leishmaniasis
caused by Leishmania donovani and Leishmania
infantum, Chagas disease caused by Trypanosoma cruzi
and Human African Trypanosomiasis caused by
Trypanosoma brucei.[4]
In continuation of our pharmacomodulation
work on the nitroimidazooxazole series, we report the
synthesis of new 5-substituted 6-nitroimidazooxazole
derivatives. Our aim was to evaluate how
functionalization of the 5-position of the 6-
nitroimidazooxazole scaffold affects antileishmanial and
antitrypanosomal in vitro activities.
Twenty-one
original compounds were synthesized and evaluated for
their in vitro antileishmanial (L. donovani) and
antitrypanosomal (T. cruzi) properties. Pallado-
catalyzed cross-coupling reactions were used to
introduce an aryl or ethynyl aryl substituent in 5-
position from a 5-brominated-6-nitroimidazooxazole
starting product. Unfortunately, the first series of
compounds bearing an aryl group in 5-position
presented limited in vitro activities against L. donovani
and T. cruzi, with IC50 > 10 µM (vs 0.18 µM and 2.31 µM
Epidemiological data from the World Health
Organization (WHO) show between 700 000 and 1
million new cases of leishmaniasis worldwide every
year, mainly in Africa, Asia and Latin America, with
more than 20 000 deaths annually.[5] There are three
clinical manifestations of leishmaniasis according to the
Leishmania species involved: cutaneous (the most
common), mucocutaneous and visceral (the most
severe). The most severe visceral form leads to a fatal
prognosis without treatment. Current guidelines for the
management of leishmaniasis are based on various
parameters, like Leishmania species, clinical
manifestations, geographical location and tolerance
profile. The main molecules used are pentavalent
antimonials (sodium stibogluconate and meglumine
antimoniate), injectable amphotericin B, pentamidine
isethionate and miltefosine (the only oral form
available). However, there are several limitations to
these conventional therapies, such side effects, long-
term parenteral administration, high cost in endemic
countries and resistances.[6]
for the reference drugs amphotericin
B
and
benznidazole respectively). Interestingly, the second
series of compounds bearing an ethynyl aryl substituent
in 5-position showed more promising, particularly
against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had
better activity than the reference drug benznidazole
(0.92 µM ≤ IC50 ≤ 2.18 µM vs IC50 = 2.31 µM), whereas
the
non-functionalized
2-methyl-6-nitro-2,3-
dihydroimidazo [2,1-b]oxazole 2 was not active against
T. cruzi (IC50 > 10 µM).
Keywords
Imidazo[2,1-b]oxazole, Nitroheterocycles, Pallado-
Concerning trypanosomiasis, it is important to
catalyzed cross-coupling reaction,
Trypanosoma,
distinguish
between
the
Human
African
Leishmania
Trypanosomiasis (HAT), called sleeping sickness, and
the American Trypanosomiasis called Chagas disease.
HAT is endemic in sub-Saharan African countries, mainly
in the Democratic Republic of the Congo.[7] For 50 years,
the number of new cases has been decreasing. In 2018,
1. Introduction
The Kinetoplastidæ order includes two families
of flagellated eukaryotic parasites: the uniflagellate
trypanosomatids and the biflagellate bodonids which of
1

it was less than 1000 thanks to the WHO.[8] The first oral
treatment, fexinidazole, was recently approved by the
European Medicines Agency (EMA) and appeared on
the 2019 WHO model list of essential medicines for the
management of the first and second stages of Human
African Trypanosomiasis due to Trypanosoma brucei
gambiense infection, according to the recent WHO
guidelines. [8-10] On the other hand, the management of
the American Trypanosomiasis is more difficult because
current treatments (nifurtimox and benznidazole) are
appropriate only for the first stage of the disease,
usually asymptomatic and misdiagnosed. Chagas
disease represents a major health problem, with a
worldwide prevalence estimated at 7 million, mainly in
Fig. 2. Structure-Activity Relationship (SAR) of DNDI-VL-
2098 for visceral leishmaniasis.
Extending this work, we report herein the synthesis of
5-substituted 6-nitroimidazooxazole compounds aimed
at determining whether 5-functionalization might yield
compounds with antileishmanial activity. It has been
established that 6-nitroimidazooxazole bearing a small
substituent at 1-position, such as an ethyl group found
in CGI-17341, leads to good antileishmanial activity
Central and South America, and 7000 annual deaths in
[12]
Latin America.[11],
The lack of treatment for the
second stage of the disease, where there is risk of
cardiac and digestive complications, makes the search
for new molecules active against T. cruzi vital.[13]
(Fig.3).[19] Thus, we synthesized
a series of 6-
Antikinetoplastid activity by 6-nitro-2,3-
dihydroimidazo[2,1-b]oxazole derivatives was found for
the first time from a screening of nitroimidazole
derivatives initiated by DNDi (the Drugs for Neglected
Diseases initiative). One compound, DNDI-VL-2098, was
selected for preclinical evaluation as a potential
candidate for visceral leishmaniasis (Fig.1) but its
development was stopped because of testicular
toxicity.[14] Further studies showed that 6-
nitroimidazooxazole compounds substituted by
a
simple methyl group at 1-position and various aryl or
alkyne substituents at 5-position. These new
compounds were evaluated for their in vitro
antileishmanial and antitrypanosomal properties.
nitroimidazooxazole
compounds
could
have
antitrypanosomal activity.[15], [16]
Fig. 3. Structure and in vitro activity of CGI-17341[19]
2. Results and discussion
2.1. Chemistry
The most commonly described methodology for
the synthesis of 6-nitroimidazooxazole uses 2,4-
dinitroimidazole as starting product.[20], [21]
Fig. 1. Structure and in vitro activity of DNDI-VL-2098[14]
Recently, alternative conditions were developed for
enhanced safety of the synthesis of 6-
nitroimidazooxazole compounds. In accordance with
Several Structure-Activity Relationships (SAR)
of nitroimidazooxazoles for visceral leishmaniasis have
been reported (Fig. 2).[14]
Thompson et al.,[14] we used
a 2-bromo-4(5)-
nitroimidazole as starting product in the presence of
DIPEA as base and propylene oxide to introduce an
alcohol chain at 1-position (Scheme 1). In these
conditions, 4-nitro isomer was obtained in good yield
and only traces of 5-nitro isomer were observed. Then,
intramolecular cyclization occurred with sodium
hydride, at 0 °C in DMF for 65 min, to afford the
synthesis of the cyclized compound 2.
As part of our pharmacomodulation work on the
nitroimidazooxazole series, we previously synthesized
two new series of 5-substituted 7-nitro-2,3-
dihydroimidazo[5,1-b]oxazole and 6-substituted 5-nitro-
2,3-dihydroimidazo[2,1-b]oxazole compounds that did
not display antileishmanial activity.[17], [18]
2

conditions, the first parameters studied were the
solvent and the temperature. Using DME at 110 °C,
product 3 was observed by LC-MS monitoring with an
extrapolated yield of 30 % (Table 1, entries 3-4). Then,
we changed the base and used Cs2CO3 (Table 1, entry
5), leading to an increased yield of 37%. Heating to
more than 110 °C led to the formation of degradation
products and only traces of the desired product 3
(entries 6-7). The best isolated yield obtained (Table 1,
entry 5) was very moderate, so this reaction
optimization was stopped. We decided to use another
pallado-catalyzed cross-coupling methodology after
bromination of the 5-position of compound 2 with N-
bromosuccinimide (Scheme 2).
Scheme 1. Synthesis of 6-nitromidazooxazole 2: a)
propylene oxide (1.5 equiv.), DIPEA (5 equiv.), 110 °C,
MW, 1.5 h. b) NaH (2 equiv.), DMF, N2, 0 °C, 65 min.
To functionalize the 5-position, we sought to
optimize the CH-activation reaction between starting
product 2 and arylbromide (Table 1).
T°
(°C)
Time Yield
Yield
3 (%)
Scheme 2. Synthesis of 5-bromo-2-methyl-6-nitro-2,3-
dihydroimidazo[2,1-b]oxazole 4: a) NBS (1 equiv.),
CH3CN, rt, 1 h.
Entry
1a
Base
Solvent
DMA
(h)
2 (%)
K2CO3,
1.3
equiv.
K2CO3,
1.3
equiv.
K2CO3,
1.3
equiv.
K2CO3,
3
equiv.
Cs2CO3,
3
equiv.
Cs2CO3,
3
equiv.
Cs2CO3,
3
MW
130
c
-
1.5
0
To functionalize the 5-position of compound 4
with various aryl or alkyne substituents, we performed
a Suzuki-Miyaura or a Sonogashira cross-coupling
reaction using experimental conditions previously
described in 5-nitroimidazole series (Scheme 3).[18]
MW
110
c
-
2a
3a
4a
5b
6a
7a
DMF
DME
DME
DME
DME
DME
1.5
1.5
1.5
1.5
1.5
17
100
70
70
0
MW
110
30
30
37
MW
110
MW
110
MW
130
c
-
0
c
-
Scheme 3. General procedure for the pallado-catalyzed
cross-coupling reactions on 4: a) Boronic acid (1.3
equiv.), Na2CO3 (3 equiv.), Pd(PPh3)4 (0.05 equiv.),
DME/H2O (3/1), MW, 100 °C, 1.5 h. b) Alkynes (1.3
equiv.), CuI (0.1 equiv.), Pd(PPh3)2Cl2 (0.05 equiv.), Et3N
(3 equiv.), DMF, rt, 6 h.
130
0
equiv.
a LC-MS monitoring
b Isolated yield after purification by chromatography column
c Only traces of product were observed by LC-MS monitoring
Table 1. Optimization of the CH-activation reaction
between substrate 2 and aryl bromide.
A series of 11 new compounds was obtained by
Suzuki-Miyaura reaction, with isolated yields varying
from 54% {[4-(hydroxymethyl)phenyl]boronic acid} to
82% (p-tolylboronic acid) (Table 2). A series of 8 new
compounds was synthezised by Sonogashira reaction,
with isolated yields varying from 35% (3-ethynylaniline)
to 95% (ethynylbenzene). To confirm the
regioselectivity of the cyclization reaction, the X-ray
The initial conditions (Table 1, entry 1) were
inspired from a previously reported protocol for CH-
activation reaction in 4-nitroimidazole series involving
Pd(PPh3)2Cl2, CuI and pivalic acid as catalyst, K2CO3 as
base, in DMA as solvent at 130 °C.[22] Only traces of the
desired product 3 were obtained, and unidentified
degradation products were observed from LC-MS
monitoring. For the optimization of the reaction
3

structure crystal was determined for compound 5h
sufficient to conclude on the higher toxicity of
metabolite compounds.
(Fig.4).
Regarding antileishmanial activity, only
compound 6b with an ethynyl-3-methoxyphenyl
substituent and compound 6f with an ethynyl-4-(tert-
butyl)phenyl substituent have a selectivity index > 8.
Moreover, compound 6f displays activity close to the
activity of the antileishmanial reference drug
amphotericin B (IC50 = 0.61 µM vs 0.18 µM). The
functionalization of the acetylenic group with a
saturated cycle (6d, 6g) or an alcohol function (6c, 6g)
seems to reduce the activity on L. donovani. According
to the clogP values, the two most active compounds (6b
and 6f) of the acetylenic series are the most lipophilic
(clogP ≥ 3). Contrastingly, the three least lipophilic
compounds 6c, 6d and 6g (clogP < 2.1) are the least
active. Hydrophilic substituents seem to lead to
decreased antileishmanial activity.
Fig.4. X-ray structure of compound 5h
2.2. Biology
All
6-nitroimidazooxazole
compounds
synthesized were evaluated in vitro for their
antileishmanial activity against Leishmania donovani
promastigote and their antitrypanosomal activity
against Trypanosoma cruzi amastigote forms. Their
cytotoxicity against two different adherent cell lines
was evaluated to assess their selectivity of action (Table
2). Thus, the HepG2 cell line was tested because it is a
commonly used human-derived hepatocarcinome cell
line expressing many of the hepatocyte-specific
metabolic enzymes. The aim of this assay using HepG2
cells was to evaluate the impact of metabolic activation
of this series of original synthetic compounds on cell
viability.[23] Another cancer cell line was used, CHO, an
epithelial cell line derived from the ovary of the Chinese
hamster. These CHO cells do not display any metabolic
activation, nor any immune modulation.
Regarding antitrypanosomal activity, five
compounds (6a, 6b, 6c, 6g and 6h) have IC50 values
lower than that of the antitrypanosomal reference drug
benznidazole. One compound (6b) seems particularly
interesting, with an IC50 < 1 µM on T. cruzi and a
selectivity index > 10. The other compounds show
homogeneous antitrypanosomal activity, and there are
no significant differences according to the substituents
of the acetylenic group. We do not observe a
correlation between antitrypanosomal activity and the
lipophilicity of the compounds.
Intermediate product 2 without a substituent in
5-position showed better activity against L. donovani
(IC50 = 0.10 µM) than the antileishmanial reference drug
amphotericin B (IC50 = 0.18 µM), with low cytotoxicity
(CC50 > 500 µM) and a very high selectivity index (SI >
5000). Some non-functionalized 6-nitroimidazooxazoles
in 5-position are known to exhibit antikinetoplastid
activity.[16] However, this compound 2 did not show
antitrypanosomal activity, with an IC50 > 10 µM. The
addition of a bromine atom (4) led to limited activity
against L. donovani and T. cruzi (IC50 = 6.71 µM). The
addition of an aryl group directly linked to the
imidazooxazole bicycle (5a-5k) led to a loss of activity
against L. donovani and T. cruzi (IC50 > 10 µM), while
these compounds displayed no cytotoxicity whatever
the used cell line (51 µM < CC50 ≤ 500 µM). An
acetylenic function between the imidazooxazole bicycle
and the aryl group (compounds 6a-6h) enhanced the
activity against L. donovani and T. cruzi but at the
expense of their cytotoxicity (3.54 µM ≤ CC50 ≤ 18.14
µM), leading to low selectivity indexes. Nevertheless,
the difference between the two cell lines is not
We observed a difference in the activity of our
compounds between L. donovani and T. cruzi. Indeed, L.
donovani activity decreased with the 5-functionalization
by an acetylenic function from IC50 = 0.10 µM (SI >
5000) for compound 2 to 0.61 µM ≤ IC50 ≤ 4.67 µM (1.4
≤ SI ≤ 10.8) for compounds 6a-6h whereas T. cruzi
activity increased from IC50 ≥ 10 µM for compound 2 to
0.92 µM ≤ IC50 ≤ 4.1 µM for compounds 6a-6h. It has
been described in the literature that the dissociation of
the imidazole derivatives activity between Leishmania
and Trypanosoma could come from a difference in the
affinity for an enzyme involved in the synthesis of
sterols, the 14α-demethylase (CYP51).[24],[25],[26] Indeed,
the CYP51 active site volume and surface area are
smaller in Leishmania than in T. cruzi.[24] This hypothesis
could explain that the functionalization of the 5-
position of our compounds leads to a steric hindrance
which reduced binding to the Leishmania CYP51 active
site with for consequence a limited activity on
Leishmania. These results suggest that the anti T. cruzi
4

activity could come from the inhibition of CYP51 and
not only from the reduction of the nitro group
frequently involved in the antikinetoplastid activity of
nitro derivatives.[27],[28] This work opens up new
perspectives for pharmacomodulation to reduce the
toxicity of our compounds, which is currently the factor
limiting their therapeutic interest. The synthesis of non-
nitrate analogues by deletion or replacement of the
nitro group and replacement of the acetylenic function
are the first modifications to be carried out in the
attempt to reduce toxicity and increase the selectivity
index of our compounds on T. cruzi.
functionalization led to lower antileishmanial activity
and higher cytotoxicity compared to compound 2
bearing a hydrogen atom at 5-position. On the other
hand, some 5-substituted compounds led to better
activity against T. cruzi than compound 2 and the
reference drug benznidazole. Biological results showed
that the first series of eleven compounds with an aryl
group directly linked to the 6-nitroimidazooxazole
bicycle (5a-5k) was not active. The introduction of an
acetylenic function between the 6-nitroimidazooxazole
bicycle and the aryl group enhanced activity but also
cytotoxicity. However, one compound (6b) bearing an
ethynyl-3-methoxyphenyl substituent showed good
activity against T. cruzi, with a selectivity index > 10. In
further extensions of this work, the acetylenic group
will be replaced by an ethylenic or saturated chain and
the nitro group will be replaced or deleted.
3. Conclusion
Twenty-one
nitroimidazooxazole compounds were synthesized and
evaluated for their antileishmanial and
antitrypanosomal activities. On the one hand, 5-
new
5-substituted
6-
L. donovani
T.cruzi
CC50
HepG2
µMb
CC50
CHO
µMb
promastigote
amastigote
Yield clogP
(%)
Compounds
R
-
a
c
IC50
e
IC50
ISd
ISf
(µM)
(µM)
0.10
±
55
70
0.66
1.24
> 500
> 500j
> 5000
> 10
-
-
0.01
20.05 ±
2.96
6.71
± 2.8
-
9.19
1.4
> 10
3k or 5al
5b
3-CF3-C6H4
4-CH2OH-C6H4
3,4,5-CH3O-C6H2
4-Cl-C6H4
79
54
80
60
82
59
63
80
76
2.82
2.05
2.51
2.91
2.67
2.28
2.51
2.86
3.63
> 250
> 500
> 250
> 140
> 125
> 500
> 500
> 250
> 62.5
> 250j
> 500j
> 125j
> 250j
> 250j
> 500j
> 500j
> 125j
> 125j
255.19
± 2.42
> 125j
> 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
-
-
-
-
-
-
-
-
-
> 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
> 10
-
-
-
-
-
-
-
-
-
5c
5d
5e
4-CH3-C6H4
5f
3-CN-C6H4
5g
C6H5
5h
5-methylthiophen-2-yl
4-CH3(CH2)2O-C6H4
5i
5j
4-CHO-C6H4
4-CF3O-C6H4
58
80
2.07
3.56
> 51
> 10
> 10
-
-
> 10
> 10
-
-
5k
> 184
4.44 ±
0.7
5.47 ±
0.6
1.66
± 0.7
2.18 ±
0.6
6a
6b
6c
6d
4-CH3-C6H4
3-CH3O-C6H4
4-CH2OH-C6H4
Cyclopropyl
83
85
64
45
2.94
3.00
2.08
2.03
3.3
8.1
2.1
1.4
2.5
14
6.41 ±
1.9
12.86 ± 1.58
0.92 ±
0.6
0.3
8.77 ±
0.2
± 0.9
4.11
± 1.7
4.59
± 1.8
3.49
± 0.8
0.61
1.61 ±
0.4
9 ± 0.8
5.4
1.6
14.77 ±
4.2
6.45 ±
0.1
4.1 ±
1.8
8.30 ±
2.1
18.14 ±
1.2
3.63 ±
2.0
6e
6f
3-NH2-C6H4
35
2.23
5.2
5
4-(tert-butyl)-C6H4
76
4.48
4.22 ±
6.62 ±
10.8
2.86 ±
2.3
5

0.9
8.35 ±
3.1
0.6
6.65 ±
0.6
± 0.4
4.67
± 2.9
2.08
± 0.7
1.2
2.11 ±
0.4
6g
6h
Cyclopentanol
C6H5
75
95
1.50
2.65
1.4
1.7
3.1
2.4
5.40 ±
2.0
3.54 ±
0.3
1.46 ±
0.3
0.06 ±
0.01
4.65 ±
0.08
Doxorubicing
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.18
±
0.03
Amphotericin
Bh
-
-
2.31 ±
0.1
Benznidazolei
-
-
a Calculated by Alogps version 2.1 software. b Results are the mean ± SD of three independent biological replicates. c Results are the mean ± SD of
at least three independent biological replicates. d SI = CC50 CHO cells/IC50 L. donovani. Results are the mean ± SD of four independent biological
e
f
g
h
replicates. SI = CC50 CHO cells/IC50 T. cruzi. Doxorubicin was used as a cytotoxic reference drug. Amphotericin B was used as antileishmanial
reference drug. i Benznidazole was used as antitrypanosomal reference drug. j The product could not be tested at higher concentrations in aqueous
medium. k The product was synthesized by direct arylation. l The product was synthesized by Suzuki-Miyaura reaction.
Table 2. In vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) activity and cytotoxicity of synthesized
imidazooxazoles.
4. Experimental section
4.1. Chemistry
chromatographic analysis, total duration of 8 min, was
performed with the following gradient of solvents: t = 0
min, water/methanol 50/50; 0 < t < 4 min, linear
increase in the proportion of water to
a
4.1.1. General procedure
water/methanol ratio of 95/5; 4 < t < 6 min,
water/methanol 95/5; 6 < t < 7 min, linear decrease in
All commercially available solvents and reagents were
purchased from commercial suppliers (Fluorochem or
Sigma Aldrich) and used without further purification.
Melting points were determined in open capillary tubes
the proportion of water to return to
water/methanol of 50/50;
a
7
ratio
min,
6
<
t
<
water/methanol 50/50. The water used was buffered
with 5 mM ammonium acetate. Microwave reactions
were performed with a Biotage® Initiator Microwave
oven using 2–5 mL sealed vials; temperatures were
measured with an IR-sensor and reaction times are
given as hold times.
1
with a Büchi apparatus B-540 and are uncorrected. H
and 13C NMR spectra were recorded on a Brucker
Avance 250 or 400 MHz instrument at the Faculté de
Pharmacie de Marseille and Faculté des Sciences de St
Jérôme (Marseille) at 24 °C in CDCl3 and DMSO-d6
solvents. Chemical shifts are given in δ values
referenced to the solvent and using tetramethylsilane
(TMS) as an internal standard. High resolution mass
4.1.2. Synthesis of intermediate products
4.1.2.1. 1-(2-Bromo-4-nitro-1H-imidazol-1-yl)propan-2-
spectra were recorded on
a QStar Elite mass
ol (1)
spectrometer at the Spectropôle department of the
Faculté des Sciences de St Jérôme. PEG was the matrix
for HRMS. Silica Gel 60 (Merck, particle size 0.063–
0.200 mm, 70–230 mesh ASTM) was used for column
chromatography. TLC was performed on aluminium
plates coated with silica gel 60F-254 (Merk) in an
appropriate eluent, with visualization undo ultraviolet
light (234 nm). Progress of the reactions and purity of
the synthesized compounds were monitored by LC-MS
analyses realized at the Faculté de Pharmacie de
Marseille on a Thermo Scientific Accela High Speed LC
System® coupled with a single quadrupole mass
spectrometer Thermo MSQ Plus®. The RP-HPLC column
used is a Thermo Hypersil Gold® 50 _ 2.1mm (C13
bounded), with particles of 1.9 mM diameter. The
volume of sample injected on the column was 1 mL. The
To a solution of 2-bromo-4(5)-nitro-1H-imidazole[29]
(500 mg, 2.61 mmol, 1 equiv.) in DIPEA (1.69 g, 13
mmol, 2.3 mL, 5 equiv.), propylene oxyde (227 mg, 3.91
mmol, 0.27 mL, 1.5 equiv.) was added. The reaction
mixture was stirred for 1.5 h at 110 °C under microwave
irradiation. After cooling, the reaction mixture was
poured into an ice-NaHCO3 aqueous solution (60 mL)
and extracted four times with CH2Cl2 (4 × 60 mL). The
organic layer was washed three times with brine (3 ×
100 mL), dried over Na2SO4, filtered and evaporated
under reduced pressure. The residue was purified by
column chromatography (silica gel, CH2Cl2/MeOH, 99:1
and recrystallized from i-PrOH).
Yield: 391 mg (65%); yellow solid; mp 116 °C.
6

3
2
1H NMR (400 MHz, DMSO-d6): δ = 1.12 (d, 3JH-H = 5.6 Hz,
4.38 (dd, JH-H = 7.9 Hz, JH-H = 10.2, 1H, CH2); 5.45-5.54
3
3H, CH3); 3.88-4.08 (m, 3H, CH, CH2); 5.17 (d, JH-H = 5.2
(m, 1H, CH).
Hz, 1H, OH); 8.51 (s, 1H, CHAr).
13C NMR (62.5 MHz, CDCl3): δ = 20.5 (CH3); 49.9 (CH2);
13C NMR (62.5 MHz, DMSO-d6): δ = 20.9 (CH3); 55.5
80.3 (C); 83.9 (CH); 96.9 (C); 155.3 (C).
(CH2); 65.1 (CH); 121.4 (C); 125.4 (CH); 146.4 (C).
HRMS: m/z [M + H]+ calcd for [C6H6BrN3O3]+: 247.9665;
HRMS: m/z [M + H]+ calcd for [C6H8BrN3O3]+: 249.9822;
found: 247.9662.
found: 249.9824.
4.1.3. General procedure for the Suzuki-Miyaura
4.1.2.2. 2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]
reaction of 4 with various boronic acids
oxazole (2)
To a sealed glass vial were added the brominated
derivative 4 (100 mg, 0.4 mmol, 1 equiv.), boronic acid
derivative (1.3 equiv.), Pd(PPh3)4 (5 mol%), and Na2CO3
(3 equiv.) in DME/H2O mixture (1.5 mL/0.5 mL). The
vessel was capped, and the solution was heated for 1.5
h at 100 °C. After cooling, the reaction mixture was
filtered on celite. The solution was poured in water (40
mL) and extracted three times with CH2Cl2 (40 mL). The
organic layer was washed three times with brine (3 ×
100 mL), dried over Na2SO4, filtered and evaporated
under reduced pressure. The crude product was
purified by column chromatography (silica gel,
CH2Cl2/MeOH, 99:1) and recrystallized from i-PrOH.
A
solution of 1-(2-bromo-4-nitro-1H-imidazol-1-
yl)propan-2-ol 1 (1 g, 40 mmol, 1 equiv.) in N,N-
dimethylformamide anhydrous (20 mL) under N2 at 0 °C
was treated with 60% NaH (321 mg, 80 mmol, 2 equiv.).
The resulting mixture was stirred at 0 °C for 65 min,
quenched with ice/aqueous NaHCO3 (50 mL) and
extracted with ethyl acetate (5 × 50 mL). The organic
layer was washed five times with brine (5 × 100 mL),
dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue was purified by column
chromatography (silica gel, CH2Cl2/MeOH, 99:1 and
recrystallized from i-PrOH).
Yield: 373 mg (55%); white solid; mp 62 °C.
4.1.3.1. 2-Methyl-6-nitro-5-[3-(trifluoromethyl)phenyl]-
2,3-dihydroimidazo[2,1-b]oxazole (5a = 3)
1H NMR (400 MHz, CDCl3): δ = 1.67 (d, 3JH-H = 6.3 Hz, 3H,
3
2
CH3); 3.88 (dd, JH-H = 7.5 Hz, JH-H = 10.2 Hz, 1H, CH2);
Yield: 100 mg (79%); brown oil solidified by trituration
in cyclohexane.
3
2
4.40 (dd, JH-H = 8.1 Hz, JH-H = 10.2, 1H, CH2); 5.40-5.48
(m, 1H, CH); 7.54 (s, 1H, CHAr).
3
1H NMR (400 MHz, CDCl3): δ = 1.68 (d, JH-H = 6.4 Hz,
13C NMR (62.5 MHz, CDCl3): δ = 20.3 (CH3); 50.2 (CH2);
83.8 (CH); 112.5 (CH); 156.5 (C) (C-NO2 was not
observed in these conditions).
3H, CH3); 3.80 (dd, JH-H = 7.5 Hz, JH-H = 10.2 Hz, 1H,
3
2
3
2
CH2); 4.35 (dd, JH-H = 8.1 Hz, JH-H = 10.2 Hz, 1H, CH2);
5.45-5.54 (m, 1H, CH); 7.61-7.65 (m, 1H, CHAr); 7.72-7.77
(m, 3H, 3CHAr).
HRMS: m/z [M + H]+ calcd for [C6H7N3O3]+: 170.0560;
found: 170.0561.
13C NMR (100 MHz, CDCl3): δ = 20.5 (CH3); 50.1 (CH2);
3
84.2 (CH); 122.5 (C); 125.2 (CH); 126.2 (q, JC-F = 4.4 Hz,
4.1.2.3. 5-Bromo-2-methyl-6-nitro-2,3-dihydroimidazo
3
CH); 127.0 (q, JC-F = 3.7 Hz, CH); 127.7 (CH); 129.5 (C);
[2,1-b]oxazole (4)
1
131.6 (q, JC-F = 281.0 Hz, C); 133.1 (C); 142.7 (C); 155.5
(C).
To
a
solution
of
2-methyl-6-nitro-2,3-
dihydroimidazo[2,1-b]oxazole 2 (300 mg, 1.77 mmol, 1
equiv.) in acetonitrile (7 mL), N-bromosuccinimide (1.77
mmol, 315 mg, 1 equiv.) was added and the reaction
mixture was stirred 1 h at room temperature. After
evaporation under reduced pressure, the residue was
purified by column chromatography (silica gel,
CH2Cl2/MeOH, 99:1 and recrystallized from i-PrOH).
HRMS: m/z [M+H]+ calcd for [C13H10F3N3O3]+: 314.0747;
found: 314.0746.
4.1.3.2.
[4-(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-
b]oxazol-5-yl)phenyl]methanol (5b)
Yield: 60 mg (54%); yellow solid; mp 80 °C.
1H NMR (400 MHz, CDCl3): δ = 1.67 (d, 3JH-H = 6.2 Hz, 3H,
Yield: 307 mg (70%); yellow solid; mp 135 °C.
3
2
CH3); 3.78 (dd, JH-H = 7.6 Hz, JH-H = 10.1 Hz, 1H, CH2);
4.31 (dd, 3JH-H = 7.9 Hz, 2JH-H = 10.1, 1H, CH2); 4.78 (s, 2H,
3
1H NMR (400 MHz, CDCl3): δ = 1.68 (d, JH-H = 6.4, 3H,
3
2
3
CH3); 3.85 (dd, JH-H = 7.6 Hz, JH-H = 10.1 Hz, 1H, CH2) ;
CH2); 5.43-5.48 (m, 1H, CH); 7.50 (d, JH-H = 8.2 Hz, 2H,
7

3
2CHAr ); 7.53 (d, JH-H = 8.2 Hz, 2H, 2CHAr). (OH was not
13C NMR (100 MHz, CDCl3): δ = 20.4 (CH3); 21.4 (CH3);
49.8 (CH2); 83.7 (CH); 123.7 (C); 127.3 (C); 129.1 (2CH);
129.4 (2CH); 140.5 (C); 142.0 (C); 154.9 (C).
observed in these conditions)
13C NMR (62.5 MHz, CDCl3): δ = 20.4 (CH3); 49.9 (CH2);
64.6 (CH2); 83.8 (CH); 125.7 (C); 126.1 (C); 127.0 (2CH);
128.2 (C); 129.5 (2CH); 143.1 (C); 155.1 (C).
HRMS: m/z [M+H]+ calcd for [C13H13N3O3]+: 260.1030;
found: 260.1029.
HRMS: m/z [M+H]+ calcd for [C13H13N3O4]+: 276.0979;
4.1.3.6. 3-(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]
found: 276.0980.
oxazol-5-yl)benzonitrile (5f)
4.1.3.3. 2-Methyl-6-nitro-5-(3,4,5-trimethoxyphenyl)2,3-
Yield: 64 mg (59%); yellow solid; mp 159 °C.
dihydroimidazo[2,1-b]oxazole (5c)
1H NMR (400 MHz, CDCl3): δ = 1.68 (d, 3JH-H = 6.4 Hz, 3H,
3
2
Yield: 108 mg (80%); yellow solid; mp 173 °C.
CH3); 3.84 (dd, JH-H = 7.7 Hz, JH-H = 10.1 Hz, 1H, CH2);
3
2
4.38 (dd, JH-H = 8.1 Hz, JH-H = 10.1 Hz, 1H, CH2); 5.49-
1H NMR (400 MHz, CDCl3): δ = 1.67 (d, 3JH-H = 6.2 Hz, 3H,
3
5.54 (m, 1H, CH); 7.62 (t, JH-H = 8.1 Hz, 1H, CHAr); 7.74
3
2
CH3); 3.79 (dd, JH-H = 7.7 Hz, JH-H = 10.2 Hz, 1H, CH2);
3
3
(d, JH-H = 7.8 Hz, 1H, CHAr); 7.83 (d, JH-H = 6.0 Hz, 2H,
3
3.87 (s, 6H, 2OCH3); 3.91 (s, 3H, OCH3); 4.35 (dd, JH-H
=
2CHAr).
2
7.9 Hz, JH-H = 10.2 Hz, 1H, CH2); 5.44-5.50 (m, 1H, CH);
6.76 (s, 2H, 2CHAr ).
13C NMR (100 MHz, CDCl3): δ = 20.3 (CH3); 50.0 (CH2);
84.0 (CH); 113.3 (C); 115.8 (C); 117.7 (C); 128.3 (C);
129.7 (CH); 132.5 (CH); 133.3 (CH); 133.9 (CH); 142.9
(C); 155.5 (C).
13C NMR (100 MHz, CDCl3): δ = 20.5 (CH3); 50.2 (CH2);
56.6 (2OCH3); 61.1 (OCH3); 83.9 (CH); 107.2 (2CH); 121.8
(C); 127.2 (C); 139.9 (C); 142.2 (C); 153.5 (2C); 155.0 (C).
HRMS: m/z [M+H]+ calcd for [C13H10N4O3]+: 271.0826;
HRMS: m/z [M+H]+ calcd for [C15H17N3O6]+: 336.1190;
found: 271.0826.
found: 336.1191.
4.1.3.7. 2-Methyl-6-nitro-5-phenyl-2,3-dihydroimidazo
4.1.3.4. 5-(4-Chlorophenyl)-2-methyl-6-nitro-2,3-dihydro
[2,1-b]oxazole (5g)
imidazo[2,1-b]oxazole (5d)
Yield: 62 mg (63%); yellow solid; mp 153 °C.
Yield: 67 mg (60%); yellow solid (solidification after
trituration in cyclohexane); mp 71 °C.
1H NMR (400 MHz, CDCl3): δ = 1.67 (d, 3JH-H = 6.4 Hz, 3H,
3
2
CH3); 3.78 (dd, JH-H = 7.7 Hz, JH-H = 10.0 Hz, 1H, CH2);
1H NMR (400 MHz, CDCl3): δ = 1.66 (d, 3JH-H = 6.4 Hz, 3H,
3
2
4.30 (dd, JH-H = 8.1 Hz, JH-H = 10.0 Hz, 1H, CH2); 5.44-
3
2
CH3); 3.76 (dd, JH-H = 7.7 Hz, JH-H = 10.1 Hz, 1H, CH2);
5.50 (m, 1H, CH); 7.47-7.54 (m, 5H, 5CHAr).
3
2
4.32 (dd, JH-H = 8.1 Hz, JH-H = 10.1 Hz, 1H, CH2); 5.44-
5.49 (m, 1H, CH); 7.45-7.51 (m, 4H, 4CHAr).
13C NMR (100 MHz, CDCl3): δ = 20.4 (CH3); 49.9 (CH2);
83.7 (CH); 126.7 (C); 126.9 (C); 128.7 (2CH); 129.3 (2CH);
130.1 (CH); 142.2 (C); 155.0 (C).
13C NMR (100 MHz, CDCl3): δ = 20.4 (CH3); 49.9 (CH2) ;
83.8 (CH); 125.1 (C); 127.5 (C); 129.1 (2CH); 130.6 (2CH);
131.6 (C); 136.3 (C); 155.2 (C).
HRMS: m/z [M+H]+ calcd for [C12H11N3O3]+: 246.0873;
found: 246.0873.
HRMS: m/z [M+H]+ calcd for [C12H10ClN3O3]+: 280.0483;
found: 280.0486.
4.1.3.8. 2-Methyl-5-(5-methylthiophen-2-yl)-6-nitro-2,3-
dihydroimidazo[2,1-b]oxazole (5h)
4.1.3.5. 2-Methyl-6-nitro-5-(p-tolyl)-2,3-dihydroimidazo
[2,1-b]oxazole (5e)
Yield: 86 mg (80%); yellow solid; mp 155 °C.
Yield: 86 mg (82%); yellow solid; mp 174 °C.
1H NMR (400 MHz, CDCl3): δ = 1.69 (d, 3JH-H = 6.4 Hz, 3H,
3
CH3); 2.55 (s, 3H, CH3); 3.97 (dd, JH-H = 7.5 Hz, 2JH-H = 9.8
3
1H NMR (400 MHz, CDCl3): δ = 1.66 (d, JH-H = 6.4 Hz,
3
2
Hz, 1H, CH2); 4.53 (dd, JH-H = 8.3 Hz, JH-H = 9.7 Hz, 1H,
3H, CH3); 2.41 (s, 3H, CH3); 3.75 (dd, 3JH-H = 7.6 Hz, 2JH-H
=
3
CH2); 5.45-5.50 (m, 1H, CH); 6.83 (d, JH-H = 3.5 Hz, 1H,
10.1 Hz, 1H, CH2); 4.30 (dd, 3JH-H = 8.0 Hz, 2JH-H = 10.1 Hz,
CHAr); 7.50 (d, 3JH-H = 3.7 Hz, 1H, CHAr).
3
1H, CH2); 5.41-5.46 (m, 1H, CH); 7.27 (d, JH-H = 3.7 Hz,
2H, 2CHAr); 7.43 (d, 3JH-H = 8.2 Hz, 2H, 2CHAr).
13C NMR (100 MHz, CDCl3): δ = 15.5 (CH3); 20.7 (CH3);
51.5 (CH2); 83.9 (CH); 123.0 (C); 125.1 (C); 126.4 (CH);
131.1 (CH); 141.4 (C); 144.8 (C); 155.1 (C).
8

HRMS: m/z [M+H]+ calcd for [C11H11N3O3S]+: 266.0594;
125.5 (C); 125.8 (C); 131.4 (2CH); 142.7 (C); 150.5 (C);
155.5 (C).
found: 266.0593.
4.1.3.9. 2-Methyl-6-nitro-5-(4-propoxyphenyl)-2,3-
HRMS: m/z [M+H]+ calcd for [C13H10F3N3O4]+: 330.0696;
dihydroimidazo[2,1-b]oxazole (5i)
found: 330.0698.
Yield: 93 mg (76%); yellow solid; mp 116 °C.
4.1.4. General procedure for the Sonogashira reaction of
4 with various alkynes
1H NMR (400 MHz, CDCl3): δ = 1.06 (t, 3JH-H = 4.4 Hz, 3H,
3
CH3); 1.67 (d, JH-H = 6.4 Hz, 3H, CH3); 1.82-1.87 (m, 2H,
To a sealed glass vial were added the brominated
derivative 4 (100 mg, 0.4 mmol, 1 equiv.), alkyne
derivative (0.6 mmol, 1.5 equiv.), CuI (7.7 mg, 0.04
mmol, 0.1 equiv.), Pd(PPh3)2Cl2 (14.2 mg, 0.02 mmol, 5
mol%), and Et3N (82 mg, 0.8 mmol, 0.11 mL, 3 equiv.) in
DMF (3 mL). The vessel was capped and then evacuated
and backfilled with N2 (process repeated 3×). The
solution was stirred at room temperature for 6 h. The
reaction mixture was then filtered on celite, poured in
water (40 mL) and extracted three times with ethyl
acetate (40 mL). The organic layer was washed five
times with brine (5 × 100 mL), dried over Na2SO4,
filtered and evaporated under reduced pressure. The
crude product was purified by column chromatography
(silica gel, CH2Cl2/MeOH, 99:1) and recrystallized from i-
PrOH.
3
2
CH2); 3.78 (dd, JH-H = 7.6 Hz, JH-H = 10.2 Hz, 1H, CH2);
3
3
3.98 (t, JH-H = 6.5 Hz, 2H, CH2); 4.30 (dd, JH-H = 7.9 Hz,
2JH-H = 10.0 Hz, 1H, CH2); 5.42-5.47 (m, 1H, CH); 6.98 (d,
3
3JH-H = 8.8 Hz, 2H, 2CHAr); 7.48 (d, JH-H = 8.7 Hz, 2H,
2CHAr).
13C NMR (100 MHz, CDCl3): δ = 10.5 (CH3); 20.4 (CH3);
22.5 (CH2); 49.9 (CH2); 69.7 (CH2); 83.6 (CH); 114.7
(2CH); 118.4 (C); 130.8 (2CH); 141.9 (C); 154.8 (C); 160.5
(C). (C-NO2 was not observed in these conditions).
HRMS: m/z [M+H]+ calcd for [C15H17N3O4]+: 304.1292;
found: 304.1288.
4.1.3.10. 4-(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-
b]oxazol-5-yl)benzaldehyde (5j)
Yield: 64 mg (58%); yellow solid; mp 74 °C.
4.1.4.1. 2-Methyl-6-nitro-5-(p-tolylethynyl)-2,3-dihydro
1H NMR (400 MHz, CDCl3): δ = 1.70 (d, 3JH-H = 6.4 Hz, 3H,
CH3); 3.84 (dd, 3JH-H = 7.8 Hz, 2JH-H = 9.8 Hz, 1H, CH2); 4.36
imidazo[2,1-b]oxazole (6a)
Yield: 94 mg (83%); yellow solid; mp 128 °C.
3
2
(dd, JH-H = 8.2 Hz, JH-H = 9.8 Hz, 1H, CH2); 5.48-5.55 (m,
1H NMR (400 MHz, CDCl3): δ = 1.69 (d, 3JH-H = 6.2 Hz, 3H,
3
1H, CH); 7.72 (d, 3JH-H = 8.2 Hz, 2H, 2CHAr ); 8.0 (d, JH-H
=
CH3); 2.38 (s, 3H, CH3); 3.88-3.93 (m, 1H, CH2); 4.44 (m,
8.1 Hz, 2H, 2CHAr); 10.08 (s, 1H, CHAr).
3
1H, CH2); 5.50 (m, 1H, CH); 7.19 (d, JH-H = 7.7 Hz, 2H,
2CHAr); 7.46 (d, 3JH-H = 7.8 Hz, 2H, 2CHAr).
13C NMR (100 MHz, CDCl3): δ = 20.5 (CH3); 50.2 (CH2);
84.1 (CH); 125.3 (C); 129.9 (2CHAr); 130.1 (2CHAr); 132.5
(C); 137.0 (C); 143.0 (C); 155.7 (C); 191.3 (C).
13C NMR (100 MHz, CDCl3): δ = 20.6 (CH3); 21.8 (CH3);
49.4 (CH2); 75.3 (C); 84.4 (CH) ; 101.5 (C); 109.7 (C);
118.1 (C); 129.5 (2CH); 132.0 (2CH); 140.7 (C); 155.1 (C).
(C-NO2 was not observed in these conditions).
HRMS: m/z [M+H]+ calcd for [C13H11N3O4]+: 274.0822;
found: 274.0822.
HRMS: m/z [M+H]+ calcd for [C15H13N3O3]+: 284.1030;
4.1.3.11. 2-Methyl-6-nitro-5-[4-(trifluoromethoxy)
phenyl]-2,3-dihydroimidazo[2,1-b]oxazole (5k)
found: 284.1031.
Yield: 105 mg (80%); yellow solid (solidification after
trituration in cyclohexane); mp 73 °C.
4.1.4.2. 5-[(3-Methoxyphenyl)ethynyl]-2-methyl-6-nitro-
2,3-dihydroimidazo[2,1-b]oxazole (6b)
1H NMR (400 MHz, CDCl3): 1.66 (d, JH-H = 6.4 Hz, 3H,
3
Yield: 103 mg (85%); yellow solid; mp 148 °C.
3
2
CH3); 3.79 (dd, JH-H = 7.8 Hz, JH-H = 10.1 Hz, 1H, CH2);
1H NMR (400 MHz, CDCl3): δ = 1.69 (d, 3JH-H = 6.3 Hz, 3H,
3
2
4.34 (dd, JH-H = 8.1 Hz, JH-H = 10.0 Hz, 1H, CH2); 5.45-
5.50 (m, 1H, CH); 7.32 (d, 3JH-H = 8.3 Hz, 2H, 2CHAr); 7.60
(d, 3JH-H = 8.7 Hz, 2H, 2CHAr).
CH3); 3.82 (s, 3H, CH3); 3.90-3.97 (m, 1H, CH2); 4.42-4.49
3
(m, 1H, CH2); 5.46-5.53 (m, 1H, CH); 6.97 (d, JH-H = 8.1
Hz, 1H, CH); 7.06 (s, 1H, CHAr); 7.15 (d, 3JH-H = 7.1 Hz, 1H,
13C NMR (100 MHz, CDCl3): δ = 20.6 (CH3); 50.2 (CH2);
CH); 7.28-7.30 (m, 1H, CHAr).
1
84.2 (CH); 120.6 (q, JC-F = 259.0 Hz, C); 121.2 (2CH);
9

13C NMR (100 MHz, CDCl3): δ = 20.8 (CH3); 49.6 (CH2);
55.7 (CH3); 75.7 (C); 84.6 (CH); 101.0 (C); 109.5 (C);
116.9 (CH); 116.9 (CH); 122.3 (C); 124.8 (CH); 130.0
(CH); 148.1 (C); 155.4 (C); 159.7 (C).
13C NMR (100 MHz, DMSO-d6): δ = 19.7 (CH3); 48.7
(CH2); 75.3 (C); 85.5 (CH); 101.0 (C); 109.8 (C); 116.0
(CH); 116.1 (CH); 119.0 (CH); 120.6 (C); 129.5 (CH);
146.4 (C); 149.0 (C); 155.1 (C).
HRMS: m/z [M+H]+ calcd for [C15H13N3O4]+: 300.0979;
HRMS: m/z [M+H]+ calcd for [C14H12N4O3]+: 285.0982;
found: 300.0985.
found: 285.0983.
4.1.4.3. {4-[(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-
4.1.4.6. 5-{[4-(Tert-butyl)phenyl]ethynyl}-2-methyl-6-
b]oxazol-5-yl)ethynyl]phenyl}methanol (6c)
nitro-2,3-dihydroimidazo[2,1-b]oxazole (6f)
Yield: 78 mg (64%); yellow solid; mp 192 °C.
Yield: 100 mg (76%); yellow solid; mp 154 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.57 (d, 3JH-H = 6.3 Hz,
1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 9H, 3CH3); 1.70
3
2
3
3H, CH3); 4.05 (dd, JH-H = 7.4 Hz, JH-H = 9.9 Hz, 1H, CH2);
(d, JH-H = 6.2 Hz, 3H, CH3); 3.90-3.95 (m, 1H, CH2); 4.42-
3
2
4.51 (dd, JH-H = 8.2 Hz, JH-H = 9.9 Hz, 1H, CH2); 4.56 (d,
4.47 (m, 1H, CH2); 5.48-5.53 (m, 1H, CH); 7.40-7.42 (d,
3
3
3JH-H = 5.5 Hz, 2H, CH2); 5.35 (t, JH-H = 5.7 Hz, 1H, OH);
3JH-H = 8.1 Hz, 2H, 2CHAr); 7.52 (d, JH-H = 8.1 Hz, 2H,
5.54-5.63 (m, 1H, CH); 7.43 (d, 3JH-H = 8.2 Hz, 2H, 2CHAr);
7.58 (d, 3JH-H = 8.2 Hz, 2H, 2CHAr).
2CHAr).
13C NMR (100 MHz, CDCl3): 20.5 (CH3); 31.1 (3CH3); 35.0
(C); 49.3 (CH2); 75.2 (C); 84.2 (CH); 101.3 (C); 109.6 (C);
118.0 (C); 125.7 (2CH); 131.8 (2CH); 153.6 (C); 155.0 (C).
(C-NO2 was not observed in these conditions).
13C NMR (100 MHz, DMSO-d6): δ = 19.5 (CH3); 48.5
(CH2); 62.2 (CH2); 76.0 (C); 85.4 (CH); 99.8 (C); 109.4 (C);
118.4 (C); 126.5 (2CH); 131.3 (2CH); 145.0 (C); 146.3 (C);
155.0 (C).
HRMS: m/z [M+H]+ calcd for [C18H19N3O3]+: 326.1499;
HRMS: m/z [M+H]+ calcd for [C15H13N3O4]+: 300.0979;
found: 326.1500.
found: 300.0981.
4.1.4.7. 1-[(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]
4.1.4.4. 5-(Cyclopropylethynyl)-2-methyl-6-nitro-2,3-
oxazol-5-yl)ethynyl]cyclopentanol (6g)
dihydroimidazo[2,1-b]oxazole (6d)
Yield: 100 mg (75%); yellow solid; mp 172 °C.
Yield: 50 mg (45%); yellow solid; mp 137 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.55 (d, 3JH-H = 6.4 Hz,
3H, CH3); 1.70-1.77 (m, 4H, 2CH2); 1.93 (m, 4H, 2CH2);
3.92 (dd, 3JH-H = 7.4 Hz, 2JH-H = 10.0 Hz, 1H, CH2); 4.40 (dd,
1H NMR (400 MHz, CDCl3): δ = 0.91-1.04 (m, 4H, 2CH2);
3
1.51-1.59 (m, 1H, CH); 1.65 (d, JH-H = 6.5 Hz, 3H, CH3);
3.80 (dd, 3JH-H = 7.4 Hz, 2JH-H = 10.1 Hz, 1H, CH2); 4.33 (dd,
3JH-H = 8.3 Hz, JH-H = 10.0 Hz, 1H, CH2); 5.49-5.57 (m, 1H,
2
2
3JH-H = 8.2 Hz, JH-H = 10.1 Hz, 1H, CH2); 5.41-5.49 (m, 1H,
CH); 5.60 (s, H, OH).
CH).
13C NMR (100 MHz, DMSO-d6): 19.7 (CH3); 23.0 (2CH);
41.8 (2CH); 48.6 (CH2); 68.9 (C); 73.1 (C); 85.4 (CH);
106.4 (C); 109.6 (C); 146.1 (C); 154.9 (C).
13C NMR (100 MHz, CDCl3): 1.0 (CH); 9.9 (2CH2); 20.7
(CH3); 49.4 (CH2); 62.7 (C); 84.4 (CH); 107.2 (C); 110.3
(C); 147.7 (C); 154.7 (C).
HRMS: m/z [M+H]+ calcd for [C13H15N3O4]+: 278.1135;
HRMS: m/z [M+H]+ calcd for [C11H11N3O3]+: 234.0873;
found: 278.1140.
found: 234.0874.
4.1.4.8. 2-Methyl-6-nitro-5-(phenylethynyl)-2,3-dihydro
4.1.4.5. 3-[(2-Methyl-6-nitro-2,3-dihydroimidazo[2,1-b]
imidazo[2,1-b]oxazole (6h)
oxazol-5-yl)ethynyl]aniline (6e)
Yield: 103 mg (95%); yellow solid; mp 172 °C.
Yield: 42 mg (35%); yellow solid; mp 176 °C.
1H NMR (400 MHz, CDCl3): δ = 1.69 (d, 3JH-H = 6.4 Hz, 3H,
1H NMR (400 MHz, DMSO-d6): δ = 1.57 (d, 3JH-H = 6.4 Hz,
3H, CH3); 4.02 (dd, 3JH-H = 7.3 Hz, 2JH-H = 10.0 Hz, 1H, CH2);
CH3); 3.92 (dd, JH-H = 7.5 Hz, JH-H = 10.1 Hz, 1H, CH2);
3
2
3
2
4.44 (dd, JH-H = 8.1 Hz, JH-H = 10.1 Hz, 1H, CH2); 5.46-
5.54 (m, 1H, CH); 7.35-7.40 (m, 3H, 3CHAr); 7.55-7.57
(m, 2H, 2CHAr).
3
2
4.49 (dd, JH-H = 8.3 Hz, JH-H = 10.0 Hz, 1H, CH2); 5.38 (s,
2H, NH2); 5.56 (m, 1H, CH); 6.68-6.78 (m, 2H, 2CHAr);
7.09-7.13 (m, 2H, 2CHAr).
10

13C NMR (100 MHz, CDCl3): δ = 20.8 (CH3); 49.6 (CH2);
75.9 (C); 84.6 (CH); 101.1 (C); 109.6 (C); 121.4 (C); 128.9
(2CH); 130.3 (CH); 132.3 (2CH); 148.1 (C); 155.4 (C).
absorbance measured in a plate reader at 570 nm in a
BIO-TEK ELx808 Absorbance Microplate Reader. The IC50
was defined as the concentration of drug required to
inhibit by 50% of the metabolic activity of L. donovani
promastigotes compared to the control. IC50 values
were calculated by non-linear regression analysis of
data from dose-response curves, using TableCurve 2D
V5.0 software (Systat Software, San Jose, CA, USA). IC50
values is are reported as means calculated from at least
three independent experiments.
HRMS: m/z [M+H]+ calcd for [C14H11N3O3]+: 270.0873;
found: 270.0876.
4.1.5. Crystal Data for Compound 5h
C11H11N3O3S, M = 265.29, a = 15.1000 (3) Å, b =
8.7277(2) Å, c = 179273(5) Å, α = 90, β = 90, γ = 90, V =
2362.61(10) Å3, T = 298 K, space group P1 Z = 8,7755
reflections measured, 2264 independent reflections (Rint
= 2264). The final R1 values were 0.0445 (I > 2σ(I)). The
final wR(F2) values were 0.1259 (I > 2σ(I)). The final R1
values were 0.0501 (all data). The final wR(F2) values
were 0.1310 (all data). The goodness of fit on F2 was
1.143. CCDC 1951503 contains the supplementary
crystallographic data for this paper. These data can be
4.2.2. Antitrypanosomal activity assay on T. cruzi
amastigotes.
Experiments were performed using tdTomato labeled
trypomastigotes with the modifications described by
Recher et al.[32] IC50 values were determined by non-
linear regression analysis using SigmaPlot.
obtained
free
of
charge
from
at
the
www.cdcc.cam.ac.uk/data_request/cif
Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; Fax: + 44 (1223) 336033;
email: deposit@ccdc.cam.ac.uk.
4.2.3. Cytotoxicity in vitro assays on CHO and HepG2 cell
lines.
A cytotoxicity evaluation was realized according to the
method of Mosmann[30] with slight modifications[33] to
determine the cytotoxic concentrations 50% (CC50) and
using doxorubicin as a cytotoxic reference compound.
These assays were performed toward two adherent cell
lines: i) the human HepG2 cell line (hepatocarcinoma
cell line purchased from ATCC, ref HB-8065), ii) the
mammal CHO cell line (Chinese Hamster Ovarian cell
line purchased from ATCC, ref CCL-61).
4.2. Biology
4.2.1. Antileishmanial in vitro activity assay against L.
donovani promastigote forms.
L. donovani (MHOM/IN/00/DEVI) used in this study was
provided by the CNR Leishmania (Montpellier, France).
The effects of the tested compound on the growth of L.
donovani (MHOM/IN/00/DEVI) promastigotes were
assessed by MTT assay.[30] Briefly, promastigotes in log-
phase in Schneider’s medium supplemented with 20%
fetal calf serum (FCS), 2 mM L-glutamine and antibiotics
(100 U/mL penicillin and 100 µg/mL streptomycin),
were incubated at an average density of 106
parasites/mL in sterile 96-well plates with various
concentrations of compounds dissolved in DMSO (final
concentration less than 0.5% v/v), in duplicate.
Appropriate controls treated by DMSO and
amphotericin B (reference drug purchased from Sigma-
Aldrich) were added to each set of experiments. After
72 h incubation period at 27 °C, parasite metabolic
activity was determined. Each well was microscopically
examined for precipitate formation. To each well was
added 20 µL of a 5 mg/mL MTT [3-(4,5-dimethylthiazol-
Briefly, an adjusted culture of cells in 100 µL of culture
medium supplemented with 10% FCS, 1% L-glutamine
(200 mM) and penicillin (100 U/mL) / streptomycin (100
µg/mL) (complete RPMI medium), was inoculated into
each well of 96-well plates and incubated at 37 °C in a
humidified 5% CO2. After 24 h incubation to obtain
adherent cells, 100 µL of medium with various product
concentrations dissolved in DMSO (final concentration
less than 0.5% v/v) were added and the plates were
incubated for 24 h (CHO) to 72 h (HepG2) at 37 °C.
Duplicate assays were performed for each sample. Each
plate-well was then microscope-examined for detecting
possible precipitate formation before the medium was
aspirated from the cells. 100 µL of MTT (3-(4,5-
dimethyl-2-thiazolyl)-2,5-diphenyl-2H-
2-yl)-2,5-diphenyltetrazolium
bromide)]
solution
tetrazoliumbromide) solution (0.5 mg/mL in medium
without FCS) were then added to each well. Cells were
incubated for 2 h at 37 °C to allow MTT oxidation by
mitochondrial dehydrogenase in the viable cells. After
this time, the MTT solution was removed and DMSO
11
followed by incubation for another 4 h. The enzyme
reaction was stopped by addition of 100 µL of 50%
isopropanol/10% sodium dodecyl sulfate.[31] Plates were
shaken vigorously (300 rpm) for 10 min, and the

(100 µL) was added to dissolve the resulting blue
formazan crystals. Plates were shaken vigorously (300
rpm) for 5 min. The absorbance was measured at 570
nm with 630 nm as reference wavelength
spectrophotometer using a BIO-TEK ELx808 Absorbance
Microplate Reader. DMSO was used as blank and
doxorubicin (purchased from Sigma Aldrich) as positive
control. Cell viability was calculated as percentage of
control (cells incubated without compound). The 50%
cytotoxic concentrations (HepG2 CC50 and CHO CC50
respectively) were determined by non-linear regression
analysis processed on dose-response curves, using the
Table Curve software 2D v.5.0. CC50 values represent
the mean value calculated from three independent
experiments.
6. Le Pape, P. Development of new antileishmanial
drugs – current knowledge and future prospects. J.
Enzyme Inhib. Med. Chem. 2008, 23, 708–718.
7. https://www.who.int/fr/news-room/fact-
sheets/detail/trypanosomiasis-human-african-
(sleeping-sickness) (Accessed 19 Sept 2019).
8. WHO interim guidelines for the treatment of
gambiense human African trypanosomiasis, WHO,
2019.
9. Deeks, E. D. Fexinidazole: First Global Approval.
Drugs 2019, 79, 215–220.
10. https://apps.who.int/iris/bitstream/handle/10665/
325771/WHO-MVP-EMP-IAU-2019.06-eng.pdf?ua=
1 (Accessed 19 Sept 2019).
11. https://www.yumpu.com/en/document/read/3707
4971/1a9bnbk/5. (Accessed 19 Sept 2019).
12. Bonney, K. M.; Luthringer, D. J.; Kim, S. A.; Garg, N.
J.; Engman, D. M. Pathology and Pathogenesis of
Chagas Heart Disease. Annu. Rev. Pathol. Mech. Dis.
2019, 14, 421-447.
13. Primas, N.; Ducros, C.; Vanelle, P.; Verhaeghe, P.
The renewal of interest in nitroaromatic drugs:
toward new anti-kinetoplastid agents in
Jayaprakash, V.; Castagnolo, D.; Ozkay, Y. (Eds)
Medicinal Chemistry of Neglected Tropical
Diseases, CRC Press, 2019, 250-280.
Acknowledgments
This work was supported by the CNRS (Centre National
de la Recherche Scientifique) and Aix-Marseille
University. The authors thank V. Remusat for NMR
spectra recording, M. Piednoel for the synthesis of the
starting products and the Spectropole team for various
analytical measurements.
Drug screening on T. cruzi amastigote growth was
supported by U.S. National Institutes of Health grant
AI107663 to R.D.
14. Thompson, A. M.; O’Connor, P. D.; Blaser, A.;
Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Martin,
D.; Franzblau, S. G.; Wan, B.; Wan, Y.; Ma, Z.;
Denny, W. A. Repositioning Antitubercular 6-Nitro-
Appendix A. Supplementary data
Supplementary data related to this article is available.
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14

Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as
antikinetoplastid agents†
Fanny Mathiasa, Anita Cohenb, Youssef Kabria, Núria Waddington Negrãoc, Maxime D. Crozeta,
Roberto Docampoc,d, Nadine Azasb, Patrice Vanellea*.
a
Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de
Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385, Marseille Cedex 05, France.
b Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France.
c Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602, U.S.A.
d Department of Cellular Biology, University of Georgia, Athens, GA 30602, U.S.A.
†This paper is dedicated to the late Professor Alain Gueiffier.
•
Investigation of the pallado-catalyzed cross-coupling reactions on imidazooxazole
scaffold.
•
•
Evaluation of the antiparasitic properties against T. cruzi and L. donovani.
Evaluation of the cytotoxicity against two cell lines.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: