Design and synthesis of novel quinoxaline derivatives as potential candidates for treatment of multidrug-resistant and latent tuberculosis

Article abstract of DOI:10.1016/j.bmcl.2016.03.066

Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-Glo microbial cell viability assay. Five compounds showed MIC values <3.1 μM and IC₅₀ values <1.5 μM in primary screening and therefore, they

Full text of DOI:10.1016/j.bmcl.2016.03.066

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of novel quinoxaline derivatives
as potential candidates for treatment of multidrug-resistant
and latent tuberculosis
Mery Santivañez-Veliz a,b, Silvia Pérez-Silanes a,b, Enrique Torres a, Elsa Moreno-Viguri a,b,
⇑
a Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea s/n, 31008 Pamplona, Spain
b Institute of Tropical Health, University of Navarra, Irunlarrea s/n, E-31008 Pamplona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Twenty-four quinoxaline derivatives were evaluated for their antimycobacterial activity using BacTiter-
Glo microbial cell viability assay. Five compounds showed MIC values <3.1 M and IC50 values <1.5 M in
primary screening and therefore, they were moved on for further evaluation. Compounds 21 and 18 stand
out, showing MIC values of 1.6 M and IC50 values of 0.5 and 1.0 M, respectively. Both compounds were
the most potent against three evaluated drug-resistant strains. Moreover, they exhibited intracellular
activity in infected macrophages, considering log-reduction and cellular viability. In addition, compounds
16 and 21 were potent against non-replicating Mycobacterium tuberculosis and compound 21 was
bactericidal. Therefore, quinoxaline derivatives could be considered for making further advances in the
future development of antimycobacterial agents.
Received 15 January 2016
Revised 15 March 2016
Accepted 16 March 2016
Available online xxxx
l
l
l
l
Keywords:
Tuberculosis
Antimycobacterial
Quinoxaline
Intracellular activity
Ó 2016 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is a chronic infection caused by Mycobac-
terium tuberculosis (M. Tb.), which is the second cause of death from
a single infectious agent. Due to its high infectivity it is estimated
that a third of the world population is a reservoir of Mycobacterium.
In 2000, within the Millennium Development Goals (MDG6),
the United Nations proposed to halt the spread and reverse the
incidence of TB by 2015. Some of these objectives have already
been achieved. The TB mortality rate has decreased 45% since
1990 and more people have access to effective treatments and to
early and sensitive diagnostic methods. However, epidemiological
data are still alarming.1 According to World Health Organization
(WHO) data, 9 million people were infected by tuberculosis bacil-
lus in 2013, including 1.1 million cases among people living with
HIV. In 2013, 1.5 million people died due to tuberculosis infection,
with this being the main cause of death among people affected by
HIV. In addition, the number of infected people with multidrug-
resistant TB (MDR-TB) is increasing annually. The ability of M. Tb.
to develop resistance to drugs and the difficulties faced in the
treatment of the TB-disease has facilitated the development of
resistant strains. MDR-TB has been spreading rapidly in the last
decades, especially in recent years; the number of individuals
infected with MDR-TB tripled between 2009 and 2013, and
reached 136,000 worldwide.2
These data indicate the urgent need to continue working in the
development of new compounds against new targets and with new
mechanisms of action for treating MDR-TB. It is also important to
shorten the long periods of treatment because they are a common
reason for treatment discontinuation on the part of the patient, and
stopping the treatment too early is related with the appearance of
resistant strains.3 With this aim, our group has been working for
several years on the synthesis and biological evaluation of new
structures derived from quinoxalines. Quinoxaline derivatives
show very interesting biological properties. Several studies have
been published which justify the interest in these derivatives as
antibacterial agents. As a result of our anti-tuberculosis research
project, several papers have been published in which both synthe-
sis and biological activity assessments have been described for a
large number of quinoxaline and quinoxaline 1,4-di-N-oxide
derivatives with a variety of substituents. Some of them have
shown growth inhibition values of 99% and 100%.4–9
Abbreviations: TB, tuberculosis; M. Tb., Mycobacterium tuberculosis; BTG,
BacTiter-Glo microbial cell viability assay; MDG, Millennium Development Goals;
BFX, benzofuroxan; NRP, non-replicating persistence; MBC, Minimal bactericidal
concentration; LORA, Low Oxygen Recovery Assay; SDR, single drug-resistant; FBS,
bovine serum; NA, not available; RIF, rifampin; INH, isoniazid; OFX, ofloxacin.
This indicates that these types of structures are very interesting
for developing new anti-TB molecules. Furthermore, it has been
reported that oxidation of the nitrogen in the quinoxaline ring
⇑
Corresponding author.
E-mail address: emviguri@unav.es (E. Moreno-Viguri).
http://dx.doi.org/10.1016/j.bmcl.2016.03.066
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
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M. Santivañez-Veliz et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
provides a significant increase in the antibacterial biological activ-
ity.10 It has also been reported that the quinoxaline 1,4-di-N-oxide
derivatives suffer a bioreduction process under hypoxic condi-
tions.11 This behavior could be interesting because in the caseous
core of the tuberculous granulomas there is a low concentration
of oxygen where non-replicating persistence (NRP) forms of M.
Tb. bacilli can survive.12 These forms are thought to be the reason
behind the need for long treatments and the development of toler-
ance to the treatment.13
previously synthesized was used as the ketone. The new deriva-
tives 1–10 were unsubstituted or substituted in R1 or R2 positions
by methyl moiety as electron-releasing groups and by chlorine
moiety as electron-withdrawing groups.
The methodologies for the synthesis of compounds 11–15,
17–20 and 22–24 were previously described by our group.19
Compounds 16 and 21 were obtained by nucleophilic aromatic
substitution of chlorine or fluorine linked to R1/R2 substituent on
the quinoxaline ring. Morpholine and 1-(4-fluorophenyl)piperazine
were used as the nucleophilic amine. Compound 16 was obtained
by reflux using N,N-DMF and compound 21 was obtained using
DBU as base.
Chalcones are precursors of flavonoids and isoflavonoids, which
consist in two aromatic rings linked by a 3 carbons chain present-
ing an
a,b-unsaturated ketone system. Chalcones exhibit a wide
range of biological activities such as anticancer, anti-leishmaniasis,
anti-inflammatory, anti-oxidant and anti-tuberculosis. With regard
to the anti-mycobacterial activity of chalcones, there are numerous
publications that justify their use in the search for new anti-TB
compounds.14,15
Fluoroquinolones are an important group of broad spectrum
antibiotics and they are present in many molecules with high anti-
tuberculosis activity such as gatifloxacin and moxifloxacin, which
are under development in clinical trials.16
With the aim of developing new antitubercular drug candidates,
we have synthesized and evaluated 24 quinoxaline derivatives. The
design was based on the molecular hybridization of the quinoxa-
line 1,4-di-N-oxide with chalcone and fluoroquinolones scaffolds.17
We report the design and synthesis of the quinoxaline 1,4-di-N-
oxide derivatives 1–24. The biological evaluation of the compounds
included a M. Tb. H37Rv dose–response assay (primary screening) in
which the IC50, IC90 and MIC against M. Tb. were determined. The
most active compounds were moved on to a more advanced testing
stage for antimycobacterial activity. These assays included the eval-
uation against single drug-resistant (SDR) strains of M. Tb., Minimal
bactericidal concentration (MBC), Low Oxygen Recovery Assay
(LORA) and intracellular drug activity. All results are reported and
structure–activity relationships (SARs) are discussed.
The identification of novel interesting compounds begins with a
primary screening. This initial dose response assay evaluates the
ability of compounds to inhibit the M. Tb. replication. The IC90
,
IC50 and MIC of the 24 quinoxaline 1,4-di-N-oxide derivatives were
determined against M. Tb. H37Rv (ATCC 27294) using BacTiter-Glo
(BTG) microbial cell viability assay.
The structure and anti-tuberculosis activity data of the 24 com-
pounds are shown in Table 1. Nine out of twenty-four evaluated
compounds exhibited MIC values 66.2
ues <3.7 M. Compounds 3, 16, 18, 21 and 24 were the most active,
showing MIC values among 1.6–3.1 M and IC50 values among 0.5–
1.5 M. These MIC and IC50 values were lower than those of the
lM
and IC50 val-
l
l
l
second-line reference drugs cycloserine and pyrimethamine, and
also by the first-line drug ethambutol. It is worth noting that 4
out of the 5 most active compounds (16, 18, 21 and 24) are fluoro-
quinolone analogs while compound 3 belongs to chalcone analogs.
In comparison with fluoroquinolones, the presence of an elec-
tron-withdrawing substituent (fluorine or chlorine) in only one
of the R1 and R2 positions in the quinoxaline ring is important for
biological activity. This behavior is observed comparing the biolog-
ical results obtained for compounds 3 versus 1 and 2, 6 versus 5, 9
versus 7, 8 and 10, 13 versus 14, 18 versus 19 and 24 versus 23.
With respect to R4 substitutions, 8 out of 9 most active com-
pounds present a trifluoromethyl group. The substitution of hydro-
gen by its bioisostere fluorine is a widely used strategy in the
search for new compounds. The presence of fluorine atoms can
change and radically modulate the physicochemical properties of
organic compounds modifying its biological behavior.23 However,
it is not possible to carry out a SAR study due to the limited struc-
tural variability in this position.
The quinoxaline 1,4-di-N-oxide derivatives were synthesized
through the synthetic process illustrated in Scheme 1.
The starting benzofuroxans, were commercially available or
were obtained by previously described methods.18 The synthesis
of quinoxaline 1,4-di-N-oxide intermediates were carried out by
a variation of the Beirut reaction following the procedure described
in the literature.19–21
The 10 novel chalcone analogs (1–10) were prepared by Clai-
sen–Schmidt condensation.22 Benzaldehyde, 5-nitro-2-furalde-
hyde and 5-nitro-2-thiophenecarboxylaldehyde were used as the
starting aldehyde. The corresponding quinoxaline 1,4-di-N-oxide
With regard to R3 position, it seems to be less important for the
anti-mycobacterial activity.
With regard to N-oxide groups of the quinoxaline ring,
these groups seem to be essential for the activity as we can see
R1
R2
NO2
NH2
O-
N+
O
O
R1
R2
i
Ar
H
Ar
O-
N+
O
N+
O-
O-
N+
O
R1
R2
iv-v
R1
R2
R3
1 - 10
N+
O-
R4
ii, iii
N
W
11-14
NH
O-
N+
O
W
W
O-
N+
O
W
vi-viii
N
N
R3
R3
N
N+
O-
CF3
N+
O-
CF3
R2
15-18, 20-22, 24
19, 23
Scheme 1. General synthesis of quinoxaline 1,4-di-N-oxide derivatives. Reagents and conditions: (i) N,N-DMF, NaOCl, low temperature; (ii) ethanolamine, CaCl2; (iii)
microwave assisted synthesis; (iv) NaOH, MeOH, ice bath; (v) NaOH, MeOH, freezing bath; (vi) N,N-DMF, reflux; (vii) CH3CN, Et3N, rt; (viii) CH3CN, DBU, 50 °C.
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M. Santivañez-Veliz et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
Biological results against M. Tb. H37Rv dose–response assay
Activity against M. Tb. under aerobic conditions
Code
R4
R3
R2
R1
IC50
M)
IC90
M)
MICd
M)
b
c
(
l
(
l
(
l
1
2
3
CH3
CH3
CH3
H
H
H
H
5.8
7.2
1.5
11.5
14.7
1.7
12.5
25.0
3.1
CH3
Cl
4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
Cl
H
17.3
29.7
13.5
>100
>100
7.3
24.6
38.1
20.8
>100
>100
13.0
>100
25.0
50.0
25.0
—
5
CH3
Cl
6
7
H
8
CH3
Cl
—
9
25.0
—
10
Cl
>100
11
12
13
CF3
CF3
CF3
H
Cl
H
Cl
Cl
F
3.7
3.6
3.1
4.5
4.5
4.0
6.2
6.2
6.2
14
CF3
CF3
CF3
F
F
5.2
8.0
12.5
—
15a
16
Cl
Cl
F
>100
1.2
>100
2.1
3.1
17
18
19
CF3
CF3
CF3
CH3
CH3
CH3
5.4
1.0
2.2
10.7
1.5
12.5
1.6
F
4.6
6.2
20
21
CF3
CF3
CH3
F
4.0
0.5
7.2
0.8
12.5
1.6
O-CH3
H
22a
23
CF3
CF3
CF3
OCH2CH3
CH(CH3)2
CH3
Cl
>100
8.3
>100
17.9
1.8
—
25.0
3.1
24
F
1.3
Amikacin
0.1
0.1
0.2
Cycloserine
Ethambutol
Isoniazid
20.8
1.2
0.1
33.1
1.8
0.2
50.0
6.2
0.3
Pyrimethamine
Rifampicin
23.6
0.02
36.0
0.03
50.0
0.04
a
b
c
Quinoxaline-1-N-oxide.
IC50 against M. tuberculosis H37Rv.
IC90 against M. tuberculosis H37Rv.
MIC against M. tuberculosis H37Rv.
d
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M. Santivañez-Veliz et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 2
Minimum inhibitory concentration against single-drug resistant strains of M. Tb.
Code
Structure
H37Rv
INH-R
M. Tb.
RIF-R
M. Tb.
OFX-R
M. Tb.
SRI 1345 strain
SRI 1369 strain
SRI 1367 strain
SRI 4000 strain
MIC
% inha
MIC
% inh.
Rb
2
MIC
% inh.
Rb
4
MIC
% inh.
100
76
Rb
4
l
g/mL
lg/mL
l
g/mL
lg/mL
3
2
80
61
78
1
64
0.5
51
0.5
16
18
2
1
0.5
78
4
0.5
66
4
0.25
0.25
8
0.25
57
8
0.25
68
8
84
8
21
24
1.5
78
0.19
51
8
1
0.19
73
8
2
0.19
81
8
4
0.75
0.05
51
55
0.75
0.05
89
72
0.38
0.02
75
55
0.19
62
53
RIF
INH
0.195
INR-R: isoniazid-resistant.
RIF-R: rifampin-resistant.
OFX-R: ofloxacin-resistant.
a
Percentage inhibition at the MIC concentration.
R: Ratio of MIC H37Rv/MIC Resistant-strain.
b
Table 3
Minimal bactericidal concentration and Low Oxygen Recovery Assay results
Code
MIC H37Rv
MBC
LORA
lg/mL
% inha
lg/mL
MBC/MICH37Rv
lg/mL
MIC H37Rv/LORA
3
2
2
1
1.5
0.75
0.05
80
61
78
78
51
55
NA
TNTC
NA
4
NA
—
—
—
2.6
—
UR
0.25
>8
0.375
>12
0.39
—
8
Nd
4
Nd
—
16
18
21
24
RIF
0.78
15.6
a
Percentage inhibition at the MIC concentration. UR: unreportable: compound precipitated out of solution. NA: not applicable: colony counts above the established
rejection value P40. TNTC: too numerous to count. Nd: not determinated.
comparing compounds 15 versus 16. This important loss of activity
confirmed again that the presence of the both N-oxide groups is a
structural requirement for biological activity.24,25
According to obtained results, compounds 3, 16, 18, 21 and 24
(MIC <6.25 lM) were submitted for advanced anti-mycobacterial
susceptibility profiling. This advanced screening includes the
determination of MIC against SDR strains of M. Tb., MBC, LORA as
well as intracellular drug screening study in infected macrophages
and a MTT cell proliferation study in uninfected macrophages at
different concentrations.
Table 2 shows the MIC values of the selected compounds
against rifampin (RIF), isoniazid (INH) and ofloxacin (OFX) resis-
tant strains and a retested MIC value against a susceptible strain.
In general, the OFX-resistant M. Tb. strain was the most sensi-
tive to the 5 tested compounds. The susceptibilities of INH, RIF
and OFX-resistant strains can be considered greater than those of
These results suggest that all compounds were active against
RIF, INH and OFX-resistant M. Tb. strains. Therefore, there is no
cross-resistance with the antitubercular drugs used in the assay,
supporting the idea that our compounds act through a different
mechanism of action. These results are promising for the develop-
ment of new effective compounds against the growing number of
drug-resistant strains.
A compound is considered as bactericidal if the ratio MBC/MIC
is 64.26 This is important because bactericidal drugs can poten-
tially shorten the standard treatment regimen, which is a mini-
mum of 6 months for tuberculosis. Therefore and according to
the results showed in Table 3, compound 21 could be considered
as bactericidal due to the low ratio obtained. If a compound lacks
bactericidal activity, many times the colony-forming units (CFUs)
are too numerous to count (TNTC) as observed with compound
16.27
H
37Rv, as indicated by the ratios of MICs against non-resistant
It is well known that quinoxaline 1,4-di-N-oxide possess a
selective toxicity against hypoxic tumoral cells through a bioreduc-
tive activation process.28 In the case of tuberculosis, the granulo-
matous lesions formed in the infected lungs present a hypoxic
and resistant strains which are between 2 and 8. Only compound
24 showed low resistance with INH-resistant strain with
ratio = 1.
a
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M. Santivañez-Veliz et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
5
Table 4
Intracellular activity in M. Tb. infected J774 macrophages
Code
Log reductiona
% of cellular viability
Mid concb
Low concb
Mid concb
High concb
Low concb
High concb
3
2.11
1.68
1.74
1.43
2.17
0.48
1.68
1.57
1.5
1.41
1.66
1.73
1.76
2.67
2.66
3.86
1.76
2.68
70
88
83
60
70
93
81
37
53
64
81
87
26
37
65
47
26
80
16
18
21
24
RIF
a
Intracellular drug activity is reported as log reduction values calculated as reduction in Mtb concentration from zero hour to 7 days post-infection.
The three concentrations chosen were based on the MIC data generated in the HTS primary screen. The mid concentration bracketed the reported MIC with the lower
b
concentration ten-fold below the mid and the higher concentration ten-fold above the mid.
environment where TB bacilli are in a latent state of low metabolic
activity. These nonreplicating persistence (NRP) M. Tb. bacilli is
thought to be a main factor responsible for the long treatment peri-
ods and the emergence of antimicrobial tolerance.29 Therefore,
special attention should be paid to the NRP state of M. Tb. from
the early stages of the drug discovery process. Therefore, the LORA
assay, conducted under low oxygen conditions, has been included
in the biological evaluation with the aim of identifying compounds
able to acting on the non-replicative bacilli. As shown in Table 3,
compounds 16 and 21 were more potent against NPR M. Tb. being
8-fold and 4-fold more active under anaerobic conditions than aer-
obic conditions respectively. These results offer an important
approach for studying this family of compounds in these condi-
tions due to the important role that NRP M. Tb. bacilli play in influ-
encing the duration of treatment.
Moreover, the MIC and LORA assay show that compound 21 is
potent not only against replicating M. Tb but also against NRP M.
Tb. In addition, compound 21 could be classified as bactericidal
according to the MBC and has also stand out in the intracellular
drug activity assay. The mechanism of action of these compounds
has not yet been studied.
Acknowledgements
‘This project has been funded in whole or in part with Federal
funds from the Division of Microbiology and Infectious Diseases,
National Institute of Allergy and Infectious Diseases, National Insti-
tutes of Health, Department of Health and Human Services, under
Contract No. HHSN272201100009I’.
M.S. is indebted to Government of Navarra for grant ‘Interna-
tional Talent’ and with University of Navarra for a grant. E.T. is
indebted to the University of Navarra for a grant.
M. Tb can evade the immune response of macrophages and has
the ability to reside inside them in a latent state. This evasion
mechanism makes the effectiveness of treatment difficult and
increases the microbial resistance.30,31
Supplementary data
With the aim of assessing the intracellular effectiveness of the 5
selected compounds in this infection phase, the activity in J774
infected macrophages was evaluated. Compounds 3, 16, 18, 21
and 24 were tested at three 10-fold concentrations based on their
MIC values against M. Tb. H37Rv.
All of the evaluated compounds showed high log-reduction in
the burden of the intracellular bacilli (Table 4). However, it was
observed that none of the evaluated compounds showed dose
response log-reduction in contrast to RIF.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.03.
066.
References and notes
1. The Millennium Development Goals Report; United Nations, 2015. http://www.
un.org/millenniumgoals/2015_MDG_Report/pdf/MDG%202015%20rev%20(July
%201).pdf, p 72.
2. WHO.
World
Health
Organization.
http://www.who.
At the lowest concentration, compounds 3 and 24 showed val-
ues >2-log-reduction (>99% inhibition) while compounds 16, 18
and 21 showed values >1-log-reduction (>90% inhibition). There-
fore, the 5 evaluated compounds exhibited log-reduction among
3 to 4.5-fold more than RIF.
Compounds 16, 18 and 21 showed the highest log-reduction at
the highest concentration and presented values of 26%, 65% and
47% of cellular viability respectively at this concentration. There-
fore, compounds 18 and 21 stand out as being the most potent
derivatives against intracellular bacilli, considering log-reduction
and cell viability values.
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In conclusion, we describe the synthesis of 12 new compounds
and the antimycobacterial evaluation of 24 quinoxaline di-N-oxide
derivatives. Five of the tested compounds passed the first cut-off
established in the primary screening against H37Rv, thereby justi-
fying the great interest in this family of compounds. The results
obtained in the advanced screening (MIC against H37Rv and
SDR-strains, MBC, LORA, intracellular activity and MTT cell prolif-
eration) confirm the promising pharmacological profile of these
derivatives.
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