On the search for potential antimycobacterial drugs: Synthesis of naphthoquinoidal, phenazinic and 1,2,3-triazolic compounds and evaluation against Mycobacterium tuberculosis

Article abstract of DOI:10.5935/0103-5053.20150067

Fifteen naphthoquinones, sixteen phenazines and fifteen aryl triazoles were synthesized and evaluated against Mycobacterium tuberculosis. Twenty five substances are reported here for the first time and, among all of the compounds evaluated, six presented MIC (minimal inhibitory concentration) values ≤ 6.25 μg mL-1. These substances are promising antimycobacterial prototypes.

Full text of DOI:10.5935/0103-5053.20150067

http://dx.doi.org/10.5935/0103-5053.20150067
J. Braz. Chem. Soc., Vol. 26, No. 5, 1013-1027, 2015.
Printed in Brazil - ©2015 Sociedade Brasileira de Química
0
103 - 5053 $6.00+0.00
Article
A
On the Search for Potential Antimycobacterial Drugs: Synthesis of
Naphthoquinoidal, Phenazinic and 1,2,3-Triazolic Compounds and Evaluation
Against Mycobacterium tuberculosis
a
a
a,d
Guilherme A. M. Jardim, Eduardo H. G. Cruz, Wagner O. Valença,
a
b
c
d
Jarbas M. Resende, Bernardo L. Rodrigues, Daniela F. Ramos, Ronaldo N. Oliveira,
c,
a,
Pedro E. A. Silva * and Eufrânio N. da Silva Júnior *
a
b
Laboratório de Química Sintética e Heterocíclica and Laboratório de Cristalografia, Instituto de
Ciências Exatas, Departamento de Química, Universidade Federal de Minas Gerais,
3
1270-901 Belo Horizonte-MG, Brazil
Laboratório de Micobacterias, Faculdade de Medicina, Universidade Federal do Rio Grande,
6200-190 Rio Grande-RS, Brazil
Departamento de Ciências Moleculares, Universidade Federal Rural de Pernanbuco,
2171-900 Recife-PE, Brazil
c
9
d
5
Fifteen naphthoquinones, sixteen phenazines and fifteen aryl triazoles were synthesized and
evaluated against Mycobacterium tuberculosis. Twenty five substances are reported here for the
first time and, among all of the compounds evaluated, six presented MIC (minimal inhibitory
-1
concentration) values ≤ 6.25 μg mL . These substances are promising antimycobacterial prototypes.
Keywords: lapachol, phenazines, Mycobacterium tuberculosis, antitubercular, triazoles
Introduction
an attractive strategy, from economical, pharmaceutical,
and clinical viewpoints, is the development of new anti-TB
drugs from known molecules, especially those for which
anti-TB therapeutic use has already been demonstrated to
Tuberculosis (TB), a disease caused mainly
by Mycobacterium tuberculosis, is responsible for
approximately 1.4 million deaths annually worldwide. In
the absence of an effective vaccine the best way to control
dissemination of TB, is by treatment, but the length of this,
1
6
be safe and effective. Clofazimine, a phenazine compound,
7
was originally reported as a potent antituberculosis agent.
Phenazine-1-carboxamides have also recently been
2,3
typically six months, is a major problem faced by patients.
described as having potent activity against M. tuberculosis
8
The increasing problem of multidrug resistance (MDR)
and associated treatment failure represents a threat for
the control of this disease. This is driving the necessity
to discover new anti-TB drugs that are effective against
active or persistent infections, as well as against sensitive or
resistant strains. This, in turn, would lead to a reduction of
the treatment time and would therefore reduce toxic effects
in comparison with current chemotherapy.
Although, in recent years, a large number of molecules
have been identified as potential new anti-TB drugs, only
(Figure 1). Naphthoquinoidal compounds are considered to
be privileged structures with remarkable pharmacological
9
potential. Lapachol (1) and β-lapachone (2) are quinones
with notable activities and are representative of a select
group of bioactive substances, which, for instance, exhibit
10
11
antitumor and trypanocidal activities, and can be used
as models to obtain new drugs. Recently, our research
4
12
13
group investigated the leishmanicidal, trypanocidal, and
1
4
antimalarial activities of a large number of substances
prepared from lapachol (1) as part of our search for new
5
15,16
a few examples have emerged for clinical use. Moreover,
potential drugs against neglected diseases. Within this
context, we have described the synthesis and evaluation
1
7
of quinonoid, naphthoimidazole, naphthoxazole, and
phenazine compounds from lapachol (1) with marked
activity against M. tuberculosis (Figure 1).
*
e-mail: pedrefurg@gmail.com; eufranio@ufmg.br
1
8
This article is part of the Special Issue Rare and Neglected Diseases -
Vol. 25, No. 10 (2014).

1
014
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
Cl
N
Phenazine-1-carboxamides
R = Aryl groups
R
N
HN
O
O
O
N
N
O
N
OH
N
NH
Clofazimine
N
Cl
H
N
N
O
N
N
O
O
N
H
O
O
N
H
N
NC
CF3
Figure 1. Clofazimine, phenazine-1-carboxamides, and examples of compounds obtained from lapachol (1) with activity against M. tuberculosis.
1
,2,3-Triazoles are well known for their various
sodium acetate and acetic acid to obtain the phenazine
compounds 11-15. The same conditions were applied to
key intermediate 4, and phenazine 5 was generated in
good yield. Compounds 5-15 were obtained in racemic
form, but the trans-stereochemistry was confirmed by
X-ray crystallography analysis of compound 12 and by
biological activities, including anti-TB and antifungal
activity, and these arise by inhibition of cell wall synthesis.
Recently, our group has devoted efforts to the preparation of
new triazoles with potent biological activities, including,
for instance, β-lapachone and nor-β-lapachone-based
19
15
2
0,21
20
1
,2,3-triazoles as potent trypanocidal compounds.
In
comparison with previously reported data.
this context, as a continuation of our programme to develop
new antimycobacterial compounds, we describe herein
the synthesis of lapachone-based 1,2,3-triazoles and their
respective phenazine derivatives, besides aryl triazoles. We
also outline the evaluation these new derivatives against
pan-susceptible M. tuberculosis H Rv (ATCC 27294).
The second group of compounds was obtained
from 3-azido-nor-β-lapachone (17) following a
24
previously described procedure. Initially, 1,2,3-triazolic
naphthoquinone derivatives possessing either aryl
1
3,24
25
groups 19-24
or alkyl groups 31-34 were prepared
(Scheme 2). To evaluate redox centre modification, the
respective phenazines were prepared by the methodology
described above, and novel compounds 25-30 and 35-38
were obtained in high yields (Scheme 2).
37
Results and Discussion
Initially, β-lapachone-based 1,2,3-triazoles 6-10 were
prepared from lapachol (1) (Scheme 1). As previously
A new class of naphthoquinoidal and phenazine
compounds, containing a pendant 1,2,3-triazole motif,
was prepared from C-allyl lawsone (Scheme 3). The first
step involved iodination to provide compound 40 using
2
2
described, lapachol (1) underwent cyclisation to
β-lapachone (2) in the presence of H SO . Compound 2
2
4
26
was reacted with N-bromosuccinimide (NBS) in CCl , with
methodology described by Pinto and co-workers. This
reaction generates two regioisomeric products (ortho
and para isomers), which were separated by column
chromatography; only ortho isomer 40 was used for
subsequent studies. Reaction of 40 with sodium azide
in dimethylformamide gave the corresponding azide 41
in high yield. CuAAC was used to prepare the new
naphthoquinone-based 1,2,3-triazole 42. The reaction was
accomplished using classic click chemistry conditions
4
benzoyl peroxide as an initiator, to produce 3,4-dibromo-
2
0
β-lapachone (3). In the next step, 3 was stirred overnight
with sodium azide in dichloromethane, to prepare 4 as
20
previously described. Two major products were obtained:
3
-bromo-4-azide-α-lapachone and 3-bromo-4-azide-
β-lapachone (4). Key intermediate 4 was isolated by
column chromatography and used to prepare the respective
2
0
β-lapachone-based 1,2,3-triazoles 6-10. Cu-catalyzed
23
.
4
azide-alkyne cycloaddition (CuAAC), a well-established
click chemistry reaction that employs a Cu(I) source,
was used to produce the desired 1,2,3-triazoles, as
shown in Scheme 1. The final step involved reaction of
with phenylacetylene, CuSO 5H O as catalyst and sodium
2
ascorbate as the reducing agent, in CH Cl :H O (1:1). The
2
2
2
final step was the preparation of the respective phenazine
by the reaction of 42 with ortho-phenylenediamine in the
presence of sodium acetate and acetic acid.
6
-10 with ortho-phenylenediamine in the presence of

Vol. 26, No. 5, 2015
Jardim et al.
1015
O
OH
O
(
1)
O
O
O
O
O
O
2
eq. NBS
H2SO4
9%
Br
Br
CCl , In.
4
9
3
5%
(
2)
(3)
NaN3
CH Cl2
2
R
35%
NH2
N
O
O
O
O
NH2
R
N
O
O
CH Cl /H O 1:1
2
2
2
N3
Br
N
N
6 - R = H (65%)
7
- R = Br (59%)
AcONa
AcOH
N3
.
CuSO 5H O
4
N
2
Na-ascorbate
8 - R = F (63%)
9 - R = OMe (67%)
0 - R = Me (55%)
O
Br
7
2%
Br
1
(
5)
(4)
NH2
NH2
AcONa
AcOH
R
N
O
1
1
1
1
1
1 - R = H (82%)
2 - R = Br (75%)
3 - R = F (78%)
4 - R = OMe (82%)
5 - R = Me (77%)
N
N
N
N
Br
Scheme 1. Synthetic route used to prepare novel phenazine compounds 5, 11-15.
In the last few years, the synthesis and evaluation
against TB of nitrophenyl-triazoles were described
and these compounds exhibited remarkable activities.
spectra data was also obtained. Selected compounds were
recrystallised, and crystals of 12, 19, and 29 obtained
were suitable for X-ray crystallographic analysis. The
ORTEP-3 projections are shown in Figure 2, and Table S1
(Supplementary Information) lists the main crystallographic
parameters. For compounds 27 and 42, only H NMR
spectra were obtained due to the low solubility of these
derivatives.
2
7
Bearing in mind the potential antimicrobial activity of
these structures, the last class of compounds described
herein was obtained by reaction of azide derivative 44
with a range of alkynes (Scheme 4). Our aim was to
obtain 1,2,3-triazoles that possess an aryl-nitro group at
N-1 and diverse substituted aryl or alkyl groups at C-4.
Compounds 45-59 were easily obtained as crystalline
solids (Scheme 4) and evaluated against M. tuberculosis
H Rv (ATCC 27294). Compounds 45-47 and 51-53 are
1
Our research group has recently described quinoidal
compounds with potent activity against neglected diseases,
1
2
17,18
such as leishmaniasis, tuberculosis,
and Chagas
13,24
disease. As a continuation of our screening programme
for the discovery of novel antimycobacterial compounds, we
describe here the synthesis of a series of naphthoquinones
and their phenazine derivatives, as well as the evaluation
of these compounds against Mycobacterium tuberculosis
H Rv.
3
7
described herein for the first time. Spectroscopic data
for all previously published 1,2,3-triazoles 48-50 and
5
4-59 are in agreement with the data reported in the
2
8-32
literature.
The structures of all novel compounds were determined
37
1
13
by infrared (IR) and H and C nuclear magnetic resonance
NMR) spectroscopies. Electrospray ionization mass
The structures were designed based on the activities
previously reported for β-lapachone and their phenazine
(

1
016
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
R
O
O
N
OH
N
N
25 - R = H (74%)
26 - R = F (82%)
27 - R = Br (68%)
N
N3
N
N
O
N
28 - R = NO2 (65%)
29 - R = OMe (78%)
(
18)
(
1)
O
3
0 - R = CH (72%)
Na2CO3
3
1
.
NH2
NH2
H O
2
2
NH2
NH2
THF, 60 ºC
THF
2
.
7
8%
NaOH/Na CO3
2
AcONa
AcOH
AcONa
AcOH
CuSO4
R
5
4%
19 - R = H (95%)
20 - R = F (92%)
O
O
O
O
R
OH
1. Br , 0 ºC
2
O
O
N
2
2
1 - R = Br (88%)
2
. CH Cl , NaN
2
CH Cl /H O 1:1
2 2 2
2
3
2 - R = NO (85%)
N
2
N3
.
CuSO 5H O
2
N
23 - R = OMe (96%)
24 - R = Me (98%)
4
9
9%
O
O
(
17)
Na-ascorbate
(
16)
n
CH Cl /H O 1:1
2
2
2
.
CuSO 5H O
4
2
Na-ascorbate
NH2
O
N
NH2
O
N
n
n
N
N
N
N
AcONa
AcOH
N
N
O
O
31 - n = 1 (93%)
32 - n = 2 (92%)
33 - n = 3 (88%)
34 - n = 4 (95%)
35 - n = 1 (72%)
36 - n = 2 (73%)
37 - n = 3 (85%)
38 - n = 4 (81%)
Scheme 2. Synthetic route used to prepare nor-β-lapachone-based 1,2,3-triazoles and their phenazine derivatives.
3
4
derivatives against H Rv strain of M. tuberculosis, as
compounds presented antibacterial and antitubercular
properties.
3
7
illustrated in the Scheme 5. The compound β-lapachone (2)
presented activity against both susceptible and resistant
Finally, by using the strategy of redox centre
modification, the phenazine derivatives were prepared
(Scheme 5). As discussed before, this class of compounds
presents activity against M. tuberculosis and is also a
subject of our study.
3
4
strains of TB and this molecule represents an important
starting point for the synthesis of new compounds.
1
5
As recently published by our group, redox centre
and C-ring modifications in prototype 2 are important
strategies used in the preparation of compounds with
diverse biological activities. These strategies were used
with success in the synthesis of anti-TB compounds from
Thefirstclassofcompoundsevaluatedwerephenazines5
and 11-15 and their precursors quinones 6-10 (Table 1).
Low activities were observed for the phenazine derivatives,
3
4
-1
-1
β-lapachone (2) as previously described (Scheme 5).
with average MIC values = 100 μg mL or > 200 μg mL ,
indicating that incorporation of the 1,2,3-triazole in the
presence of the phenazine moiety was not effective from
the biological point of view. A hypothesis for observation
is that the presence of the 1,2,3-triazole in the C-ring of
phenazines could hinder the penetration of the compound
into the lipid mycobacterial membrane. In contrast,
potent activities were observed for β-lapachone-based
Based on these principles, 1,2,3-triazole heterocyclic rings
were coupled to the C-ring of lapachones (Scheme 5).
The incorporation of this class of heterocyclic ring
was successful in the preparation of trypanocidal and
1
2,13,33
leishmanicidal compounds.
Another important
35
example of molecular hybridization was recently reported
by Pyta et al. Hybrids were prepared by the coupling of
3
6
-1
triazole to 3-formylrifamycin moieties and the reported
1,2,3-triazoles 6-10, with MIC values ≤ 6.25 μg mL , and

Vol. 26, No. 5, 2015
Jardim et al.
1017
O
O
OH
(
39)
I2, Py
CH Cl2
2
O
O
O
O
O
O
NaN3
DMF
CH Cl /H O 1:1
2 2 2
.
CuSO 5H O
2
O
O
4
O
Na-ascorbate
I
N3
N
N
(4
0, 35%)
(41, 96%)
(42, 100%)
N
NH2
NH2
N
N
O
AcONa
AcOH
N
N
N
(
43, 73%)
Scheme 3. Synthesis of phenazine 43 from C-allyl lawsone (39).
4
4
4
4
5 - R = NH (80%)
2
N
N
6 - R = NO2 (93%)
NO2
N3
R
R
NO2
N
7 - R = OCH (79%)
3
8 - R = CH (77%)
CuI
CH CN
3
44
49 - R = H (81%)
0 - R = Br (61%)
3
5
5
1 - R = Phth (93%)
2 - R = -(CH ) CH (89%)
5
5
5
5
5
5
5
5
2
2
3
N
N
N
3 - R = -(CH ) CH (90%)
R
2 3
3
R
NO2
4 - R = -CH CH Br (94%)
2
2
CuI
5 - R = -CH OH (68%)
2
CH CN
3
6 - R = -CH(Me)OH (75%)
7 - R = -C(Me) OH (50%)
2
8 - R = -CCyOH (72%)
9 - R = -COOCH CH (85%)
2
3
Scheme 4. Synthesis of 1,2,3-triazoles from azide derivative 44.
these structures were considered important prototypes to
further studies against TB.
With the aim of improving bacillus membrane lipid
penetration, we planned the synthesis of phenazines 35-38,
which are modified with linear aliphatic substituents.
Unfortunately, our strategy was not successful, and
compounds 35-38 were also inactive against M. tuberculosis,
Differences between the β-lapachone (dihydropyran
ring) versus nor-β-lapachone derivatives (dihydrofuran
ring) were also investigated. Initially, phenazines 25-30
were prepared which possess an aryl ring with either
electron withdrawing or donating groups. As observed for
phenazines 11-15, compounds 25-30 were also inactive,
-
1
with MIC values = 100 μg mL . As observed for the
β-lapachone derivatives, the quinones used to prepare the
respective phenazines, 35-38, presented MIC values in the
-1
-1
with a majority having MIC values > 200 μg mL (Table 1).
range of 12.5-25 μg mL (Table 1).
Finally, quinones 21, 22, and 24 showed moderate activity
In the case of naphthoquinoidal compounds, the
importance of the dihydropyran ring for biological
activitity was highlighted, as compounds 6-10 (MIC
-
1
against TB, with MIC values of 12 μg mL ; the value
-
1
observed for 19 was ≤ 6.25 μg mL , highlighting the
-
1
potential of this structure (Table 1).
value ≤ 6.25 μg mL ) showed generally stronger activities

1
018
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
M. tuberculosis H Rv of compound 43, obtained by C-ring
37
modification of compound 40. Our strategy, based on the
molecular hybridization by appendage of a 1,2,3-triazole,
was not effective since the new phenazine 43 was also
-1
inactive (MIC > 200 μg mL ) (Scheme 6).
Although the phenazines were not active against TB, the
quinones described herein showed potential as effective anti-
TB agents and these structures represent an important starting
pointforthedevelopmentofnewdrugs. Forinstance, strategies
for structural modification, such as molecular hybridization
with potent antimycobacterial moieties, could be considered
to improve the activity of the naphthoquinones 5-10, which
-1
have MIC values ≤ 6.25 μg mL .
Finally, we also undertook the pharmacological
evaluation of 1,2,3-triazoles (45-59), which do not possess
a quinoidal system. Unfortunately, these compounds were
-1
inactive with MIC values > 100 μg mL (Table 1).
Conclusions
Twenty five novel compounds are described herein, and
forty-six substances were evaluated against M. tuberculosis
H Rv. Among these structures, six compounds are
3
7
considered to be potential antimycobacterial agents,
-
1
with MIC values ≤ 6.25 μg mL . These compounds were
obtained from lapachol, an abundant natural product,
using a simple synthetic route, representing a facile
strategy to obtain anti-TB drugs.As part of our programme
to identify novel drugs, the compounds described here will
be modified further to obtain compounds that are more
active than drugs currently used in the therapeutic fight
against tuberculosis.
Experimental
Chemistry
Figure 2. ORTEP-3 projections of molecules 12, 19 and 29 showing the
atom-numbering and displacement ellipsoids at the 20% (for 12 and 19)
and 50% (29) probability level.
Melting points were obtained on Thomas Hoover
apparatus and are uncorrected. Analytical grade solvents
were used. Column chromatography was performed
on silica gel (Acros Organics, 0.035-0.070 mm, pore
diameter ca. 6 nm). Infrared spectra were recorded on
a Shimadzu IR Prestige-21 Fourier transform infrared
(FTIR) spectrometer. H and C NMR spectra were
recorded at room temperature using a Varian Unity Plus
300, Bruker AVANCE DPX200 and AVANCE DRX400,
in the solvents indicated, with tetramethylsilane (TMS) as
internal reference. Chemical shifts (d) are given in ppm and
coupling constants (J) in Hertz. Mass spectra (electrospray
ionization) were obtained using a MicroTOF Ic (Bruker
compared to the respective nor-β-lapachone derivatives
-
1
2
(
1, 22, 24, 33 and 34, with MIC values ≤ 12.5 μg mL
Table 1).
Lapachones prepared from C-allyl lawsone (39)
1
13
represent an unexplored class of substances with potential
activities. Recently, we described the antitumor properties
of iodinated and methylated naphthoquinones synthesized
3
7
34
from 39. Coelho et al. reported that the phenazine obtained
-
1
from 40 has an MIC value > 100 μg mL (Scheme 6).
Herein, we described the synthesis and evaluation against

Vol. 26, No. 5, 2015
Jardim et al.
1019
MIC = 6.25 µg/mL for H37Rv
Reference 34
β-lapachone (2)
Redox centre
modification
O
N
CF3
Redox centre
and C-ring
modifications
O
NH
N
N
C
O
O
O
Br
MIC = 1.56 µg/mL for H37Rv MIC = 1.56 µg/mL for H37Rv
Reference 34 Reference 17
Phenazine compound
with activity against TB
Compounds evaluated in this work
against M. tuberculosis H37Rv
O
N
O
O
N
R
R
O
N
O
R
N
R
N
N
N
N
N
N
N
N
N
N
C
C
C
N
C
N
O
O
O
Br
Br
R = aryl groups
β-lapachone
C-ring modified
R = aryl groups
Redox centre and
C-ring modifications
R = alkyl and
aryl groups
C-ring modification
R = alkyl and aryl groups
Redox centre and
C-ring modifications
Dihydropyran ring
Scheme 5. Structures of the compounds evaluated against M. tuberculosis.
Second structural modification
Pyran vs. Furan ring
MIC > 100 µg/mL for H37Rv
Reference 34
N
N
Redox centre
modification
O
N
C
O
N
O
N
N
N
C-ring
modification
C
O
Molecular hybridization
Insertion of 1,2,3-triazole
O
I
I
Scheme 6. Strategy used for the design of the compound 43.
2
0
Daltonics). For the mass spectra analysis, methanol was
used as solvent. Some parameters: positive ion mode,
acquisition m/z: 200.0000-700.0000, event time: 300 ms
and ion accumulation: 10.00 ms.
3,4-dibromo-β-lapachone (3), as previously reported.
From lapachol (1), nor-lapachol (16) was prepared in two
steps using Hooker oxidation.
38
Synthetic procedure to prepare the phenazine compounds
Preparation of the synthetic precursors 1, 2, 3 and 16
All the phenazines 5, 11-15, 25-30, 35-38 and 43 were
Lapachol (1) was extracted from the heartwood
of Tabebuia sp. (Tecoma) and purified by a series of
recrystallizations. The compound β-lapachone (2)
was prepared from 1, by reaction with sulfuric acid,
and used to prepare the respective bromine derivative,
prepared according to the classical methodology described
by Hooker from the reaction of the appropriated quinones
39
with ortho-phenylenediamine.All compounds are described
33
here for the first time with exception of compound 25.
A mixture of the quinone (0.5 mmol), sodium acetate

1
020
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
Table 1. MIC of the tested compounds against Mycobacterium
tuberculosis H Rv
(0.95 mmol), ortho-phenylenediamine (0.55 mmol) in 3 mL
of glacial acetic acid was stirred and monitored by silica gel
thin-layer chromatography (TLC). After, the crude reaction
product was poured into water and the precipitate formed was
filtrate and then purified in silica gel chromatography, using
a mixture of hexane-ethyl acetate, increasing polarity. In the
case that did not form precipitate, the residue was extracted
with organic solvent, dried over anhydrous sodium sulfate,
followed by concentration under vacuum and purification
by column chromatography.
37
MIC /
Compound
Classes of the evaluated compound
Phenazine (dihydropyran ring)
-1
(
μg mL )
> 200
≤ 6.25
≤ 6.25
≤ 6.25
≤ 6.25
≤ 6.25
100
5
6
7
8
9
β-Lapachone-based 1,2,3-triazole (quinone)
β-Lapachone-based 1,2,3-triazole (quinone)
β-Lapachone-based 1,2,3-triazole (quinone)
β-Lapachone-based 1,2,3-triazole (quinone)
β-Lapachone-based 1,2,3-triazole (quinone)
Phenazine (dihydropyran ring)
Phenazine (dihydropyran ring)
Phenazine (dihydropyran ring)
Phenazine (dihydropyran ring)
Phenazine (dihydropyran ring)
Phenazine (dihydrofuran ring)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
nor-β-lapachone-based 1,2,3-triazole (Quinone)
nor-β-Lapachone-based 1,2,3-triazole (quinone)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Phenazine (dihydrofuran ring)
Nitrophenyl triazole
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
0
1
2
3
4
5
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
3
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
> 200
> 200
> 200
> 200
25
1
-Azido-2-bromo-3,3-dimethyl-2,3-dihydro-1H-benzo[a]
pyrano[2,3-c]phenazine (5)
The reaction of compound 4 (181 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.55 mmol) in the presence
of sodium acetate (78 mg, 0.95 mmol) in 3 mL of acetic
acid yielded product 5, (167 mg, 0.360 mmol, 72% yield),
≤ 6.25
nd
-1
12.5
12.5
nd
as a yellow solid; mp 154-156 ºC; IR (KBr) ν / cm 2102
(N ), 1633 (C=N), 3061 (C=C), 760 (Ar-CH ), 2975 (C-H);
3
3
1
H NMR (200 MHz, CDCl ) d 9.36 (d, 1H, J 7.2 Hz),
3
12.5
100
8
.43-8.19 (3H, m), 7.94-7.72 (4H, m), 5.80 (d, 1H, J 5.5 Hz),
13
4.48 (d, 1H, J 5.5 Hz), 2.08 (3H, s), 1.80 (3H, m); C NMR
> 200
> 200
> 200
> 200
100
(
50 MHz, CDCl ) d 143.2, 142.1, 140.8, 140.6, 140.0, 131.6,
3
129.8, 129.4, 129.8, 128.8, 125.2, 122.0, 107.9, 107.3, 83.2,
7
9.0, 66.9, 61.4, 57.0, 26.2, 24.2; ESI-MS m/z, calcd. for
+
[C H BrN OH ]: 434.0616; found: 434.1029.
21 16
5
25
25
2-Bromo-3,3-dimethyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)-
2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine (11)
The reaction of compound 6 (232 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.55 mmol) in the
presence of sodium acetate (78 mg, 0.95 mmol) in 3 mL
of acetic acid yielded product 11, (219 mg, 0.410 mmol,
12.5
12.5
100
100
100
100
8
2% yield), as a yellow solid; mp 249-250 ºC; IR (KBr)
> 200
> 200
> 200
> 200
> 200
> 200
> 200
200
-1
ν / cm 1603 (C=N), 3133 (C=C), 760 (Ar-CH ), 2912
3
1
(
C-H); H NMR (200 MHz, CDCl ) d 9.26 (d, 1H,
3
Nitrophenyl triazole
J 6.5 Hz), 8.30 (d, 1H, J 8.8 Hz), 8.17-8.12 (1H, m), 8.08
1H, s), 7.89-7.71 (5H, m), 7.67-7.51 (2H, m), 7.34-7.18
(3H, m), 6.60 (d, 1H, J 8.1 Hz), 5.16 (d, 1H, J 8.1 Hz),
Nitrophenyl triazole
(
Nitrophenyl triazole
Nitrophenyl triazole
13
Nitrophenyl triazole
1.70 (3H, s), 1.65 (3H, s); C NMR (50 MHz, CDCl3)
Nitrophenyl triazole
d 153.2, 146.5, 142.3, 142.1, 140.7, 140.2, 132.2, 131.0,
Nitrophenyl triazole
200
1
1
30.3, 130.2, 129.7, 129.6, 129.3, 128.9, 128.8, 128.1,
25.9, 125.5, 123.4, 122.6, 106.6, 80.8, 61.2, 57.2, 27.7,
Nitrophenyl triazole
200
Nitrophenyl triazole
100
+
21.3; ESI-MS m/z, calcd. for [C H BrN OH ]: 536.10861;
29
22
5
Nitrophenyl triazole
100
found: 536.1193.
Nitrophenyl triazole
50
Nitrophenyl triazole
> 200
> 200
100
2
-Bromo-1-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)-3,3-
dimethyl-2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine
12)
Nitrophenyl triazole
Nitrophenyl triazole
(
Etambutol
4
Streptomycin
1
The reaction of compound 7 (271 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.55 mmol) in the
nd: not determined.

Vol. 26, No. 5, 2015
Jardim et al.
1021
presence of sodium acetate (78 mg, 0.95 mmol) in 3 mL
of acetic acid yielded product 12, (201 mg, 0.375 mmol,
80.9, 61.1, 57.5, 55.5, 27.8, 21.1; ESI-MS m/z, calcd. for
+
[C H BrN O H ]: 566.1299; found: 566.1226.
30
24
5
2
7
5% yield), as a yellow solid; mp 232-235 ºC; IR (KBr)
-1
ν / cm 1633 (C=N), 3124 (C=C), 773 (Ar-CH ), 2922
2-Bromo-3,3-dimethyl-1-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)-
2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine (15)
The reaction of compound 10 (239 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 15, (211 mg, 0.385 mmol, 77% yield), as
3
1
(
C-H); H NMR (200 MHz, CDCl ) d 9.35 (d, 1H,
3
J 9.1 Hz), 8.41-8.36 (1H, m), 8.29-8.20 (1H, m), 8.19 (1H,
s), 7.93-7.78 (3H, m), 7.75-7.62 (4H, m), 7.57-7.46 (2H, m),
6
1
1
1
1
.66 (d, 1H, J 8.3 Hz), 5.21 (d, 1H, J 8.3 Hz), 1.80 (3H, s),
1
3
.73 (3H, s); C NMR (50 MHz, CDCl ) d 154.2, 146.5,
3
-1
43.3, 143.2, 141.7, 141.2, 133.2, 131.5, 131.3, 130.9,
30.8, 130.7, 130.3, 129.8, 129.1, 128.5, 126.7, 124.5,
23.8, 122.9, 107.6, 81.9, 62.4, 58.3, 28.8, 22.7.
a yellow solid; mp 246-248 ºC; IR (KBr) ν / cm 1418
1
(C=N), 2915 (C=C), 770 (Ar-CH ), 3127 (C-H); HNMR
3
(400 MHz, CDCl /DMSO) d 9.33 (d, 1H, J 8.5 Hz),
3
8
.38 (d, 1H, J 7.0 Hz), 8.21 (d, 1H, J 7.6 Hz), 8.16 (1H,
2
-Bromo-1-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,3-
s), 7.94-7.81 (3H, m), 7.73-7.68 (4H, m), 7.18 (d, 2H,
dimethyl-2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine
13)
J 8.0 Hz), 6.65 (d, 1H, J 8.3 Hz), 5.21 (d, 1H, J 8.3 Hz),
2.34 (3H, s), 1.78 (3H, s), 1.72 (3H, s); C NMR (100 MHz,
13
(
The reaction of compound 8 (241 mg, 0.5 mmol),
CDCl /DMSO) d 153.1, 146.6, 142.3, 142.1, 140,7,
3
ortho-phenylenediamine (60 mg, 0.5 mmol) in the
presence of sodium acetate (78 mg, 0.95 mmol) in 3 mL
of acetic acid yielded product 13, (216 mg, 0.390 mmol,
140.1, 137.9, 132.1, 130.3, 130.3, 129.7, 129.6, 129.3,
128.8, 128.2, 128.1, 125.8, 125.5, 123.4, 122.4, 106.8,
80.9, 61.2, 57.4, 27.8, 21.5, 21.1; ESI-MS m/z, calcd. for
+
7
8% yield), as a yellow solid; mp 263-264 ºC; IR (KBr)
[C H BrN OH ]: 550.1242; found: 550.1207.
30
24
5
-
1
ν / cm 1484 (C=N), 2915 (C=C-H), 776 (Ar-CH ),
3
3
1
127 (C-H); H NMR (400 MHz, CDCl /DMSO) d 9.34
1-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-
1,2-dihydrobenzo[a]furo[2,3-c]phenazine (26)
3
(
8
d, 1H, J 9.0 Hz), 8.39 (d, 1H, J 9.0 Hz), 8.24 (1H, s),
.22 (d, 1H, J 7.8 Hz), 7.89-7.81 (3H, m), 7.80-7.67 (4H,
m), 7.07 (t, 2H, J 8.6 Hz), 6.67 (d, 1H, J 8.5 Hz), 5.20
The reaction of compound 20 (194 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 26, (189 mg, 0.410 mmol, 82% yield), as a
1
3
(
(
d, 1H, J 8.4 Hz), 1.82 (3H, s), 1.73 (3H, s); C NMR
100 MHz, CDCl /DMSO) d 161.2 (246.5 Hz, d) 152.9,
3
-1
1
1
1
45.3, 142.0, 141.8, 140.4, 139.9, 131.8, 130.1, 130.0,
29.6, 129.4, 129.1, 128.5, 127.8, 127.3 (J 8.0 Hz, d),
27.1 (J 3.0 Hz, d), 125.2, 123.2, 122.4, 115.7 (J 21.6 Hz,
yellow solid; mp 291-293 ºC; IR (KBr) ν / cm 1596 (C=N),
1
3091 (C=C), 1428 (C-F), 3412 (C-H); H NMR (400 MHz,
CDCl ) d 9.45 (d, 1H, J 8.0 Hz), 8.29-8.24 (1H, m), 8.21
3
d), 106.5, 80.8, 61.0, 57.2, 27.7, 20.7; ESI-MS m/z, calcd.
(d, 1H, J 7.7 Hz), 8.03-7.98 (1H, m), 7.93 (t, 1H, J 7.5 Hz),
7.86 (t, 1H, J 7.2 Hz), 7.76-7.71 (2H, m), 7.65-7.59 (2H,
m), 7.28 (1H, s), 6.95 (t, 2H, J 8.5 Hz), 6.70 (1H, s), 1.83
+
for [C H BrFN OH ]: 554.0991; found: 554.1006.
2
9
21
5
13
2
-Bromo-1-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3,3-
dimethyl-2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazine
14)
(3H, s), 1.36 (3H, s); C NMR (100 MHz, CDCl ) d 162.5
3
(d, J 246.7 Hz), 160.2, 146.5, 142.8, 141.6, 140.9, 140.5,
133.4, 130.3, 130.0 (d, J 6.8 Hz), 129.7, 129.0, 128.8, 127.4,
127.3, 126.7 (d, J 3.2 Hz), 126.2, 124.1, 123.2, 118.6, 115.5
(d, J 21.7 Hz), 108.8, 92.8, 68.7, 27.9, 21.5; ESI-MS m/z,
(
The reaction of compound 9 (247 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.95 mmol) in 3 mL of acetic acid
yielded product 14, (232 mg, 0.410 mmol, 82% yield), as a
+
calcd. for [C H FN OH ]: 462.1730; found: 462.1697.
28
20
5
-1
yellow solid; mp 248-249 ºC; IR (KBr) ν / cm 1494 (C=N),
1-(4-(4-Bromophenyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-
1,2-dihydrobenzo[a]furo[2,3-c]phenazine (27)
1
2
981 (C=C), 1252 (Ar-O-CH ), 3124 (C-H); H NMR
3
(
(
(
(
(
400 MHz, CDCl /DMSO) d 9.30 (d, 1H, J 6.1 Hz), 8.36
The reaction of compound 21 (225 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 27, (177 mg, 0.340 mmol, 68% yield), as
3
d, 1H, J 7.2 Hz), 8.19-8.16 (1H, m), 8.16 (1H, s), 7.85-7.81
3H, m), 7.73-7.63 (4H, m), 6.90 (d, 2H, J 8.6 Hz), 6.65
d, 1H, J 8.3 Hz), 5.20 (d, 1H, J 8.3 Hz), 3.78 (3H, s), 1.78
13
-1
3H, s), 1.71 (3H, s); C NMR (100 MHz, CDCl /DMSO)
a yellow solid; mp 297-299 ºC; IR (KBr) ν / cm 1596
3
1
d 159.6, 153.0, 149.8, 146.3, 142.3, 142.1, 140.6, 140.1,
(C=N), 2988 (C=C), 1047 (C-Br), 3081 (C-H); H NMR
1
1
36.4, 130.0, 130.2, 129.7, 129.6, 129.2, 128.7, 128.1,
27.1, 125.5, 124.0, 123.7, 123.4, 122.1, 114.4, 106.8,
(400 MHz, CDCl ) d 9.48 (d, 1H, J 7.5 Hz), 8.29 (d, 1H,
J 5.1 Hz), 8.23 (d, 1H, J 7.7 Hz), 8.11-8.06 (1H, m), 7.93
3

1
022
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
(
dt, 2H, J 26.2, 7.2 Hz), 7.82-7.70 (2H, m), 7.55 (d, 2H,
CDCl ) d 147.4, 142.7, 141.6, 140.8, 140.4, 137.8, 133.3,
3
J 8.3 Hz), 7.41 (d, 2H, J 8.3 Hz), 7.33 (1H, s), 6.72 (1H,
130.2, 129.9, 129.8, 129.6, 129.3, 129.0, 128.8, 127.7,
126.2, 125.4, 124.1, 123.2, 118.5, 108.8, 92.8, 68.7, 29.7,
s), 1.83 (3H, s), 1.35 (3H, s). ESI-MS m/z, calcd. for
+
+
[
C H BrN OH ]: 522.0798; found: 522.0800.
27.5, 21.5, 21.1; ESI-MS m/z, calcd. for [C H N OH ]:
2
8
20
5
29 23
5
4
58.1902; found: 458.1950.
2,2-Dimethyl-1-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)-1,2-
dihydrobenzo[a]furo[2,3-c]phenazine (28)
2,2-Dimethyl-1-(4-propyl-1H-1,2,3-triazol-1-yl)-1,2-
dihydrobenzo[a]furo[2,3-c]phenazine (35)
The reaction of compound 22 (208 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 28, (158 mg, 0.325 mmol, 65% yield), as a
The reaction of compound 31 (168 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the
presence of sodium acetate (78 mg, 0.5 mmol) in 3 mL
of acetic acid yielded product 35, (147 mg, 0.360 mmol,
72% yield), as a yellow solid; mp 278-280 ºC; IR (KBr)
-
1
yellow solid; mp 289-291 ºC; IR (KBr) ν / cm 1336 (NO ),
2
1
517 (C-NO ), 3073 (C=C), 756 (Ar-NO ), 3412 (C-H);
2
2
1
-1
H NMR (400 MHz, CDCl ) d 9.46 (d, 1H, J 8.3 Hz),
ν / cm 1596 (C=N), 2925 (C=C), 753 (Ar-CH ), 3107
3
3
1
8
.28-7.84 (8H, m), 7.78-7.58 (3H, m), 7.48 (1H, s), 6.76
(C-H); H NMR (400 MHz, CDCl ) d 9.44 (d, 1H,
3
13
(
1H, s), 1.38 (3H, s), 1.27 (3H, s); C NMR (100 MHz,
J 6.5 Hz), 8.32-8.24 (1H, m), 8.21 (d, 1H, J 6.6 Hz), 8.04-
7.84 (3H, m), 7.80-7.72 (2H, m), 6.98 (1H, s), 6.62 (1H,
s), 2.61-2.48 (2H, m), 1.81 (3H, s), 1.55 (dt, 2H, J 14.7,
CDCl /DMSO) d 160.2, 146.8, 144.8, 142.4, 140.2, 129.8,
3
1
29.5, 128.6, 128.5, 128.5, 126.0, 125.9, 123.9, 123.8,
1
3
123.1, 113.8, 108.3, 92.5, 92.5, 68.7, 68.4, 55.0, 29.4, 27.4,
7.3 Hz), 1.29 (3H, s), 0.80 (t, 3H, J 7.3 Hz); C NMR
+
2
1.4; ESI-MS m/z, calcd. for [C H N O H ]: 489.1675;
(100 MHz, CDCl ) d 159.5, 147.1, 142.1, 141.2, 140.4,
28
20
6
3
3
found: 489.1655.
139.8, 132.6, 129.7, 129.5, 129.3, 129.2, 128.2, 128.2,
1
25.6, 123.6, 122.7, 119.9, 108.4, 92.2, 67.9, 27.1, 27.0,
+
1-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-
21.9, 20.8, 13.0. ESI-MS m/z, calcd. for [C H N OH ]:
2
5
23
5
1
,2-dihydrobenzo[a]furo[2,3-c]phenazine (29)
410.1980; found: 410.1897.
The reaction of compound 23 (200 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 29, (184 mg, 0.39 mmol, 78% yield), as a
1-(4-Butyl-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-1,2-
dihydrobenzo[a]furo[2,3-c]phenazine (36)
The reaction of compound 31 (175 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic
acid yielded product 36, (154 mg, 0.36 mmol, 73% yield),
-1
yellow solid; mp 269-270 ºC; IR (KBr) ν / cm 1597 (C=N),
1
3
094 (C=C), 1247 (Ar-O-CH ), 3413 (C-H); H NMR
3
(
400 MHz, CDCl ) d 9.46 (d, 1H, J 8.0 Hz), 8.34-8.19 (2H,
3
-1
m), 8.08-7.84 (4H, m), 7.80-7.70 (2H, m), 7.66-7.54 (2H,
as a yellow solid; mp 269-270 ºC; IR (KBr) ν / cm 1596
1
m), 6.81 (d, 2H, J 8.5 Hz), 6.72 (1H, s), 3.74 (3H, s), 1.83
(C=N), 2955 (C=C), 763 (Ar-CH ), 3071 (C-H); HNMR
3
13
(
3H, s), 1.36 (3H, s); C NMR (100 MHz, CDCl ) d 160.2,
(400 MHz, CDCl ) d 9.43 (d, 1H, J 7.9 Hz), 8.28 (dd, 1H,
3
3
1
1
1
59.4, 147.2, 142.6, 141.6, 140.9, 140.4, 130.2, 129.9,
29.8, 129.6, 128.9, 128.8, 126.9, 126.2, 124.1, 123.2,
J 3.5, 7.3 Hz), 8.21 (d, 1H, J 7.6 Hz), 8.00-7.87 (3H, m),
7.81-7.76 (2H, m), 7.05 (s, 1H), 6.61 (s, 1H), 2.65-2.51
(2H, m), 1.82 (3H, s), 1.57-1.44 (2H, m), 1.29 (3H, s),
18.0, 114.0, 108.9, 92.9, 68.6, 55.2, 27.9, 21.5; ESI-MS
+
13
m/z, calcd. for [C H N O H ]: 474.1930; found: 474.1897.
1.21 (2H, m), 0.79 (t, 3H, J 7.3 Hz); C NMR (100 MHz,
29
23
5
2
CDCl ) d 159.5, 147.2, 142.0, 141.2, 140.3, 139.7, 132.5,
3
2
,2-Dimethyl-1-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)-1,2-
129.7, 129.5, 129.3, 129.1, 128.2, 123.6, 122.7, 125.6,
125.4, 119.9, 108.6, 92.1, 67.2, 30.8, 27.1, 24.7, 21.5, 20.8,
dihydrobenzo[a]furo[2,3-c]phenazine (30)
+
The reaction of compound 24 (192 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 30, (164 mg, 0.360 mmol, 72% yield), as
a yellow solid; mp 269-271 ºC; IR (KBr) ν / cm 1633
C=N), 3095 (C=C), 756 (Ar-CH3), 3413 (C-H); H NMR
400 MHz, CDCl ) d 9.48 (d, 1H, J 6.9 Hz), 8.30-8.21 (2H,
m), 8.08-7.83 (3H, m), 7.79-7.69 (2H, m), 7.62-7.51 (2H,
m), 7.31 (1H, s), 7.08 (d, 2H, J 6.3 Hz), 6.72 (1H, s), 2.28
3H, s), 1.83 (3H, s), 1.35 (3H, s); C NMR (100 MHz,
13.2; ESI-MS m/z, calcd. for [C H N OH ]: 424.2137;
26
25
5
found: 424.2099.
2,2-Dimethyl-1-(4-pentyl-1H-1,2,3-triazol-1-yl)-1,2-
dihydrobenzo[a]furo[2,3-c]phenazine (37)
-1
1
(
(
The reaction of compound 33 (182 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 37, (185 mg, 0.425 mmol, 85% yield), as
3
13
-1
(
a yellow solid; mp 261-263 ºC; IR (KBr) ν / cm 1597

Vol. 26, No. 5, 2015
Jardim et al.
1023
1
(
(
C=N), 2958 (C=C), 760 (Ar-CH ), 3072 (C-H); HNMR
2-(Azidomethyl)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione
(41)
3
400 MHz, CDCl ) d 9.43 (d, 1H, J 7.8 Hz), 8.28 (dd,
3
1
H, J 6.6, 3.1 Hz), 8.21 (d, 1H, J 7.6 Hz), 8.05-7.84 (3H,
Compound 40 (255 mg, 1.0 mmol) was stirred in
presence of sodium azide (120 mg, 1.85 mmol) in 2 mL of
dimethylformamide (DMF), generating product41, (238 mg,
0.930 mmol, 93% yield), as a red solid; mp 172-174 ºC; IR
m), 7.77 (dd, 2H, J 6.6, 3.1 Hz), 7.01 (1H, s), 6.62 (1H,
s), 2.67-2.47 (2H, m), 1.82 (3H, s), 1.63-1.43 (2H, m),
1
.30 (3H, s), 1.24-1.11 (4H, m), 0.75 (t, 3H, J 6.6 Hz);
13
-1
1
C NMR (100 MHz, CDCl ) d 159.8, 147.6, 142.3, 141.5,
(KBr) ν / cm 2923 (CH), 2106 (N ), 1660 (C=O); H NMR
3
3
1
1
2
40.6, 140.0, 132.9, 129.9, 129.8, 129.6, 129.4, 128.5,
25.9, 125.8, 123.9, 123.0, 120.2, 108.7, 92.5, 68.2, 30.9,
(200 MHz, CDCl ) d 8.05 (d, 1H, J 7.3 Hz), 7.92-7.32 (3H,
3
m), 5.45-5.21 (1H, m), 3.84-3.49 (2H, m), 3.25 (dd, 1H,
13
8.6, 27.4, 25.3, 21.9, 21.1, 13.7; ESI-MS m/z, calcd. for
J 15.6, 10.1 Hz), 2.92 (dd, 1H, J 15.6, 7.0 Hz); C NMR
+
[C H N OH ]: 438.2293; found: 438.2210.
(50 MHz, CDCl ) d 180.9, 175.4, 169.4, 134.9, 132.3, 130.7,
2
7
27
5
3
1
30.3, 129.7, 127.2, 124.7, 85.8, 54.3, 29.6; ESI-MS m/z,
+
1
-(4-Hexyl-1H-1,2,3-triazol-1-yl)-2,2-dimethyl-1,2-
calcd. for [C H N O H ]: 256.0722; found: 256.0606.
13
9
3
3
dihydrobenzo[a]furo[2,3-c]phenazine (38)
The reaction of compound 34 (189 mg, 0.5 mmol),
ortho-phenylenediamine (60 mg, 0.5 mmol) in the presence
of sodium acetate (78 mg, 0.5 mmol) in 3 mL of acetic acid
yielded product 38, (182 mg, 0.405 mmol, 81% yield), as
Synthetic procedure to prepare quinone-based
1,2,3-triazoles
The substituted alkyne (0.83 mmol) was reacted with
respective azide compound (0.83 mmol) in 12 mL of
-1
a yellow solid; mp 259-261 ºC; IR (KBr) ν / cm 1612
1
.
4
(
C=N), 2955 (C=C), 763 (Ar-CH ), 3071 (C-H); HNMR
CH Cl /H O (1:1), CuSO 5H O (9.3 mg, 0.04 mmol) and
3
2
2
2
2
(
400 MHz, CDCl ) d 9.45 (d, 1H, J 7.8 Hz), 8.33-8.24 (1H,
sodium ascorbate (22 mg, 0.11 mmol). The mixture was
agitated at room temperature until formation of the product
was complete and monitored by TLC. The organic phase
was extracted with CH Cl , dried over sodium sulfate and
3
m), 8.20 (d, 1H, J 7.5 Hz), 8.04 (dd, 1H, J 6.2, 3.6 Hz),
7
6
1
.90 (dt, 2H, J 24.8, 7.0 Hz), 7.76 (dd, 2H, J 6.5, 3.4 Hz),
.84 (1H, s), 6.64 (1H, s), 2.68-2.44 (2H, m), 1.79 (3H, s),
.53-1.42 (2H, m), 1.28 (3H, s), 1.19-1.06 (6H, m), 0.73
2
2
concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel using
a gradient mixture of hexane/ethyl acetate with increasing
polarity up to 100% ethyl acetate as an eluent. Compounds
6-9, 19-24 and 32-34 assayed against M. tuberculosis here
13
(t, 3H, J 6.5 Hz); C NMR (100 MHz, CDCl ) d 160.0,
3
1
1
1
1
48.0, 142.7, 141.7, 140.8, 140.4, 133.2, 130.1, 129.9,
29.7, 129.6, 128.9, 128.7, 126.1, 124.1, 123.2, 119.9,
09.0, 92.8, 68.4, 31.3, 29.1, 28.6, 27.5, 25.6, 22.3, 21.3,
+
12,13,20,25
3.8; ESI-MS m/z, calcd. for [C H N OH ]: 452.2450;
were previously described.
28
29
5
found: 452.2400.
3
-Bromo-2,2-dimethyl-4-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)-
2
-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-1,2-
3,4-dihydro-2H-benzo[h]chromene-5,6-dione (10)
dihydrobenzo[a]furo[2,3-c]phenazine (43)
The alkyne employed was 1-ethynyl-4-methylbenzene
(96 mg, 0.83 mmol) with the azide 4 (300 mg, 0.83 mmol)
and the resulting compound 10 was a yellow solid (217 mg,
The reaction of compound 42 (80 mg, 0.29 mmol),
ortho-phenylenediamine (60 mg, 0.55 mmol) in the
presence of sodium acetate (100 mg, 1.22 mmol) in 4 mL
of acetic acid yielded product 43, (88.5 mg, 0.206 mmol,
-1
55% yield); mp 201-202 ºC; IR (KBr) ν / cm 1650 (C=O),
1
1605 (C=O); H NMR (200 MHz, CDCl ) d 8.11 (d, 1H,
3
7
1% yield), as a yellow solid; mp 211-213 ºC; IR (KBr)
J 7.4 Hz), 8.04 (s, 1H), 7.93 (d, 1H, J 7.7 Hz), 7.76-7.71
(m, 3H), 7.65-7.61 (m, 1H), 7.27-7,20 (m, 1H), 5.71 (d,
1H J 8.8 Hz), 5.07 (d, 1H, J 8.9 Hz), 2.37 (s, 3H), 1.76
-1
1
ν / cm 1638 (C=N), 763 (Ar-CH ), 2924 (C-H); H NMR
3
(400 MHz, CDCl ) d 9.44-9.37 (1H, m), 8.33 (dd, 1H, J 8.1,
3
13
1.4 Hz), 8.28 (d, 1H, J 7.5 Hz), 8.12-8.04 (1H, m), 8.01 (1H,
(s, 3H), 1.69 (s, 3H); C NMR (50 MHz, CDCl ) d 177.6,
3
s), 7.90-7.76 (6H, m), 7.42 (t, 2H, J 7.4 Hz), 7.33 (t, 1H,
J 7.4 Hz), 5-75-5.66 (1H, m), 4.97 (dd, 1H, J 14.5, 3.6 Hz),
176.3, 162.4, 146.6, 137.6, 134.9, 132.0, 130.4, 130.3,
129.1, 128.9, 127.3, 125.5, 124.9, 122.1, 110.2, 83.2,
58.7, 53.9, 27.12, 20.9, 20.5; ESI-MS m/z, calcd. for
4
.83 (dd, 1H, J 14.5, 7.6 Hz), 4.06 (dd, 1H, J 15.9, 10.0 Hz),
13
+
3
.67 (dd, 1H, J 15.9, 6.8 Hz); C NMR (100 MHz, CDCl )
[C H BrN O H ]: 478.0766; found: 478.0579.
3
24 20
3
3
d 163.00, 148.19, 141.39, 140.34, 131.91, 130.69, 130.46,
1
1
1
30.19, 130.16, 130.14, 130.10, 129.92, 128.91, 128.87,
28.82, 128.75, 128.74, 128.27, 126.21, 125.84, 122.10,
2,2-Dimethyl-3-(4-propyl-1H-1,2,3-triazol-1-yl)-2,3-
dihydronaphtho[1,2-b]furan-4,5-dione (31)
The alkyne employed was pent-1-yne (56 mg,
0.83 mmol), with the azide 17 (223 mg, 0.83 mmol) and
20.72, 83.15, 54.13, 32.06; ESI-MS m/z, calcd. for
+
[C H N OH ]: 430.1667; found: 430.1598.
2
7
19
5

1
024
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
the resulting compound 31 was a brown solid (260 mg,
product 46, (176 mg, 0.57 mmol, 93% yield), as an orange
-1
-1
9
3% yield); mp 173-176 ºC; IR (KBr) ν / cm 1635 (C=O),
solid; mp 268-270 ºC; IR (KBr) ν / cm 3096 (CH), 1603,
1
1
1
678 (C=O); H NMR (200 MHz, CDCl ) d 8.12-7.97 (1H,
1522 (C=C), 1344 (N=O); H NMR (400 MHz, DMSO-d )
3
6
m), 7.93-7.45 (4H, m), 5.86 (1H, s), 2.55 (t, 2H, J 7.0 Hz),
.67 (3H, s), 1.61-1.49 (2H, m), 1.09 (3H, s), 0.82 (t, 3H,
d 9.77 (1H, s), 8.79 (1H, s), 8.46 (d, 1H, J 7.8 Hz), 8.38 (3H,
m), 8.22 (d, 2H, J 9.0 Hz), 7.95 (t, 1H, J 8.2 Hz); C NMR
13
1
13
J 7.1 Hz); C NMR (50 MHz, CDCl ) d 180.2, 174.6, 171.1,
(100 MHz, DMSO-d ) d 149.1, 148.8, 148.6, 137.4, 131.6,
3
6
1
48.0, 134.9, 133.2, 131.4, 129.7, 126.7, 125.6, 120.5, 111.4,
126.4, 125.5, 122.9, 117.5, 117.3, 114.0, 112.4.; calcd. for
(C H N O ): C, 54.02; H, 2.91; N, 22.50; found: C, 54.02;
H, 3.33; N, 22.58.
96.0, 66.6, 27.6, 27.5 22.5, 20.9, 13.7; ESI-MS m/z, calcd.
14
9
5
4
+
for [C H N O H ]: 338.1504; found: 338.1517.
19
19
3
3
2
-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-
4-(4-Methoxyphenyl)-1-(3-nitrophenyl)-1H-1,2,3-triazole
(47)
dihydronaphtho[1,2-b]furan-4,5-dione (42)
The alkyne employed was ethynylbenzene (84 mg,
.83 mmol), with the azide 41 (211 mg, 0.83 mmol) and
The reaction of compound 44 (100 mg, 0.6 mmol) and
1-ethynyl-4-methoxybenzene (121 mg, 0.9 mmol) yielded
product 47, (143 mg, 0.5 mmol, 79% yield), as a yellow
0
the resulting compound 42 was a red solid (281 mg, 95%
-1
-1
yield); mp 187-188 ºC; IR (KBr) ν / cm 2921 (C-H), 1621
solid; mp 210-211 ºC; IR (KBr) ν / cm 3096 (CH), 1603,
1
1
(
C=O), 1648 (C=O); H NMR (400 MHz, CDCl ) d 8.10
1522 (C=C), 1344 (N=O); H NMR (400 MHz, DMSO-d )
3
6
(
7
d, 1H, J 7.3 Hz), 8.06-7.92 (1H, m), 7.91-7.77 (2H, m),
.71-7.65 (1H, m), 7.61 (t, 2H, J 7.1 Hz), 7.49-7.41 (2H,
d 9.39 (1H, s), 8.76 (1H, s), 8.44 (dd, 1H, J 8.4, 1.2 Hz),
8.33 (dd, 1H, J 8.0, 1.6 Hz), 7.92 (t, 1H, J 8.0 Hz), 7.88
(d, 2H, J 8.8 Hz), 7.08 (d, 2H, J 8.4 Hz), 3.82 (3H, s);
m), 7.40-7.34 (1H, m), 5.64-5.53 (1H, m), 4.86 (dd, 1H,
J 14.1, 2.7 Hz), 4.77 (dd, 1H, J 14.1, 7.0 Hz), 3.40 (dd, 1H,
J 15.6, 10.1 Hz), 3.03 (dd, 1H, J 15.6, 6.9 Hz); ESI-MS
1
3
C NMR (100 MHz, DMSO-d ) d 159.4, 148.5, 147.5,
6
137.2, 131.4, 126.7, 125.7, 122.8, 122.3, 118.8, 114.4,
114.3, 55.1.
+
m/z, calcd. for [C H N O H ]: 358.1191; found: 358.1092.
21
15
3
3
Synthetic procedure to prepare 1,2,3-triazoles (45-59)
2-((1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)
isoindoline-1,3-dione (51)
A mixture of m-NO -aryl-azide 44 (0.6 mmol),
the appropriate alkynes (0.9 mmol), copper iodide (I)
0.1 mmol) in 3 mL of acetonitrile was stirred and
monitored by silica gel TLC. The solvent was then
removed under reduced pressure and the reaction mixture
was purified on a silica gel column, using a mixture of
hexane/ethyl acetate of increasing polarity.
The reaction of compound 44 (100 mg, 0.6 mmol)
and 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (169 mg,
0.9 mmol) yielded product 51, (198 mg, 0.57 mmol, 93%
2
(
-1
yield), as a pink solid; mp 208-209 ºC; IR (KBr) ν / cm
3138 (CH), 3093 (CH), 1705 (C=O), 1530, (C=C), 1346
1
(N=O); H NMR (400 MHz, DMSO-d ) d 8.99 (1H, s),
6
8.67 (1H, s), 8.36 (dd, 1H, J 7.6, 1.2 Hz), 8.29 (dd, 1H,
13
J 8.4, 1.6 Hz), 7.93-7.84 (5H, m), 4.96 (2H, s); C NMR
4
-(1-(3-Nitrophenyl)-1H-1,2,3-triazol-4-yl)aniline (45)
The reaction of compound 44 (100 mg, 0.6 mmol) and
-ethynylaniline (100 mg, 0.9 mmol) yielded product 45,
(100 MHz, DMSO-d ) d 167.1, 148.3, 143.9, 136.9, 134.3,
6
131.5, 131.2, 125.8, 123.0, 122.9, 121.6, 114.5, 32.7; calcd.
for (C H N O × 0.6 H O): C, 56.68; H, 3.42; N, 19.45;
4
17
11
5
4
2
(
2
137 mg, 0.5 mmol, 80% yield), as an orange solid; mp
found: C, 56.25; H, 3.04; N, 19.39.
-
1
10-211 ºC; IR (KBr) ν / cm 3450, 3367 (NH), 3102
1
(CH), 1567, 1522 (C=C), 1346 (N=O); H NMR (400 MHz,
1-(3-Nitrophenyl)-4-propyl-1H-1,2,3-triazole (52)
DMSO-d ) d 9.25 (1H, s), 8.74 (1H, s), 8.42 (d, 1H,
J 8.2 Hz), 8.31 (d, 1H, J 8.2 Hz), 7.90 (t, 1H, J 8.2 Hz),
The reaction of compound 44 (100 mg, 0.6 mmol) and
pent-1-yne (62 mg, 0.9 mmol) yielded product 52, (126 mg,
0.54 mmol, 89% yield), as a yellow solid; mp 109-110 ºC;
6
7
.60 (d, 2H, J 8.2 Hz), 6.65 (d, 2H, J 8.2 Hz), 5.31 (2H,
1
3
-1
s); C NMR (100 MHz, DMSO-d ) d 149.1, 148.8, 148.6,
IR (KBr) ν / cm 3147, 3098 (CH), 1537, (C=C), 1347
6
1
1
1
37.4, 131.6, 126.4, 125.5, 122.9, 117.5, 117.3, 114.0,
12.4.; calcd. for (C H N O ): C, 59.78; H, 3.94; N, 24.90;
(N=O); H NMR (400 MHz, CDCl ) d 8.56 (1H, s), 8.27
3
(d, 1H, J 7.2 Hz), 8.19 (d, 1H, J 8.0 Hz), 7.83 (1H, s), 7.73
(t, 1H, J 7.6 Hz), 2.80 (t, 2H, J 6.8 Hz), 1.78 (2H, m), 1.03
14
11
5
2
found: C, 59.56; H, 4.09; N, 24.85.
13
(
t, 3H, J 7.2 Hz); C NMR (100 MHz, DMSO-d ) d 149.2,
6
1
-(3-nitrophenyl)-4-(4-nitrophenyl)-1H-1,2,3-triazole (46)
The reaction of compound 44 (100 mg, 0.6 mmol) and
-ethynyl-4-nitrobenzene (134 mg, 0.9 mmol) yielded
148.3, 137.3, 130.2, 125.1, 122.2, 118.0, 114.3, 27.0, 21.9,
13.1; calcd. for (C H N O ): C, 56.89; H, 5.21; N, 24.12;
found: C, 56.69; H, 5.13; N, 23.91.
11
12
4
2
1

Vol. 26, No. 5, 2015
Jardim et al.
1025
4
-Butyl-1-(3-nitrophenyl)-1H-1,2,3-triazole (53)
The reaction of compound 44 (100 mg, 0.6 mmol) and
of a plate, and a two-fold serial dilution of the compounds
(prepared in dimethyl sulfoxide (DMSO)) was made on the
-1
hex-1-yne (75 mg, 0.9 mmol) yielded product 53, (135 mg,
.55 mmol, 90% yield), as a yellow solid; mp 101-102 ºC;
plate, with range concentrations from 200 to 6.25 μg mL .
A volume of 100 μL of the inoculum was added to each
well and incubated at 37 °C for seven days. After these,
30 μL of resazurin solution were added to each well and
the plate returned to the incubator for two more days. The
alteration in the oxidized state (blue color) to reduced
state (pink) was scored as bacterial growth. The minimal
inhibition concentration (MIC) was defined was defined as
the lowest compound concentration that inhibited bacterial
growth, which prevented a color change from blue to pink.
0
-1
IR (KBr) ν / cm 3146 (CH), 3094 (CH), 1533, (C=C),
1
1346 (N=O); H NMR (400 MHz, CDCl ) d 8.56 (1H, s),
3
8.27 (d, 1H, J 8.0 Hz), 8.19 (d, 1H, J 8.0 Hz), 7.83 (1H,
s), 7.73 (t, 1H, J 8.0 Hz), 2.83 (t, 2H, J 8.0 Hz), 1.48-1.38
13
(2H, m), 0.98-0.93 (2H, m), 1.0 (t, 3H, J 8.0 Hz); C NMR
(100 MHz, DMSO-d ) d 150, 148.9, 137.9, 130.8, 125.7,
6
122.8, 118.5, 114.9, 31.3, 25.3, 22.3, 13.8.
X-ray analysis
Supplementary Information
X-ray data were collected at 150 K using MoKα
0.71073 A) on an Agilent Gemini diffractometer
equipped with a charge-coupled device (CCD) area
1
13
(
Supplementary information ( H and C NMR spectra for
all compounds and ESI-MS for unpublished compounds) is
available free of charge at http://jbcs.sbq.org.br as PDF file.
Crystallographic data for the structure were deposited in
the Cambridge Crystallographic Data Centre, with number
CCDC 976384, 976385 and 974795 for compounds 12, 19
and 29, respectively. Copies of the available material can
be obtained, free of charge on application to the director,
CCDC, 12 Union Road, Cambridge CH21EZ, UK (fax:
+44-1223-336-033, e-mail: deposit@ccdc.cam.ac.uk or at
http://www.ccdc.cam.ac.uk).
4
0
detector. The CrysAlisPro software package was used
for data collection and data reduction. The data were
corrected empirically for absorption using spherical
4
1
harmonics using the SCALE3 ABSPACK scaling
algorithm. The structure was solved by direct methods
4
2
using SHELXS-97 and refined by full-matrix least
2
43
squares on F using SHELXL-97. All non-hydrogen
atoms were successfully refined using anisotropic
displacement parameters. Hydrogen atoms were found
in the Fourier difference synthesis and fixed.
Acknowledgments
Antimycobacterial activity
This research was funded by grants from the Brazilian
National Council for Technological and Scientific
Development (CNPq) Project Universal-MCTI/CNPq
No. 14/2012 (480719/2012-8), FACEPE-PRONEM
(1232.1.06/10), FAPEMIG, CAPES, FURG, UFRPE and
UFMG. The authors would like also to thank Prof Carlos
B. Pinheiro and the student Willian Xerxes by the X-ray
analysis of compound 29 and Prof Janaína V. dos Anjos
(DQF-UFPE) by the collaboration in several aspects. We
would like to thank Prof John Bower from University of
Bristol for reviewing the manuscript.
Isolates and strain preparation
The antimicrobial activity of the compounds 5-15 and
18-38 were evaluated against M. tuberculosis H Rv (ATCC
37
2
7294) pan-susceptible. The bacterial suspensions were
prepared in sterile water containing beads of glass of 3 mm.
The suspension was homogenized by vortex agitation and
the turbidity was adjusted in agreement with tube one of
the scale of McFarland (3.2 × 106 cfu mL ). The inoculum
was prepared diluting the bacterial suspension in the
proportion of 1:20 in medium 7H9 Middlebrook (Difco,
Becton-Dickinson) enriched with 10% oleic acid, albumin,
-1
®
dextrose and catalase (OADC-BBL ).
References
Minimum inhibitory concentration determination
1. World Health Organization (WHO); Global Tuberculosis,
Report on WHO Press: Geneva, 2013.
The resazurin microtiter assay (REMA) was performed
44
adapting the technique proposed by Palomino et al. Briefly,
00 μL of sterile water was added to all outer-perimeter
2. Palomino, J. C.; Leão, S. C.; Ritacco, V. In Tuberculosis 2007:
From Basic Science to Patient Care; Silva, P. A.; Aínsa, J. A.,
eds.; Amedeo Challenge, 2007, ch.18.
2
wells of the sterile 96 well plates to minimize evaporation
of the medium in the test wells during incubation. Hereafter,
3. Rivers, E. C.; Mancera, R. L.; Drug Discov. Today 2008, 23,
1090.
100 μL of Middlebrook 7H9 broth (Difco Laboratories)
enriched with 10% OADC was placed in each tests well
4. Spigelman, M.; Gillespie, S.; Lancet 2006, 367, 945.

1
026
On the Search for Potential Antimycobacterial Drugs
J. Braz. Chem. Soc.
5
. Franzblau, S. G.; DeGroote, M. A.; Cho, S. H.; Andries, K.;
22. Hooker, S. C.; Steyermark, A.; J. Am. Chem. Soc. 1936, 58,
1202.
Nuermberger, E.; Orme, I. M.; Mdluli, K.;Angulo-Barturen, I.;
Dick, T.; Dartois,V.; Lenaerts,A. J.; Tuberculosis 2012, 92, 453.
. Palomino, J. C.; Ramos, D. F.; Silva, P. E.A.; Curr. Med. Chem.
23. Rostovtsev, V. V.; Green, G. L.; Fokin, V. V.; Sharpless, K. B.;
Angew. Chem. Int. Ed. 2002, 41, 2596.
6
7
8
2
009, 16, 1898.
24. Silva Júnior, E. N.; Menna-Barreto, R. F. S.; Pinto, M. C.; Silva,
R. S.; Teixeira, D. V.; Souza, M. C.; Simone, C. A.; Castro,
S. L.; Ferreira, V. F.; Pinto, A. V.; Eur. J. Med. Chem. 2008, 43,
1774.
. van Rensburg, C. E. J.; Jooné, G. K.; Sirgel, F. A.; Matlola,
N. M.; O’Sullivan, J. F.; Chemotherapy 2000, 46, 43.
. De Logua, A.; Palchykovska, L. A.; Kostina, V. A.; Sanna, A.;
Meleddu, R.; Chisu, L.; Alexeeva, I. V.; Shved, A. D.; Int. J.
Antimicrob. Agents 2009, 33, 223.
25. Cardoso, M. F. C.; Rodrigues, P. C.; Oliveira, M. E. I. M.; Gama,
I. L.; Silva, I. M. C. B.; Santos, I. O.; Rocha, D. R.; Pinho, R. T.;
Ferreira, V. F.; Souza, M. C. B. V.; Silva, F. C.; Silva Júnior,
F. P.; Eur. J. Med. Chem. 2014, 84, 708.
9
. Bolton, J. L.; Trush, M.A.; Penning, T. M.; Dryhurst, G.; Monks,
T. J.; Chem. Res. Toxicol. 2000, 13, 135.
1
0. Ribeiro, C. M. R.; Souza, P. P.; Ferreira, L. L. D. M.; Pereira,
S. L.; Martins, I. S.; Epifanio, R. A.; Costa-Lotufo, L. V.;
Jimenez, P. C.; Pessoa, C.; Moraes, M. O.; Lett. Org. Chem.
26. Silva, R. S. F.; Costa, E. M.; Trindade, U. L. T.; Teixeira, D. V.;
Pinto, M. C. F. R.; Santos, G. L.; Malta,V. R. S.; Simone, C.A.;
Pinto, A. V.; Castro, S. L.; Eur. J. Med. Chem. 2006, 41, 526.
27. Boechat, N.; Ferreira, V. F.; Ferreira, S. B.; Ferreira, M. L. G.;
Silva, F. C.; Bastos, M. M.; Costa, M. S.; Lourenço, M. C. S.;
Pinto,A. C.; Krettli,A. U.;Aguiar,A. C.; Teixeira, B. M.; Silva,
N. V.; Martins, P. R. C.; Bezerra, F. A. F. M.; Camilo, A. L. S.;
Silva, G. P.; Costa, C. C. P.; J. Med. Chem. 2011, 54, 5988.
28. Xia, W. Z.; Li, Q. H.; Chem. Commun. 2003, 19, 2450.
29. Ramana, C.V.; Chatterjee, S.; Durugkar, K.A.; Gonnade, G. R.
CrystEngComm 2009, 11, 143.
2
011, 8, 347.
1
1
1. Pinto, A. V.; Menna-Barreto, R. F. S.; Castro, S. L.; Recent
Progress in Medicinal Plants, Studium Press: Houston, 2006,
vol. 16, p. 109.
2. Guimarães, T. T.; Pinto, M. C. F. R.; Lanza, J. S.; Melo, M. N.;
Monte-Neto, R. L.; Melo, I. M. M.; Diogo, E. B. T.; Ferreira,
V. F.; Camara, C. A.; Valença, W. O.; Oliveira, R. N.; Frézard,
F.; Silva Júnior, E. N.; Eur. J. Med. Chem. 2013, 63, 523.
3. Silva Júnior, E. N.; Melo, I. M. M.; Diogo, E. B. T.; Costa,V.A.;
Souza Filho, J. D.; Valença, W. O.; Camara, C. A.; Oliveira,
R. N.;Araujo,A. S.; Emery, F. S.; Santos, M. R.; Simone, C. A.;
Menna-Barreto, R. F. S.; Castro, S. L.; Eur. J. Med. Chem. 2012,
1
1
30. Jia, S. Y.; Bing, R. L.; Mei, W. D.; Chin. J. Chem. 2007, 25,
1202.
31. Alfred, D.; Konrad, R.; Chem. Ber. 1958, 91, 1841.
32. Jabeen, F.; Oliferenko, P. V.; Oliferenko, A. A.; Pillai, G. G.;
Ansari, F. L.; Hall, C. D.; Katritzky, A. R.; Eur. J. Med. Chem.
2014, 80, 228.
5
2, 304.
4. Souza, N. B.; Andrade, I. M.; Carneiro, P. F.; Jardim, G. A. M.;
Melo, I. M. M.; Silva Júnior, E. N.; Krettli, A. U.; Mem. Inst.
Oswaldo Cruz 2014, 109, 546.
33. Diogo, E. B. T.; Dias, G. G.; Rodrigues, B. L.; Guimarães, T. T.;
Valença, W. O.; Camara, C. A.; Oliveira, R. N.; Silva, M. G.;
Ferreira,V. F.; de Paiva,Y. G.; Goulart, M. O. F.; Menna-Barreto,
R. F. S.; Castro, S. L.; Silva Júnior, E. N.; Bioorg. Med. Chem.
2013, 21, 6337.
1
1
1
5. Castro, S. L.; Emery, F. S.; Silva Júnior, E. N.; Eur. J. Med.
Chem. 2013, 69, 678.
6. Nair, D. K.; Menna-Barreto, R. F. S.; Silva Júnior, E. N.; Mobin,
S. M.; Namboothiri, I. N. N.; Chem. Commun. 2014, 50, 6973.
7. Moura, K. C. G.; Carneiro, P. F.; Pinto, M. C. F. R.; Silva, J. A.;
Malta, V. R. S.; Simone, C. A.; Dias, G. G.; Jardim, G. A. M.;
Cantos, J.; Coelho, T. S.; Silva, P. E. A.; Silva Júnior, E. N.;
Bioorg. Med. Chem. 2012, 20, 6482.
34. Coelho, T. S.; Silva, R. S. F.; Pinto, A. V.; Pinto, M. C.; Scaini,
C. J.; Moura, K. C. G.; Silva, P.A.; Tuberculosis 2010, 90, 293.
35. Viegas Júnior, C.; Danuello, A. C.; Bolzani, V. S.; Barreiro,
E. J.; Fraga, C. A. M.; Curr. Med. Chem. 2007, 14, 1829.
36. Pyta, K.; Klich, K.; Domagalska, J.; Przybylski, P.; Eur. J. Med.
Chem. 2014, 84, 651.
1
8. Carneiro, P. F.; Pinto, M. C. F. R.; Coelho, T. S.; Cavalcanti,
B. C.; Pessoa, C.; Simone, C. A.; Nunes, I. K. C.; Oliveira,
N. M.; Almeida, R. G.; Pinto, A. V.; Moura, K. C. G.; Silva
P. A.; Silva Júnior, E. N.; Eur. J. Med. Chem. 2011, 46, 4521.
9. Kumar, D.; Beena, Khare, G.; Kidwai, S.; Tyagi, A. K.; Singh,
R.; Rawat, D. S.; Eur. J. Med. Chem. 2014, 81, 301.
37. Cavalcanti, B. C.; Cabral, I. O.; Rodrigues, F. A. R.; Barros, F.
W. A.; Rocha, D. D.; Magalhães, H. I. F.; Moura, D. J.; Saffi,
J.; Henriques, J. A. P.; Carvalho, T. S. C.; Moraes, M. O.;
Pessoa, C.; Melo, I. M. M.; Silva Júnior, E. N.; J. Braz. Chem.
Soc. 2013, 24, 145.
1
2
0. Silva Júnior, E. N.; Guimarães, T. T.; Menna-Barreto, R. F. S.;
Pinto, M. C.; Simone, C. A.; Pessoa, C.; Cavalcanti, B. C.;
Sabino, J. R.; Andrade, C. K.; Goulart, M. O. F.; Castro, S. L.;
Pinto, A. V.; Bioorg. Med. Chem. 2010, 18, 3224.
38. Fieser, L. F.; Fieser, M.; J. Am. Chem. Soc. 1948, 70, 3215.
39. Hooker, S. C.; J. Chem. Soc., Trans. 1893, 63, 1376.
Pro
40. CrysAlis ; Data Collection and Processing Software for our
Small Molecule and Protein X-ray Diffraction Systems;Agilent
Technologies, USA, 2012 (Version 1.171.35.21, release 20-01-
2012 CrysAlis171.NET).
2
1. Fernandes, M. C.; Silva Júnior, E. N.; Pinto,A.V.; Castro, S. L.;
Menna-Barreto, R. F.; Parasitology 2012, 139, 26.

Vol. 26, No. 5, 2015
Jardim et al.
1027
4
1. SCALE3 ABSPACK; Scaling Algorithm CrysAlis; Agilent
Technologies, USA, 2012 (Version 1.171.35.21, release 20-
1-2012 CrysAlis171.NET).
44. Palomino, J. C.; Martin, A.; Camacho, M.; Guerra, H.;
Swings, J.; Portaels, F.; Antimicrob. Agents Chemother. 2002,
46, 2720.
0
4
4
2. Sheldrick, G. M.; SHELXS-97; Program for the Solution of
Crystal Structures; University of Göttingen, Germany, 1997.
3. Sheldrick, G. M.; SHELXL-97; Program for the Refinement of
Crystal Structures; University of Göttingen, Germany, 1997.
Submitted: September 1, 2014
Published online: March 20, 2015
FAPERGS has sponsored the publication of this article.