On the investigation of hybrid quinones: Synthesis, electrochemical studies and evaluation of trypanocidal activity

Article abstract of DOI:10.1039/c5ra16213k

In our continued search for novel trypanocidal compounds, arylamine, chalcone, triazolic, triazole-carbohydrate and chalcogenium derivatives containing a naphthoquinone scaffold were prepared; in addition to electrochemical studies, these compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Among the thirty-eight compounds herein evaluated, six were found to be more potent against trypomastigotes than the standard drug benznidazole, with IC₅₀/24 h values between 52.9 and 89.5 μM.

Full text of DOI:10.1039/c5ra16213k

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On the investigation of hybrid quinones: synthesis,
electrochemical studies and evaluation of
trypanocidal activity†
Cite this: RSC Adv., 2015, 5, 78047
Guilherme A. M. Jardim,a Wallace J. Reis,a Matheus F. Ribeiro,a Flaviano M. Ottoni,b
Ricardo J. Alves,b Thaissa L. Silva,c Marilia O. F. Goulart,c Antonio L. Braga,d
Rubem F. S. Menna-Barreto,e Kelly Salomao,e Solange L. de Castroe
˜
a
*
and Eufranio N. da Silva Junior
ˆ
´
In our continued search for novel trypanocidal compounds, arylamine, chalcone, triazolic, triazole–
carbohydrate and chalcogenium derivatives containing a naphthoquinone scaffold were prepared; in
addition to electrochemical studies, these compounds were evaluated against the infective bloodstream
form of Trypanosoma cruzi, the etiological agent of Chagas disease. Among the thirty-eight compounds
herein evaluated, six were found to be more potent against trypomastigotes than the standard drug
benznidazole, with IC50/24 h values between 52.9 and 89.5 mM.
Received 12th August 2015
Accepted 8th September 2015
DOI: 10.1039/c5ra16213k
www.rsc.org/advances
amastigote, which aer several reproductive cycles, transforms
into the trypomastigote form, which is responsible for dissem-
Introduction
ination of the infection.
Chagas disease is caused by the protozoan Trypanosoma cruzi (T.
cruzi) and affects approximately 5.7 million individuals in Latin
America, of whom 30–40% either have or will develop cardio-
myopathy, digestive megasyndromes or both.1 The trans-
mission of Chagas disease occurs through the faeces of sucking
triatominae insects, blood transfusions, organ transplantation,
oral contamination through laboratory accidents and congen-
ital routes.2 A current major concern is related to outbreaks of
acute Chagas disease associated with the ingestion of contam-
inated food and drink.3,4 Another concern is the disease's
emergence in non-endemic areas such as North America and
Europe, a phenomenon that is likely due to the immigration of
infected individuals.5,6 This disease is characterised by two
clinical phases: a short, acute phase dened by patent para-
sitaemia and a long, progressive chronic phase.7
The available chemotherapy for this illness includes two
nitroheterocyclic agents, nifurtimox and benznidazole (Bnz).
These two agents are effective against acute infections but show
poor activity, severe collateral effects and limited efficacy
against different parasitic isolates in the late chronic phase.
Thus, there is an urgent need to identify better drugs to treat
chagasic patients.9,10
Among several naturally occurring compounds, the naph-
thoquinones have emerged with a broad distribution in the
plant kingdom; naphthoquinones are involved in oxidative
processes due to their structural properties and their capacity to
generate reactive oxygen species.11,12 Quinoidal compounds can
be found in various plant families or as synthetic substances13,14
and are the focus of research aimed at the identication of
derivatives with efficacy and selectivity toward T. cruzi.15
Lapachol (1) is an important natural naphthoquinone; our
group has focused on synthesising and evaluating the trypa-
nocidal activity of lapachones substituted with 1,2,3-triazole
moieties.15 The broad and potent activity of triazole and their
derivatives has established them as pharmacologically signi-
cant scaffolds.16,17 The catalysis by Cu(I) of 1,3-dipolar cycload-
ditions between azides and terminal alkynes18 led to enhanced
reactivity and regioselectivity, resulting in the formation of 1,4-
disubstituted 1,2,3-triazoles.19 This conversion has been used
increasingly in drug discovery due to its reliability, specicity,
and biocompatibility; also, triazoles can act as both a bio-
isostere and a linker that readily associates with biological
targets through hydrogen-bonding and dipole interactions.20
The life cycle of T. cruzi involves obligatory passage through
vertebrate and invertebrate hosts in a series of different devel-
opmental stages.8 The trypomastigote is ingested by the insect
and differentiates into epimastigote form, which differentiates
into the metacyclic trypomastigote form. Following the invasion
of vertebrate host cells, this form differentiates into the
aInstitute of Exact Sciences, Department of Chemistry, UFMG, Belo Horizonte, MG,
31270-901, Brazil. E-mail: eufranio@ufmg.br
bSchool of Pharmacy, UFMG, Belo Horizonte, MG, 31270-901, Brazil
c
´
Institute of Chemistry and Biotechnology, UFAL, Maceio, AL, 57072-970, Brazil
d
´
Department of Chemistry, UFSC, Florianopolis, SC, 88040-900, Brazil
eLaboratory of Cellular Biology, IOC, FIOCRUZ, Rio de Janeiro, RJ, 21045-900, Brazil
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra16213k
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Over the years, our group has investigated the synthesis, with nor-b-lapachone dibromo-substituted arylamine exhibit-
selectivity, and mechanisms of action of quinoidal compounds ing approximately four times more activity than Bnz, the stan-
in relation to T. cruzi.21 The synthetic strategies involved A-ring, dard drug (Scheme 1a).25 Nor-b-lapachone-based 1,2,3-triazole
C-ring and redox centre modications of lapachones.15,21,22 For (which is two times more active than Bnz) was also effective
instance, naphthoimidazoles were prepared by redox centre against the proliferative forms of T. cruzi (Scheme 1a).26,27 Silva
modication of b-lapachone; among the derivatives assayed, and co-workers28 described the synthesis of iodinated and
three compounds were active against bloodstream trypomasti- methylated naphthoquinones obtained from C-allyl lawsone
gotes of T. cruzi (Scheme 1a).23,24 3-Arylamino nor-b-lapachones (Scheme 1a) that were active against epimastigotes and trypo-
represent an important example of C-ring-modied lapachones. mastigotes of T. cruzi, with the main target being the
The compounds were effective against trypomastigote forms, mitochondrion.29
Scheme 1 Overview. * IC50/24 h values for the lytic activity on bloodstream trypomastigotes.
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The triazole moiety is also used for the synthesis of glyco- linked to monosaccharides: sugar residues are able to modulate
sylated structures.30 For example, a series of sugar triazoles has physicochemical parameters, such as solubility and interactions
been synthesized, and 1,2,3-triazole-linked sialic acid-6-O- with cell surface components, which are both important
galactose was active in vitro against T. cruzi.31 Recently, Campo parameters enabling a drug to act on intracellular parasites; and
and co-workers described 1,4-disubstituted 1,2,3-triazole-sialic (v) selenium- and sulphur-containing lapachones: for the rst
acid derivatives containing galactose, glucose or gulose as time, this class of compounds is evaluated against T. cruzi and
potential inhibitors of T. cruzi trans-sialidase (Scheme 1b).32
Chalcones can be readily synthesized by the Claisen–
Schmidt condensation method,33 and they represent a key
moiety in medicinal chemistry, displaying a wide range of
pharmacological activities.34 Hybrids of chalcone with quinoli-
none,35 paullone36 and benzoxaborole37 have shown signicant
activity against pathogenic trypanosomatids and low cytotox-
icity to mammalian cells (Scheme 1b).
Finally, several reports have described chalcogen-containing
quinones with antibacterial, antifungal38 and antitumor activi-
ties,39 and the last two decades have witnessed a growing
interest in selenium-containing compounds with potential
‘redox modulating’ properties. Certain redox catalysts contain-
ing quinone- and chalcogen-bearing building blocks have
shown considerable importance, with activity against cancer
cells and other biological targets.40
In this context, we herein describe the synthesis and trypa-
nocidal activity of (i) a-lapachone arylamines: as discussed above,
the presence of an arylamino group in nor-b-lapachone improves
the trypanocidal activity, and the biological activity of 4-aryla-
mino a-lapachone remains unexplored; (ii) nor-b-lapachone-
based chalcones: we aim to obtain active compounds, due to
the well-known bioactivity of each individual moiety; (iii)
quinone-based 1,2,3-triazoles from C-allyl lawsone: the insertion
of 1,2,3-triazole could enhance the trypanocidal activity of the
derivatives previously shown to be less active than Bnz, as dis-
played in Scheme 1a;15 (iv) naphthoquinone-based 1,2,3-triazole
subjected to concise electrochemical studies (Scheme 1c).
Results and discussion
Chemistry
To obtain a-lapachone arylamines, a-lapachone (2) was prepared
in an initial step from lapachol (1) in acidic conditions.41 Then, 2
was reacted with NBS in CCl4 using benzoyl peroxide as an initi-
ator to afford 4-bromo-a-lapachone; a nucleophilic substitution
reaction with substituted anilines gave the compounds 3–14
(Scheme 2). We recently reported compounds 3–7, 9–10 and 14,42
and compounds 8, 11–13 are herein described for the rst time. In
order to achieve nor-b-lapachone-based chalcones, amino-
chalcones were synthesized via a Claisen condensation reaction
with 40-aminoacetophenone and different aldehydes in the pres-
ence of sodium hydroxide in ethanol.43 Then, nor-lapachol (15)44
was treated with excess bromine to obtain 3-bromo-nor-b-lapa-
chone (16) in quantitative yield.41 Through a nucleophilic substi-
tution reaction with amino-chalcones and 16, compounds 17–21
were prepared as previously published (Scheme 2).45
To obtain the third class of substances, C-allyl-lawsone (22)
was prepared in an initial step from the reaction of lawsone with
allyl bromide.46 In a second step, 22 was treated with excess
iodine,28 forming the para and ortho regioisomers. The iodin-
ated naphthoquinone 23 (ortho-derivative) was obtained in
moderate yield as a crystalline red solid aer separation by
column chromatography. Compound 24 was synthesized in
Scheme 2 Synthesis of a-lapachone arylamines and nor-b-lapachone-based chalcones.
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Scheme 3 Synthesis of quinone-based 1,2,3-triazoles 26–30 and linkage to monosaccharides to give 30 and 31. Conditions (i): CuSO4$5H2O,
sodium ascorbate, CH2Cl2/H2O.
good yield via nucleophilic substitution of 23 with sodium azide of 24 with CuSO4$5H2O/sodium ascorbate and the corre-
in dimethylformamide (DMF), as previously described.47 The sponding alkynes in a mixture of CH2Cl2/H2O, giving 25–29.
1,2,3-triazole derivatives were obtained through a click reaction Alkyne derivatives of monosaccharides were also used in the
Scheme 4 Synthesis of nor-b-lapachone-based 1,2,3-triazole-carbohydrates 33–35.
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click reaction, providing 30–31 (Scheme 3). These alkyne- compounds against T. cruzi were 14, 26–29 and 41, which
carbohydrate derivatives were obtained using two different exhibited IC50/24 h values in the range of 52.9 to 89.5 mM, in
methods of acetylation.48,49 For the glucose and galactose comparison with the IC50/24 h value of 103.6 mM for the refer-
derivatives, D-glucose and D-galactose were subjected to per- ence drug, Bnz. Thus, in general, these compounds are
acetylation with NaOAc in acetic anhydride, and the compounds approximately two times more potent than Bnz (Table 1).
were prepared in moderate yields. For the mannose derivative,
catalytic amounts of I2 were used instead of NaOAc. The product
was reacted with propargyl alcohol and catalytic amounts of
BF3$Et2O in CH2Cl2 to achieve the alkyne derivative.50
Table 1 Activity of compounds against the trypomastigote form of
T. cruzi
To prepare nor-b-lapachone-based monosaccharide-linked
1,2,3-triazoles, bromo derivative 16 was subjected to a nucleo-
philic substitution reaction with sodium azide in dichloro-
methane to obtain 32 in quantitative yield, as previously
reported.26 From the reaction of 32 with CuSO4$5H2O/sodium
ascorbate and the alkyne derivatives of glucose, mannose and
galactose in a mixture of CH2Cl2/H2O, compounds 33–35 were
obtained in good yields (Scheme 4).
Finally, as recently described,51 the chalcogenylation of
lapachol (1) was induced under microwave irradiation and
using molecular iodine as a catalyst, DMSO as a stoichiometric
oxidant and different chalcogenium compounds, affording the
selenium- and sulphur-containing b-lapachone derivatives
(Scheme 5).
Compd
IC50/24 ha (mM)
Compd
IC50/24 ha (mM)
1
2
3
4
5
6
7
8
410.8 ꢀ 53.2b
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
89.5 ꢀ 2.8
>4000b
52.9 ꢀ 2.1
>4000
55.3 ꢀ 5.2
911.0 ꢀ 42.2
374.5 ꢀ 179.5
>4000
86.7 ꢀ 5.4
300.3 ꢀ 21.1
174.9 ꢀ 10.6
50.2 ꢀ 3.8d
472.2 ꢀ 16.5
208.9 ꢀ 7.3
202.3 ꢀ 6.0
102.9 ꢀ 0.0
1677.8 ꢀ 113.3
207.6 ꢀ 33.52
360.5 ꢀ 34.6
477.1 ꢀ 14.83
54.9 ꢀ 3.19
251.9 ꢀ 52.51
>4000
>4000
1471.3 ꢀ 171.6
9
>4000
10
11
12
13
14
15
17
18
19
20
21
22
23
25
1093.8 ꢀ 133.1
>4000
440.6 ꢀ 73.0
>4000
89.3 ꢀ 6.0
1280.6 ꢀ 167.2b
>4000
The structures of the novel compounds 8, 11–13, 25–31 and
1
33–35 were determined by H and 13C NMR. Electrospray ioni-
>4000
42
43
44
45
1
zation mass spectra were also obtained. The H and 13C NMR
787.4 ꢀ 40.6
230.2 ꢀ 71.6
>4000
281.8 ꢀ 3.45
109.2 ꢀ 33.2
>4000
spectra for all unpublished compounds are included in the
ESI.†
352.0 ꢀ 29.0c
398.0 ꢀ 56.0c
213.5 ꢀ 8.4
46
Benznidazoled
Crystal violetb
103.6 ꢀ 0.6
Biological and electrochemical analysis
536.0 ꢀ 3.0
a
b
The compounds 3–14, 17–21, 25–31 and 33–46 were evaluated
against trypomastigote forms of T. cruzi. The more active
Mean ꢀ SD of at least three independent experiments. Ref. 23c.
c
Ref. 28. d Ref. 26.
Scheme 5 Chalcogenium-containing b-lapachone derivatives 36–46 evaluated against T. cruzi.
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We recently described the arylamino-substituted a-lapa- will be considered for further studies. These derivatives were
chone compounds 3–14 as having moderate antitumor obtained in only three steps from C-allyl lawsone (22), and 27
activity.42 Herein, we prepared a series of arylamino-substituted and 28 were almost twice as active as Bnz. Additionally, we
a-lapachone compounds possessing electron-withdrawing and prepared lapachone coupled with carbohydrate derivatives 30,
electron-donating groups. No clear structure–activity relation- 31 and 33–35 to evaluate the ability of these compounds to
ship was observed, and all the compounds were either inactive generate damage to the parasite. We observed that these new
or presented low activity, with the exception of compound 14 compounds presented moderate activity against T. cruzi, but the
(IC50/24 h of 89.3 mM).
compounds were less active than Bnz. In general terms, the
As discussed before, chalcones represent an important class strategy was efficient, but further structural modications will
of compounds with trypanocidal activity.33–37 Based on this be required to improve the biological potential of these
previously determined biological activity, we prepared and compounds.
evaluated the nor-b-lapachone-based chalcone hybrids 17–21.
We recently described the last class of compounds as pos-
These compounds were previously shown to possess potent sessing potential antitumor activity.51 Selenium- and sulphur-
antitumor activity.45 Unfortunately, the compounds failed to kill containing b-lapachone derivatives 33–46 were active against
T. cruzi, and the derivatives were considered inactive; the T. cruzi with generally moderate activity; however, compounds
exception was compound 20 (IC50/24 h of 230.2 mM), which 41 (IC50/24 h ¼ 54.9 mM), 36 (IC50/24 h ¼ 102.9 mM) and 45 (IC50/
presented moderate activity against trypomastigote forms of the 24 h ¼ 109.2 mM) exhibited IC50 values similar to that of Bnz,
parasite.
and 41 was 2-fold more potent than Bnz. Herein, we describe
The third class of compounds, lapachone derivatives detailed studies of the electrochemical aspects of these
obtained from C-allyl lawsone (22), are promising trypanocidal compounds, as only few examples of chalcogenium-
a
agents. We recently used molecular hybridization of naph- containing lapachones have been reported, along with evalua-
thoquinoidal compounds and 1,2,3-triazoles to design trypa- tion of anticancer activity. To the best of our knowledge, this is
nocidal derivatives.25,26,52 We discovered, for instance, four the rst joint report of electrochemistry and trypanocidal
classes of naphthoquinone-based 1,2,3-triazoles, which are activity results, related to this class of compounds.
exemplied by compounds 47–52 (Fig. 1), which have the
In addition, we also evaluated the cytotoxicity of the most
pronounced ability to inhibit the infective bloodstream form of active compounds against peritoneal macrophages. The results
T. cruzi and are more active than Bnz. We described some showed that the active substances were more toxic to the
insights about the mechanism of action of 48. This substance parasites than to the cell lines tested. Finally, our results
induced reservosome disruption, agellar blebbing and Golgi demonstrated that compounds 14 and 26–29 are the most active
disorganization in the parasites. According to our studies, against this trypanosomatid and may represent promising
autophagy could be a part of the mechanism of action for this compounds for treatment of Chagas disease.
derivative.53
Molecular electrochemistry, through non-destructive tech-
In our search for novel quinone-based 1,2,3-triazoles, we niques such as cyclic voltammetry in aprotic and protic media,
herein describe for the rst time a series of triazolic derivatives has proved to be very useful for characterizing electron transfers
prepared from C-allyl lawsone (22) (Scheme 3). Compounds 26, and deciphering chemical reaction mechanisms that are asso-
27, 28 and 29, with IC50/24 h values of 89.5, 52.9, 55.3 and 86.7 ciated with electron transfer, with some correlation with redox-
mM, respectively, presented important trypanocidal activity and based biological activity.12,54 In this context, our group has
described the synthesis and electrochemical studies of several
quinones in an attempt to correlate them with trypanocidal
activity,55 as well as the electrochemical aspects of arylamino-
substituted a-lapachones and nor-b-lapachones.42,52,56
Among all the investigated multifunctional compounds
herein described, only a few examples of electrochemical
studies on chalcogen-containing quinones have been reported
in the literature.40 In order to corroborate the biological aspects
of selenium- and sulphur-containing b-lapachones and estab-
lish more insight using electrochemical parameters, we per-
formed experiments with the compounds 36–39, 40, 41 and 45.
Using cyclic voltammetric studies in aprotic (DMF/TBAPF6) and
protic (ethanolic phosphate buffered medium at pH 7.4) media,
the two redox centres (quinoidal and organochalcogen moie-
ties) were investigated.57 The electrochemical properties of
organic selenium compounds58,59 qualitatively resemble those
of the more abundant sulphur compounds, although they are
much less explored. The number of redox potentials of orga-
Fig. 1 Trypanocidal compounds designed by molecular hybridization
noselenium organic compounds is limited. The products of
electrochemical oxidation are remarkably dependent upon the
of quinones and 1,2,3-triazoles. * IC50/24 h values for the lytic activity
on bloodstream trypomastigotes.
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structure of the organic moiety, the water content of the solvent,
and the supporting electrolyte.58
In the present case, cyclic voltammogram (CV) was used to
investigate the electrochemical behaviour of the seven seleno-
quinones 36–39, 40, 41, and 45, which were recently reported as
antitumor compounds.51 The obtained proles conrmed the
presence of two individual redox centres.
In typical measurements, CVs were recorded in aprotic
medium (DMF + TBAPF6, 0.1 mol Lꢁ1) to resemble the
membrane environment at a scan rate of 100 mV sꢁ1. This
enabled the determination of the electrochemical reduction
(from 0.5 up to ꢁ3.0 V) and oxidation (from ꢁ0.5 up to 2.0 V)
behaviours of each compound. Cathodic and anodic peak
potentials for each compound are listed in Table 2. All the
compounds showed electrochemical activity in the cathodic
and anodic arms of the CVs, as represented by compound 38
(Fig. 2).
Fig. 2 Cyclic voltammograms (first cycle) of compound 38, in DMF +
TBAPF6 (0.1 mol Lꢁ1). Glassy carbon electrode, n ¼ 100 mV sꢁ1, (c ¼ 1
mmol Lꢁ1). Black: potential range from +0.5 V to ꢁ3.0 V, cathodic
direction; red: potential range from ꢁ0.5 V to +2.0 V, anodic direction.
The voltammograms for compounds 36–39, 40, 41 and 45
displayed similar proles in the cathodic and anodic regions.
Fig. 3 shows the electrochemical behaviour of compound 40 as a
representative of the series.
selenium-containing b-lapachone derivatives are voltammetri-
cally interrogated in DMF and displayed only one irreversible
oxidation peak between +1.126 V and +1.252 V vs. Ag|AgCl, Clꢁ
(Table 2).
The rst monoelectronic transfer leads to the formation of
the corresponding Se radical-cation. Three reaction paths are
generally available to alkylphenyl chalcogenide radical-cations:
deprotonation; nucleophilic attack at the chalcogen atom; and
C–chalcogen bond cleavage. The relative weight of each of these
reaction pathways is governed by the nature of the chalcogen
and of the alkyl group linked to it, as well as by the nature of the
electrolysis medium.61
The electrochemical oxidation is shown to follow an overall
EC-type mechanism, in which the electro-generated selenium-
based cation radical undergoes an irreversible carbon–chal-
cogen bond rupture,58 similar to the pathway followed by gly-
cosylchalcogenides.59 This cleavage produces the corresponding
unsaturated quinone, which undergoes reduction in the reverse
cycle (wave IVc), together with the intermediate organic sele-
nium radical. The organic selenium radical reacts further to
form the selenoxide specie, which can follow several pathways
depending on the amount of water in the supporting
As expected, the overall CV proles for the quinonoid
compounds are similar to those reported for other
quinones.42,53,60 One couple of cathodic and anodic peaks is
represented by a diffusional (EpIc f n1/2) quasi-reversible nature
(Ic/Ia). This rst pair is related to the anion-radical (semi-
quinone) formation, and the second pair of peaks is broader
and ill-dened (IIc/IIa), as observed before,60 due to a possible
disproportionation of ortho-quinones (Fig. 3a and b). In the
anodic region, a sharp, irreversible peak (IVa) appears, with at
least a duplicated current intensity. In the reversed cycle, a
reduction wave (IVc) is observed close to 0 V; in the successive
scan, it is observed that the reduced product formed can be re-
oxidized (IVa0) (Fig. 2c). In the case of compound 38, anodic
peak IVa is followed by a more positive one (Va) due to the
presence of an electron-donating group. Electrochemical data
are displayed in Table 2.
The values of EpIc varied from ꢁ0.644 V up to ꢁ0.674 V (Table
2). As the selenium–phenyl moiety is coupled to the reducible
quinone moiety without conjugation, there is only a slight
change in the reduction potentials, with compound 40 (p-Br)
being the most easily reduced; the aliphatic selenium derivative
is reduced at more negative potentials. The majority of
Table 2 Main electrochemical parameters for the analysed compounds 36–39, 40, 41, and 45 in DMF + TBAPF6 (0.1 mol Lꢁ1). Glassy carbon
electrode, n ¼ 100 mV sꢁ1 (c ¼ 1 mmol Lꢁ1 a
)
Compd
ꢁEpIc (V)
ꢁEpIIc (V)
ꢁEpIIIc (V)
ꢁEpIa (V)
ꢁEpIIa (V)
ꢁEpIIIa (V)
EpIVa (V)
EpVa (V)
EpVIa (V)
36
37
38
39
40
41
45
0.655
0.655
0.668
0.658
0.644
0.662
0.674
1.134
1.061
1.140
1.140
1.098
1.123
1.154
1.340
—
—
—
—
1.269
0.923
0.945
1.028
0.913
0.939
0.937
1.063
0.566
0.580
0.554
0.542
0.566
0.584
0.548
0.211
—
0.168
0.132
0.214
0.247
0.301
0.371
0.328
0.301
0.337
0.386
0.309
1.126
1.131
1.252
1.163
1.198
1.233
1.137
—
—
1.534
—
—
—
—
—
—
a
Nd. not determined.
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Fig. 4 Cyclic voltammograms of compound 37, in phosphate buffer
(pH 7.4) + 20% ethanol. Glassy carbon electrode, n ¼ 100 mV sꢁ1, (c ¼
0.1 mmol Lꢁ1).
electrolyte.57 The resulting cathodic wave IVc is a composed one,
possibly related to more than one reduction pathway. The
mechanism will be further explored and presented elsewhere.
The electrochemical oxidation prole, based on the values of
EpVa (Table 2, column 9), is related to effects of the substituents
and the order of oxidation facility was found to be: 36 ꢂ 37 ꢂ 45
> 39 > 40 > 41 > 38.
We also studied the behaviour of the compounds in protic
medium. The two redox centres in compounds 36–39, 40, 41
and 45 were then analysed by cyclic voltammetry in protic
media. The latter assessment provides insight into the oxida-
tion and reduction processes in which compounds might
participate both in vitro and in vivo. This medium resembles the
hydrophilic regions of the biological matrixes.12,54
The CV in protic medium is represented by a reversible peak
system (Ic/Ia) in the cathodic region, typical of quinones,62 and
one irreversible peak (IIa) with at least twice the current inten-
sity in the anodic region. Fig. 4 represents a general electro-
chemical prole.
The present compounds exhibited two distinct redox
behaviours that were indicative of one quinone and one chal-
cogen centre (Table 3). At pH 7.4, the quinone redox couple (EpIa
and EpIc) appeared in the range of ꢁ0.260 V up to ꢁ0.288 V vs.
Ag|AgCl, with quasi-reversible characteristics. Regarding the
oxidation of chalcogen centres, CVs displayed irreversible
oxidation peaks (EpIIa) between +0.707 V (compound 36) and
Table
3 Main electrochemical parameters for the analysed
compounds in phosphate buffer (pH 7.4) + 20% ethanol. Glassy carbon
electrode, n ¼ 100 mV sꢁ1 (c ¼ 0.1 mmol Lꢁ1
)
Compd
ꢁEpc (V)
ꢁEpc (V)
ꢁEpa (V)
Epa (V)
Others (V)
1
2
1
2
Fig. 3 Cyclic voltammograms of compound 40 in DMF + TBAPF6 (0.1
mol Lꢁ1). Glassy carbon electrode, n ¼ 100 mV sꢁ1 (c ¼ 1 mmol Lꢁ1). (a)
Potential range from +0.5 V to ꢁ2.0 V, 2 successive cycles. (b)
Potential range from +0.5 V to ꢁ2.0 V, several values for potential
inversion. (c) Potential range from ꢁ0.5 V to +1.5 V, 2 successive
cycles.
36
37
39
40
41
45
0.260
0.288
0.284
0.273
0.263
0.269
0.410
—
—
—
—
0.221
0.215
0.189
0.209
0.205
0.223
0.707
1.362
1.460
1.336
1.445
1.316
0.082
—
0.278
0.171
—
—
—
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+1.460 V (compound 39). The oxidation peaks are probably due trypomastigotes of the Y strain were obtained at the peak of
to the formation of the intermediate radical species, rapidly parasitaemia from infected albino mice, isolated by differential
followed by reaction with water to form the chalcogen oxide.39
centrifugation and resuspended in Dulbecco's modied Eagle
Overall, cyclic voltammetry conrmed the presence of two medium (DME) to a parasite concentration of 107 cells per mL
individual redox centres. While the centres inuenced each in the presence of 10% of mouse blood. This suspension (100 mL
other, e.g., via electron withdrawing effects, there was little was added in the same volume of each compound previously
enhancement or synergy between them. This was not prepared at twice the desired nal concentrations). Cell counts
surprising, as there was a substantial difference between the were performed in a Neubauer chamber, and the trypanocidal
organochalcogen and quinone redox potentials and no conju- activity was expressed as IC50, corresponding to the concentra-
gation between them.
tion that leads to lysis of 50% of the parasites.
Toxicity to macrophages
Conclusions
The cytotoxicity assays were performed using primary cultures
of peritoneal macrophages obtained from Swiss mice.63 For the
experiments, 6 ꢃ 104 cells in 100 mL of RPMI-1640 medium (pH
7.2 plus 10% foetal bovine serum and 2 mM glutamine) were
added to each well of a 96-well microtiter plate and incubated
for 24 h at 37 ꢄC. The treatment of the cultures was performed in
fresh supplemented medium without phenol red (200 mL per
well for 24 h at 37 ꢄC). Aer this period, 110 mL of the medium
was discarded and 10 mL of PrestoBlue (Invitrogen) was added to
complete the nal volume of 100 mL. Then, the plate was
incubated for 5 h, and the measurement was performed at 570
and 600 nm, as recommended by the manufacturer. The results
are expressed as the difference in the percentage of reduction
between the treated and untreated cells as the LC50 value, cor-
responding to the concentration that leads to damage of 50% of
the mammalian cells.
We described thirty-eight compounds that were evaluated for
their effects on the infective bloodstream form of T. cruzi, the
etiological agent of Chagas disease. Six compounds were
discovered to have potent trypanocidal activity. The quinone-
based 1,2,3-triazoles showed the best results in the series,
with 4 representatives (26–29) being more active than Bnz.
The strategy of preparing a wide range of multifunctional
catalysts for generating oxidative stress, with two or even
more redox centres combined in chemically simple mole-
cules, was shown to be effective. Based on current assess-
ments, structural aspects and electrochemical parameters do
not show correlation with trypanocidal activity. This work
represents an important contribution to the discovery of new
drugs to combat T. cruzi and therefore provides the impetus
for follow-up investigations involving synthetic chemistry,
electrochemistry and cell biology.
Statistical analysis
Experimental section
General
The comparison between the IC50 values for T. cruzi was per-
formed using ANOVA followed by the Student–Newman–Keuls
and Mann–Whitney tests (p < 0.05).
Melting points were obtained on a Thomas Hoover apparatus
and are uncorrected. Analytical grade solvents were used.
Column chromatography was performed on silica gel (Silia-
Electrochemical studies
ꢀ
Flash G60 UltraPure – 60–200 mm, 60 A). Infrared spectra were
Cyclic voltammetry (CV) experiments were performed with a
conventional three electrode cell in an Autolab PGSTAT-30
potentiostat (Echo Chemie, Utrecht, the Netherlands) coupled
to a PC microcomputer, using GPES 4.9 soware. The working
electrode was a glassy carbon electrode (GCE) BAS (d ¼ 3 mm),
the counter electrode was a Pt wire, and the reference electrode
was an Ag|AgCl, Clꢁ (sat.). All electrodes were contained in a
recorded on an FTIR Spectrometer IR Prestige-21 – Shimadzu.
1H- and 13C-NMR were recorded at room temperature using a
Bruker AVANCE DRX200 and DRX 400 in the solvents indicated,
with TMS as an internal reference. Chemical shis (d) are given
in ppm and coupling constants (J) in Hertz. High-resolution
mass spectra (electrospray ionization) were obtained using a
Shimadzu LCMS-IT-TOF. Lapachol (1) was extracted from the
heartwood of Tabebuia sp. (Tecoma) and puried by a series of
recrystallizations. Nor-lapachol (15) was obtained as a crystal-
line orange solid by Hooker oxidation44 of quinone 1.
Compounds 17–21 and 36–46 were prepared as recently repor-
ted by our research group.45,51
one-compartment electrochemical cell with
a volumetric
capacity of 10 mL. The GC electrode was cleaned up by polish-
ing with alumina on a polishing felt (BAS polishing kit). The
solvent used was N,N-dimethylformamide extra dry 99.8%,
´
acquired from Acros Organics. In CV experiments, the scan rate
varied from 10 to 500 mV sꢁ1. Electrochemical reduction was
performed in aprotic media (DMF + TBAPF6 0.1 mol Lꢁ1) at
Trypanocidal assay
ꢁ3
ꢄ
room temperature (25 ꢀ 2 C). Each compound (1 ꢃ 10 mol
Stock solutions of the compounds were prepared in dimethyl Lꢁ1) was added to the supporting electrolyte, and the solution
sulfoxide (DMSO, with the nal concentration of the latter was deoxygenated with argon before the CV measurements.
in the experiments never exceeding 0.1%). Preliminary experi- Different potential ranges were used from the cathodic to
ments showed that concentrations of up to 0.5% DMSO have anodic scan. The most representative range was from 0 to ꢁ3.0
no deleterious effect on the parasites. Bloodstream V vs. Ag|AgCl, Clꢁ (sat.) and was chosen for the investigation
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and representation of all the compounds. Anodic scans until 43.0, 37.2, 28.9, 26.1. ESI-MS: (m/z) [C22H21NO4H]+: 364.143.
+1.0 V were performed.
Cald. for [C22H21NO4H]+: 364.1549.
General procedure for the synthesis of compounds 25–29
To a mixture of 255 mg (1.0 mmol) of 24, CuSO4$5H2O (12.48
General procedure for the synthesis of compounds 3–14
To a mixture of 242 mg (1.0 mmol) of 2 and 267 mg (1.5 mmol) mg, 5 mol%) and sodium ascorbate (19.81 mg, 5 mol%) in 8 mL
of N-bromosuccinimide in 30 mL of CCl4, 2 mg of benzoyl CH2Cl2/H2O (1 : 1 v/v), the corresponding alkyne (1.1 equiva-
peroxide was added. The mixture was heated (80 ꢄC) for ve lents) was added. The mixture was stirred overnight at room
hours. The CCl4 was then removed by reduce pressure and 25 temperature. The organic phase was extracted with dichloro-
mL of dichloromethane and the corresponding aniline was methane, dried with NaSO4 and concentrated under reduced
added. The resulting mixture was stirred overnight at room pressure. The residue obtained was puried by column chro-
temperature. The crude material was then submitted to column matography on silica gel using as eluent a gradient mixture of
chromatography utilizing a mixture of ethyl acetate/hexane as hexane/ethyl acetate with increasing polarity.
an eluent.
2-((4-Cyclohexyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydronaph-
4-((4-Fluorophenyl)amino)-2,2-dimethyl-3,4-dihydro-2H- tho[1,2-b]furan-4,5-dione (25). Using ethynylcyclohexane (118 mg,
benzo[g]chromene-5,10-dione (8). Compound 8 was obtained as 1.1 mmol), 25 was obtained as a red solid (298 mg, 0.82 mmol,
an orange solid (210 mg, 0.6 mmol, 60% yield); mp 173–175 ꢄC. 82% yield); mp 163–164 ꢄC. 1H NMR (400 MHz, CDCl3) d: 8.05 (d,
1H NMR (200 MHz, CDCl3) d: 8.08–8.01 (m, 2H), 7.79–7.62 (m, 1H, J ¼ 7.4 Hz), 7.70–7.66 (m, 1H), 7.62–7.58 (m, 2H), 7.54 (s, 1H),
2H), 7.02–6.93 (m, 2H), 6.76–6.69 (m, 2H), 4.68–4.58 (m, 2H), 6.52 (s, 1H), 5.56–5.49 (m, 1H), 4.80–4.68 (m, 2H), 3.40–3.28 (m,
2.24 (dd, 1H, J ¼ 3.7 and 14.3 Hz), 2.01 (dd, 1H, J ¼ 5.3 and 14.3 1H), 2.97 (dd, 1H, J ¼ 6.9 and 15.6 Hz), 2.42–2.31 (m, 2H), 2.27–
Hz), 1.56 (s, 3H), 1.51 (s, 3H). 13C NMR (50 MHz, CDCl3) d: 184.3, 2.13 (m, 4H), 1.84–1.62 (m, 4H). 13C NMR (100 MHz, CDCl3) d:
180.2, 155.8, 143.1, 134.7, 133.6, 132.4, 131.1, 128.9, 127.4, 126.7 180.5, 175.2, 168.9, 149.9, 134.7, 132.3, 130.6, 129.7, 127.0, 125.7,
(d, J ¼ 11.2 Hz), 119.1, 116.4, 116.1 (d, J ¼ 10.2 Hz), 116.0, 79.6, 124.4, 119.2, 114.8, 84.6, 53.2, 30.9, 29.6, 26.3, 25.3, 22.4, 22.1. ESI-
65.7, 45.1, 37.8, 28.8, 26.8. ESI-MS: (m/z) [C21H18FNO3]+: MS: (m/z) [C21H21N3O3]ꢁ: 362.1893. Cald. for [C21H21N3O3]ꢁ:
351.1270. Cald. for [C21H18FNO3]+: 351.1271.
362.1510.
2-((4-(1-Hydroxycyclohexyl)-1H-1,2,3-triazol-1-yl)methyl)-2,3-
4-((3-Iodophenyl)amino)-2,2-dimethyl-3,4-dihydro-2H-benzo[g]-
chromene-5,10-dione (11). Compound 11 was obtained as a brown dihydronaphtho[1,2-b]furan-4,5-dione (26). Using 1-ethynylcy-
solid (321 mg, 0.7 mmol, 70% yield); mp 190–192 ꢄC. 1H NMR (200 clohexanol (136 mg, 1.1 mmol), 26 was obtained as a red solid
1
MHz, CDCl3) d: 7.97–7.93 (m, 2H), 7.67–7.63 (m, 2H), 7.04–6.96 (m, (345 mg, 0.91 mmol, 90% yield); mp 92–93 ꢄC. H NMR (400
1H), 6.88 (t, 1H, J ¼ 7.9 Hz), 6.65 (d, 1H, J ¼ 7.9 Hz), 4.68 (s, 1H), MHz, CDCl3) d: 8.03 (d, 1H, J ¼ 7.2 Hz), 7.71–7.64 (m, 2H), 7.61–
4.61 (s, 1H), 2.25 (dd, 1H, J ¼ 3.7 and 14.3 Hz), 1.96 (dd, 1H, J ¼ 5.3 7.58 (m, 2H), 5.56–5.50 (m, 1H), 4.82–4.69 (m, 2H), 3.36–3.30
and 14.3 Hz), 1.53 (s, 6H). 13C NMR (50 MHz, CDCl3) d: 183.4, (m, 1H), 2.98 (dd, 1H, J ¼ 6.7 and 15.7 Hz), 2.17 (s, 1H), 2.02–
179.7, 155.3, 148.0, 134.3, 133.2, 131.8, 130.7, 128.4, 126.9, 126.3, 1.92 (m, 2H), 1.89–1.78 (m, 2H), 1.76–1.68 (m, 2H), 1.54–1.47
126.0, 121.9, 118.3, 112.8, 95.3, 79.1, 42.9, 37.1, 29.0, 26.0. ESI-MS: (m, 2H), 1.36–1.24 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 180.4,
(m/z) [C21H18INO3Na]+: 482.0433. Cald. for [C21H18INO3Na]+: 175.1, 168.9, 134.8, 132.3, 130.5, 129.7, 126.9, 124.5, 120.9,
482.0229.
114.8, 84.5, 69.6, 53.4, 38.1, 38.0, 29.6, 25.3, 22.0. ESI-MS: (m/z)
4-((3-Chlorophenyl)amino)-2,2-dimethyl-3,4-dihydro-2H- [C21H21N3O4Na]+: 402.1518. Cald. for [C21H21N3O4Na]+:
benzo[g]chromene-5,10-dione (12). Compound 12 was obtained 402.1424.
as a yellow solid (220 mg, 0.6 mmol, 60% yield); mp 177–179 ꢄC.
2-((4-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-tri-
1H NMR (200 MHz, CDCl3) d: 8.06–7.97 (m, 2H), 7.72–7.63 (m, azol-1-yl)methyl)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione (27).
2H), 7.11–7.07 (m, 1H), 6.77–6.63 (m, 2H), 6.58–6.56 (m, 1H), Using 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (154 mg, 1.1
4.65 (s, 1H), 2.26 (dd, 1H, J ¼ 2.7 and 14.4 Hz), 1.99 (dd, 1H, J ¼ mmol), 27 was obtained as a red solid (324 mg, 0.82 mmol, 82%
5.2 and 14.4 Hz), 1.54 (s, 3H), 1.53 (s, 3H). 13C NMR (50 MHz, yield); mp 86–87 ꢄC. 1H NMR (400 MHz, CDCl3) d: 8.02 (d, 1H, J ¼
CDCl3) d: 183.4, 179.7, 155.3, 148.1, 135.0, 134.3, 133.2, 132.0, 7.1 Hz), 7.72 (s, 1H), 7.67–7.63 (m, 1H), 7.59–7.56 (m, 2H), 5.56–
130.8, 130.2, 126.3, 126.1, 118.5, 117.9, 113.1, 111.8, 79.0, 43.11, 5.49 (m, 1H), 4.89–4.64 (m, 6H), 3.90–3.82 (m, 1H), 3.54–3.51 (m,
37.4, 28.9, 26.1. ESI-MS: (m/z) [C21H18ClNO3]+: 367.0962. Cald. 1H), 3.37–3.30 (m, 1H), 2.97–2.91 (m, 1H), 1.80–1.66 (m, 2H),
for [C21H18ClNO3]+: 367.0975.
1.57–1.50 (m, 3H). 13C NMR (100 MHz, CDCl3) d: 180.4, 175.2,
4-((3-Methoxyphenyl)amino)-2,2-dimethyl-3,4-dihydro-2H- 134.7, 132.3, 130.6, 129.7, 126.9, 124.5, 123.6, 114.8, 98.3, 98.3,
benzo[g]chromene-5,10-dione (13). Compound 13 was obtained 84.5, 62.5, 60.5, 53.3, 30.9, 30.4, 29.6, 25.3, 19.4. ESI-MS: (m/z)
as a brown solid (254 mg, 0.7 mmol, 70% yield); mp 88–90 C. [C21H21N3O5Na]+: 418.1016. Cald. for [C21H21N3O5Na]+: 418.1379.
ꢄ
1H NMR (200 MHz, CDCl3) d: 7.92–7.91 (m, 2H), 7.70–7.53 (m,
2-((4-(Cyclohex-1-en-1-yl)-1H-1,2,3-triazol-1-yl)methyl)-2,3-
2H), 7.06 (t, 1H, J ¼ 7.9 Hz), 6.42–6.18 (m, 3H), 4.63 (s, 1H), 3.73 dihydronaphtho[1,2-b]furan-4,5-dione (28). Using 1-
(s, 3H), 2.28 (dd, 1H, J ¼ 2.7 and 14.4 Hz), 1.92 (dd, 1H, J ¼ 5.2 ethynylcyclohex-1-ene (116 mg, 1.1 mmol), 28 was obtained as a
1
and 14.4 Hz), 1.53 (s, 3H), 1.49 (s, 3H). 13C NMR (50 MHz, red solid (336 mg, 0.93 mmol, 93% yield); mp 112–113 C. H
ꢄ
CDCl3) d: 183.3, 179.7, 160.7, 155.1, 148.2, 134.2, 133.1, 131.9, NMR (400 MHz, CDCl3) d: 8.03 (d, 1H, J ¼ 7.4 Hz), 7.70–7.66 (t,
130.6, 130.0, 126.2, 126.0, 118.8, 106.6, 103.0, 99.6, 79.0, 55.0, 1H, J ¼ 16.3 Hz), 7.61–7.54 (m, 2H), 7.54 (s, 1H), 6.55–6.49 (m,
78056 | RSC Adv., 2015, 5, 78047–78060
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1H), 5.56–5.49 (m, 1H), 4.80–4.68 (m, 2H), 3.33 (dd, 1H, J ¼ 10.2 (m, 2H), 5.55–5.44 (m, 1H), 5.39 (s, 1H), 5.26–5.15 (m, 1H), 5.06–
and 15.7 Hz), 2.96 (dd, 1H, J ¼ 7.0 and 15.7 Hz), 2.41–2.16 (m, 4.95 (m, 2H), 4.81–4.67 (m, 4H), 4.20–4.12 (m, 2H), 3.98 (s, 1H),
3H), 1.82–1.61 (m, 4H), 0.92–0.83 (m, 1H). 13C NMR (100 MHz, 3.39–3.33 (m, 1H), 2.98–2.93 (m, 1H), 2.15 (s, 3H), 2.06 (s, 3H),
CDCl3) d: 180.5, 175.2, 168.9, 149.9, 134.8, 132.3, 130.6, 129.7, 1.99 (s, 6H). 13C NMR (100 MHz, CDCl3) d: 180.4, 175.3, 171.1,
127.0, 125.7, 124.5, 119.2, 114.8, 84.6, 53.2, 29.6, 26.3, 25.3, 22.4, 170.1, 170.0, 169.6, 169.5, 144.8, 134.9, 132.4, 130.6, 129.8,
22.1. ESI-MS: (m/z) [C21H20N3O3]+: 362.1978. Cald. for 126.9, 124.6, 123.6, 114.7, 100.0, 84.6, 70.9, 70.8, 68.8, 67.1, 63.0,
[C21H20N3O3]+: 362.1499.
61.2, 60.4, 53.1, 29.7, 21.0, 20.6, 20.5, 19.0, 14.2. ESI-MS: (m/z)
2-((4-Hexyl-1H-1,2,3-triazol-1-yl)methyl)-2,3-dihydronaphtho- [C30H31N3O13Na]+: 664.1762. Cald. for [C30H31N3O13Na]+:
[1,2-b]furan-4,5-dione (29). Using oct-1-yne (121 mg, 1.1 mmol), 664.1755.
29 was obtained as a red solid (332 mg, 0.91 mmol, 91% yield);
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-((1-(2,2-dimethyl-4,5-
mp 121–123 ꢄC. 1H NMR (400 MHz, CDCl3) d: 8.04 (d, 1H, J ¼ 8.2 dioxo-2,3,4,5-tetrahydronaphtho[1,2-b]furan-3-yl)-1H-1,2,3-tri-
Hz), 7.67 (t, 1H, J ¼ 7.4 Hz), 7.59–7.57 (m, 2H), 7.45 (s, 1H), 5.57– azol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (33).
5.49 (m, 1H), 4.81–4.69 (m, 2H), 3.31 (dd, 1H, J ¼ 10.2 and 15.7 Using (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)-
Hz), 2.96 (dd, 1H, J ¼ 6.9 and 15.7 Hz), 2.72 (t, 2H, J ¼ 7.2 Hz), tetrahydro-2H-pyran-3,4,5-triyl triacetate (424 mg, 1.1 mmol), 33
1.67–1.60 (m, 2H), 1.35–1.28 (m, 6H), 0.89–0.86 (m, 3H). 13C was obtained as a yellow solid (537 mg, 0.82 mmol, 82% yield);
1
ꢄ
NMR (100 MHz, CDCl3) d: 180.5, 175.1, 168.9, 148.9, 134.7, mp 88–90 C. H NMR (400 MHz, CDCl3) d: 8.20–8.17 (m, 1H),
132.3, 130.5, 129.7, 126.9, 124.4, 121.6, 114.8, 84.7, 53.2, 31.5, 7.82–7.71 (m, 3H), 7.55/7.51 (s, 1H), 5.98/5.97 (s, 1H), 5.25–5.15
29.6, 29.3, 28.8, 25.6, 22.5, 14.1. ESI-MS: (m/z) [C21H24N3O3]+: (m, 1H), 5.07 (t, 1H, J ¼ 10 Hz), 5.00–4.78 (m, 3H), 4.67 (t, 1H, J ¼
366.2340. Cald. for [C21H24N3O3]+: 366.1812.
7.6 Hz), 4.30–4.10 (m, 2H), 3.77–3.70 (m, 1H), 2.07, 2.01, 2.00,
1.98, 1.97, 1.77 (six singlets observed, 12H), 1.19 (s, 3H), 0.98–
0.83 (m, 3H). 13C NMR (100 MHz, CDCl3) d: 180.0, 180.0, 174.6,
174.5, 171.3, 171.2, 170.7, 170.6, 170.1, 170.1, 169.6, 169.5,
169.4, 144.4, 144.2, 134.8, 134.8, 133.4, 133.4, 131.6, 131.5,
General procedure for the synthesis of compounds 30, 31 and
33–35
To a mixture of 256 mg (1 mmol) of 24 or 269 mg (1.0 mmol) of 130.0, 130.0, 126.6, 126.6, 125.6, 125.5, 122.6, 122.3, 111.1,
32 with CuSO4$5H2O (12.48 mg, 5 mol %) and sodium ascorbate 100.2, 99.9, 95.9, 95.8, 72.8, 72.6, 71.9, 71.3, 71.2, 68.3, 68.3,
(19.81 mg, 5 mol%) in 8 mL CH2Cl2/H2O (1 : 1 v/v), the corre- 67.0, 66.9, 63.3, 63.0, 61.8, 61.7, 31.5, 29.0, 27.7, 27.6, 22.6, 22.6,
sponding alkyne-carbohydrate (1.1 equivalents) was added. The 21.1, 20.7, 20.6, 20.5, 20.5, 20.4, 14.1, 11.4. ESI-MS: (m/z)
mixture was stirred overnight at room temperature. The organic [C31H33N3O13Na]+: 678.1925. Cald. for [C31H33N3O13Na]+:
phase was extracted with dichloromethane, dried with NaSO4 678.1911.
and concentrated under reduced pressure. The residue
obtained was puried by column chromatography on silica gel dioxo-2,3,4,5-tetrahydronaphtho[1,2-b]furan-3-yl)-1H-1,2,3-tri-
using as eluent a gradient mixture of hexane/ethyl acetate with azol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate
increasing polarity. The products 33–35 were obtained as dia- (34). Using (2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(prop-2-yn-1-
stereomers (diastereomer ratio 1 : 1).
yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (424 mg, 1.1
(2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-((1-(2,2-dimethyl-4,5-
(2S,3S,4R,5S,6S)-2-(Acetoxymethyl)-6-((1-((4,5-dioxo-2,3,4,5-tet- mmol), 34 was obtained as a yellow solid (543 mg, 0.83 mmol,
rahydronaphtho[1,2-b]furan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)- 83% yield); mp 118–119 ꢄC. 1H NMR (400 MHz, CDCl3) d: 8.20/
methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (30). Using 8.18 (s, 1H), 7.88–7.78 (m, 3H), 7.60 (s, 1H), 5.99/5,98 (s, 1H),
(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)tetrahy- 5.33–5.20 (m, 3H), 4.95–4.80 (m, 2H), 4.77–4.66 (m, 1H), 4.3 (dd,
dro-2H-pyran-3,4,5-triyl triacetate (424 mg, 1.1 mmol), 30 was 1H, J ¼ 12 and 4.8 Hz), 4.18–4.00 (m, 2H), 2.09, 1.97, 1.95, 1.78
obtained as a yellow solid (544 mg, 0.8 mmol, 85% yield); mp (four singlets observed, 12H), 1.24/1.23 (s, 3H), 0.90–0.84 (m,
117–119 C. H NMR (400 MHz, CDCl3) d: 8.06 (bs, 1H), 7.76– 3H). 13C NMR (100 MHz, CDCl3) d: 180.0, 174.6, 171.4, 171.3,
1
ꢄ
7.67 (m, 2H), 7.61–7.59 (bs, 2H), 5.53–5.48 (m, 1H), 5.25–4.70 170.7, 170.2, 170.0, 170.0, 169.7, 143.6, 134.8, 134.7, 133.4,
(m, 8H), 4.25–4.15 (m, 2H), 3.77 (d, 1H, J ¼ 4 Hz), 3.38–3.32 (m, 131.6, 131.6, 130.0, 129.9, 126.7, 126.6, 125.7, 122.4, 122.3,
1H), 2.98–2.93 (m, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 111.1, 111.1, 97.1, 96.8, 95.9, 95.9, 69.5, 69.5, 69.0, 68.8, 68.7,
1.97 (s, 3H). 13C NMR (100 MHz, CDCl3) d: 180.4, 178.7, 175.2, 67.0, 67.0, 66.1, 66.0, 62.4, 62.3, 61.4, 61.3, 36.1, 34.6, 31.6, 29.0,
173.8, 170.6, 170.1, 169.4, 144.7, 134.9, 132.4, 130.5, 129.7, 27.7, 27.7, 22.6, 22.6, 22.1, 21.3, 20.8, 20.7, 20.6, 20.4, 18.7, 14.1,
126.8, 124.6, 123.8, 114.7, 100.0, 84.5, 72.7, 72.0, 71.2, 68.3, 63.2, 11.4. ESI-MS: (m/z) [C31H33N3O13Na]+: 678.1913. Cald. for
61.8, 53.4, 29.7, 20.7, 20.7, 20.6, 20.6. ESI-MS: (m/z) [C31H33N3O13Na]+: 678.1911.
[C30H31N3O13Na]+: 664.1768. Cald. for [C30H31N3O13Na]+:
664.1755.
(2R,3R,4S,5S,6S)-2-(Acetoxymethyl)-6-((1-(2,2-dimethyl-4,5-
dioxo-2,3,4,5-tetrahydronaphtho[1,2-b]furan-3-yl)-1H-1,2,3-tri-
(2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-((1-((4,5-dioxo-2,3,4,5-tet- azol-4-yl)methoxy)tetrahydro-2H-pyran-3,4,5-triyl
triacetate
rahydronaphtho[1,2-b]furan-2-yl)methyl)-1H-1,2,3-triazol-4-yl)- (35). Using (2R,3R,4S,5S,6S)-2-(acetoxymethyl)-6-(prop-2-yn-1-
methoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (31). Using yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (424 mg, 1.1
(2R,3S,4S,5R,6R)-2-(acetoxymethyl)-6-(prop-2-yn-1-yloxy)tetrahy-
mmol), 35 was obtained as a yellow solid (556 mg, 0.85 mmol,
dro-2H-pyran-3,4,5-triyl triacetate, 31 was obtained as a yellow 85% yield); mp 104–107 ꢄC. 1H NMR (400 MHz, CDCl3) d: 8.20/
1
ꢄ
solid (512 mg, 0.8 mmol, 80% yield); mp 121–122 C. H NMR 8.18 (m, 1H), 7.84–7.72 (m, 3H), 7.52/7.49 (s, 1H), 5.98/5.95 (s,
(400 MHz, CDCl3) d: 8.09 (bs, 1H), 7.73–7.69 (m, 2H), 7.63–7.58 1H), 5.39/5.38 (s, 1H), 5.22–5.12 (m, 1H), 5.03–4.92 (m, 2H),
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C
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Acknowledgements
This research was funded by grants from the Conselho Nacional
´
´
de Desenvolvimento Cientıco e Tecnologico (CNPq 480719/
2012-8, PVE 401193/2014-4, PQ-SR CNPq 302613/2013-7),
FAPEMIG (Edital 01/2014), CAPES, FAPERJ, FAPEAL, CAPES/
PROCAD and PAPES/Fiocruz.
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