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Synthesis, characterization and biological


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activities of 3-aryl-1,4-naphthoquinones – green


Cite this: New J. Chem., 2016,
40, 7643 palladium-catalysed Suzuki cross coupling†
Aline da R. Louvis,a Nayane A. A. Silva,a Felipe S. Semaan,b Fernando de C. da Silva,a
Gabriela Saramago,c Laı́s C. S. V. de Souza,c Bruno L. A. Ferreira,c Helena C. Castro,c
Juliana P. Salles,d André L. A. Souza,e Robson X. Faria,d Vitor F. Ferreira*a and
Daniela de L. Martins*a

Quinones are important scaffolds that are present in a variety of natural products or synthetic bioactive
molecules. Arylation is an important strategy for accomplishing structural modifications, leading to new
potential candidates for use as drugs. In the present work, palladium-catalysed, ligandless and phosphine-
free Suzuki coupling reactions between 2-hydroxy-3-iodo-1,4-naphthoquinone and boronic acids were
employed to prepare several 2-hydroxy-3-aryl-1,4-naphthoquinones in aqueous conditions using microwave
irradiation or conventional heating. Because of the biological activities of quinones, which are related to their
ability to accept electrons to form semiquinones and hydroquinones, the electrochemical behaviour of the
Received (in Montpellier, France)
18th March 2016, synthesized molecules was investigated. The Osiris and Molinspiration Cheminformatics programs, utilizing
Accepted 4th July 2016 in silico analyses, imply that these naphthoquinones are candidates for use as drugs which was reinforced
DOI: 10.1039/c6nj00872k by the outcomes of the in vitro antifungal and trypanocidal activity tests. Our in vitro data indicated a MIC
1
value of 8 mg mL against Candida albicans ATCC 24433 strains, and an EC50 of 0.67 mM with respect
www.rsc.org/njc to trypanocidal activity against Trypanosoma cruzi epimastigote strains (Y).

Introduction
Quinones occur widely in nature and play important roles in
the life cycle of cells. Quinone-based compounds display a
variety of pharmacological activities, such as anticancer, anti-
viral and anti-neurodegenerative activities, among others.1
Atovaquone (Fig. 1) is a potent anti-malarial drug that inhibits the Fig. 1 Atovaquone.
mitochondrial electron transport chain (cytochrome bc1 complex)
of parasites. The naphthoquinone moiety in atovaquone interacts
with highly conserved amino acid residues of cytochrome b by Other biologically active molecules were synthesized based
multiple non-polar interactions. Currently, atovaquone is used on 1 as the lead compound using rational drug design.2
for the treatment and prophylaxis of malaria in association with Fungi are eukaryotic organisms that are found in the commensal
proguanil hydrochloride (Malarones, GlaxoSmithKline, UK). microbiota of healthy humans. They may colonize mucosal surfaces
such as the skin, gastrointestinal tract and oral cavity. These
organisms may present different forms, including a rounded
a
Departamento de Quı́mica Orgânica, Universidade Federal Fluminense,
form, a hyphal form or a dimorphic form.3
Campus do Valonguinho, Centro, Niterói 24020-141, Brazil.
E-mail: [email protected]ff.br
Candida spp are fungi of clinical importance that undergo
b
Departamento de Quı́mica Analı́tica, Universidade Federal Fluminense, phenotypic switching from yeast to hyphal forms, becoming
Campus do Valonguinho, Centro, Niterói 24020-141, Brazil infectious and causing candidiasis. There are several predisposing
c
LABioMol – Laboratório de Antibióticos, Bioquı́mica e Modelagem Molecular, factors for the development of candidiasis, such as AIDS, diabetes,
Instituto de Biologia, Universidade Federal Fluminense, Niterói 24210-130, Brazil
d
cytotoxic therapy and prolonged antibiotic therapy.4
Laboratory of Toxoplasmosis and other Protozooses – Oswaldo Cruz
Institute – Fiocruz, Brazil
Over the last few years, Candida strains have been recognized
e
Laboratory of Biochemistry of Peptides, Oswaldo Cruz Institute – Fiocruz, Brazil as a major cause of opportunistic fungal infections that occur
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nj00872k around the world. They represent a great threat, especially to

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immune compromised patients, and cause significant morbid- prepared that displayed promising chemotherapeutic activity
ity and mortality.5 In this regard, Candida albicans is the most against T. cruzi.
common aetiological agent of candidiasis, but non-albicans T. cruzi shows some similarities to fungi in terms of the sterol
Candida species, such as C. glabrata, C. krusei, C. parapsilosis lipid biosynthesis, being both susceptible to the inhibitors
and C. tropicalis, are also important in causing this infection. of the sterol biosynthesis. Antifungals such as posaconazole or
Currently, there are a few classes of antifungal agents that ketoconazole can inhibit the growth of T. cruzi strains.15
are available for the treatment of candidiasis. They include Arylation is an interesting approach that can accomplish
polyenes, azoles and echinocandins, but none of them are fully structural modifications of quinones and naphthoquinones
effective due to their lack of efficacy or their toxicity. This with the goal of synthesizing new substances with biological
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scenario worsens because of the emergence of and/or increase activities.16 In this regard, palladium-catalysed Suzuki coupling
in fungal resistance against the antifungals that are clinically in between boronic acids and electrophiles is an important C–C
use. Widespread and non-rational use of these antifungal bond-forming tool. Additionally, greener protocols, including
agents has led to a strong selection of resistant strains.6 reactions in aqueous medium, have been developed to accom-
The emergence of antifungal resistance and the side effects plish the Suzuki coupling reactions.17
of current antifungal therapy make it difficult to treat fungal 3-Aryl-2-hydroxy-1,4-naphthoquinones can be considered
infections. Therefore, new treatment options ought to be developed as analogues of atovaquone, but with a simpler structure.
by researching new antifungal prototypes with effective activities This is very interesting because although atovaquone is a
against Candida strains and with low toxicity. highly active and safe drug against protozoan infections, its
A similar scenario is observed in a protozoan infection that production costs have precluded its use in the developing
affects millions of people and kills 12 000 per year. Chagas countries.
disease is caused by the protozoan parasite Trypanosoma cruzi. Arylations of naphthoquinones have already been reported
The transmission of such a disease can occur in different ways in the literature by using C–H activation procedures,18 diazo-
(e.g., via the faeces of bloodsucking bugs known as ‘kissing nium salts, Lewis acid-catalyzed arylations with aromatic
bugs’). Within urban areas, it is not only caused by transfusion aldehydes, arenes or hydrazines, and Stille and Suzuki cross-
of contaminated blood, but also by food contaminated with the coupling reactions.18 Many of the procedures reported fail
parasite, as well as by urine or anal secretions from infected when it comes to introducing electron-poor groups at the C-3
marsupials, to name a few. Additionally, infected mothers can position of the naphthoquinones. Additionally, there are few
transmit T. cruzi to their foetus during pregnancy.7 reports regarding the arylation of unprotected 2-hydroxy-1,4-
In Latin America, Chagas disease affects mainly poor naphthoquinones. Spyroudis and co-workers19 reported the
communities, where it sets in endemically. However, this neglected Suzuki cross-coupling of phenyliodonium ylides of hydroxyqui-
disease has spread to other continents, and more than 6 million nones with arylboronic acids (0.5 mmol of iodonium, 1.1 mmol
people are estimated to be infected.8 of boronic acid, 4% Pd(OAc)2, LiOH, DME : H2O, R3P, 5–8 h).
The main drugs used in the treatment of Chagas disease are The yields were found to be dependent on the phosphine
nifurtimox 2 and benznidazole 3 (Fig. 2). These drugs are very employed, with better yields when P(t-Bu)3 was used, which
effective if applied in the acute phase, but not in the chronic was attributed to the minimization of transylidation reaction
phase, when the effectiveness decreases. In addition, treatments with formation of the corresponding phosphonium ylides.
with these drugs are of long duration and have severe side Iodobenzene was formed as a side product, which on coupling
effects.9 Similar to the Candidiasis scenario, it is also necessary with the excess of the boronic acids resulted in the formation
to discover new trypanocidal agents to replace the few that are of Ph–Ar. 3-Aryl-2-hydroxy-1,4-naphthoquinones bearing electron-
currently available for treating Chagas disease. withdrawing groups (F, CHO or CN) in the phenyl ring were
Several reports in the literature describe the potential not synthesized using the procedure reported by Spyroudis.
of naphthoquinones as antifungal and trypanocidal agents. 2-Hydroxy-3-iodo-1,4-naphthoquinone or 2-amino-3-iodo-1,4-
Tran and co-workers demonstrated the antifungal activity of naphthoquinone was not employed in the Suzuki cross-coupling
several halo-1,4-naphthoquinones,10 Yoshizaki and co-workers reactions, phosphine-free coupling reactions were not reported for
reported on the antifungal activity of naphthoquinone deriva- these substrates, as well as the effect of microwave irradiation in
tives constituting Lithospermum erythrorhizon11 and terpenyl- these reactions was not investigated. Furthermore, the 3-aryl-2-
1,4-naphthoquinones were considered active in vitro against hydroxy-1,4-naphthoquinones were not evaluated with respect to
pathogenic yeasts and filamentous fungi.12 In our research their antifungal or trypanocidal activities.
group and in others,13,14 several naphthoquinones were We prepared different 3-aryl-2-hydroxy-1,4-naphthoquinone
analogues of atovaquone under aqueous conditions, employing
conventional heating or microwave irradiation using inexpensive
phosphine-free sources of palladium and inexpensive bases. These
molecules were tested for in vitro antifungal and trypanocidal
activities, and an in silico study was performed to evaluate their
potential as pharmaceuticals, as well as their pharmacokinetic
Fig. 2 Trypanocidal agents. properties and toxicity.

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Results and discussion


Different 3-arylnaphthoquinones were prepared via palladium-
catalysed Suzuki coupling reactions between arylboronic acids
and 3-iodo-naphthoquinones in aqueous conditions, using
conventional heating or microwave irradiation.
Scheme 2 Preparation of 3-bromo-lawsone.

Synthesis and characterization of 3-halo-1,4-naphthoquinones


Initially, a morpholine–iodine complex 4 was prepared by
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3-Iodo-1,4-naphthoquinones must be stored protected from


reacting morpholine and iodine20 in an aqueous solution light to prevent the loss of iodine. 2-Amino-3-iodo-1,4-
(Scheme 1). This complex was, then, used in the iodination of naphthoquinone 7 appears to be less prone to iodine loss, as
2-amino-1,4-naphthoquinone and 2-hydroxy-1,4-naphthoquinone it can be stored for a longer period of time without loss of
under basic conditions. The 3-iodonaphthoquinones 6 and 7 iodine. This compound is resistant to GC/MS (EI) analysis
were obtained in excellent yields (82 and 93%, respectively) after conditions and the molecular ion (m/z = 299) can be recognized
acidification with a concentrated phosphoric acid solution.21 as being the most prominent signal in the spectrum, followed
Iodination at position C-3 was confirmed by the absence of a by a peak that corresponds to the loss of iodine (m/z = 172).
signal at 6.20 ppm (DMSO-d6) in the 1H-NMR spectrum which 2-Hydroxy-3-iodo-1,4-naphthoquinone 6, however, is more prone
corresponds to the vinylic CH of lawsone 5a (3-hydroxy-1,4- to the deiodination process and therefore must be stored
naphthoquinone). In lawsone, the C-3 signal in the 13C-NMR carefully. This compound does not survive the conditions under
spectrum is located at 110.9 ppm, whereas halogenation of this which GC/MS analysis is performed, and the molecular ion
position produces a shielding effect, and the C-3 of 2-hydroxy-3- cannot be observed. Iodo-lawsone 6 appears to lose iodine in
iodo-1,4-naphthoquinone resonates at 92.7 ppm. The upfield the chromatographic step.
trend in the chemical shifts caused by bromination or iodination Substitution of hydrogen in the C-3 position by halogen
of a carbon is attributed to an increase in the diamagnetic atoms resulted in the appearance of an additional band at
shielding, which is due to the introduction of a large number approximately 414 nm in the UV electromagnetic spectrum,
of electrons by the bromine or iodine atoms. The ‘‘shielding indicating halogenation at this position.23
effect’’ on the a-carbon is known as the ‘‘heavy atom effect’’.
Bromo-1,4-naphthoquinone can also decompose, but this Synthesis and characterization of 3-aryl-1,4-naphthoquinones
process seems to be slower than the iodine loss. Halogenation 3-Halo-1,4-naphthoquinones were subject to Suzuki coupling
of 2-amino-1,4-naphthoquinone 5b was confirmed in a similar reactions with boronic acids. Perez and co-workers24 employed
manner: a signal for the vinylic CH of the reagent (5.8 ppm) was Pd(OAc)2/K2CO3/H2O to couple 3-iodolawsone with electron-
absent in the 1H-NMR spectrum of the product, and the deficient olefins in a Heck coupling procedure and obtained
iodination of C-3 produces a shielding effect: from 102.3 ppm coupled naphthoquinones in high yields. Therefore, we used
in 2-amino-1,4-naphthoquinone to 82.2 ppm in 2-amino-3- the conditions described by Perez as the initial conditions
iodo-1,4-naphthoquinone (DMSO-d6). for the Suzuki coupling reactions in the present work, using
Lawsone was also brominated at the C-3 position using the reaction between 2-hydroxy-3-iodo-1,4-naphthoquinone 6
bromine in acetonitrile (Scheme 2), and 3-bromo-2-hydroxy- and phenylboronic acid 9 as a model system. Palladium was
1,4-naphthoquinone22 8 was obtained in 77% yield. Although tested from different sources, bases and solvents (Table 1 and
bromine can, in principle, also cause an upfield effect in the Scheme 3).
chemical shifts of the Ca signal, the ‘‘heavy atom effect’’ due to
bromination wasn’t observed at the C-3 position of the brominated
lawsone, because this carbon resonates at 111.11 ppm (lawsone Table 1 Suzuki coupling with phenylboronic acid
C-3 = 110.9 ppm).
Conditions Catalyst Base Solvent Recovery (%)
1 Pd(OAc)2 K2CO3 H2O 85 (53)a
2 Pd(OAc)2 K2CO3 EtOH 66
3 Pd(OAc)2 Na2CO3 H2O 69
4 PdCl2 K2CO3 H2O 44
5 Pd2dba3 K2CO3 H2O 84 (54)a
6 PdCl2(PPh3)2 K2CO3 H2O 99
7 Pd/C K2CO3 H2O 86
8 Pd(II)/BaSO4 K2CO3 H2O 75
9 Pd(0)/CaCO3 K2CO3 H2O 81
Reaction conditions: 0.5 mmol of 2-hydroxy-3-iodo-1,4-naphthoquinone,
0.75 mmol of boronic acid, 5 mol% of the palladium source, 2.5 mmol of
K2CO3 and 5 mL of solvent. The reactions were monitored by TLC analysis,
and after 6 h, virtually no more consumption of 6 occurred; however
by-products began to form. Reactions were performed in water and crude
Scheme 1 Preparation of iodo-1,4-naphthoquinones 6 and 7. products were analysed by 1H-NMR. a Yield after column chromatography.

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Scheme 3 Suzuki coupling with phenylboronic acid.

Under basic conditions for the Suzuki coupling reactions,


2-hydroxy-3-iodo-1,4-naphthoquinone 6 (yellow) is soluble in
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water, as it forms the lawsonate (red), as well as the reaction


product is in the form of a salt. After acidification of the
aqueous reaction medium, the crude product precipitates from Scheme 4 Suzuki coupling of 6 with different boronic acids.
water (crude yields are shown in Table 1). We analysed the
aqueous phase and observed that the majority of the product
precipitates. Therefore, extraction of the aqueous phase was not irradiation in cross-coupling reactions have already been
necessary to improve the recovery of the product. reported in the literature.25 Therefore, we employed the condi-
The products were obtained with low crude yields when tions that were determined to be optimal for coupling with
alcohol was employed as the solvent (entry 2) and 1H-NMR conventional heating (5% Pd(OAc)2, K2CO3, H2O). Intensive
analysis indicated a 4% yield of lawsone (product of deiodination). deiodination occurred when 5% Pd(OAc)2 was employed, using
This is likely due to the insolubility of carbonate in ethanol, thus microwave heating (P = 300 W, T = 120 1C, 10 min). Increasing
producing heterogeneous conditions, whereas both the base temperatures (150, 200 1C) also resulted in deiodination of
(carbonate) and the substrate are soluble under aqueous basic 2-hydroxy-3-iodo-1,4-naphthoquinone 6. At 80 1C, a large amount
conditions. No lawsone was observed when Pd(OAc)2/K2CO3/H2O of unreacted iodo compounds were recovered. The best reaction
(entry 1) was employed, whereas 9% lawsone was obtained using conditions were 1% Pd(OAc)2/100 1C/H2O. Therefore, using
Pd(OAc)2/Na2CO3/H2O (entry 3). Water was considered the best microwave irradiation, excellent results were obtained using a
solvent, and potassium carbonate the best base. Several catalysts lower loading of palladium (1% with irradiation versus 5% with
were tested using H2O/K2CO3. conventional) and shorter reaction times (10 min versus 6 h).
During homogeneous catalysis, palladium dichloride exhib- Using these conditions, different boronic acids were employed in
ited the worst performance. TLC indicated a high content of 6, cross-coupling reactions with 3-halo-1,4-naphthoquinones (Table 2).
which was confirmed by NMR analysis. Although a high recov- The products that were obtained were higher in purity than
ery of the product from acidified water was accomplished when those obtained using the conventional conditions, and better
Pd2dba3 and PdCl2(PPh3)2 (entries 5 and 6) were employed, TLC yields were obtained using flash chromatography (yields are an
analysis of the crude products revealed a significant formation average of duplicates). Moderate to good yields were obtained,
of lawsone, and in the case of Pd2dba3, a significant amount of except for that of the reaction with 2-thiopheneboronic acid
iodo-lawsone 6 remained. NMR analysis identified numerous (entry 4). Several conditions were evaluated to improve the yield
impurities in the aromatic region. (increasing temperatures, catalyst loading, time or different
Supported catalysts were also evaluated (entries 7–9). All of solvents), but in all cases a low conversion of the iodinated
the catalysts that were tested were successful in the Suzuki precursor was obtained.
coupling reactions, but the reactions appeared to be slower with Pd/C is a low cost, interesting, heterogeneous pre-catalyst.
Pd/CaCO3 and Pd/BaSO4 (entries 8 and 9), because after 6 h, Therefore, in this work, we also tested this catalyst with micro-
a significant amount of iodo-lawsone remained. Alternatively, wave heating for the reactions of 6 with formylbenzeneboronic
when Pd/C was used, 6% lawsone was obtained, and some acids to obtain compounds 10f and 10g (entries 6 and 7). The
impurities were detected in the resonance spectra. moderate isolated yields that were obtained with formylbenze-
When the reactions were heated for more than 6–8 h, neboronic acids were due to the small retention factor (rf)
by-products began to form, and iodo-lawsone was not fully difference between the products (10f and 10g) and the boronic
consumed. acids (3-formylphenylboronic acid and 4-formylphenylboronic
The conditions described in Table 1, entry 1 (5% Pd(OAc)2, acid, respectively). This small difference made the purification by
K2CO3, H2O) were considered the best of those that were column chromatography difficult. The difference between 10f and
evaluated and were applied to the synthesis of other aryl- 3-formylphenylboronic acid, however, was slightly larger than the
naphthoquinones for use in the coupling of 3-halo-1,4- difference between 10g and 4-formylphenylboronic acid. Hence,
naphthoquinones with different arylboronic acids (Scheme 4). the isolated yields were higher in all the reactions with 3-formyl-
Crude products were recovered easily (60–99%) from the acid- phenylboronic acid, despite reaction conditions (microwave versus
ified solutions. However, low to moderate yields were obtained conventional heating and Pd(OAc)2 versus Pd/C).
after flash chromatography. Because of the apparent greater stability of 3-bromo-2-
Microwave irradiation can improve the yield and accelerate hydroxy-1,4-naphthoquinone compared with 2-hydroxy-3-iodo-
many organic reactions. Beneficial effects of the use of microwave 1,4-naphthoquinone, coupling reactions with the former were

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Table 2 Suzuki reactions under microwave irradiation

Compounds Yielda (%)

1 71

Scheme 5 Coupling reactions with 8.

2 64
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3 78

Scheme 6 Coupling reactions with naphthoquinone 7.


4 4

conditions using microwave heating. The best conditions that led to


5 72 the greatest conversion of 3-bromo-2-hydroxy-1,4-naphthoquinone
were 5% Pd(OAc)2/H2O/25 min/8 : PhB(OH)2 (2 : 1) (Y = 40%).
The low solubility of 2-amino-3-iodo-1,4-naphthoquinone
affected its conversion to the product. Therefore, a mixture
6 60 (83)b
4 : 1 water/EtOH was employed in the coupling reactions with
this naphthoquinone. The coupling product 11 is partially
soluble in water and could not be recovered in higher yields
7 43 (65)b by filtration (47% crude product). The pure product was
obtained at 26% yield by extraction of the aqueous acidified
phase. Microwave conditions were also tested in the coupling of
2-amino-3-iodo-1,4-naphthoquinone with phenylboronic acid.
8 75 The best condition obtained using microwave irradiation was
5% Pd(OAc)2/H2O : EtOH (1 : 1)/25 min, using 100% excess of
PhB(OH)2, instead of 50% that was used with 6 (yield = 54%,
column chromatography) (Scheme 6).
9 66
In silico analysis of 3-aryl-1,4-naphthoquinones
Recently, several research groups have exploited the potential
10 43 of cheminformatic tools to develop a rational approach to drug
design. Currently, these tools are used in partnership with
experimental tests.26 In view of the interest in the synthesis
of new antifungal and trypanocidal drug candidates and the
11 77 potential of naphthoquinones, compounds 10a–10k were eval-
uated in silico using the Osiris Property Explorer27 and Molin-
spiration Cheminformatics programs.28 The toxicological risks,
Reaction conditions: (0.5 mmol of 6), 0.75 mmol of boronic acid, bioavailability properties and biological activity scores for six
1.0 mol% of Pd(OAc)2, 2.5 mmol of K2CO3, and 5 mL of H2O. a Isolated
yields (flash column chromatography). b Pd/C (1%).
receptor classes (GPCR ligands, ion channel modulators, kinase
inhibitors, nuclear receptor ligands, protease inhibitors and
enzyme inhibitors) were calculated for all of the compounds and
also studied (Scheme 5). Under conventional heating and were compared with those of fluconazole and benznidazole,
employing the best conditions that were employed in the which are antifungal and trypanocidal drugs, respectively.
coupling reactions with 2-hydroxy-3-iodo-1,4-naphthoquinone According to our in silico analysis, most of the 3-aryl-1,4-
(Pd(OAc)2/K2CO3/H2O/6 h), a low conversion was observed. naphthoquinones presented a low toxic risk profile regarding
Increasing the time of the reaction to 24 hours did not improve mutagenic, tumourigenic, irritant and reproductive effects. This
the conversion rate. Taking into consideration the observation that low toxicity theoretical profile was as low as, or even lower
microwave irradiation was beneficial to the coupling reactions than, that of the antifungal positive control (fluconazole) or the
with 2-hydroxy-3-iodo-1,4-naphthoquinone, we evaluated different trypanocidal positive control (benznidazole) (Table 3).

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Table 3 Comparison of the in silico results of the 3-aryl-1,4-naphthoquinone series

c log P Sol M T Ref I DL DS L. R. viol. GCPRL ICM KI NRL PI EI


10a 2.19 3.16 1.12 0.53 0 0.26 0.28 0.15 0.09 0.40 0.27
10b 2.3 4.04 1.79 0.46 0 0.20 0.29 0.22 0.01 0.37 0.25
10c 2.3 4.04 4.76 0.41 0 0.17 0.27 0.25 0.04 0.34 0.26
10d 2.06 3.74 0.29 0.66 0 0.40 0.40 0.01 0.23 0.57 0.10
10e 1.98 3.63 1.63 0.5 0 0.32 0.28 0.23 0.15 0.47 0.26
10f 2.13 4.05 + + 5.89 0.26 0 0.24 0.29 0.18 0.12 0.43 0.23
10g 2.13 4.05 + 8.8 0.24 0 0.27 0.31 0.14 0.07 0.46 0.20
10h 2.12 3.75 + 1.29 0.30 0 0.21 0.34 0.16 0.02 0.34 0.20
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10i 2.12 3.75 2.07 0.46 0 0.22 0.34 0.19 0.01 0.36 0.21
10j 2.03 4.50 10.0 0.38 0 0.14 0.27 0.31 0.12 0.25 0.30
10k 2.54 4.07 2.59 0.43 0 0.26 0.37 0.12 0.07 0.41 0.19
Benz 0.25 1.62 + 1.66 0.33 0 0.33 0.39 0.49 0.71 0.05 0.02
Flu 0.31 1.55 4.84 0.95 0 0.04 0.01 0.09 0.23 0.09 0.03
Properties calculated using the Osiris Explorer program: c log P, Sol = solubility, M = mutagenic, T = tumourigenic, Ref = reproductive effect, I =
irritant, DL = druglikeness and DS = drug-score. Properties estimated using the Molinspiration program: L. R. viol. = number of violations of
Lipinski’s rule. Theoretical inhibitory profile against GPCRL = GPCR ligand, ICM = ion channel modulator, KI = kinase inhibitor, NRL = nuclear
receptor ligand, PI = protease inhibitor, EI = enzyme inhibitor. Flu = fluconazole, Benz = benznidazole.

Water solubility is an important parameter to be evaluated Table 4 Comparison of the inhibitory effects (halo = mm) of the active
for the drug candidates because it is related to their distribu- naphthoquinones (10a, 10b, 10d and 10e) in the DDST against Candida
strains of clinical importance
tion in the body. Interestingly, suitable values for logs 4 4
were observed for the naphthoquinones that were synthesized Inhibition growth zone (halo = mm)
herein. Analogously, lipophilicity and hydrophilicity are impor- Compounds Control
tant properties that affect the absorption of a drug in the body.
MO strain 10a 10b 10d 10e Fluconazole
On this subject, the Lipinski’s rule of five29 is used to predict
oral bioavailability. According to our analysis, none of the C. tropicalis ATCC 750 0 11 11 15 14
C. glabrata ATCC 90030 09 15 0 0 12
compounds studied violated Lipinski’s rule of five, which C. krusei ATCC 34135 13 11 11 0 14
indicates a good theoretical bioavailability. C. albicans ATCC 24433 13 18 11 0 13
Our in silico analyses revealed negative values for the drugli-
keness parameter of these naphthoquinones, which suggested Table 5 Comparison of the minimum inhibitory concentration (MIC)
fragments different from those present in commercial pharma- values for the derivatives that presented antifungal activities in the DDST
ceuticals. The drug-score, which is a global parameter that is 1
MIC mg mL
related to the potential of a molecule to be a drug candidate,
indicates that the 3-aryl-1,4-naphthoquinones are good drug MO strain 10a 10b 10d 10e Fluconazole
candidates. Analysis of the predictions of bioactivities, accord- C. albicans ATCC 24433 16 16 0.8 — 0.75
ing to the Molinspiration tool, indicated the inhibition of C. krusei ATCC 34135 4512 128 256 — 64
C. tropicalis ATCC 750 — 4512 32 32 0.3
kinase and other enzymes as latent activities of the compounds C. glabrata ATCC 90030 16 32 — — 0.3
under study. In agreement, most of the drugs that interact with
enzymes in the body show c log P values between 2 and 5 and all
of the naphthoquinones that were evaluated herein presented
c log P values in this range.
Based on the in silico analyses that suggested the potential
biological profiles for this new series, we performed in vitro
antifungal and antiparasitic tests to search for biological activ-
ities associated with the arylnaphthoquinones. Among all of
the compounds that were tested, 10a, 10b, 10d and 10e were
found to inhibit the growth of Candida strains, whereas com-
pound 10e exhibited a high trypanocidal activity, which was
superior to that observed with benznidazole (Tables 4 and 5
Fig. 3 Naphthoquinone-induced injury. J774.G8 cells treated with
and Fig. 3–7). These data are in agreement with those of the naphthoquinones (100 mM) for 24 h. Cytotoxicity was measured using
active compounds detected in silico that presented drug-scores resazurin reduction to resorufin as an index of proliferation. Data shown
higher than 0.4 except for compound 10d, and scores for kinase are the mean  SD of four independent experiments. Comparisons: *** or
inhibitors and enzyme inhibitors greater than 0.2. These *, treated vs. non-treated. n.s. – no significant difference.
experimental observations reinforced our in silico predictions,
as the in vitro data are in good agreement with them. The low viability studies in mice primary cells that were exposed to
theoretical toxicity value was also confirmed by the in vitro the arylnaphthoquinones. These results supported additional

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Fig. 4 Naphthoquinone-induced injury. Mouse peritoneal macrophages


were treated with naphthoquinones (100 mM) for 24 h. Cytotoxicity was Fig. 7 Analysis of the trypanocidal effect of 10e after 72 h using increasing
measured using resazurin reduction to resorufin as an index of prolifera- concentrations (1 nM to 1 mM) against Y strains. This graph is representa-
tion. Data shown are the mean  SD of four independent experiments. tive of triplicate treatments performed on 3 distinct days.
Comparisons: ***, treated vs. non-treated. n.s. – no significant difference.

peritoneal macrophages (Fig. 4), were measured in terms of


the ability to reduce resazurin. Cell viability decreased signifi-
cantly when J774.G8 cells were exposed to naphthoquinones at
a concentration of 100 mM for 24 h (Fig. 3). However, the
concentration used in the tests is 10–100 times greater than
the concentration that was applied in the subsequent biological
assays. None of the naphthoquinones displayed toxicity when
tested with wild type primary cells.

Disk diffusion susceptibility test (DDST)


Among the naphthoquinones that were tested (6, 8, 10a–k), four
exhibited antifungal activity. Compound 10b presented the highest
inhibition growth zone against C. albicans ATCC 24433, as well as
the widest spectrum of action of all compounds that were tested.
Fig. 5 Trypanocidal activity in 24 h (10 mM naphthoquinones, n = 3, Y
Compounds 10a, 10b and 10d showed a great spectrum of action,
strain). This graph is representative of triplicate treatments performed on 4
distinct days. being able to inhibit the growth of three strains. None of the
compounds were active against the strain C. parapsilosis, ATCC
90028 (data not shown).

Determination of the minimum inhibitory concentrations


(DMIC)
The four compounds that were active in the DDST were sub-
mitted to the MIC test to determine the minimum inhibitory
concentration. Compound 10d presented the lowest MIC
against C. albicans ATCC 24433 (MIC = 8 mg mL 1) (Table 5).
Most of the compounds had MIC values that were at the same
level as those of the antifungals most used in clinical practice
(0.125 to 32 mg mL 1) (listed in CLINICAL LABORATORY
STANDARDS INSTITUTE – Reference Method for Broth Dilution
Antifungal Susceptibility Testing of Yeasts; Approved Standard –
Second Edition. M27-A2. CLSI, Wayne, PA.2013). This level of
Fig. 6 Trypanocidal activity in 72 h (10 mM naphthoquinones, n = 3, Y activity suggested their use as food molecules for further explora-
strain). This graph is representative of triplicate treatments performed on 4 tion against multiresistant strains.
distinct days.
In vitro antiparasitic activity
studies on the spectrum and level of their biological activities, The effect of 3-aryl-1,4-naphthoquinones on in vitro cultures of
which we present in the in vitro assays that follow. epimastigotes of T. cruzi was evaluated in comparison with
benznidazole. Initially, we treated the cells with a fixed dose
Toxicity assay in mouse cell lines of 10 mM naphthoquinones (see the Experimental section and
Naphthoquinone-induced injuries to J774.G8 mouse macro- Fig. 5) and compared the results with those obtained with
phage cells derived from a sarcoma (Fig. 3), or mouse primary benznidazole treatment. Treatment with 100 mM benznidazole

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was considered as our positive control (approximately 0–30%


survive), whereas untreated cells were the negative control
(approximately 90–100% survive). The results are shown in
Fig. 5 as % of trypanocidal activity. The derivative that reduced
the trypanosome viability below 75% (compared with the
positive control) was selected for additional assays and MTT
was used to perform the initial screening of activity.
According to our data the analogues 5a, 6, 10a, 10b, 10c, 10d, 10e,
10f, 10g and 11 did not exhibit a response comparable to that of
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benznidazole after 24 h (Fig. 5). After 72 h of continuous exposure,


only the derivative 10e exhibited trypanocidal activity (Fig. 6). There-
fore, this naphthoquinone analogue was tested against epimastigote
T. cruzi strains (Y) using increasing concentrations ranging from
1 nM to 1 mM for 72 h (Fig. 7). Interestingly, the EC50 value for 10e Fig. 8 Cyclic voltammogram of 10c: 200 mV s 1.
to cause trypanocidal activity (0.67 mM) was more potent than that
described for benznidazole (EC50 = 40 mM).30 Thus, although the
(assessing this time from 0.00 to +2.00 V). Within this
effects of the derivative 10e were observed only after 72 h, the
new potential window it was possible to note that the peaks,
potency that was measured was approximately 59 times greater
which appear at more positive potentials, are independent of
than that with benznidazole, indicating that the development
the others (Fig. 8).
of new derivatives of this class would be desirable.
Thus the electrochemical studies demonstrated that the
Electroanalytical studies assessed naphthoquinones have quasi-reversible redox peaks.
A diffusion-controlled mass transport may be considered limiting
Naphthoquinones are known for their biological activities that
in this case, because a linear relationship was obtained between
are often related to their ability to accept electrons (in general
Ip (mA) and v1/2 (mV s 1). From the series of synthesized com-
one or two), forming semiquinones and hydroquinones.31–33
pounds, three were exceptional, because during voltammetric
Such interesting electrochemical behaviour encouraged us to
measurements, solutions containing compounds 5a, 10a and 10d
conduct electroanalytical studies. Thus, cyclic voltammetry33
exhibited colour changes from colourless to red (Fig. 9) in the
was chosen as the exploratory technique. For the assessment of
surroundings of the working and counter electrodes; such
the electroanalytical behaviour of the synthesized naphthoqui-
changes were monitored by coupling electroanalytical (this
nones, voltammetric measurements were performed using an
time using an ITO transparent electrode and fixing the
IVIUM CompactSTAT potentiostat (IviumTechnologies). The
potential at suitable values) and spectrophotometric measure-
synthesized naphthoquinones (from 5a, 6, 10a–k) were added to
ments (Red Tide Fiber Optic Spectrometer USB-650-UV-Vis).
a 10 mL electrochemical cell filled with a supporting electrolyte,
When the UV-Vis spectrum was obtained by applying a potential
and in which a three electrode arrangement was assembled. The
when a colour change occurred on the working electrode, a new
electrodes consisted of a platinum wire as a counter electrode,
band was detected in the spectrum. According to Singh,23 this is
Ag|AgCl(sat.) as a pseudo-reference electrode, and a commercially
due to a broad local excitation band (L. E.) in the 400–500 nm
available glassy carbon as a working electrode (f = 0.0519 cm2,
region which is attributable to a n - p* transition of the
Metrohm). Initially, solutions prepared by direct solubilization
quinone carbonyls.
of lithium perchlorate or tetrabutylammonium perchlorate
Although naphthoquinone activities can, in many cases, be
(0.1 mol L 1) in acetonitrile were used as supporting electrolytes;
related to their redox properties, in the present work, it was not
however, because noisy and non-reproductive electroanalytical
possible to correlate the electrochemical behaviour of the
responses were obtained using the former, all subsequent
synthesized arylnaphthoquinones with their biological activities,
studies were performed in tetrabutylammonium perchlorate
as both bioactive and inactive compounds exhibited the same
solutions. Analytes were assessed by direct dissolution of
reduction and oxidation values. Chemical activity, in this case,
suitable amounts in the supporting electrolytes, reaching a
may involve another mechanism of action.
final concentration of 1 mmol L 1 just before the electroche-
mical measurements were conducted. Cyclic voltammograms
were recorded from 2.00 to +1.25 V, at different scan rates Conclusions
(from 50 to 200 mV s 1), and were assessed against respective
blanks. From these experiments, some issues were raised. It Arylnaphthoquinones were obtained in moderate to good yield
could be noted that the arylnaphthoquinones exhibited one by conducting palladium-catalysed Suzuki reactions using
reduction peak (from 1.33 to 1.24 V) and one oxidation peak conventional heating and microwave irradiation. Suzuki cou-
(from 1.16 to 1.28 V).32 Complementary experiments were pling reactions were performed under aqueous conditions
performed by inverting the sweep rate, from +1.25 to 2.00 V, using inexpensive palladium phosphine-free pre-catalysts.
which indicated independence between the observed peaks, Microwave irradiation resulted in an improvement of the iso-
which was then confirmed by narrowing the potential window lated yields, decreasing reaction times and decreasing catalyst

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2-Hydroxy-1,4-naphthoquinone and other reagents and solvents


were purchased from Sigma Aldrich Brazil LTDA. Column flash
chromatography was performed using silica gel 60 (35–70 mm).
Analytical thin-layer chromatography was conducted on silica gel
plates (Silicycle Ultrapure Silica Gels, F254) and the spots were
visualized using UV light or iodine vapours. Yields refer to
isolated yields after flash chromatography. Melting points were
recorded on a Fisatom 413D apparatus. Infrared spectra were
measured using KBr pellets on a Perkin-Elmer model 1420 FT-IR
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spectrophotometer. NMR spectra were recorded on a Varian


VNMRS (300 MHz or 500 MHz) instrument in DMSO-d6 or
CDCl3. The chemical shift data are reported in units of d
(ppm) downfield from tetramethylsilane, which was used as an
internal standard. Coupling constants ( J) are reported in Hertz
units and refer to apparent peak multiplicities. The gas chroma-
tography/mass spectrometry (GS/MS) analysis was conducted on
an Agilents 6890 chromatograph coupled to an Agilents 5973
mass spectrometer. The fragmentation values and molecular
ions are reported in m/z units. An Agilents 122-5532 DB-5MS
column was used for GC analysis. High-resolution mass spectra
(HRMS) were recorded on a MICROTOF Bruker Daltonics mass
spectrometer. Samples were dissolved in CH3Cl and diluted in
MeOH and could not be ionized in the positive mode.

Biological assays
Five fungal strains of different species of the genus Candida were
obtained from America Type Culture Collection and were used
Fig. 9 (a) Cyclic voltammogram of 10a, (b) UV-Vis of 10a at a potential of to evaluate the antifungal activity of the naphthoquinones:
1.19 V. C. parapsilosis ATCC 90028, C. albicans ATCC 24433, C. krusei
ATCC 34135, C. glabrata ATCC 90030 and C. tropicalis ATCC 750.

load (1% with microwave vs. 5% with conventional heating). Disk diffusion susceptibility test (DDST)
Five of the aryl-naphthoquinones synthesized herein are new.
To determine the susceptibility of each of the five Candida
Arylnaphthoquinones were evaluated in silico with respect to
ATCC strains to the compounds used, a suspension of each
their ADME/Tox and druglikeness properties. The in silico
strain in 5 mL of saline solution was prepared. Then, an aliquot
analysis indicated good biological and toxicological profiles
of 500 mL was inoculated onto a Sabouraud-dextrose agar plate,
for the synthesized naphthoquinones, and this was reinforced
and a 6 mm filter paper disk impregnated with the naphtho-
by the biological assays. None of the arylnaphthoquinones
quinones diluted in dimethyl sulfoxide (DMSO) (5 mg mL 1)
displayed toxicity to wild type mouse primary peritoneal macro-
was placed on the agar plate. The plate was then incubated for
phages at a concentration of 100 mM (24 h). Four of the
24–48 h at a temperature of 35 1C. Fungal growth inhibition
arylnaphthoquinones that were prepared (10a, 10b, 10d and
zones were measured when the compounds displayed activity
10e) exhibited antifungal activities against strains of clinical
against the Candida strains tested. DMSO was used as a
importance (10d, MIC = 8 mg mL 1, against C. albicans ATCC
negative control, and fluconazole (5 mg mL 1) was used as a
24433). Compound 10d exhibited an antiparasitic effect against
positive control.
the epimastigote strain (Y) of T. cruzi, with an EC50 of 0.67 mM.
Although the trypanocidal effects were observed only after 72 h, Determination of minimum inhibitory concentrations (DMIC)
this EC50 value is 59 times higher than the reported EC50 value
The compounds that exhibited antifungal activity in the DDST
for benznidazole, a trypanocidal agent that is used clinically.
were evaluated further to define the lowest concentrations of
These results indicate that arylnaphthoquinones are promising
the compounds that inhibited visible growth of the Candida
hit compounds whose structures deserve to be optimized.
strains (MIC). Serial dilutions of the compounds were prepared
using Sabouraud-dextrose broth medium in a 96-well microtiter
Experimental plate (0.5 mg mL 1 to 512 mg mL 1) and 100 mL inoculums of the
Candida strains. The microtiter plate was incubated for 24–48 h
Materials and measurements at a temperature of 35 1C, and the minimum inhibitory concen-
Boronic acids were purchased from Sigma Aldrich Brazil LTDA tration (MIC) was defined as the lowest concentration that was
and Combi-Blocks. They were used without further purification. capable of inhibiting visible fungal growth.

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In silico analysis of the toxicity were counted using a Neubauer chamber, maintained in
The compounds 10a–10k were submitted to toxicological ana- serum-free medium for macrophages (Gibco, USA) and cultured
lysis in silico using the Osiris Property Explorer27 and Molin- at 37 1C in an atmosphere of 5% CO2 for 24 hours. Our
spiration programs.28 The Osiris program presents a predictive protocols adhered to the Ethical Principles in Animal Experi-
algorithm that evaluates the potential toxicological risks of the mentation adopted by the Brazilian College of Animal Experi-
compounds tested by analysis of the molecular structure using a mentation and were approved by the Fiocruz Research Ethics
database of 3300 drugs. This program predicts whether the com- Committee (number L-041/08).
pounds are mutagenic, tumourigenic, irritants, or have reproductive The murine macrophage line J774.G8 was used in all experi-
ments. This strain is derived from the original J774.A1 cell line
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effects. Other properties, including solubility, lipophilicity, druglike-


ness, TPSA (permeability of the molecule in the plasma membrane) from the American Type Cell Collection (ATCC, Rockville, MD).
and molecular weights, are also estimated. The Osiris program The cells were cultured in Dulbecco’s modified Eagle’s medium
indicates the potential toxicological risks using a colour table in (DMEM) (Sigma, St. Louis, MO) containing 10% foetal bovine
which a green colour represents a low potential toxic risk, a yellow serum (FBS) (Cultilab – Campinas, Brazil) at 37 1C in a humidi-
colour represents a medium potential toxic risk, and a red colour fied atmosphere with 5% CO2. On reaching 80–90% confluence,
represents a high potential toxic risk. the cells were detached using a solution of 0.025% trypsin and
Violations of the Lipinski’s rule of five29 were determined using 0.4% EDTA (ethylene diamine tetraacetic acid) for 1 minute and
Molinspiration web based software. Important pharmacokinetic then used in flow cytometry experiments.
properties in humans (absorption, distribution, metabolism,
excretion and toxicity – ADME/Tox) are described by this rule. Resazurin (Alamar Blue) proliferation assay
The activity scores for GPCR ligands, ion channel modulators, Reduction of the dye resazurin to resorufin was used to
nuclear receptor ligands, kinase inhibitors, protease inhibitors measure proliferation of the cells in cultures. Cells were seeded
and enzyme inhibitors were calculated using Molinspiration. at 1  105 trypan blue excluding cells per mL in 96-well
The results obtained were compared with the values obtained microtiter plates.34 After incubating for 24 h, the DMEM
with standard drugs. Molecules with positive scores are con- medium was removed and replaced with fresh medium con-
sidered active. Scores between 5.0 and 0.0 indicate moderate taining 40 mM resazurin, followed by an incubation period of
activities and scores below 5.0 are considered inactive. 24 h, after which reduction of resazurin to resorufin was deter-
mined by fluorescence (excitation 530 nm; emission 590 nm)
Trypanosomatid cultures using a M5 microplate fluorometer (Molecular Devices, Florida,
T. cruzi epimastigote Y strains were cultured in LIT medium USA). Appropriate cell free controls were included in the test to
(tryptose liver infusion) supplemented with 10% foetal calf account for potential interactions between the derivatives and
serum at a temperature of 28 1C, with strong agitation (100 rpm) resazurin.
as reported previously, in the absence or presence of either
naphthoquinone derivatives or benznidazole. Live parasites were Synthesis of 3-halo-1,4-naphthoquinones
counted daily using a Neubauer chamber. The initial parasite
Iodination of 1,4-naphthoquinones 5a and 5b. The morpholine–
concentration was 106 parasites per mL. Either the drug or vehicle
iodine complex was synthesized using the procedure described by
(DMSO) was added after 24 h and 72 h for each condition. At least
Frota and co-workers and then stored protected from light.21
3 independent experiments were performed for each drug and
The morpholine–iodine complex (12.8 g, 37.5 mmol) was
dose, and the 50% effective concentration (EC50) was determined
added to a 500 mL Erlenmeyer flask containing 1,4-naphtho-
using Prisma GraphPad 5.0.
quinone (lawsone 5a or 2-amine-1,4-naphthoquinone 5b 30 mmol),
K2CO3 (12.4 g, 90 mmol) and distilled water (300 mL) in small
Trypomastigote viability assay
portions every 15 minutes over a period of two hours. The
Viability assays were performed using the formazan formation reaction mixture was then stirred for at least 30 minutes.
method, also referred to as the 3-(4,5-dimethylthiazol-2-yl)-2,5- Subsequently, the mixture was cooled using an ice bath and
diphenyltetrazolium bromide (MTT) assay, as previously acidified with concentrated H3PO4. The solution was left to
described.33 Briefly, 1  107 trypomastigotes were incubated in react under agitation at room temperature for at least 24 hours,
RPMI 1640 culture medium at 37 1C for 24 h with and without the after which the mixture was filtered using a vacuum, and the
addition of the naphthoquinones at a final concentration of solid obtained was washed with ice-cold water. The solid was
10 mg M and then incubated for 24 or 72 h. Naphthoquinones with dried at room temperature protected from light and then stored
trypanocidal activities were tested at concentrations ranging from protected from light and under refrigeration.21
1 nM to 1 mM. Formation of formazan was monitored at 570 nm 2-Hydroxy-3-iodonaphthalene-1,4-dione (6). The reaction
in a multi-well reader (Spectramax M5, Molecular Devices). produced the compound 6 (7.38 g, 82%) as an orange solid,
mp 172–173 1C (lit. 177 1C).21 IR (KBr) nmax/cm 1 1620 (CQO),
Cell cultures 1670 (CQO), 3161 (OH). dH (500 MHz; DMSO-d6; TMS) 8.06–
Macrophages were obtained from the peritoneal cavities of 7.98 (2H, m), 7.85–7.78 (2H, m). dC (125 MHz; DMSO-d6) 179.5,
4-week-old Swiss Webster mice. After centrifugation, the cells 177.2, 162.2, 134.4, 133.3, 130.7, 129.6, 126.6, 126.3, 92.7 ppm.

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2-Amino-3-iodonaphthalene-1,4-dione. The reaction pro- 7.95 (1H, td, J = 1.5, 7.5 Hz); 7.55–7.45 (5H, m, Ph). dC (125 MHz;
duced the compound 7 (0.592 g, 91%) as a red-brick solid, CDCl3) 183.7, 181.8, 152.2, 135.3, 133.1, 132.8, 130.6, 130.0,
mp 188–190 1C (lit. 201–202 1C).21 IR (KBr) nmax/cm 1 1271 (C– 129.3, 128.6, 127.9, 127.3, 126.1, 122.2 ppm. MS (EI+) m/z (%):
N), 1579 (N–H), 1621 (CQO), 1671 (CQO), 3346 and 3447 250 (M+, 100), 221 (19) 194 (21), 165 (47).
(NH2). dH (500 MHz; DMSO-d6; J in Hz) 8.12–8.10 (2H, m), 2-(4-Fluorophenyl)-3-phenylnaphthalene-1,4-dione (10b). The
7.91 (1H, td, J = 1.5, 7.5 Hz), 7.88–7.85 (1H, m). dC (125 MHz; reaction produced the compound 10b as a yellow solid (0.086 g,
DMSO-d6) 177.3, 176.5, 152.5, 134.5, 132.5, 131.5, 129.4, 126.4, 0.321 mmol, 64%), mp 185–188 1C. IR (KBr) nmax/cm 1
126.3, 82.2 ppm. 1643 (CQO), 1665 (CQO), 3330 (OH). dH (500 MHz; DMSO-d6;
2-Bromo-3-hydroxynaphthalene-1,4-dione (8). Lawsone 5a J in Hz) 8.07 (1H, dd, J = 1.0, 7.5 Hz); 8.03 (1H, dd, J = 1.5, 7.5 Hz);
Published on 05 July 2016. Downloaded by UNIVERSITY OF ADELAIDE on 12/10/2017 07:06:05.

(1.16 g, 6.7 mmol) and acetonitrile (100 mL) were added to a 7.88 (1H, td, J = 1.5, 7.5 Hz); 7.84 (1H, td, J = 1.5, 7.5 Hz); 7.45–
250 mL flask equipped with a magnetic stirrer. Bromine (0.5 mL) 7.41 (2H, m); 7.27–7.22 (2H, m). dC (125 MHz; CDCl3) 183.3,
was added after solubilization of 5a and the resulting solution 181.3, 163.0, 159.8, 154.9, 134.6, 133.2, 132.8, 132.0, 129.9, 127.6,
was refluxed for 3 hours and then 1.2 mL of cyclohexene was 126.0, 125.5, 121.1, 114.4 ppm. MS (EI+) m/z (%): 268 (M+, 100),
added. Solvents were removed using a rotary evaporator. The 239 (18) 240 (19), 183 (57).
residue was washed with hexane, solubilized in ether and treated 2-(3-Fluorophenyl)-3-phenylnaphthalene-1,4-dione (10c). The
with charcoal. Subsequently, the solution was filtered, and the reaction produced the compound 10c as an orange solid (0.105 g,
ether was evaporated. The solid that was obtained was dried at 0.391 mmol, 78%), mp 163–165 1C. IR (KBr) nmax/cm 1 1648 (CQO),
room temperature protected from light and was then stored 1672 (CQO), 3246 (OH). dH (500 MHz; DMSO-d6; J in Hz) 8.07 (1H,
protected from light and under refrigeration. This reaction dd, J = 1.5, 7.5 Hz); 8.04 (1H, dd, J = 1.0, 7.5 Hz); 7.89 (1H, td, J = 1.5,
produced compound 8 (1.306 g, 77%) as a yellow solid, mp 7.5 Hz); 7.84 (1H, td, J = 1.5, 7.5 Hz); 7.48–7.43 (1H, m); 7.23 (1H, dd,
203–205 1C (lit. 201–203 1C).22,35 IR (KBr) nmax/cm 1 3176 (O–H), J = 1.0, 7.5 Hz); 7.20–7.17 (2H, m). dC (125 MHz; DMSO-d6) 183.4,
1672 (CQO), 1580 and 1454 (CQC), 3161 (OH). dH (500 MHz; 181.5, 162.6, 160.7, 155.3, 135.0, 133.9, 133.5, 132.1, 130.1, 129.5,
DMSO-d6; J in Hz) 8.03–8.00 (2H, m); 7.85–7.80 (2H, m). dC 127.1, 126.3, 125.8, 121.0, 117.6, 114.6 ppm. HRMS (ESI) m/z calc. for
(125 MHz; DMSO-d6) 179.2, 178.6, 158.7, 135.1, 134.0, 131.9, C16H9FO3 [M H] 267.0457, found 267.0462.
130.2, 126.9, 126.8, 111.1 ppm. 2-Hydroxy-3-(thiophen-2-yl)naphthalene-1,4-dione (10d).
The reaction produced the compound 10d as a purple solid
General procedure for preparing 3-arylnaphthoquinones under (0.046 g, 0.179 mmol, 36%), mp 146–147 1C (lit. 134–137 1C).16d
conventional heating 10a–k IR (KBr) nmax/cm 1 1652 (CQO), 3344 (OH). dH (500 MHz;
2-Hydroxy-3-iodo-1,4-naphthoquinone (0.150 g, 0.5 mmol), DMSO-d6; J in Hz) 8.27 (1H, dd, J = 1.0, 4.0 Hz); 8.18 (1H, dd, J =
K2CO3 (0.346 g, 2.5 mmol), arylboronic acid (0.75 mmol) and 1.0, 7.5 Hz); 8.13 (1H, dd, J = 1.0, 7.5 Hz); 7.98 (1H, td, J = 1.0, 7.5
Pd(OAc)2 (0.005 g, 5 mol%) were added to a 25 mL round- Hz); 7.94–7.91 (1H, m); 7.85 (1H, dd, J = 1.0, 5.5 Hz); 7.32–7.30
bottom flask equipped with a reflux condenser and a magnetic (1H, m). dC (125 MHz; DMSO-d6) 183.5, 180.5, 153.4, 134.7,
stirrer. Then, 5.0 mL of distilled water was added. The reaction 133.4, 132.0, 131.9, 130.9, 129.8, 129.7, 126.5, 126.4, 125.5,
mixture was refluxed for 6 h. The reaction mixture was acidified 115.4 ppm. MS (EI+) m/z (%): 256 (M+, 100), 228 (33), 172 (27),
with concentrated H3PO4 (pH D 2). The solid that formed was 171 (64), 76 (17).
vacuum filtered, dried at room temperature and purified by 2-Hydroxy-3-(thiophen-3-yl)naphthalene-1,4-dione (10e).
flash chromatography using silica gel and was eluted with an The reaction produced the compound 10e as a red-brick solid
increasing polarity gradient mixture of hexane and dichloro- (0.092 g, 0.359 mmol, 72%), mp 132–134 1C (lit. 125–127 1C).16
methane – 4 : 1 to 1 : 1. IR (KBr) nmax/cm 1 1649 (CQO), 3325 (OH). dH (500 MHz;
DMSO-d6; J in Hz) 8.06–8.03 (2H, m); 7.94–7.93 (1H, m); 7.87
General procedure for preparing 3-arylnaphthoquinones under (1H, td, J = 1.5, 7.5 Hz); 7.82 (1H, td, J = 1.5, 7.5 Hz); 7.56–7.53
microwave irradiation 10a–k (2H, m). dC (125 MHz; DMSO-d6) 183.5, 181.2, 154.4, 134.6,
A 10 mL Pyrex tube equipped with a magnetic stirrer was 133.2, 132.2, 130.8, 129.9, 129.8, 127.9, 126.2, 125.4, 123.7,
charged with 3-halo-1,4-naphthoquinone (0.5 mmol), K2CO3 117.0 ppm. MS (EI+) m/z (%): 256 (M+, 100), 228 (63), 172 (34),
(0.346 g, 2.5 mmol), arylboronic acid (0.75 mmol) and 171 (95), 76 (28).
Pd(OAc)2 (0.001 g, 1 mol%). The mixture was irradiated for 3-(3-Hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzalde-
10 min at 100 1C. Then, the reaction media were acidified with hyde (10f). The reaction produced the compound 10f as a yellow
H3PO4 (pH D 2). The solid that was obtained was purified solid (0.083 g, 0.300 mmol, 60%), mp 221–223 1C. IR (KBr)
by flash column chromatography on silica gel and eluted nmax/cm 1 1667 (CQO), 1691 (CQO), 3137 (OH). dH (500 MHz;
with an increasing polarity gradient mixture of hexane and DMSO-d6; J in Hz) 10.05 (1H, s, CHO); 8.09–8.04 (2H, m);
dichloromethane. 7.93 (1H, s); 7.91–7.88 (2H, m); 7.86–7.83 (1H, m); 7.73
2-Hydroxy-3-phenylnaphthalene-1,4-dione (10a). Product 10a (1H, dt, J = 1.5; 7.5 Hz); 7.66 (1H, t, J = 7.5 Hz). dC (125 MHz;
was obtained as a yellow solid (0.089 g, 0.356 mmol, 71%), mp DMSO-d6) 193.0, 183.3, 181.3, 155.4, 136.8, 135.6, 134.7, 133.3,
145–146 1C (lit. 146 1C).36 IR (KBr) nmax/cm 1 1649 (CQO), 1659 132.5, 132.0, 131.6, 130.0, 128.8, 128.3, 126.1, 125.6, 120.8 ppm.
(CQO), 3346 (OH). dH (500 MHz; DMSO-d6; J in Hz) 8.19 (1H, dd, HRMS (ESI) m/z calc. for C17H10O4 [M H] 277.0501, found
J = 1.0, 7.5 Hz); 8.15 (1H, dd, J = 1.0, 7.5 Hz); 8.02–7.99 (1H, m), 277.0510.

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4-(3-Hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzalde- stirrer. Then, 4.0 mL of distilled water and 1.0 mL of ethanol


hyde (10g). The reaction produced the compound 10g as a were added. The reaction mixture was refluxed for 6 h. The
yellow solid (0.058 g, 0.208 mmol, 42%), mp 217–218 1C. IR reaction mixture was then acidified with concentrated H3PO4
(KBr) nmax/cm 1 1671 (CQO), 1689 (CQO), 3261 (OH). dH (pH D 2). The solid that formed was filtered, dried at room
(500 MHz; DMSO-d6; J in Hz) 10. 05 (1H, s, CHO); 8.07 temperature and purified by extraction with ethyl acetate.
(1H, dd, J = 1.0, 7.5 Hz); 8.04 (1H, dd, J = 1.0, 7.5 Hz); 7.95 2-Amino-3-phenylnaphthalene-1,4-dione (11). The reaction
(2H, d, J = 8.0 Hz); 7.89 (1H, td, J = 1.0, 7.5 Hz); 7.84 (1H, td, produced the compound 11 in 24% as a dark red solid, mp 177–
J = 1.0, 7.5 Hz); 7.62 (2H, d, J = 8.0 Hz). dC (125 MHz; DMSO-d6) 178 1C (lit. 178–179 1C).37 IR (KBr) nmax/cm 1 1603 (CQO), 1675
192.6, 183.0, 181.2, 155.4, 137.9, 135.0, 134.7, 133.2, 131.9, (CQO), 3343 and 3416 (NH2). dH (500 MHz; DMSO-d6; J in Hz)
Published on 05 July 2016. Downloaded by UNIVERSITY OF ADELAIDE on 12/10/2017 07:06:05.

131.4, 129.9, 128.4, 126.0, 125.6, 120.9 ppm. HRMS (ESI) m/z 8.13 (1H, d, J = 7.5 Hz); 8.10 (1H, d, J = 7.0 Hz); 7.95 (1H, td,
calc. for C17H10O4 [M H] 277.0501, found 277.0509. J = 1.0, 7.5 Hz); 7.86 (1H, td, J = 1.0, 7.5 Hz); 7.57 (2H, t,
2-Hydroxy-3-(4-methoxyphenyl)naphthalene-1,4-dione (10h). J = 7.5 Hz); 7.47 (1H, t, J = 7.5 Hz); 7.41–7.39 (2H, m). dC
The reaction produced the compound 10h as a dark red solid (125 MHz; DMSO-d6) 181.7, 180.2, 146.1, 134.7, 130.4, 128.3,
(0.106 g, 0.378 mmol, 75%), mp 180–182 1C (lit. 172–173 1C).18f 127.3, 125.7, 125.5, 114.8 ppm.
IR (KBr) nmax/cm 1 1609 (CQO), 1635 (CQO), 3366 (OH). dH
(500 MHz; DMSO-d6; J in Hz) 8.07–8.01 (2H, m), 7.90–7.79 (2H,
m), 7.37–7.32 (2H, m), 7.00–6.95 (2H, m), 3.80 (3H, s, CH3). dC Acknowledgements
(125 MHz; DMSO-d6) 184.4, 181.8, 159.2, 154.9, 135.2, 133.8,
We acknowledge CNP-q/Universal (455739/2014-5), CAPES (for
132.5, 132.4, 130.3, 126.6, 126.0, 123.7, 122.5, 113.5, 55.6 ppm.
the student scholarships and research fellowships), FAPERJ/
2-Hydroxy-3-(3-methoxyphenyl)naphthalene-1,4-dione (10i).
APQ-1 (E26/110.724/2012/2), and FAPERJ (Support for Studies of
The reaction produced the compound 10i as a yellow solid
Neglected and Reemerging Diseases – E-26/010.001535/2014),
(0.092 g, 0.328 mmol, 66%), mp 126–127 1C. IR (KBr) nmax/cm 1
and Brazilian foundations for financial support and research
1652 (CQO), 1661 (CQO), 3359 (OH). dH (500 MHz; DMSO-d6;
fellowships. We thank Dr. Ivano Philippis, responsible for the
J in Hz) 8.06 (1H, dd, J = 0.5, 7.5 Hz), 8.03 (1H, dd, J = 1.0,
Reference Microorganisms Collection (CMRVS) – Fiocruz, for the
7.5 Hz); 7.88 (1H, td, J = 1.5, 7.5 Hz); 7.83 (1H, td, J = 1.0, 7.5 Hz);
donation of the fungal strains. We also thank Dr Marcos da
7.34–7.31 (1H, m); 6.94–6.92 (3H, m); 3.76 (3H, s, CH3). dC
Veiga Kalil for allowing the use of his laboratory facilities to
(125 MHz; DMSO-d6) 183.4, 181.4, 158.4, 154.8, 134.6, 133.1,
perform some antifungal assays and Professor Elias Barreto for
132.7, 132.0, 129.9, 128.3, 126.0, 125.5, 123.0, 122.1, 116.4,
his kind suggestions with regard to writing in English.
113.0, 55.0 ppm. HRMS (ESI) m/z calc. for C17H12O4 [M H]
279.0657, found 279.0658.
4-(3-Hydroxy-14-dioxo-1,4-dioxo-1,4-dihydronaphthalen-2- Notes and references
yl)benzonitrile (10j). The reaction produced the compound
10j as a yellow solid (0.059 g, 0.214 mmol, 43%), mp 253– 1 (a) V. F. Ferreira, S. B. Ferreira and F. C. da Silva, Org.
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(CRN), 3211 (OH). dH (500 MHz; DMSO-d6; J in Hz) 8.07 S. L. Castro, Molecules, 2009, 14, 4570–4590; (c) F. Epifano,
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