Thiobarbiturates as potential antifungal agents to control human infections caused by Candida and Cryptococcus species

Article abstract of DOI:10.1007/s00044-017-2126-0

Hospitalized patients can suffer from Candida and Crytptococcus infections, aggravating underlying health conditions. Due to the development of drug-resistant microorganisms, we report here on the potential of some arylidene-thiobarbiturate to control fiv

Full text of DOI:10.1007/s00044-017-2126-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-2126-0
ORIGINAL RESEARCH
Thiobarbiturates as potential antifungal agents to control human
infections caused by Candida and Cryptococcus species
1,2
Muhammad Shabeer1 Luiz C. A. Barbosa
Milandip Karak1,2
●
●
●
Amanda C. S. Coelho1 Jacqueline A. Takahashi1
●
Received: 12 September 2017 / Accepted: 5 December 2017
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract Hospitalized patients can suffer from Candida
and Crytptococcus infections, aggravating underlying
health conditions. Due to the development of drug-resistant
microorganisms, we report here on the potential of some
arylidene-thiobarbiturate to control five Candida spp. and
one Cryptococcus species of medical interest. Initially, a
bismuth nitrate catalyzed Knoevenagel condensation with
thiobarbituric acid and aromatic aldehydes was developed.
This new procedure generated seven new and thirteen
known arylidene-thiobarbiturate derivatives (1–20) with
excellent yields (81–95%), with a reaction time within 20
min. The antimicrobial activities of all compounds were
evaluated against Candida albicans, C. tropicalis, C.
parapsilosis, C. lusitaniae, C. dubliniensis, and Crypto-
coccus neoformans. Several compounds were as active as
Introduction
Fungal infections have been increasing to alarming levels in
all regions of the world, including underdeveloped and
developed countries. The mortality rates associated with
multidrug resistance fungal infections are unacceptably high
(Monk and Goffeau 2008; Mathew and Nath 2009; Rajen-
dran et al. 2016). The emergence of fluconazole resistance
among different pathogenic strains (Pfaller et al. 2007) and
the high toxicity of amphotericin B (Kullberg and Pauw
1999; Sheehan et al. 1999) intensified the search for newer,
safer, and more effective agents to combat serious fungal
infections. To search for a lead for a new antifungal com-
pound we focused on barbituric acid derivatives (BAs)
among the many classes of small organic molecules with
known biological activities (Gurib-Fakim 2006; Bello et al.
2008; Baell and Holloway 2010; Taferner et al. 2011;
Nigam et al. 2014).
BAs have contributed to the development of many
commercially available hypnotic, sedative and antic-
onvulsant drugs, such as Veronal (Fig. 1a) (Lemke et al.
2012). More recently, benzylidene-derivatives like B (Fig.
1) were shown to be active against Mycobacterium tuber-
culosis (IC50 = 4.71 μg mL−1), (Laxmi et al. 2011) while
compound C (Fig. 1) was effective against Candida albi-
cans (X=O, IC50 = 12.5 μg mL−1) (Faidallah and Khan
2012). Other reported activities of BAs include anticancer
(Dhorajiya et al. 2014) and protein tyrosine phosphatase
inhibition (Kafle et al. 2011).
the commercially available drugs (IC50 < 1.95 µg mL−1
)
towards at least one microbial strain. The results suggest
that some of the new compounds can serve as leads for new
antimicrobial agents for the treatment of human fungal
infections.
●
●
Keywords Thiobarbituric acid Knoevenagel condensation
●
Antimicrobial activity Antifungal compounds
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00044-017-2126-0) contains supplementary
material, which is available to authorized users.
* Luiz C. A. Barbosa
In addition to the BAs, the thiobarbiturate derivatives
(TBAs, Fig. 1) exhibit highly sought after biological prop-
erties such as antifungal (C, IC50 = 25 μg mL−1, X=S)
lcab@ufmg.br
1
Department of Chemistry, Universidade Federal de Minas Gerais,
(Faidallah and Khan 2012), urease inhibition (D, IC50
=
Belo Horizonte, MG CEP 31270-901, Brazil
2
1.61 μΜ) (Khan et al. 2014a), antibacterial (Jin et al. 2012;
Khan et al. 2014b; Yan et al. 2009) and anti-inflammatory
Department of Chemistry, Universidade Federal de Viçosa,
Viçosa, MG CEP 36570-900, Brazil

Med Chem Res
Fig. 1 Structures of commercial
BA drug Veronal (a) and some
biologically active BAs and
TBAs (b–e)
properties (Kopff et al. 2007). Some studies have also
demonstrated that thiobarbiturate derivative E is effective
for the treatment of non-alcoholic fatty liver disease (Ma
et al. 2011).
Despite the large array of biological activities of barbi-
turates as mentioned above, few reports on the antifungal
activities of TBAs are known (Faidallah and Khan 2012;
Khan et al. 2014b; Neumann et al. 2014). Thus, we planned
to investigate the effect of some known and other new
thiobarbiturate derivatives against five Candida and one
Cryptococcus species. Among the investigated species, C.
albicans is a harmless microorganism present in healthy
bodies, which can adapt and generate genetically altered
variants, more adapted to the host environment. However,
in immunocompromised patients, C. albicans can cause
serious symptomatic infections; such as oropharyngeal
candidiasis in AIDS patients (Morschhäuser 2016) and
candidemia associated with high mortality rates in cancer
patients (Jung et al. 2015). Nevertheless, the importance of
C. albicans as a human pathogen, and other species of
Candida genus like C. tropicalis and C. parapsilosis are
relevant sources of invasive Candida infections, especially
in surgical patients (Smeekens et al. 2016). On the other
hand, Cryptococcus neoformans, an opportunistic yeast that
causes lung infections, also deserves attention due to its
clinical relevance in individuals with compromised host
defences (Schmalzle et al. 2016). It is worth mentioning that
antifungal multi-drug resistance in C. neoformans is of great
concern (Perfect and Cox 1999).
Considering the limited reports on the antifungal activ-
ities of thiobarbiturate derivatives, and in line with our
continuous efforts to synthesize antimicrobial heterocyclic
compounds (Pereira et al. 2014a, b; Karak et al. 2016), we
report here on the expeditious synthesis of arylidene TBAs
and their antifungal activities against five Candida spp. and
one Cryptococcus species. Considering previous reports on
anti-Candida activities of some benzylidene barbiturates
(Fig. 1, R=H, Me or aryl; X=O) (Faidallah and Khan 2012;
Khan et al. 2014b; Neumann et al. 2014), we propose the
preparation of the corresponding TBAs (Fig. 2, X=S;
R=H), and expand the structural diversity of such
Fig. 2 Proposed structural modifications on thiobarbituric acid
derivatives
compounds possessing electron-withdrawing groups (Fig.
2, Y=CN, CF3, NO2, and Halogen) and heteroaromatic ring
(pyridine). We also included a thiophene unit as a spacer
between the TBA core and the arylidene unit.
Experimental
Chemicals and instruments
All chemicals and materials were acquired from Sigma
Aldrich Chemicals Ltd. and used without further purifica-
tion. IR spectra were recorded in KBr on Shimadzu IR
1
Affinity-1 FT-IR spectrophotometer and H and 13C NMR
spectra were recorded on a BrukerAvance II 300 and 400
MHz NMR spectrometers in DMSO using TMS as an
internal standard. Mass spectra were recorded on Waters, Q-
TofMicromass (LCMS) spectrometer and Varian Inc. 410
Prostar Binary LC with 500 Mass Spectrophotometer.
Melting points are uncorrected and were measured with a
MQAPF-301 apparatus.
General procedure for the synthesis of thiobarbituric
acid derivatives (1–20)
To a 50 mL round-bottomed flask charged with penta-
hydrated bismuth nitrate (0.032 g, 0.065 mmol) in ethanol
(20 mL) were added thiobarbituric acid (0.144 g, 1.0 mmol)

Med Chem Res
and aromatic aldehydes (1.0 mmol). The reaction mixture
was stirred for 10–20 min at 80 °C, when thin layer chro-
matography analyzes revealed it was completed. After
completion the precipitated product was separated by fil-
tration, dried, and recrystallized from ethanol. Full physical
and spectroscopic data and yields for all compounds are
presented in the supporting information (SI).
has increased considerably over the years due to its thermal
stability, low cost, low toxicity and stability to air (Bothwell
et al. 2011), we investigated its effect on the condensation
of TBA with aldehydes (SI, Table S1). Initially we carried
out the condensation of 4-hydroxybenzaldehyde and thio-
barbituric acid under a variety of conditions (SI, Table S1)
and found that the use of 20 mol% of Bi(NO3)3·5H2O in
ethanol at 80 °C, efficiently catalyzes the condensation,
resulting in the desired products in 10–20 min (Table 1). We
envisage that the catalysis takes place via a transition state
formed by coordination of bismuth (III) with the formyl
group increasing its electrophilicity. Since bismuth (III) can
be hydrolyzed producing an acidic solution, a protic cata-
lysis cannot be ruled out without experimental evidence
(Aggen et al. 2004). So, a control experiment reacting of 4-
hydroxybenzaldehyde with TBA in the presence of 60 mol
% of HNO3 was carried out and no product was formed
within 20 min. After one hour only 30% of product 1 was
isolated (SI, Table S1), confirming the effect of bismuth
(III) as the catalyst. A similar catalytic effect of bismuth
(III) on the conversion of aromatic aldehydes to a variety of
acylals has been reported (Aggen et al. 2004).
As can be observed from Table 1, the yields were gen-
erally high (compounds 1–20, yields 81–95%). Aldehydes
bearing electron donating or electron withdrawing func-
tional groups such as hydroxy (1–5), methoxy (6 and 7),
bromo (8), chloro, fluoro (9), cyano (11), trifluoromethyl
(12) and nitro (10) react well under this procedure. Fur-
thermore, excellent yields were also obtained with the 2-
naphthaldehyde (20), 4-phenylbenzaldehyde (19) and some
heteroaromatic aldehydes (13–18). The structures of all the
new compounds (9, 11, 13, 14, 16–18) were determined by
the spectroscopic analysis and the data are reported in the
SI. For the known compounds, the spectroscopic data were
identical to those from the literature (See the SI).
Biological activity
The bioassays were conducted with six yeast strains (C.
albicans ATCC 18804, C. dubliniensis clinical isolate 28,
C. lusitaniae CBS 6936, C. parapsilosis ATCC 22019, C.
tropicalis ATCC 750 and Cryptococcus neoformans ATCC
24067).
To determine the IC50 values for compounds 1–20, the
yeasts were inoculated in Sabouraud broth. Assays were
performed according to Clinical and Laboratory Standard
Institute guidelines (CSLI 2002). The microorganisms were
incubated in an oven at 37 °C for 24 h. The suspensions
containing the six yeast strains were transferred to tubes
containing sterile distilled water to reach a suspension
(inoculum) compatible with the McFarland scale 0.5 (108
cells mL−1). To assay the compounds 1–20, 96-well
microtiter plates containing the appropriate broth were
used (Brain Heart infusion for yeasts and bacterium and
Potato Dextrose Broth for filamentous fungi). The samples
were dissolved and microdiluted in DMSO (250.00, 125.00,
62.50, 31.25, 15.63, 7.81, 3.90, and 1.95 µg mL−1) in the
microtiter plates. The inoculum was added equally to each
well. The plates were incubated in an oven at 37 °C for 24
h. The readings were obtained after 24 h of incubation on a
microplate reader at 600 nm. The IC50 values were calcu-
lated for the samples that showed an inhibition higher than
50% in the highest concentration assayed. Commercially
available drugs, i.e., miconazole and nystatin, were used as
positive standards. All the tests were performed twice under
the same conditions.
Biological activity
All the synthesized compounds have been screened for their
antimicrobial activities against the yeast strains Candida
albicans, C. dubliniensis, C. tropicalis, C. parapsilosis, C.
lusitaniae, and Cryptococcus neoformans. Positive control
experiments were carried out using miconazole and
nystatin.
Results and discussion
Chemistry
Our synthetic study commenced from the Knoevenagel
condensation between aldehydes and thiobarbituric acid
(Table 1). Although this condensation can conventionally
be carried out under acid or base catalysis (Li et al. 2006;
Khan et al. 2014a, b; Rahimov and Avdeev 2009; Mital
et al. 2015) or even in an uncatalyzed manner (Ahmed and
Karrar 2013; Chen et al. 2014), it normally requires high
temperature and a long reaction time. Considering that the
use of bismuth (III) nitrate [Bi(NO3)3·5H2O] as a catalyst
For all yeasts assayed, most of the compounds showed a
good correlation between the concentrations tested and the
percentage of growth inhibition, indicating that the anti-
microbial activity provided by this class of compounds is
dose-dependent. Therefore, the IC50 values for the active
compounds were determined as shown in Table 2.
In general, the activities of this series of compounds on
the microorganisms varied according to the structure and
the species tested. Among the six yeast strains assayed,

Med Chem Res
Table 1 Bismuth(III) nitrate facilitated synthesis of thiobarbituric acid derivatives
C. albicans, C. dubliniensis, and C. lusitaniae were resistant
to most of the compounds, while the growth of C. para-
psilosis, C. tropicalis, and Cryptococcus neoformans were
more effectively inhibited.
The less sensitive strains, C. albicans, C. dubliniensis,
and C. lusitaneae, were more affected by compounds 14
(IC50 < 1.95, 9.39, and 6.18 µg mL−1, respectively) and 13
(31.45, 44.33, and 76.83 µg mL−1, respectively). Com-
pound 15 was also significantly active against C. albicans
(IC50 = 12.77 µg mL−1). TBAs 14 and 15, which were
active against C. albicans, are promising since the corre-
sponding BAs showed weak activity (Neumann et al. 2014).
Compound 20 with IC50 = 172.38 µg mL−1, is slightly less
active than its oxo-analog (MIC80 of 125 µg mL−1, pre-
viously reported by Neumann et al. 2014), suggesting that
sulfur could have a restrictive effect on bioactivity. As
found by Neumann et al. (2014), our results also showed
that the compounds bearing OH or OMe groups (one or
more, at various positions) are generally not active against
C. albicans. This is also consistent for C. dublinensis and C.

Med Chem Res
Table 2 IC50 for the
compounds 1–20 for six yeast
strains
Compound IC50 (µg mL−1
)
C. albicans C. dubliniensis C. lusitaniae C. parapsilosis C. tropicalis C. neoformans
a
1
–
–
–
4.21
4.24
–
–
14.31
9.25
2
–
–
–
–
3
–
–
–
–
155.79
45.61
–
4
218.48
92.64
129.14
–
–
5
–
–
–
48.49
<1.95
<1.95
<1.95
8.12
3.17
–
–
6
–
–
–
<1.95
<1.95
<1.95
–
27.38
<1.95
123.53
17.73
68.41
–
7
214.73
187.31
194.46
8
–
–
–
9
–
–
–
10
11
12
13
14
15
16
17
18
19
20
–
–
–
26.27
–
–
–
–
–
–
–
<1.95
<1.95
<1.95
<1.95
–
<1.95
<1.95
<1.95
<1.95
–
81.26
6.39
31.45
<1.95
12.77
–
44.33
9.39
56.21
–
76.83
6.18
34.46
–
<1.95
53.58
–
–
–
–
–
–
–
–
–
–
<1.95
9.78
3.60
<1.95
<1.95
–
12.63
12.36
11.35
<1.95
<1.95
221.69
172.38
–
166.62
192.03
<1.95
<1.95
<1.95
<1.95
<1.95
<1.95
196.92
<1.95
<1.95
Miconazole <1.95
Nystatin <1.95
a (–) IC50 value was not calculated since inhibition was lower than 50% at the higher concentration assayed
lusitanea that no previous study has been found in this
context. Although the inhibitory activities of some N,N-
dimethylbarbiturates have been reported for C. albicans
(Khan et al. 2014b), it was not possible to compare these
results with ours since a different bioassay (disc diffusion
method at a fixed dose of 100 μg) was adopted.
Compounds 13–15 also showed potent activity against
C. parapsilosis, C. tropicalis, and Cryptococcus neofor-
mans (IC50 = <1.95 µg mL−1 for most cases), whose IC50
values are comparable to those of miconazole and nystatin.
The inhibitory activity of BAs and TBAs against C. para-
psilosis, herein reported for the first time, is especially
noteworthy in view of the great demand for effective and
selective agents to treat infections of cancer patients (Sabino
et al. 2015).
Structurally, 13–15 possess five-membered ring hetero-
aromatic aldehydes. On the other hand, compounds com-
posed of substituted benzaldehyde, six-membered
heteroaromatic aldehydes and naphthalene carbaldehyde
were inactive against C. albicans, C. dubliniensis, and C.
lusitaniae. Substitution by a phenyl group at α or β position
in the thiophene ring makes 14 to be linear, while 15 to be
angular-shaped. Such modifications seemed to have a
dramatic effect on the activities except for C. parapsilosis
and C. tropicalis, both showing low IC50 (1.95 µg mL−1).
As already mentioned, C. parapsilosis, C. tropicalis and
C. neoformans were in general more sensitive to TBAs
derivatives. The IC50 values of compounds 6, 7, 8, 12, 13,
14, 15, and 18 were lower than the minimum concentration
tested (<1.95 µg mL−1) for C. parapsilosis. For 6, 7, 8, 12,
13, 14, 15, 19, and 20, the IC50 values were <1.95 µg mL−1
for C. tropicallis, which is also an organism of great con-
cern since it causes invasive candidiasis in hospitalized
patients worldwide (Xiao et al. 2014). Moreover, it was
noteworthy that compounds 7 and 14 showed IC50 < 1.95
µg mL−1 against C. neoformans, which were as potent as
the antimicrobial drugs, miconazole and nystatin.
Among the phenolic derivatives (1-5), only 1 and 2 were
highly active (IC50 = 4.21 µg mL−1) against C. para-
psitosis. Derivatives of benzaldehydes bearing electron-
donating (OMe) or electron-withdrawing groups at various
positions (F, Cl, Br, CN, CF3, and NO2) were all active. The
naphthalene derivative 20 and the biphenyl derivative 19
were very active against C. parapsilosis, C. tropicalis and
C. neoformans. Although we could not determine a clear
structure–activity relationship (SAR), we envisaged that the

Med Chem Res
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more active substances.
Conclusion
In conclusion, we have described the expeditious synthesis
of TBA derivatives via bismuth (III) nitrate catalyzed
Knoevenagel condensation between aryl-carbaldehydes and
TBA. The reactions proceeded smoothly to afford the
desired 5-arylidenethiobarbiturates in high yields within 20
min. Using this methodology, seven new and thirteen
known TBAs were prepared and their inhibitory potential
was evaluated against five Candida spp. and one Crypto-
coccus species. Several compounds had activities compar-
able to the commercial drugs. The preliminary SAR
analysis suggested that (i) the presence of OH/OMe groups
on the benzene ring and (ii) the substitution of benzene to
naphthalene or pyridine moieties are detrimental for activ-
ities. On the other hand, the most active compounds against
all Candida species had a thiophene spacer between the
thiobarbiturate and the benzene ring. The position of the
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activity, with the linear-shaped compound being more
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can be further modified for the development of new anti-
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Acknowledgements We are grateful to Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq, grant 400746-
2014) and Fundação de Amparo à Pesquisa de Minas Gerais
(FAPEMIG, grant APQ1557-15) for research fellowships (JAT,
LCAB). We also thank the World Academy of Sciences for the
advancement of science in developing countries (TWAS) and Coor-
denação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
for PhD fellowships for MS and MK. We would also like to
acknowledge the Coleção de Culturas Tropical (CCT, Brazil) for
donating some microbial strains.
Karak M, Acosta JAM, Barbosa LCA, Boukouvalas J (2016) Late-
stage bromination enables the synthesis of rubrolides B, I, K, and
O. Eur J Org Chem 2016:3780–3787
Khan KM, Rahim F, Khan A, Shabeer M, Hussain S, Rehman W,
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22:4119–4123
Khan M, Khan K, Ahmad M, Irshad A, Kardono S, Broto L, Fazal R,
Haider M, Ahmed S, Shahnaz P (2014b) Antibacterial and anti-
fungal activities of 5-arylidene-N,N-dimethylbarbiturates deriva-
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Compliance with ethical standards
Kopff M, Kopff A, Kowalczyk E (2007) The effect of nonsteroidal
anti-inflammatory drugs on oxidative/antioxidative balance. Pol
Merkur Lek 23:184–187
Conflict of interest The authors declare that they have no conflict of
interest.
Kullberg BJ, Pauw BE (1999) Therapy of invasive fungal infections.
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Laxmi LV, Reddy YT, Kuarm BS, Reddy PN, Crooks PA, Rajitha B
(2011) Synthesis and evaluation of chromenyl barbiturates and
thiobarbiturates as potential antitubercular agents. Bioorg Med
Chem Lett 21:4329–4331
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