2-amino-4-arylthiazole derivatives as anti-giardial agents: Synthesis, biological evaluation and QSAR studies

Article abstract of DOI:10.1515/chem-2015-0127

A series of seven 2-amino-4-arylthiazoles were prepared following Hantzsch's modified method under microwave irradiation. A set of 50 derivatives was obtained and the in vitro activity against Giardia intestinalis was evaluated. The results on the biological activity revealed that, in general, the N-(5-bromo-4-aryl-thiazol-2-yl)-acetamide scaffold showed high bioactivity. In particular, compounds 6e (IC₅₀= 0.39 μM) and 6b (IC₅₀= 0.87 μM) were found to be more potent than the positive control metronidazole. Citoxicity and acute toxicity tests performed showed low toxicity and high selectivity of the most active compounds (6e SI = 139, 6b SI = 52.3). A QSAR analysis was applied to a data set of 37 obtained 2-amino-4-arylthiazoles derivatives and the best model described a strongly correlation between the anti-giardiasic activity and molecular descriptors as E2M, RDF115m, F10, MATS6v, and Hypnotic-80, with high statistical quality. This finding indicates that N-substituted aminothiazole scaffold should be investigated for the development of highly selective anti-giardial agent.

Full text of DOI:10.1515/chem-2015-0127

Open Chem., 2015; 13: 1127–1136
Research Article
Open Access
Raul Mocelo-Castell, Carlos Villanueva-Novelo, David Cáceres-Castillo, Ruben M. Carballo,
Ramiro F. Quijano-Quiñones, Mariana Quesadas-Rojas, Zulema Cantillo-Ciau,
R2o-bAertmo Ceidnilolo--R4ive-raa,rRyoslatEh. Mioaoz-Poucl,eLaiDla Me.rMiovuajirt, GivonezasloaJ. sMena-Rejón*
Anti-giardial Agents: Synthesis,
Biological Evaluation and QSAR Studies
DOI: 10.1515/chem-2015-0127
received November 4, 2014; accepted June 20, 2015.
statistical quality. This finding indicates that N-substituted
aminothiazole scaffold should be investigated for the
Abstract: A series of seven 2-amino-4-arylthiazoles development of highly selective anti-giardial agent.
were prepared following Hantzsch’s modified method
under microwave irradiation. A set of 50 derivatives Keywords: 2-amino-4-arylthiazole, Anti-protozoal
was obtained and the in vitro activity against Giardia activity, Giardia intestinalis, QSAR
intestinalis was evaluated. The results on the biological
activity revealed that, in general, the N-(5-bromo-4-aryl-
thiazol-2-yl)-acetamide scaffold showed high bioactivity.
In particular, compounds 6e (IC50 = 0.39 μM) and 6b
1 Introduction
(IC50 = 0.87 μM) were found to be more potent than the
Giardia intestinalis (syn. Giardia duodenalis, Giardia
positive control metronidazole. Citoxicity and acute
lamblia) is an enteric protozoan pathogen that infects
toxicity tests performed showed low toxicity and high
humans, domestic animals and wildlife worldwide. The
selectivity of the most active compounds (6e SI = 139,
clinical manifestations of G. intestinalis infection are
6b SI = 52.3). A QSAR analysis was applied to a data set
highly variable between individuals and can range from
of 37 obtained 2-amino-4-arylthiazoles derivatives and
acute to chronic infections, while some hosts may remain
the best model described a strongly correlation between
asymptomatic. When present, clinical signs of infection
the anti-giardiasic activity and molecular descriptors as
may include nausea, weight loss, bloating, abdominal
E2M, RDF115m, F10, MATS6v, and Hypnotic-80, with high
pain, and diarrhea [1]. In Asia, Africa, and Latin America,
about 200 million people have symptomatic giardiasis,
with more than 500,000 new cases reported every year. In
*Corresponding author: Gonzalo J. Mena-Rejón: Laboratorio de
developed countries, where the prevalence of giardiasis
Química Farmacéutica, Facultad de Química, Universidad Autónoma
varies from approximately 3−7%, it is referred to as
a re-emerging infectious disease [2]. Due to these facts,
since ten years ago, this parasite was included in the
World Health Organization (WHO) Neglected Disease
Initiative [3].
Currently, the classes of chemotherapeutic
agents available for the treatment of giardiasis
are: 5-nitroimidazoles (Metronidazole, Tinidazole,
de Yucatán, Calle 41 No. 421, Col. Industrial, C.P. 97150 Mérida,
Yucatán, México, E-mail: mrejon@uady.mx
Raul Mocelo-Castell: Facultad de Química, Universidad de La
Habana, Zapata s/n entre G y Carlitos Aguirre, Vedado, Plaza de la
Revolución, CP 1040 Ciudad de La Habana, Cuba
Carlos Villanueva-Novelo, David Cáceres-Castillo, Ruben M. Carballo,
Ramiro F. Quijano-Quiñones, Mariana Quesadas-Rojas,
Zulema Cantillo-Ciau: Laboratorio de Química Farmacéutica,
Facultad de Química, Universidad Autónoma de Yucatán,
Calle 41 No. 421, Col. Industrial, C.P. 97150 Mérida, Yucatán, México
Cedillo-Rivera, Rosa E. Moo-Puc: Unidad de Investigación Médica
Yucatán, Unidad Médica de Alta Especialidad, Centro Médico
Ignacio García Téllez IMSS, Calle 41, N. 439, Col. Industrial, Mérida,
Yucatán, 97150 México
Secnidazole,
(Furazolidone),
and
Ornidazole),
5-nitrofurans
(Nitazoxanide),
5-nitrothiazoles
benzimidazoles (Albendazole, Mebendazole), quinolines
(Chloroquine),acridins(Quinacrine),andaminoglycosides
(Paromomycin) [4].
Although 5-nitroimidazoles are the most commonly
used anti-giardiasic drugs, recent studies have shown
Laila M. Moujir: Departamento de Microbiología y Biología Celular,
Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 2,
38206, Tenerife, Islas Canarias, España.
© 2015 Raul Mocelo-Castell et al., licensee De Gruyter Open.
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
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that Metronidazole (MTZ) has several toxic effects such as 2 Experimental procedure
headache,vertigo,nausea,andinsomecasesneurotoxicity
[5,6]. Moreover, previous studies have also demonstrated 2.1 General
mutagenic, teratogenic, and other cytotoxic effects [7,8]. In
addition Giardia strains have been developing resistance All reagents were obtained from Sigma-Aldrich and used
to MTZ in vivo and manifesting cross-resistance to other as received. Solvents were dried and distilled before use.
nitroimidazole analogues, which results in treatment Precoated TLC silica gel 60 F254 aluminum sheets from
failures in up to 20% of cases [8-10]. Early in the last Sigma-Aldrich were used for thin-layer chromatography
decade, US Food and Drug Administration has approved (0.25 and 0.5 mm layer thickness for analytical and
the use of nitazoxanide (NIT) for treatment giardiasis. preparative TLC, respectively) and visualized under short
Nitazoxanide, (Alinia®; Romark Laboratories), is a drug (254 nm) and long (366 nm) wavelength UV light or oleum
introduced as an alternative option that shows excellent reagent (H2SO4:AcOH:H2O, 1:20:4).
in vitro activity against a wide variety of protozoa [11]. In
Melting points were measured using an
a clinical trial involving children with diarrheal illness Electrothermal IA 9100 melting point apparatus and are
1
13
associated with G. intestinalis, this nitrothiazolide was uncorrected. H NMR and C NMR spectra were recorded
effective at reducing the duration of it [12] and the most at 400 MHz and 100 MHz, respectively on a Bruker Avance
common side effect is gastrointestinal upset [13].
400 spectrometer at 25°C. The chemical shifs are given
In contrast, the other alternative agents for treating in δ (ppm) with the residual solvent peak as an internal.
giardiasis show variable efficacies besides adverse High-resolution mass spectra (HRMS) were measured on
effects. Then, Furazolidone can cause mild hemolysis in a VG Micromass LTD-ZAB-2F Fisons Instrument apparatus
patients deficient in glucose-6-phosphate dehydrogenase. operating with electronic impact source at 70 eV. A CEM
Albendazole can be as effective as Metronidazole, but Discover Focused Microwave Synthesis System operating
its efficacy varies markedly (25–90%) depending on the at 2450 MHz was used at an output of 50 W.
dosing regimen. Quinacrine possess a highly efficacy
(90%), however it can produce yellow discoloration of skin
sclera, and exfoliative dermatitis. The aminoglycoside 2.2 Synthesis
Paromomycin is less effective among adults with
metronidazole-refractory disease. Chloroquine is an old General procedures
anti-malarial drug with anti-giardial activity that is no
longer available in the US or Canada [13].
Preparation of compounds 1a-g
The thiazole ring system is a useful structural motif A mixture of p-substituted acetophenone (8.6 mmol),
found in numerous biologically active molecules and is thiourea 2 (17.2 mmol, 1.3 g) and iodine (8.6 mmol, 2.2 g)
an interesting group as anti-infective agents [14]. In the was placed in an open vessel containing a Teflon coated
chemotherapy field of protozoan diseases, substituted stir bar. The vessel was placed in the microwave cavity
2-aminothiazoles have been investigated due to their and subjected to MW irradiation (50 W) at a temperature
broad anti-parasitic spectrum. These structures have been between 140−150°C for 10 min. Afer the completion of
tested as pharmacophores in many synthetic compounds the reaction, the crude mixture was cooled until 70°C
and have shown in vitro and in vivo activities against and was triturated, filtered, and washed with Et2O. The
Trypanosoma [15], Leishmania [16], Plasmodium [17] and crude product was dissolved in hot water and the pH was
Toxoplasma [18], among others protozoa [19].
adjusted between 11−12 with NH4OH. The precipitated was
Based on our earlier laboratory experiences where filtered and crystallized from EtOH:H2O (1:4) to obtain the
2-amino-4-arylthiazole derivatives were reported to poses 2-amino-4-aryl-1,3-thiazole (1a-g).
anti-microbial activity [20], it appeared of interest to
explore this bioactive system for anti-parasitic activity.
Hence, small library around the 2-amino-4-arylthiazole Preparation of compounds 2a-f and 9
scaffold were developed and evaluated for anti-giardial Sodium acetate (2 mmol) and 2-amino-4-aryl-1,3-thiazole
activity in vitro. Further, the 2-D Quantitative Structure (1a-g) (2 mmol) was added to acetic anhydride (10 mL). The
Activity Relationship (QSAR) studies were performed resulting solution was stirred at 60°C for 1 h. The reaction
using the Hantzsch approach.
was allowed to warm to rt and then were added 25 mL of
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2-Amino-4-arylthiazole Derivatives as Anti-giardial Agentsꢀ
ꢀ1129
cool water. The pH was adjusted between 11−12 with NH4OH 2.3 Biological activity
and the formed precipitate was filtered and crystallized
from EtOH:H2O (1:4) to obtain the N-(4-aryl-thiazol-2-yl)- Anti-protozoal assay
acetamide (2a-f) and acetic acid 4-(2-acetylamino-thiazol-
4-yl)-phenyl ester (9).
Giardia intestinalis IMSS:0696:1 isolate, obtained from
an individual with symptomatic giardiasis, was used.
Trophozoites were cultured in TYI-S-33 modified medium,
supplemented with 10% calf serum, and subcultured
Preparation of compounds 3a-f and 4a-f
Triethylamine (2 mmol) and 2-amino-4-aryl-1,3-thiazole twice a week; for the assay, trophozoites were tested in
(1a-g) (2 mmol) was added to benzoyl chloride or furan- their log phase of growth.
2-carbonyl chloride (5 mmol). The resulting solution
Stock solutions of pure compounds were prepared
was stirred at 90°C for 1 h. The reaction was allowed to with dimethyl sulfoxide (DMSO, 20 mg mL-1), from which,
warm to rt and then were added cool water, the formed by means of two folded serial dilutions with TYI-S-33
precipitate was filtered and dissolved in EtOH. To the modified medium, four final solutions in a range of
solution were added cool water and the formed precipitate 1.66−13.33 μg mL-1 were obtained. Each solution was
was filtered and crystallized from EtOH:H2O (1:4) to obtain inoculated with G. intestinalis to achieve an inoculums of
the N-(4-aryl-thiazol-2-yl)-benzamide (3a-g) or the furan-2- 7.5 × 104 trophozoites mL-1. The test included Metronidazole
carboxylic acid (4-aryl-thiazol-2-yl)-amide (4a-g).
as the drug of reference, a control (culture medium with
trophozoites and DMSO), and a blank (culture medium).
Afer 48 h at 37°C, parasites were detached by chilling
and 50 μL of each culture tube were subcultured in
Preparation of compounds 5a-e
A solution of Br2 (2.84 mmol) in glacial acetic acid fresh medium without extracts or drug and incubated
(2 mL) were added slowly to a solution sulfuric acid (20%, for 48 h at 37°C. Cell proliferation was measured with
5 mL) and 2-amino-4-aryl-1,3-thiazole (1a-h) (2.84 mmol). a hemocytometer, and the percentage of trophozoite
The resulting solution was stirred at rt for 18 h. The growth inhibition was calculated by comparison with
reaction was then quenched by addition of Et2O and the controls. The percentage of inhibition calculated for
formed precipitate was filtered. The crude product was each concentration was transformed into Probit units. The
dissolved in hot water (25 mL) and the pH was adjusted plot of Probit against log concentration was made; the
between 10−11 with NH4OH. The new precipitated was best straight line was determined by regression analysis
filtered to obtain the 5-bromo-4-aryl-thiazol-2-ylamine and the 50% inhibitory concentration (IC50) values were
(5a-e).
calculated. The experiments were done in duplicate and
repeated at least three times.
Preparation of compounds 6a-f, 7a-f, 8a-f and 10
To a solution of the N-(4-aryl-thiazol-2-yl)-acetamide Acute toxicity assay
(2a-f) (1 mmol), N-(4-aryl-thiazol-2-yl)-benzamide (3a-
f) (1 mmol) or furan-2-carboxylic acid (4-aryl-thiazol-2- The brine shrimp test was performed against freshly
yl)-amide (4a-f) (1 mmol) in glacial acetic acid (1 mL) at hatched nauplii of Artemia salina. Briefly, the compounds
0°C were added slowly Br2 (1 mmol) in glacial acetic acid were dissolved in DMSO and diluted by artificial seawater
(1 mL). The resulting solution was stirred for 1 h, and then so that an appropriate range of concentrations was
were added cool water, the formed precipitate was filtered obtained. The final concentration of DMSO was 1% and
and the pH was adjusted between 10−11 with NH4OH. the number of nauplii was 10. Surviving nauplii were
The precipitated was filtered and crystallized from counted afer 24 h, and LC50 (concentration lethal to 50%
EtOH:H2O (1:4) to obtain the N-(5-Bromo-4-aryl-thiazol- of the nauplii) were determined afer statistical analysis.
2-yl)-acetamide (6a-f), N-(5-Bromo-4- aryl -thiazol-2-yl)-
benzamide (7a-f), furan-2-carboxylic acid (5-bromo-4- aryl
-thiazol-2-yl)-amide (8a-f) or acetic acid 4-(2-acetylamino- Cytoxicity assay
5-bromo-thiazol-4-yl)-phenyl ester (10).
The characterization data of all synthesized Vero (African green monkey kidney) cell lines from the
compounds are presented as Supporting Information.
American Type Culture Collection (ATCC) were grown
as a monolayer in Dulbecco’s modified Eagle’s medium,
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1130ꢀ
ꢀ Raul Mocelo-Castell et al.
DMEM, supplemented with 5% fetal calf serum and 1% of divided into multiple chemically diverse training and
penicillin-streptomycin mixture (10,000 UI mL-1). The cells test sets with the rational approach hierarchical cluster
were maintained at 37oC in 5% CO2 and 90% humidity. analyses (HCA) using Ward’s algorithm [26]. The splitting
The cytotoxic activity was assessed using colorimetric procedure led to a training and a validation set consisting
MTT
bromide) reduction assay. 1.4 × 104 cells/well were training set was used to generate the QSAR model.
incubated in a microtiter 96 well plate with the The variable selection for obtain the QSAR were
3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium of 37 (74%) and 13 (26%) compounds, respectively. The
compounds at 6.25, 12.5, 25 and 50 µg mL-1 dissolved performed using the SYSTAT 12 program with the stepwise
in DMSO at a maximum concentration of 0.05%. Afer linear regression [27]. The stepwise method add to the
48 h the optical density was measured using a microELISA model only one descriptor at a time, in the order of most
at 550 nm afer dissolving the MTT formazan with DMSO significant to lest significant in terms of F-test values with
(150µL). Thepercentageviability(IC50)wascalculatedfrom at level of confidence of 0.99. The goodness of the model
the curve. All the experiments were repeated three times. was tested calculating the regression coefficient (R2),
Theselectivityindex(SI)ofthecompoundsisdefinedasthe adjusted square of the correlation coefficient (R2adj) and
ratio of cytotoxicity on normal cells to anti-giardial activity the F coefficient. The intercorrelation between descriptors
(SI = IC50 Vero cells/IC50 G. intestinalis).
was checked, in order to avoid that the descriptors in
the model are highly correlated. The internal predictive
ability of the model was assessed by the cross-validate
squared correlation coefficient (q2), which is calculated
from the cross-validation method with the leave on out
(LOO) scheme [28]. The predictive power of the model
was confirmed calculating the correlation coefficient R2
2.4 Computational Details
Data set preparation
TheQSARmodelwasderivedbymultiplelinearregressions between the predicted and observed activities for the test
using the observed biological activity as dependent set (R2test). The residuals were calculated in order to confirm
variables and the chosen descriptors as the independent the absence of systematic error in the QSAR relationship.
variables.
The quantum chemical calculations were performed
in SPARTAN 06 program [21] and Gaussian 09. [22] The
3 Results and discussion
moleculargeometriesofallcompoundswerefullyoptimized
using Density Functional Theory (DFT) with a 6−31+ G (d,p)
basis set. The water solvent effects are included using the 3.1 Synthesis of thiazoles
polarizable continuum model (PCM) [23]. The exchange-
correlation potential was evaluated using the Beckes´s The thiazole core was synthesized following Hantzsch’s
three parameter hybrid density functional B3LYP [24]. modified method reported before and shown in
From this calculation the Homo, Lumo, Mulliken, natural, Scheme 1 [29]. The rapid and efficient solvent-free
the Hirshfeld, and electrostatic-fit charges; Dipole and reaction of p-substituted acetophenones with thiourea
higher moments and polarizabilities descriptors were and iodine under microwave irradiation led to 2-amino-
obtained. For each compound, the harmonic-vibrational 4-arylthiazoles (1a-g). In order to increase structural
modes were calculated and no imaginary frequency was diversity a set of 43 derivatives were obtained from
observed.
seven thiazoles (1a-g). Compounds 1a-f was treated with
acetic anhydride, benzoyl chloride and 2-furoyl chloride,
respectively, to obtain thiazoles 2a-f, 3a-f and 4a-f
(Scheme 1). The reaction of 1g and acetic anhydride led
the diacetyl compound 9.
Molecular descriptors selection
The DRAGON Professional 5.5 program was used to
The bromine derivatives of 1a-e, 2a-f, 3a-f, 4a-f and 9
calculate1000descriptorsthatencodingtheelectronicand were obtained by the reaction of 2-amino-4-arylthiazoles,
structural information of the fully optimized structures. N-(4-arylthiazol-2-yl)-acetamide,
N-(4-arylthiazol-2-yl)-
All descriptors were auto-scaled because in this way they benzamide, furan-2-carboxylic acid (4-aryl-thiazol-2-
are less susceptible to the influence of compounds with yl)-amide and acetic acid 4-(2-acetylamino-thiazol-4-
extreme values [25]. The dataset of 50 compounds was yl)-phenyl ester, with molecular bromine under acid
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2-Amino-4-arylthiazole Derivatives as Anti-giardial Agentsꢀ
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R
R
R
S
e
a
O
N
+
N
H2N
NH2
NH2
NH2
S
=
H 1b R
Cl
S
r
B
=
r
,
,
R
H
M
B
M
N
O
Cl
O
H
,
,
,
2
a
=
R
=
1
c
,
;
,
e
e
O
,
a-e
5
r
=
1
R
B
1d R
,
N
O2
,
;
e
1
=
e
M
=
e
M
O
R
1f R
,
,
;
=
H
O
1
,
g
R
b
d
c
b
O
R
R
O
R
O
O
N
S
f
O
N
N
O
N
S
O
NH
N
NH
NH
H
S
S
a-
2
a-
f
a-
f
4
3
9
f
f
f
f
O
R
R
O
R
O
O
N
O
N
N
O
N
S
O
NH
NH
NH
NH
S
r
B
S
S
r
B
r
B
r
B
a-
6
f
a-
8
f
a-
7
f
1
0
Scheme 1: Synthesis of thiazoles derivatives. Reagents and conditions: (a) I2, neat, MW, 140°C, 10 min.; (b) AcONa, Ac2O, 60°C, 1 h; (c) Et3N,
BzCl, 90°C, 1 h; (d) Et3N, FuroylCl, 90°C, 1 h; (e) Br2, AcOH (glacial), H2SO4 (20%), rt. 18 h; (f) Br2, AcOH (glacial), 0°C, 1 h.
conditions. The synthesis is summarized in Scheme 1. The As seen in Table 1, compounds 1b, 1c, and 1e having
bromination of 1f and 1g did not lead to the brominated chloro, bromo, and methyl groups at 4’ position are
compounds.
relatively active. The unsubstituted phenyl analog (1a)
Compounds 3d, 4d-e, 5b-d, 7a-f and 9a-f resulted in was markedly less potent than the remaining compounds
new structures and all the spectrometric and spectroscopic in this series.
data (HRMS, H, and C NMR) are in agreement with the
expected structures.
1
13
Knowing that parasiticidal drugs as NIT and other
thiazolides[31] possess benzamide group in the
a
aminothiazolemoiety.Theaminecomponentofthethiazole
core was surveyed for SAR comparison while holding
the substitution pattern at R1 constant. Three classes of
N-substituted aminothiazoles were obtained through the
3.2 Biological evaluation of thiazoles
In vitro susceptibility assays were performed using a introduction of acetyl (2a-f), benzoyl (3a-f), and furoyl
method previously described [30] and the results are (4a-f) groups. Introduction of a bigger NH-benzoyl group
shown in Table 1. The initial structure activity relationship in compound 1f resulted in increasing the antiprotozoal
(SAR) studies focused on variation of substituent R1 (1a-f), activity ten-fold (3f); however the presence of this group
so the substitution pattern at these positions was carefully in compounds 1b and 1c led to decrease the bioactivity
selected to confer different electronic environment to the about 4 and 4.6 times, respectively (compounds 3b and
molecules.
3c). A similar pattern was observed when the acyl or furoyl
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Table 1: In vitro activity against Giardia intestinalis of synthesized
group was introduced in compounds 1b-c, but the amides
of compounds 1d and 1e showed a different bioactivity
profile. The different patterns in anti-giardial activity of
the obtained amides revealed that steric variations are not
directly correlated with biological activity.
2-amino-4-arylthiazole derivatives.
R1
N
H
N R2
The nitrothiazole moiety is a structural motif found
in antiparasitic drugs such as NIT and Tizoxanide (TIZ).
However, it has been shown that nitro group is not
crucially instrumental in terms of parasiticidal activity.
In addition, the replacement of the potentially harmful
nitro group by a bromo moiety does not affect in vitro
efficacy of these drugs [32]. Considering that bromo
thiazolides may represent a valuable alternative to the
antiparasitic arsenal [19,33] and the introduction of the
heavier halides into aromatic scaffolds produces an
affinity gain in protein-ligand complexes [34], we decided
to explore the effect of a bromo substitution at position-5
of the thiazole nucleus. The thiazole derivatives with a
bromo group attached at carbon-5 of the heterocyclic ring
showed an improved anti-giardial activity in contrast with
unsubstituted derivatives. Enhanced potency is observed
for bromo-analogues bearing an N-acetyl group (6a-f).
In this series the compounds 6a (IC50 = 1.95 μM) and 6f
(IC50 = 2.51 μM) displayed a slightly higher bioactivity
against G. intestinalis than MTZ (IC50 = 1.40 μM).
Compounds 6b (IC50 = 0.87 μM) and 6e (IC50 = 0.39 μM)
showed the best activity and even the latter was 3.6-times
more active than MTZ, the drug of choice for the treatment
of giardiasis. The effect of 5-bromo substitution was
also observed in compound 10, derivative of compound
9, in which the introduction of halogen dramatically
improves the anti-giardial activity from 56.28 to 2.90 μM.
The bioactivity of these compounds (6a-b, 6e-f and 10)
suggest that the introduction of bromo group into the
N-acetamidothiazole core, increase the antiprotozoal
activity. Remarkably these compounds, together 8f, could
be considered as hits due their IC50 < 1 µg mL-1) [35].
According to literature, an anti-parasitic compound
must have a selectivity index (SI) ≥ 10 [35], thus the
in vitro cytotoxicity of the six compounds mentioned above
was determined using normal cells (Vero cells line) and
preliminarily, their acute toxicity through the brine shrimp
bioassay (Artemia salina) [36]. Five compounds (6a-b,
6e-f, and 8f) exhibited selectivity index values higher than
10 (Table 2) when their cytotoxic activity was evaluated;
however only three of them showed a similar selectivity
when their acute toxicity was measured. It is important
emphasize that 6e was the most potent compound against
G. intestinalis (0.39 µM), even more than MTZ (Table 1);
besides exhibited a selective indexes of 139.0 and 147.6 for
cytotoxicity and acute toxicity, respectively.
S
R3
Comp. R1
R2
H
R3 IC50 µM Comp. R1
R2
H
R3 IC50 µM
Br 59.97
1a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
108.26 5a
29.29 5b
16.97 5c
35.75 5d
20.29 5e
98.61 6a
45.88 6b
50.76 6c
142.13 6d
96.21 6e
H
1b
1c
Cl
H
Cl
H
Br 23.21
Br 11.05
Br 27.82
Br 40.42
Br 1.95
Br 0.87
Br 9.31
Br 9.03
Br 0.39
Br 2.51
Br
H
Br
NO2
Me
H
H
1d
1e
NO2
Me
OMe
OH
H
H
H
H
H
1f
H
Ac
Ac
1g
2a
2b
2c
2d
2e
2f
H
Cl
Ac
Ac
Ac
Br Ac
NO2 Ac
Me Ac
OMe Ac
Cl
Br
NO2 Ac
Me Ac
OMe Ac
9.72
6f
39.39 7a
30.77 7b
44.12 7c
119.79 7d
78.42 7e
22.13 7f
56.77 8a
H
Bz
Bz
Br 36.80
Br 11.61
Br 29.05
Br 16.70
Br 25.16
Br 9.97
Cl
3a
3b
3c
3d
3e
3f
H
Bz
Bz
Bz
Br Bz
NO2 Bz
Me Bz
OMe Bz
Cl
Br
NO2 Bz
Me Bz
OMe Bz
H
Furoyl Br 8.68
Furoyl Br 58.83
8.70
8b
Cl
4a
4b
4c
4d
4e
4f
H
Furoyl H
Furoyl H
Furoyl H
16.50 8c
43.64 8d
38.09 8e
42.18 8f
Br Furoyl Br 42.23
NO2 Furoyl Br 7.20
Me Furoyl Br 31.30
OMe Furoyl Br 1.66
Cl
Br
NO2 Furoyl H
Me Furoyl H
OMe Furoyl H
17.09
19.41
1.40
9
OAc Ac
OAc Ac
H
56.28
10
Br 2.90
a
MTZ
a Metronidazol. Positive control
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2-Amino-4-arylthiazole Derivatives as Anti-giardial Agentsꢀ
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Table 2: Antigiardial activity, toxicity, and selectivity index of N-(5-bromo-4-aryl-thiazol-2-yl)-acetamide derivatives.
Compound
Giardia intestinalis
IC50 µM
Vero Cells
IC50 µM
Selectivity
Artemia salina
LC50 µM
Selectivity
a
b
Index
Index
6a
6b
6e
6f
8f
10
1.95
0.87
0.39
2.51
1.66
2.90
56.7
45.5
54.2
61.3
52.6
19.2
29.1
52.3
139.0
24.4
31.7
6.6
31.68
39.45
57.55
9.49
4.63
0.01
16.2
45.4
147.6
3.8
2.8
3 x 10-3
aThe selectivity index is defined as the ratio of IC50 on Vero cells to IC50 on G. intestinalis.
bThe selectivity index is defined as the ratio of LC50 on A. salina to IC50 on G. intestinalis.
Although, the insertion of halogen atoms on bioactive QSAR/QSPR should be at least 5:1 [38]. The statistical
compounds is predominantly performed to exploit their parameters for the coefficients of the descriptors for Eq. 1
lipophilic effects, the halogen bonding interactions are are listed in the Table 3. The p-value for all the descriptors
responsible for the different conformation of the molecules shown a probability that the descriptor is there by chance
in the active sites [37]. Thus, in the aim to determine is less than 5%. The standard error of each coefficient is
the relationship between the anti-giardial activity and less than the magnitude of the coefficient of the descriptor,
calculated descriptors additional to lipophilicity, a QSAR and the graph of the residuals (Suppl. Fig. 1) shows the
analysis was performed.
lack of systematic error on the model. The experimental
and predicted anti-giardial activity is showed in Figure 1
and Supplementary Table 2.
From Eq. 1, it was found that the most appropriate
parameters to describe the antigiardial activity are E2M,
Quantitative Structure–Activity Relationship
The best equation (Eq. 1) for the anti-giardial activity is RDF115m, F10, MATS6v and Hypnotic-80 [39].
showed below:
The E2M belongs to Weighted Holistic Invariant
Molecular (WHIM) group descriptors that are based on
Log (1/C) = 4.7051 + 0.359 × E2M-0.181 × RDF115m + 0.162 × statistical indices calculated on the projections of the
F10-0.201 × MATS6v + 0.214 × Hypnotic-80
atoms along the principal axes of the molecules [40]. The
positive sign of the coefficient of this descriptor indicates
that a uniform distribution of the atomic mass and
polarizability along the second principal axis is significant
Where the statistical parameters are:
N = 37 R = 0.84 R2 = 0.70 R2adj = 0.66 SEE = 0.280 F = 14.81 for the anti-giardial activity. It is important to note that all
p = 0.000 q2 = 0.50 r2test = 0.74 Rmax = 0.37
of the six compounds (6a-b, 6e-f, 8f, and 10) considered
as hits present a bromine at 5 position of the thiazolic ring
The values of the molecular descriptors for Eq. 1 are and have higher values of E2M descriptor (Table 3). This
shown in Table 3. The value of maximal intercorrelation fact allows relating the assistance of the bromine to get
between the descriptors of the model (Rmax) showed poor a uniform distribution of the atomic projection along the
correlation among themselves. The q2 is not greater than second principal axis with the observed high anti-giardial
R2 which means that the model is not over-fitted. External activity.
validation was more than 0.7, indicating high predictive
The Hypnotic-80 descriptor, proposed by Ghose–
ability of the model for external dataset. The p-values of the Viswanadhan–Wendoloski, presents a positive coefficient
model indicate a 0.05% probability that the correlations with the second highest value in the equation Eq. 1. This
have occurred by chance. Finally, the standard error of the is a descriptor that can take values of 1 or 0. The value 1
estimate (SEE) was 0.280. It is important to remark that the means that the bioactive compound presents a calculated
modelcontainonlyfivedescriptorstodescribetheactivities, log P, calculated molar refractivity, molecular weight, and
following the empirical rule that, in order to minimize the number of atoms ranged between 0.5−3.9, 43−97, 162−360,
risk of chance correlations, the ratio of number of training and 20−45, respectively [41].
set compounds to the number of descriptors in the
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1134ꢀ
ꢀ Raul Mocelo-Castell et al.
Table 3: Standard error and p values for each descriptor for the best
equation.
molecule [43]. The presence of the RDF115m descriptor in
Eq. 1 suggests the occurrence of some linear dependence
between the anti-giardial activity and the 3D molecular
distribution of mass, calculated at radius of 11.5 Å from
the geometrical centers of each molecule.
Finally, MATS6v is a descriptor belonging to the group
2D autocorrelation between pairs of atoms in the molecule
and is also defined to quantify the contribution of the
atomic van der Waals volumes of a molecule [44].
The MATS6v descriptor was calculated using the
Moran algorithm weighted with the van der Waals
volume at topological distance of 6.30. In this case the
values for the MATS6v descriptor were mainly negatives,
thus the smaller their value the greater activity against
G. intestinalis. Therefore, the anti-giardial activity is affect
by the molecular volume.
Descriptor
E2M
Coefficient
0.359
Standard error
0.065
P value
0.0000
0.0004
0.0003
0.0003
0.0004
RDF115m
F10[O-O]
MATS6v
Hypnotic-80
-0.180
0.162
0.045
0.050
-0.201
0.214
0.049
0.053
4 Conclusions
A set of derivatives of 2-amino-4-arylthiazoles was
synthesized. The compounds 6e (0.39 µM) and 6b
(0.87 µM) displayed the most potent anti-giardial activity.
Additionally these thiazoles showed the higher selectivity
index (139 and 52 respectively). The developed QSAR
model gives us information about the importance of the
uniform distribution of the atomic mass and polarizability
(E2M), the 3D molecular distribution of mass (RDF115m),
Figure 1: Plot of observed versus predicted Log (1/IC50 μM).
The synthetized compounds with anti-giardiasic activity the molecular volume (MATS6v), the topological distance
at ≤ 3 µM (6a-b, 6e-f, 8f, and 10) have values for the of a pairs of oxygen atoms (F10), and the lipophilicity
physicochemical properties mentioned above that fall in (Hypnotic-80) for the anti-giardial activity of thiazole
the ranges stablished by Ghose-Viswanadhan-Wendoloski. derivatives. The resulting model displays a good fit with
The descriptor F10 is
a frequency fingerprint the experimental data. In addition cross-validation
descriptor, and measures the frequency of O-O at coefficients (q2) and the external validation coefficients
topological distance 10 [42]. The positive sign in the (R2test) are reflecting the predictive power of the regression.
coefficient of this descriptor means that the increasing Finally, the results may indicate that the anti-giardial
the number of pair of oxygen atoms at this topological activity is enhanced by the bromine at 5 position in
distance resulting in an increase of anti-giardial activity. thiazole ring but it is necessary to carry out further studies
Interesting, only two of the five most active compounds like perform substitutions with other halogens or alkyl
(8f and 10) present this characteristic, unfortunately groups at that position to prove this hypothesis.
both compounds showed selective indexes below to 10
(Table 2). Apparently, the presence of the pairs of oxygen Acknowledgments: Financial support was provided by
atoms at topological distance of 10 improves the anti- Facultad de Química of the Universidad Autónoma de
giardial activity as well as confers toxicity to compounds. Yucatán through the PIFI-2008 and grant FQUI-2008-0001.
The last two descriptors present coefficients with We are also grateful to DGSCA, UNAM for supercomputer
negative signs. The RDF is informative descriptors for time.
a molecular structure in a space. The RDF115m encodes
a molecule as spheres of radius 11.5 Å and supplies The authors have declared no conflict of interest.
information on the inter-atomic distances in the entire
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2-Amino-4-arylthiazole Derivatives as Anti-giardial Agentsꢀ
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