Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some 5-Arylidene-thiazolidine-2,4-dione Derivatives

Article abstract of DOI:10.21577/0103-5053.20180167

Derivatives of the thiazolidine-2,4-dione core represent a heterocyclic class with several correlated properties. In this context, the synthesis of structural analogues of these bioactive substances becomes attractive in the field of medicinal chemistry. These analogues act as antimicrobial agents against Gram-positives pathogens. The present work aimed to synthesize 10 different derivatives of 5-arylidene-thiazolidine-2,4-dione, employing urea as the catalyst in a solvent-free reaction medium, with yields that ranged from 45 to 99percent. The compounds obtained were submitted to an antimicrobial assay against S. aureus ATCC 29213. Two compounds presented minimum inhibitory concentration of 62.5 and 32.5 μg mL^-1 and minimum bactericidal concentration < 500 μg mL^-1, demonstrating their antibacterial potential. Principal component analysis was carried out to discriminate the compounds in active and inactive classes. Four geometric and electronic molecular descriptors were required to completely discriminate the compounds. The selected descriptors can guide us in designing new 5-arylidene-thiazolidine-2,4-dione derivatives with enhanced activity.

Full text of DOI:10.21577/0103-5053.20180167

http://dx.doi.org/10.21577/0103-5053.20180167
J. Braz. Chem. Soc., Vol. 30, No. 1, 164-172, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Article
Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some
5-Arylidene-thiazolidine-2,4-dione Derivatives
Raíssa K. C. de Paiva,a Jamerson F. da Silva,a Hudieyllen A. Moreira,a Osvaldo G. Pinto,b
Lilian T. F. M. Camargo,c,d Plínio L. F. Naves,b Ademir J. Camargo,d Luciano Ribeirod
and Luciana M. Ramos *,a
aLaboratório de Química Medicinal e Síntese Orgânica (LaQuiMeSO),
Câmpus de Ciências Exatas e Tecnológicas, Universidade Estadual de Goiás,
CP 459, 75132-400 Anápolis-GO, Brazil
bLaboratório de Microbiologia, Câmpus de Ciências Exatas e Tecnológicas,
Universidade Estadual de Goiás, CP 459, 75132-400 Anápolis-GO, Brazil
cInstituto Federal de Goiás, Av. Pedro Ludovico, s/n,
Residencial Reny Cury, 75131-457 Anápolis-GO, Brazil
dGrupo de Química Teórica e Estrutural de Anápolis (QTEA),
Câmpus de Ciências Exatas de Anápolis, Universidade Estadual de Goiás,
CP 459, 75132-400 Anápolis-GO, Brazil
Derivatives of the thiazolidine-2,4-dione core represent a heterocyclic class with several
correlated properties. In this context, the synthesis of structural analogues of these bioactive
substances becomes attractive in the field of medicinal chemistry. These analogues act as
antimicrobial agents against Gram-positives pathogens. The present work aimed to synthesize
10 different derivatives of 5-arylidene-thiazolidine-2,4-dione, employing urea as the catalyst in a
solvent-free reaction medium, with yields that ranged from 45 to 99%. The compounds obtained
were submitted to an antimicrobial assay against S. aureus ATCC 29213. Two compounds
presented minimum inhibitory concentration of 62.5 and 32.5 μg mL-1 and minimum bactericidal
concentration < 500 μg mL-1, demonstrating their antibacterial potential. Principal component
analysis was carried out to discriminate the compounds in active and inactive classes. Four geometric
and electronic molecular descriptors were required to completely discriminate the compounds. The
selected descriptors can guide us in designing new 5-arylidene-thiazolidine-2,4-dione derivatives
with enhanced activity.
Keywords: 5-arylidenethiazolidine-2,4-diones, organocatalyst, quantum chemical descriptors,
principal component analysis, structure-activity relationship
Introduction
Thiazolidine-2,4-dione (TZD) is an important and
privileged class of compounds that are derived from the
thiazolidines. TZDs consist of a 5-member ring, and their
structure contain sulfur and nitrogen atoms in positions 1
and 3, and carbonyl in position 4. Also, they can present
several substituents in positions 2, 3 and 5 (Figure 1).1,2
The first reaction in order to obtain TZD was described
in an aqueous medium with cyclization, employing
Figure 1. Nucleus of thiazolidine-2,4-dione.
monochloroacetic acid and thiourea.3 A variety of synthetic
approaches have been reported involving this core, which
presents several reactive sites that promote substitutions in
the heterocyclic ring. These approaches have demonstrated
*e-mail: luciana.ramos@ueg.br

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de Paiva et al.
165
the versatility of TZD under different reaction conditions
to produce bioactive heterocyclic compounds.3-5
Cryptococcus neoformans and Aspergillus flavus.18,19 The
inhibition of microbial growth makes these compounds
excellent candidates for the development of antibacterial
and antifungal agents.19
In recent years, 5-arylidene-thiazolidine-2,4-dione
derivatives have been emphasized in the field of synthetic
organic chemistry.1-3 Several synthetic protocols have been
reported in the process of obtaining these derivatives. The
5-arylidene-thiazolidine-2,4-diones are preferentially
obtained through Knoevenagel condensation of aromatic
aldehydes with TZD, starting from the use of catalysts such
as piperidine, nanoparticles of Zn, oxalic acid, LiBr, BiCl3,3
NaOH,4,5 tetrabutylammonium bromide (TBAB), sodium
acetate and piperidine benzylate.6,7 The development of
new methodologies, mainly focused on Green Chemistry
principles, is an important objective for a sustainable future.
To this end, protocols involving aldonitrons in polyethylene
glycol (PEG) through the addition-elimination process
have demonstrated excellent yields in obtaining these
derivatives in a shorter reaction time.8 Highly efficient,
selective and chemically correct methods for the synthesis
of Knoevenagel products catalyzed by ionic liquids such
as 1,1,2,3-tetramethylguanidine lactate ([TMG] [Lac])9
and tetramethylammonium hydroxide (Bu4NOH) in
aqueous medium10 have been reported in the literature.
Alternative catalytic methods are also being employed.
Pratap et al.11 employed an active yeast-based biocatalyst
(Saccharomyces cerevisiae), which acted as a mini-reactor,
producing a variety of specific enzymes essential for the
synthesis of 5-arylidene-4-thiazolidinone derivatives.
Synthesis of the 5-arylidene-4-thiazolidinone derivatives
generally occurs under reaction conditions involving the
use of toxic solvents and catalysts, excess reagents and
long reaction times; such conditions result in low yields,
necessitating more favorable reaction conditions via
solvent-free procedures and with catalysts of low or no
toxicity.3
Thiazolidine-2,4-dione derivatives are a class of
heterocyclic compounds whose chemical and biological
versatility is well characterized by the description of
antimicrobial,1,2 antimalarial,12,13 antiviral,14 anticonvulsant4
and anti-inflammatory activities.15,16 In addition, these
compounds have proved to be inhibitors of the enzyme
aldose-reductase, and they are effective antioxidant agents
in combating oxidative stress associated with diabetic
complications and other pathologies.17
These derivatives have shown significant activity against
Gram-positive bacteria such as Staphylococcus aureus,
Staphylococcus epidermis, Kocuria rhizophila,
Bacillus cereus, Bacillus subtilis; Gram-negative bacteria
such as Escherichia coli, Pseudomonas aeruginosa
and Klebsiella pneumoniae;18 and fungi such as
Candida maltosa, Aspergillus niger, Aspergillus fumigatus,
Due to the biological potential of TZD derivatives, the
electron spectra of these molecules have been investigated
in order to explain the characteristics that determine the
acidity and basicity, as well as the necessary protonation
and deprotonation energies involved in the synthetic route.
These energies are responsible for obtaining a series of
analogs derivatives, differing from one another by the
presence of substituent groups at defined positions of
the chemical structure of the compounds of this class.7,20
The electronic effect of electron density withdrawers
and acceptors determines their reactivity, and the effect
of these groups is well described in the literature. They
boost not only the kinetics of the reaction by promoting
a more effective synthesis, but also increase the yield of
the synthesis.21
These characteristics contribute to a better understanding
of the development of new bioactive substances based on
the correlation between theoretical and experimental
properties, since the electronic properties of potential
pharmacological agents used for the treatment of different
pathologies correlate well with their respective biological
activities.22-24
In this context and bearing in mind the biological
properties of the TZD class in medicinal chemistry, the
present work aimed to synthesize 5-arylidene-thiazolidine-
2,4-dione derivatives and, subsequently, to evaluate their
antimicrobial activity against Staphylococcus aureus
ATCC 29213.
A quantum chemical and chemometric study25 of
the 5-arylidene-2,4-thiazolidinedione analogs were also
applied on the compounds to establish the relationship
between molecular structure and activity against
Staphylococcus aureus ATCC 29213.
Experimental
General experimental procedures
All the chemicals were obtained fromAldrich and Merck
chemical company and used without further purification.
Reactions were monitored by thin layer chromatography
(TLC). TLC was performed on Merck 60 F-254 silica gel
plates with ethyl acetate and n-hexane (7: 3) or methanol
(eluent system) and visualization with ultraviolet light (UV)
or development in I2. 1H and 13C nuclear magnetic resonance
(NMR) spectra were acquired with Mercury Varian plus
300 MHz. Chemical shifts (d) are reported in parts per

166
Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some 5-Arylidene-thiazolidine-2,4-dione
J. Braz. Chem. Soc.
million and coupling constants (J) in hertz. The 1H and 13C
chemical shifts were acquired with CDCl3 or DMSO-d6 as
deuterated solvent and tetramethysilane (TMS) as internal
standard. Splitting patterns were assigned as: s for singlet,
br s for broad singlet, d for doublet, t for triplet, td for triplet
of doublets, dd for doublet of doublets, ddd for doublet of
doublet of doublets and m for multiplet. Melting points
were determined by using a Microquímica MQAPF-301
apparatus and were uncorrected. The infrared (IR) spectra
were recorded on PerkinElmer Spectrum Frontier FTIR
spectrophotometer using KBr disc method.
Gram-positive Staphylococcus aureus (ATCC 29213)
was maintained at the Microbiology Laboratories of
Universidade Estadual de Goiás (UEG). The bacterial
inoculums were prepared by suspending them in sterile
saline solution (NaCl 0.9%) until turbidity corresponding
to 0.5 of the McFarland scale was reached, obtained
by spectrophotometer reading at 625 nm (79 to 83% of
transmittance). Next, a 1:10 dilution in saline solution was
prepared to obtain a cell concentration of 107 CFU mL-1.
Determination of minimum bactericidal concentration
Synthesis of thiazolidine-2,4-dione
For the determination of minimum inhibitory
concentration, 96-well U-bottom sterile microdilution
plates were used. The compounds were solubilized
in dimethylsulfoxide (DMSO) at 5% and diluted in
Mueller Hinton (MH) broth in order to obtain the
concentrations of 1000, 500, 250, 125, 62.5, 31.2, 15.62
and 7.81 μg mL-1. The same procedure was employed for
the MIC determination of the effective antibiotic standard
chloramphenicol (Inlab) in the concentrations 64, 32, 16,
8, 4, 2 and 1 μg mL-1 for technique validation. Controls of
bacterial viability were established: DMSO at 5%, culture
medium sterility and extracts. All the experiments were
conducted in triplicate.
In a round-bottomed flask under heating, a solution of
thiourea (10 g, 131.37 mmol) and chloroacetic acid (12.4 g,
131.21 mmol) in distilled water (100 mL) was prepared.
The mixture was maintained under magnetic stirring and
reflux for 18 h at 80 ºC, and then left in the refrigerator for
24 h. The white crystals obtained were vacuum filtered and
washed with cold water.
Optimization of the reaction conditions for the synthesis of
5-arylidene-thiazolidine-2,4-dione derivatives
The previously synthesized TZD was submitted to the
reaction of interest, evaluating the catalytic system, solvent
influence, temperature, reaction time and excess of the
selected catalyst and reactants in the reaction medium.
Finally, aromatic aldehydes with different substituents
at ortho, meta and para position were employed in order
to obtain several 5-arylidene-thiazolidine-2,4-dione
derivatives.
To a 25 mL flask, 50 mg of the catalyst, 1 mmol of TZD
and 1 mmol of aldehyde were added. The reaction mixture
was maintained under constant agitation for 2 h at 80 ºC.
After the end of the 2 h reaction a precipitate was
obtained, which was taken out of the flask with cold
ethanol, washed and filtered under vacuum pressure. Then
they were recrystallized from EtOH. From the use of this
methodology, several derivatives of interest were obtained.
To the previously prepared concentrations in the
microplate, 100 μL of MH broth and 100 μL of the
compounds were added. Subsequently, 5 μL of the
adjusted inoculum was deposited in all wells of the
microplate and the initial concentration of the inoculum
was 5 × 105 CFU mL-1. The microplates were capped
and maintained in an oven at 35 ºC for 24 h. After the
incubation, the visual reading was carried out and the MIC
of the compounds was determined as being the lowest
concentration that inhibited visual bacterial growth.
Determination of minimum bactericidal concentration
The MBC values were determined after collecting a
100 μL aliquot from the wells with absence of growth
and seeded on plates containing nutrient agar, which were
incubated at 35 ºC for 24 h. The MBC was considered as
the lowest concentration of the compounds that provided
the total inhibition of bacterial growth.
Evaluation of antimicrobial activity
The synthesized compounds were submitted to the
microdilution test in broth for the determination of
minimum inhibitory concentration (MIC) and minimum
bactericidal concentration (MBC). The assay was
performed according to the method adopted by the
Clinical and Laboratory Standards Institute (CLSI) (2010)
employing a multiwell plate.
Computational procedure
In the absence of the crystallographic structure of
the thiazolidine-2,4-dione derivatives, it is important to
carry out a conformational analysis on the compounds to
establish the most stable conformation of the molecules.

Vol. 30, No. 1, 2019
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167
By checking the thiazolidine-2,4-dione derivatives we
realize that just one degree of freedom is important in this
analysis, namely, the C5–C3–C7–H19 dihedral angle. The
conformational search performed on this dihedral angle
was carried out using the molecular mechanics method
with the force field MM+.26 Next, the conformation
with the lowest energy (the most stable) of the most
active compound was picked out. For the remaining
derivatives, it was picked out the conformation found
that most resemble the conformation selected of the
most active compound. This computational procedure
ensures that all derivatives will be compared at the
same level of importance with respect to the molecular
geometry. The selected conformations were optimized at
M062X/6-311+G(d,p)27 level of theory as implemented
in g09 package of program.28 The local minimum on
the hypersurface of the potential energy was confirmed
by the absence of the imaginary frequencies for each
molecule. All the geometric and electronic molecular
descriptors were obtained at the same level of theory used
for optimization.
The correlation between the molecular descriptors and
the biological activity against the Staphylococcus aureus
ATCC 29213 was done using the principal component
analysis (PCA) as implemented in the R-Project.29 PCA is
a multivariate statistical method that allows us to reduce
the data dimensionality from a large data set without loss of
information. The reduction of the data is possible because
the variables are highly correlated. For this purpose, we
construct new variables (PC’s) that are linear combinations
of the original variables (descriptors) in such a way that the
PC’s are totally uncorrelated, i.e., they are orthogonal each
other. In generally, the PC’s are ordered in such a way that
the PC1 account for the maximum of the data variance, the
PC2 retain the second amount of the total variance of the
data set, and so on.
of reaction conditions. With the usage of different solvents
in the reaction medium, the product could not be obtained,
so a solvent-free medium was chosen.
After the establishment of a general protocol for the
synthesis of 5-arylidene-thiazolidine-2,4-dione derivatives,
different aromatic aldehydes with substituents at ortho,
meta and para positions were employed as shown at
Table 1.
The 5-arylidene-thiazolidine-2,4-dione derivatives
were obtained via Knoevenagel condensation. The yield
of the derivatives ranged from 45 to 99%, so it can
be inferred that the steric and electronic effect of the
substituted aldehydes at ortho, meta and para positions
did not influence the yields of the product. This was to
be expected, since it is reported in the literature that TZD
can undergo condensation reactions of the aldol type
involving the methylene group at the 5-position of the
ring, due to the nucleophilic character of the methylene
carbon. It becomes more evident that the reduction of the
nucleophilic character and the formation of a carbanion
in the presence of a base depends on the electron
withdrawing effect of the adjacent carbonyl, as well as
on the presence of other electron withdrawing groups at
the 2-position of the ring.3
Evaluation of antimicrobial activity
The tests showed that some synthesized 5-arylidene-
thiazolidine-2,4-dione derivatives presented antibacterial
activity, especially compounds 3f (with MIC of 62.5 μg mL-1)
and 3j (with MIC of 31.25 μg mL-1). Both compounds
presented MBC > 500 μg mL-1. The antimicrobial activity
of this series of compounds appears to be optimized with
the combination of functional groups. The MIC and MBC
values obtained in this study demonstrate the antimicrobial
action of compounds 3f and 3j on the cell growth of
S. aureus ATCC 29213.
Results and Discussion
The MBC of all the compounds were higher than the
maximum concentration tested (500 μg mL-1), even for
compounds 3f and 3j, which were active against the test
bacteria, and showed MIC of 62.5 and 31.25 μg mL-1,
respectively. This result demonstrates that the 5-arylidene-
thiazolidine-2,4-dione derivatives that are active against
S. aureus presented predominantly bacteriostatic action,
since it only inhibited bacterial growth. Compounds
3a-e and 3g-i had a lower antimicrobial activity, while
compounds 3a, 3d and 3g presented MBC of 125 μg mL-1;
in general, they showed a slight antimicrobial activity.
Compounds 3c and 3h had MIC > 500 μg mL-1 against
S. aureus ATCC 29213. All compounds presented
MBC > 500 μg mL-1 (Table 2).
Synthesis of thiazolidine-2,4-dione and optimization of the
reaction conditions of its derivatives
In a first set of experiments, different catalysts
were tested in the reaction medium, such as FeCl3,
triethyl benzyl ammonium chloride (TEBAC), sodium
acetate and urea, and then the effect of the following
solvents was analyzed: EtOH, H2O, MeCN. It was verified
that use of urea as catalyst allowed a yield of 80% of the
product of interest. In contrast, the other catalysts evaluated
did not allow the product to be obtained. Hence, urea was
fixed as the reaction catalyst for the subsequent evaluations

168
Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some 5-Arylidene-thiazolidine-2,4-dione
J. Braz. Chem. Soc.
Table 1. 5-Arylidene-thiazolidine-2,4-dione derivatives synthesized
entry
1
Aldehyde
Compound
Product
Yielda / %
80
3a
2
3
4
3b
3c
3d
50
99
89
5
6
7
8
3e
3f
62
72
75
81
3g
3h
9
3i
3j
73
45
10
aConditions: 0.833 mmol of ureia, 1 mmol of TZD and 1 mmol of aldehyde; 2 h of reaction at 100 °C.

Vol. 30, No. 1, 2019
de Paiva et al.
169
Another interesting finding was the MIC of 125 μg mL-1
of compound 3e. According to the authors, compounds
with hydroxy substituents are less active than those
that are meta-substituted, and this occurs as a result of
the intramolecular between the carboxyl group and the
ortho-hydroxy substituent.
There are few reports involving the antimicrobial
activity of 5-arylidene-thiazolidine-2,4-dione derivatives.
Generally, these derivatives are subjected to ring
substitution at the 3-position and carbonyl substitution by
thiocarbonyl, and the results have demonstrated efficient
antimicrobial activity.23
Table 2. Determination of minimum inhibitory concentration and
minimum bactericidal concentration of 5-arylidene-thiazolidine-2,4-dione
derivatives against Staphylococcus aureus ATCC 29213
Compound
MIC / (μg mL-1)
125
MBC / (μg mL-1)
> 500
3a
3b
3c
3d
3e
3f
500
> 500
> 500
125
> 500
> 500
125
> 500
62.5
> 500
3g
3h
3i
125
> 500
> 500
250
> 500
Structure-activity relationship against Staphylococcus
aureus ATCC 29213
> 500
3j
31.25
> 500
MIC: minimum inhibitory concentration; MBC: minimum bactericidal
concentration; chloramphenicol with MIC between 2-16 μg mL-1 was
used as the standard for antibacterial activities.
Table 3 shows the atomic numbering used throughout the
calculations of the molecular descriptors. There is, at first,
no reason to consider one descriptor more important than
the other in the search for the correlation between molecular
descriptors and the activity against Staphylococcus aureus
ATCC 29213. Therefore, one must give the same weight to
the descriptors in the principal component analysis. That
is done by autoscaling the descriptors, i.e., all descriptors
were mean centered and divided by standard deviation
In accordance with Holetz et al.,21 compounds with
MIC below 100 μg mL-1 present significant antimicrobial
activity; following this criterion, compounds 3f and 3j
were active against Staphylococcus aureus ATCC 29213.
Several studies with 5-arylidene-thiazolidine-2,4-dione
derivatives demonstrated the antimicrobial potential
of these compounds. Gouveia et al.22 evaluated the
antibacterial activity of compound 3f and reported
activity against several Gram-positive bacteria, including
Staphylococcus aureus, with MIC from 4-8 μg mL-1.
The mechanism of antimicrobial activity of
5-arylidene-thiazolidine-2,4-dione derivatives in general
is due to the presence of these substituents (NO2, Cl, F
and Br), these groups considerably increase the lipophilic
character of these molecules, such character facilitates
the crossing of the molecule through the microbial
cytoplasmic membrane inhibiting its growth. Zidar et al.30
reported in their studies that pharmacophore substituents
present on 5-arylidene-thiazolidine-2,4-dione derivatives
considerably increase the antimicrobial activity of these
compounds, yet according to these authors such molecules
probably act on the synthesis of wall peptidoglycan cell
growth of Gram-positive bacterial, which in turn justifies
the antibacterial inhibition of Gram-positive bacterial by
these molecules.
according to the equation
, where xij
stands for descriptor for the molecule j; is the mean
value for the descriptor i, and si stands for the respective
standard deviation. With this procedure, one can compare
all descriptors at the same level of importance, although
they have different units.
Another chemometric technique used to guide us in
selecting the best variables to be used in the PCA analysis
was the Fisher’s weight.31 Molecular descriptors with
higher Fisher’s weight values are good candidates to be
used in the PCA analysis. This technique can save us a lot
of time in searching for good variables to be used in PCA
analysis to classify the compounds in active and inactive
classes. This procedure has been applied with success in
similar works.32-37
By applying PCA procedure on the selected descriptors
by Fisher’s weight, after many attempts, the best result
was obtained with four molecular descriptors: dipole
moment (μ), bond angle between atoms 5, 6 and 18 (A5–6–18),
partial atomic charge on atom 18 (Q18) and bond orders
between atoms 5 and 17 (O5–17).
As shown in Figure 2, the PC1 is responsible alone for
the classification of the compounds in active and inactive
classes. The PC1 component responds alone for about
53.39% of the total of variance of the data set. PC1 and
PC2 account together for 83.20% of the total variance of
Zvarec et al.23 observed that compound 3a presented
cell-mediated immunity (CMI) < 64 μg mL-1 against
S. aureus ATCC 31890 and CMI of 125 μg mL-1 against
S. aureusATCC 29213. According to the authors, this may
be related to the weak lipophilic characteristics that some
of the compounds may present hindering the diffusion by
the membranes of the bacterial.

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Synthesis, Antimicrobial Activity and Structure-Activity Relationship of Some 5-Arylidene-thiazolidine-2,4-dione
J. Braz. Chem. Soc.
Table 3. Atomic numbering for 5-arylidene-thiazolidine-2,4-dione
derivatives used throughout the calculation
It is important to note that the descriptors A5–6–18, Q18,
and O5–17 are close related to the benzene ring, while the
descriptors related to the methylenethiazolidine-2,4-dione
group did not prove to be important to discriminate the
compounds. The only selected descriptor that is not
exclusively related to benzene ring is the total dipole
moment (μ). μ is an important electronic descriptor that
depends on the entire molecule and it is a measure of the
charge separation on the molecular system. In addition, it
is closely related to the solubility of the compound in the
medium.
From the selected descriptors by PC1, one can assume
that the activity is related to benzene ring and its substituent
groups. The substituent groups that decrease the dipole
moment, the partial charge on atom 18, bond order between
atoms 5 and 17, the increase in the bond angle between
atoms 5, 6 and 18, are responsible for making the compound
to be active against Staphylococcus aureus ATCC 29213.
In addition, as the activity is correlated with the decrease
of the bond order O5–17 and since the atom 17 is a hydrogen
atom for all compounds, it can be assumed that the H17 is
interacting with the target site of the Staphylococcus aureus
ATCC 29213.
Atom numbering for the substituents
Compound
15
16
21
3a
3b
3c
3d
3e
3f
H
H
H
H
H
O
NO2
O
H
H
H
OH
H
OH
H
H
Cl
H
3g
3h
3i
H
OCH3
NCH3CH3
OH
H
H
H
H
OCH3
H
3j
H
NO2
the original data. So, the PC1 and PC2 represent very well
the dimensionality of the variance of the descriptors space.
From Table 4, we can see that all selected descriptors
have positive values, and Figure 2a shows that the active
compounds have negative scores. According to Figure 2b
and equation 1 for PC1, which is responsible for the
classification, for a compound to be classified in the active
class, it should have lower values for the descriptors dipole
moment, Q18 and bond order O5–17, and higher value for
A5–6–18. On the other hand, a compound will be classified
in the inactive class if it has higher μ, Q18 and O5–17 and
lower A5–6–18 value.
Therefore, in designing new compounds that can exhibit
activity against Staphylococcus aureus ATCC 29213 we
should take in consideration the four selected descriptors,
i.e., one must select substituent groups in the benzene ring
that can modify the descriptors according to equation 1.
Conclusions
With the results obtained, it is concluded that the
methodology employed for the synthesis of arylidene
derivatives was an efficient alternative in obtaining them,
and it is chemically clean, since the catalyst employed
is non-toxic. It was possible to synthesize 10 different
PC1 = +0.581μ – 0.491A5–6–18 + 0.316Q18 + 0.565O5–17 (1)
Table 4. Electronic and geometric parameter selected for principal component analysis
Compound
Dipole moment (μ) / debye Bond angle A5–6–18 / degree Atomic charge Q18 / (a.u.)
Bond order O5–17 / (a.u.)
0.9229
3a
3b
3c
3d
3e
3f
inactive
inactive
inactive
inactive
inactive
active
3.1973
4.9826
3.8561
4.4923
4.5873
1.6363
4.1326
7.0838
3.3606
3.1789
119.90
120.03
121.95
120.00
120.22
120.98
121.55
118.80
120.13
121.82
0.097255
0.111586
0.166930
0.107659
0.106788
0.110633
0.139805
0.149931
0.139051
0.109172
0.9205
0.9225
0.9219
0.9224
0.9208
3g
3h
3i
inactive
inactive
inactive
active
0.9226
0.9236
0.9223
3j
0.9189

Vol. 30, No. 1, 2019
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171
Figure 2. (a) Scores plot for the ten compounds. The active compounds are at left side of the picture (blue color). The inactive compounds are on the right
(red color); (b) loading plot of the molecular descriptors selected by PCA model.
5-arylidene-thiazolidine-2,4-dione derivatives with the
proposed methodology, with yields that ranged from 45 to
99%. The results of antimicrobial screening revealed the
potential of the compounds obtained as new antibacterial
agent candidates, thus also evidencing the biological
potential of TZD derivatives. Compounds 3f and 3j
showed the most significant results against S. aureus
ATCC 29213. Four descriptors were selected from the
PCA analysis that explain very well the structure-activity
relationship against S. aureus ATCC 29213. PC1 is alone
responsible for the classification and it accounts for about
53% of the total variance of the selected descriptors. The
selected molecular descriptors were bond angle between
5, 6 and 18 atoms, atomic partial charge on atom 18,
dipole moment and bond orders between 5 and 17 atoms.
From these results, we can conclude that the electronic
aspect of the analogue derivatives play important role in
the activity and they strongly suggest that the hydrogen
at position 17 is involved in the activity. In addition, the
selected descriptors also can guide us in designing new
5-arylidene-thiazolidine-2,4-dione analogs with enhanced
activity against S. aureus ATCC 29213. The synthesized
derivatives are reported in the literature, but there are not
studies on the structure-activity relationships of these
derivatives from chemometric techniques. The structures
of thiazolidine-2,4-diones differ in the substitution
pattern. Therefore, they may be considered analogous
allowing using of structure-activity relationships based
computational models and can likely to exhibit similar
biological activities.
Supplementary Information
Supplementary information is available free of charge
at http://jbcs.sbq.org.br as PDF file
Acknowledgments
The authors are grateful for the financial support from
the Universidade Estadual de Goiás pró-projetos pesquisa
029/2016, Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), Universal 01/2016
and Fundação de Amparo à Pesquisa do Estado de Goiás
(FAPEG). The research was developed with support of the
High Performance Computing Center at the UEG. Plínio
L. F. Naves, Luciano Ribeiro and Luciana M. Ramos, in
particular, express their gratitude to PROBIP-UEG.
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Submitted: May 11, 2018
Published online: August 28, 2018
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