Synthesis of novel sulfamethaoxazole 4-thiazolidinone hybrids and their biological evaluation

Article abstract of DOI:10.3390/molecules25163570

A search for potent antitubercular agents prompted us to design and synthesize sulfamethaoxazole incorporated 4-thiazolidinone hybrids (7a-l) by using a cyclocondensation reaction between 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4), aryl aldehyde (5a-l), and mercapto acetic acid (6) resulting in good to excellent yields. All the newly synthesized 4-thiazolidinone derivatives were screened for their in vitro antitubercular activity against M. Bovis BCG and M. tuberculosis H37Ra (MTB) strains. The compounds 7d, 7g, 7i, 7k, and 7l revealed promising antimycobacterial activity against M. Bovis and MTB strains with IC90 values in the range of 0.058-0.22 and 0.43-5.31 μg/mL, respectively. The most active compounds were also evaluated for their cytotoxicity against MCF-7, HCT 116, and A549 cell lines and were found to be non-cytotoxic. Moreover, the synthesized compounds were also analyzed for ADME (absorption, distribution, metabolism, and excretion) properties and showed potential as good oral drug candidates.

Full text of DOI:10.3390/molecules25163570

molecules
Article
Synthesis of Novel Sulfamethaoxazole
4-Thiazolidinone Hybrids and Their
Biological Evaluation
Mashooq A. Bhat 1,
Azmat Ali Khan 1
*
, Mohamed A. Al-Omar 1 , Ahmed M. Naglah 2,3 and
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia; malomar1@ksu.edu.sa (M.A.A.-O.); azkhan@ksu.edu.sa (A.A.K.)
Department of Pharmaceutical Chemistry, Drug Exploration and Development Chair (DEDC), College of
Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; anaglah@ksu.edu.sa
Peptide Chemistry Department, Chemical Industries Research Division, National Research Centre, Dokki,
Cairo 12622, Egypt
2
3
*
Correspondence: mabhat@ksu.edu.sa; Tel.: +966-558164097
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 7 July 2020; Accepted: 31 July 2020; Published: 6 August 2020
Abstract: A search for potent antitubercular agents prompted us to design and synthesize
sulfamethaoxazole incorporated 4-thiazolidinone hybrids (7a
reaction between 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (
and mercapto acetic acid ( ) resulting in good to excellent yields. All the newly synthesized
4-thiazolidinone derivatives were screened for their in vitro antitubercular activity against M. Bovis
BCG and M. tuberculosis H37Ra (MTB) strains. The compounds 7d 7g 7i 7k, and 7l revealed
promising antimycobacterial activity against M. Bovis and MTB strains with IC90 values in the range
of 0.058–0.22 and 0.43–5.31 g/mL, respectively. The most active compounds were also evaluated for
–
l) by using a cyclocondensation
4), aryl aldehyde (5a–l),
6
,
,
,
µ
their cytotoxicity against MCF-7, HCT 116, and A549 cell lines and were found to be non-cytotoxic.
Moreover, the synthesized compounds were also analyzed for ADME (absorption, distribution,
metabolism, and excretion) properties and showed potential as good oral drug candidates.
Keywords: 4-thiazolidinones; sulfamethaoxazole; antimycobacterial activity; cytotoxicity study
1. Introduction
Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (MTB) is one of the most
infectious causes of mortality worldwide [
1]. The pathogenic synergy between TB and HIV is alarming.
Moreover, TB frequently occurs in human immunodeficiency virus (HIV)/AIDS patients [2,3
]. In 2019,
according to the World Health Organization (WHO), 1.5 million deaths were reported due to TB,
out of which 0.36 million people were infected with both HIV and TB. Worldwide, the proportion
of new cases with multidrug-resistant tuberculosis (MDR-TB) was 3.5% and has not changed in
comparison to recent years [
virulent strain of Mycobacterium bovis which has been used as a vaccine against MTB, as a recombinant
vehicle for multivalent vaccines against other infectious diseases, and as cancer immunotherapy [ ].
Therefore, the ability to rapidly and specifically identify BCG is clinically important. In addition to
this, totally drug-resistant TB (TDR-TB) has recently arisen which is resistant to all clinical drugs [ ].
Delamanid (OPC-67683) and Bedaquiline (TMC207) are the two drugs recommended by the US FDA for
multi-drug-resistant tuberculosis (MDR-TB) treatment [ ]. However, at present there are no medicinal
4]. Bacillus Calmette-Guerin (BCG) is an attenuated derivative of a
5
6
7,8
drugs under clinical trials. Because of this, there is an urgent need for novel, safe, and effective
antimycobacterial drugs which will efficiently treat XDR and MDR tuberculosis.
Molecules 2020, 25, 3570; doi:10.3390/molecules25163570
www.mdpi.com/journal/molecules

Molecules 2020, 25, 3570
2 of 17
Numerous heterocyclic compounds containing nitrogen, sulfur, and oxygen heteroatoms
have attracted the attention of chemists over the years because of their biological properties.
In particular, the thiazolidin-4-ones, a privileged pharmacophore possesses an array of biological
activities including anti-inflammatory [
anticancer [13], anti-viral [14], antidiabetic [15], antiarthritic [16], FSH agonist [17], JNK stimulating
phosphatase-1 (JSP-1) [18], CNS-penetrant [19], CDK1/Cyclin B inhibition [20], COX-2 inhibitor [21
and hypoglycemia [22] properties. In the last few years, Kucukguzel et al. developed substituted
4-thiazolidinones and among them compounds and exhibited excellent antitubercular activity with
90% and 98% inhibitions at 6.25 g/mL, respectively [23]. Jaju and co-workers reported antitubercular
activity of isonicotinyl hydrazide derivatives against M. tuberculosis H37Rv strain. Among the
synthesized isonicotinylhydrazide derivatives compound was found to be more active with
MIC = 0.31 g/mL [24]. Recently, compounds , and bearing 4-thiazolidinone scaffolds were
30]. Some representative biologically active
9], antimicrobial [10], antibiofilm [11], antiparasitic [12],
]
1
4
µ
3
µ
2
,
5
6
reported for their excellent antitubercular activities [25
–
4-thiazolidinones are shown in Figure 1.
Figure 1. 4-Thiazolidinone scaffolds showing antimycobacterial activity.
A literature survey revealed that sulfonamide derivatives are endowed with numerous therapeutic
activities as anticonvulsants, HIV protease inhibitors, and antitumor agents [31]. Sulfonamide
derivatives are also used for treating certain forms of malaria, urinary tract infections, erectile
dysfunction [32] as well as use as herbicides and dyes [33]. Isoxazole derivatives also possess
various interesting pharmacological properties. 5-methylisoxazole is present in many marketed
drugs such as Valdecoxib, Parecoxib, and Leflunomide and exhibits broad spectrum activity such as
anticancer, antiviral, antibacterial, analgesic, anticonvulsant, antinociceptive, and immunomodulating
activities [34].
The design of sulfamethaoxazole 4-thiazolidinone hybrids requires the consideration of three
different parts, as depicted in Figure 2. The 4-thiazolidinone motif is the main backbone of the design
strategy. It helps to enhance the pharmacophoric properties of the synthesized compounds [35].
The second segment is the sulfonamide unit linked to the isoxazole nucleus which is responsible for the
biological activity. Sulfonamides and isoxazole scaffolds are present in many reported drugs such as
Celecoxib and Parecoxib. Last of the all, the aryl ring with the diverse substitutional unit, is responsible
for the lipophilicity control while contributing as a highly potent pharmacological part due to the
existence of various functional groups.

Molecules 2020, 25, 3570
3 of 17
Figure 2. Molecular design of the target molecule.
According to the pharmacological importance of the above reported compounds and in
continuation of our efforts based on the design, synthesis and biological evaluation of heterocyclic
derivatives [36,37], we designed and synthesized 4-thiazolidinone hybrids by assembling, in a
single molecular framework, sulfonamides and isoxazole units, with the aim to obtain prominent
antimycobacterial activity with minimal side effects.
2. Results and Discussion
The protocol for the syntheses of a series of new sulfamethaoxazole 4-thiazolidinone hybrids
(7a–l) is reported in Schemes 1 and 2. Compounds (7a–l) were prepared from a cyclocondensation
reaction between 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (
and mercapto acetic acid (6) (Scheme 2).
4
), aryl aldehydes (5a
–l),
The required starting materials, 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (
prepared from commercially available N-acetylsulfanilyl chloride ( ) and 3-amino-5-methylisoxazole
) to give the N-acylated intermediate ( ) followed by acid hydrolysis [38] and details as depicted
in (Scheme 1). The synthesis of new sulfamethaoxazole-incorporated 4-thiazolidinone hybrids
7a ) was achieved via a cyclocondensation reaction between 4-amino-N-(5-methylisoxazol-3-yl)
benzenesulfonamide ( ), aryl aldehydes (5a ), and mercapto acetic acid ( ) in toluene at reflux
temperature for 2 h (Scheme 2).
4) were
1
(2
3
(
–l
4
–
l
3
Scheme 1. Synthesis of 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4).

Molecules 2020, 25, 3570
4 of 17
Scheme 2. Synthesis of sulfamethaoxazole 4-thiazolidinone hybrids (7a–l).
All the newly synthesized compounds were characterized by 1H NMR, 13C NMR and HRMS
techniques. The 1H NMR spectrum of compound 7a, the methylene protons of the 4-thiazolidinone
ring appeared as two distinct doublet of doublets at
protons were magnetically non-equivalent. The C–H proton of the 4-thiazolidinone ring appeared
as a singlet at 6.71 ppm. The formation of the 4-thiazolidinone ring was also proven by the
δ 3.76 and 3.72 ppm, indicating that both the
δ
appearance of peaks at 33.04 (CH2), 68.44 (CH), and 179.2 (C=O) ppm, respectively in the 13C NMR
spectrum of compound 7a. The HRMS spectrum further strengthened the structure assigned to (7a) as
N-(5-methylisoxazol-3-yl)-4-(4-oxo-2-phenylthiazolidin-3-yl)benzenesulfonamide, showing [M + H]+
ion peak at m/z 416.2147 for its molecular formula C19H18N3O4S. Experimental procedures and spectra
of 4-thiazolidinone derivatives (7a–l) are given in the Supplementary Materials. The synthetic sequence
is depicted in Scheme 1.
2.1. Anti-Mycobacterial Activity
The newly synthesized sulfamethaoxazole 4-thiazolidinone hybrids (7a–l) were screened for
in vitro antitubercular activity against M. Bovis BCG (ATCC 35743) and MTB H37Ra (ATCC 25177)
in liquid medium [39]. We explored the eminent XTT Reduction Menadione assay (XRMA) of the
anti-mycobacterial screening protocol employing first-line anti-mycobacterial rifampicin drug as a
standard reference and the IC50 and IC90 values are presented in Table 1.
The sulfamethaoxazole 4-thiazolidinone derivatives 7d
antitubercular activities with IC90 values ranging from 0.058–0.22 and 0.43–5.31
to be most active against M. bovis BCG and MTB H37Ra and strain, respectively. However, the rest
of the derivatives 7a 7b 7c 7e 7f 7h and 7j were found to be less active against M. bovis BCG and
,
7g
,
7i
,
7k, and 7l exhibited excellent
µg/mL. They are found
,
,
,
,
,
MTB H37Ra strain with IC90 = >30 µg/mL.
2.2. Structure Activity Relationship (SAR)
According to the in vitro data, the sulfamethaoxazole incorporated 4-thiazolidinone hybrids
displayed significant anti-mycobacterial activity and the results are presented in Table 1. The hybrid
molecules derived from 4-amino-N-(5-methylisoxazol-3-yl) benzenesulfonamide, aryl aldehydes,
and mercapto acetic acid have been used as a basic skeleton for the development of structural analogues,
which produced the sulfamethaoxazole incorporated 4-thiazolidinone derivatives (7a–l). The results of
the biological evaluation revealed that the activity was considerably affected by introducing various
substituents on the aryl ring.

Molecules 2020, 25, 3570
5 of 17
Table 1. Anti-mycobacterial activity of the sulfamethaoxazole incorporated 4-thiazolidinones a.
M. Bovis BCG
MTBH37Ra
Entry
7a
Structures
IC50
IC90
IC50
IC90
>30
>30
>30
>30
7b
7c
>30
>30
0.03
>30
>30
0.22
>30
>30
0.54
>30
>30
0.70
7d

Molecules 2020, 25, 3570
6 of 17
Table 1. Cont.
M. Bovis BCG
MTBH37Ra
Entry
7e
Structures
IC50
IC90
IC50
IC90
2.86
>30
1.26
>30
7f
16.75
>30
1.68
>30
7g
7h
0.02
0.13
0.12
5.31
>30
>30
>30
>30

Molecules 2020, 25, 3570
7 of 17
Table 1. Cont.
M. Bovis BCG
MTBH37Ra
Entry
Structures
IC50
IC90
IC50
IC90
7i
0.28
0.17
0.16
1.08
7j
7k
7l
>30
>30
0.15
>30
0.13
0.07
>30
0.026
0.71
0.016
0.058
0.43
b
-
0.0043 ± 0.00028
0.0173 ± 0.039
0.0019 ± 0.00022
0.020 ± 0.0021
RP
a
b
IC50/IC90 in
µ
g/mL. Anti-mycobacterial activity of each agent was determined by serial dose dependent dilutions. Rifampicin as a standard reference antitubercular drug and
positive control.

Molecules 2020, 25, 3570
8 of 17
Firstly, we discuss the anti-mycobacterial activity of synthesized compounds against M. Bovis BCG
strain. From the series (7a ), compound 7a without any substituent on the aryl ring displays lesser
potency with IC90 value >30 g/mL against M. Bovis BCG strains as compared to the standard drug
rifampicin and the results are displayed in Table 1. Compounds 7b in which (R3 = –methyl) and 7c in
which (R3 = methoxy) showed lower antitubercular activity against M. Bovis BCG strain with IC90
values >30 g/mL. The introduction of the fluoro group in compound 7d (R3 = fluoro) presented
excellent antitubercular activity against M. Bovis BCG strain with IC90 value 0.22 g/mL. Introduction
of the chloro group in the aryl ring of compound 7e (R1 = –chloro) and 7f (R2 = –chloro) showed
lesser potency against M. Bovis BCG strain with IC90 value >30 g/mL. With a chloro group in the R3
chloro) it was highly potent against M. Bovis BCG strain with an IC90
–
l
µ
−
µ
−
µ
µ
position in compound 7g (R3 =
value 0.13 µg/mL.
−
Replacing the chloro group by a bromo group 7h (R3 = –bromo) exhibits less activity towards
M. Bovis BCG strain with IC90 value >30 g/mL. Introduction of a CF3 group at the para position of
the aryl group 7i (R3 = CF3) compound displays excellent antitubercular effect against M. Bovis BCG
with 0.17 g/mL. With the introduction of a nitro group at the para position 7j (R3 = –NO2) the
µ
−
µ
compound does not show any antitubercular activity against the M. Bovis BCG strain. In compounds
7k (R1 = R4 = –fluoro) the compound showed a sharp increase in antitubercular activity against the
M. Bovis BCG strain with 0.15
showed an increase in antitubercular activity with IC90 value 0.058
Hence, among all the newly synthesized compounds (7a ), compounds 7d
µ
g/mL. With the disubstituted compound 7l (R1 = R4 =
g/mL against M. Bovis BCG strain.
7g 7i 7k, and 7l, exhibit
–chloro) it
µ
–l
,
,
,
promising anti-mycobacterial activity against M. Bovis BCG and the results are summarized in Table 1.
Now, we also screened the antitubercular activity against the MTB H37Ra strain. From the
4-thiazolidinone series (7a
anti-mycobacterial activity with IC90 value >30
shown in Table 1. Compounds 7b in which (R3 = –methyl) and 7c in which (R3 = –methoxy) showed
lower activity against MTB H37Ra strain with IC90 values >30 g/mL. With the introduction of the
fluoro) showed prominent activity against MTB H37Ra strain with
–l
), compound 7a without any substitution on the aryl ring showed lower
µg/mL against MTB H37Ra strain and the results are
µ
fluoro group, compound 7d (R3 =
IC90 value of 0.70 µg/mL.
−
Introduction of the chloro group in the aryl ring of compound 7e (R1 =
resulted in them exhibiting less potency against the MTB H37Ra strain with IC90 value >30
With a chloro group in R3 position in compound 7g (R3 = chloro), it results surprisingly with an increase
in antitubercular activity against MTB H37Ra strain with IC90 value 5.31 g/mL. Replacing the chloro
group by a bromo group 7h (R3 = –bromo) results in lower activity with IC90 value >30 g/mL against
MTB H37Ra strain. Introduction of a CF3 group at the para position of the aryl group 7i (R3 = CF3)
exhibits promising antitubercular against MTB H37Ra with IC90 value 1.08 g/mL. Introduction of
the nitro group at the para position 7j (R3 = NO2) does not show any anti-mycobacterial activity
against the MTB H37Ra strain. With disubstituted compounds 7k (R1 = R4 = –fluoro) there is displayed
excellent activity against the MTB H37Ra strain with 0.71 g/mL. Compounds 7l (R1 = R4 = –chloro)
show promising anti-mycobacterial activity with IC90 value 0.43 g/mL against MTB H37Ra strain.
Hence, among all the synthesized compounds 7a , compounds 7d 7g 7i 7k, and 7l showed excellent
−
chloro) and 7f (R2 = –chloro)
µg/mL.
−
µ
µ
−
µ
−
µ
µ
–
l
,
,
,
antitubercular activity against MTB H37Ra and the results are displayed in Table 1.
2.3. Cytotoxicity
The highly active sulfamethaoxazole incorporated 4-thiazolidinones 7d, 7g, 7i, 7k, and 7l were
tested for cytotoxicity activity against three human cancer cell lines MCF-7, HCT 116, and A549 using
the well established MTT protocol [40]. The cytotoxicity results of these compounds indicate they are
highly potent and are specific inhibitors against M. Bovis BCG and MTB H37Ra strain with GI50/GI90
(>100
µg/mL). Thus, all the most active compounds were relatively non-toxic against MCF-7, HCT 116
and A549 cell lines with (GI50/GI90) of >100 and the results are incorporated in Table 2.

Molecules 2020, 25, 3570
9 of 17
Table 2. In vitro cytotoxicity of selected 4-thiazolidinone derivatives.
MCF-7 (Breast)
Cell Line
HCT 116 (Colorectal)
Cell Line
A549 (Lung)
Cell Line
Entry
GI50 (µg/mL)
GI90 (µg/mL)
GI50 (µg/mL)
GI90 (µg/mL)
GI50 (µg/mL)
GI90 (µg/mL)
7d
7g
7i
7k
7l
>100
>100
>100
>100
>100
0.0048
>100
>100
>100
>100
>100
>100
0.075
>100
>100
>100
>100
>100
>100
>100
>100
0.0035
>100
>100
>100
>100
>100
>100
0.0706
>100
>100
>100
>100
>100
0.1279
>100
>100
>100
>100
>100
5.715
>100
Paclitaxel
Rifampicin
2.4. Selectivity Index (SI)
The selectivity index indicates that a highly potent compound is only active against mycobacteria
but it is non-toxic against host human cell lines. According to a study on the drug susceptibility of TB,
antitubercular activity was considered to be specific when the selectivity index was >10 [41]. This study
suggested that, compounds 7d, 7g, 7i, 7k, and 7l display the highest selectivity index >10, suggesting
that these compounds act as highly potent antimycobacterial agents and should be modified for the
next level. The selectivity index study results are incorporated in Table 3.
Table 3. Selectivity index against dormant M. bovis BCG and MTB H37Ra.
MCF-7
HCT 116
A549
Entry
MTB H37Ra M. Bovis BCG MTB H37Ra M. Bovis BCG MTB H37Ra M. Bovis BCG
7d
7g
7i
7k
7l
139.1
94.5
19.1
143.1
237.8
>5000
476.1
832.9
587.9
667.1
12.1
139.1
94.5
19.1
143.1
237.8
>5000
476.1
832.9
587.9
667.1
12.1
139.1
94.5
19.1
143.1
237.8
>5000
476.1
833.9
587.9
667.1
12.1
Rifampicin
1754.4
1754.4
1754.4
2.5. Antibacterial Activity
To determine the specificity of the most potent compounds 7d
,
7g, 7i, 7k, and 7l were evaluated for
their antibacterial activity against Gram-negative bacteria (P. flurescense ATCC 13525), (E. coli ATCC 25292)
and Gram-positive bacteria (B. subtillus ATCC 23857), (S. aureus ATCC 29213). The antibacterial
activity protocol suggests that all the active compounds were much less active towards bacterial strains.
All the most active compounds exhibited higher specificity towards M. Bovis BCG and MTB H37Ra
strains (Table 4).
Table 4. Antibacterial activity IC90 (µg/mL).
Entry
P. fluorescens
E. coli
B. subtillus
S. aureus
7d
7g
7i
7k
7l
>100
>100
>100
>100
>100
4.36
>100
>100
>100
>100
>100
1.46
>100
>100
>100
>100
>100
10.32
1.35
>100
>100
>100
>100
>100
1
Ampicillin
Kanamycin
0.49
1.62
>30
2.6. ADME Properties
The success of a drug is determined not only by good efficacy but also by an acceptable ADME
profile. In this study, we calculated the molecular volume (MV), the molecular weight (MW),

Molecules 2020, 25, 3570
10 of 17
the logarithm of partition coefficient (miLog P), the number of hydrogen bond acceptors (n-ON),
the number of hydrogen bonds donors (n-OHNH), the topological polar surface area (TPSA), the number
of rotatable bonds (n-ROTB) and Lipinski’s rule of five [42] using the Molinspiration online property
calculation tool kit [43]. Absorption (%ABS) was calculated by: %ABS = 109 − (0.345 × TPSA) [44].
Thedrug-likenessmodelscore(acollectivepropertyofphysico-chemicalproperties, pharmacokinetics,
and pharmacodynamics of a compound, represented by a numerical value) was computed by MolSoft
software [45]. A computational study of all the synthesized compounds was performed for prediction
of the ADME properties and the values obtained are presented in Table 4. It is apparent that the
compounds exhibited a good %ABS (%absorption) ranging from 69.11 to 85.02%.
Furthermore, the compounds 7d
(miLog P 5) and results are incorporated in Table 5. A molecule likely to be developed as an
orally active drug candidate should show no more than one violation of the following four criteria:
miLog P (octanol–water partition coefficient) 5, molecular weight 500, number of hydrogen bond
acceptors 10, and number of hydrogen bond donors 5 [46]. The larger the value of the drug likeness
, 7g, 7i, 7k, and 7l did not violate Lipinski’s rule of five
≤
≤
≤
≤
≤
model score, the higher is also the probability that the particular molecule will be active. All the tested
compounds followed the criteria for orally active drugs and therefore, these compounds may have a
good potential for eventual development as oral agents.
According to the literature survey, it was found that these type of compounds can bind to the
matrix metalloproteinase-8 (MMP-8; also known as neutrophil collagenase; PDB ID: 5h8x) [47,48].
This endopeptidase is part of a complex proteolytic MMP enzyme family, where its over expression
has been linked to several pathological processes [48]. As several articles had already described
the coordination of metals by sulfur containing compounds [49,50], we investigated whether the
sulfamethaoxazole in our compounds could coordinate the Zn2+ ion in MMP-8. This could promote
potential inhibitory activity on MMP-8, as presented by Tauro et al. [48]. According to previous reports
of molecular docking studies our target compounds should easily coordinate the Zn2+ in the receptor
cavity. The interactions of the sulfamethaoxazole moiety was identical to the interactions observed in
the original catechol ligand (hydrogen bonds with backbones of Ala161 and Leu160).

Molecules 2020, 25, 3570
11 of 17
Table 5. Pharmacokinetic parameters important for good oral bioavailability and the drug likeness model scores.
Com.
Rule
% ABS
TPSA (A2)
-
n-ROTB MV
MW
miLog P
≤5
n-ON
n-OHNH
Lipinski Violation
Drug Likeness Model Score
-
-
-
<500
<10
<5
≤1
7a
7b
7c
7d
7e
7f
7g
7h
7i
77.08
77.08
73.89
77.08
77.08
77.08
77.08
77.08
77.08
61.31
77.08
77.08
92.51
92.51
101.74
92.51
92.51
92.51
92.51
92.51
92.51
138.23
92.51
92.51
5
5
6
5
5
5
5
5
6
6
5
5
337.35
353.91
362.90
342.28
350.89
350.89
350.89
353.24
368.65
360.69
347.21
364.42
415.50
429.52
445.52
433.19
449.94
449.94
449.94
494.39
483.49
460.49
451.48
484.39
2.91
3.36
2.97
3.08
3.54
3.57
3.59
3.72
3.81
2.87
3.14
4.17
7
7
8
7
7
7
7
7
7
1
1
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
−0.10
−0.27
0.01
0.21
0.01
0.10
0.36
−0.02
−0.17
−0.12
−0.20
−0.04
7j
7k
7l
10
7
7
Com: Compound, %ABS: percentage absorption, TPSA: topological polar surface area, n-ROTB: number of rotatable bonds, MV: molecular volume, MW: molecular weight,
miLog P: logarithm of partition coefficient of compound between n-octanol and water, n-ON acceptors: number of hydrogen bond acceptors, n-OHNH donors: number of hydrogen
bonds donors.

Molecules 2020, 25, 3570
12 of 17
3. Materials and Methods
3.1. Materials
All the solvents and regents were purchased from Sigma Aldrich (Gillingham, UK) and they
were used in the reactions without purification. The progress of each reaction was monitored by
ascending thin layer chromatography (TLC) using TLC aluminum sheets, silica gel 60F254 precoated
(Merck, Darmstadt, Germany), and locating the spots using UV light as the visualizing agent or iodine
vapor. The melting points for the 4-thiazolidinone conjugates were carried out using an open capillary
1
method and they are uncorrected. H NMR spectra were obtained on a Bruker DRX-400 MHz NMR
spectrometer in DMSO-d6 (δ in ppm relative to tetramethylsilane (TMS) as an internal standard) and
13C NMR spectra were recorded (DMSO-d6) on a Bruker DRX-100 MHz spectrometer (Bruker BioSpin
MRI GmbH, Ettlingen, Germany). High-resolution mass spectra (HRMS) were obtained using an
Agilent 6520 (QTOF) ESI-HRMS model (Thermo Fisher Scientific, Waltham, MA, USA).
3.2. Typical Experimental Procedure for the Synthesis of 4-Amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (
A mixture of N-acetylsulfanilyl chloride ( ) (10 mmol), 3-amino-5-methylisoxazole ( ) (10 mmol),
and K2CO3 (5 mmol) was dissolved in acetonitrile (30 mL). The reaction mass was refluxed for 2 h to
give the N-acylation intermediate ( ) followed by acid hydrolysis. The progress of the reaction was
4)
1
2
3
monitored by using TLC. After 3 h, the reaction mass was poured into ice cold water. The obtained
solid was filtered and washed with water. The crude solid was crystallized in ethanol to afford the
corresponding pure product (4) and used for the further reaction without purification.
3.3. Typical Experimental Procedure for the Synthesis of Sulfamethaoxazole Incorporated Substituted
4-Thiazolidinone Hybrid (7a)
The mixture of appropriate 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (
4) (1 mmol),
benzaldehydes (5a) (1 mmol) and mercapto acetic acid (
6
) (1.2 mmol) in toluene (5 mL) was placed in a
round bottom flask. The mixture was refluxed at 120 ◦C for an appropriate time until the completion
of the reaction. The progress of the reaction was monitored by TLC using ethyl acetate: hexane as
a solvent system. The reaction mixture was quenched with crushed ice and extracted with ethyl
acetate (2
×
15 mL). The organic extracts were washed with brine solution (2
×
15 mL) and dried
over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to afford the
corresponding crude compounds. The obtained crude compounds were recrystallized using ethanol.
3.3.1. N-(5-methylisoxazol-3-yl)-4-(4-oxo-2-phenylthiazolidin-3-yl)benzenesulfonamide (7a)
Compound 7a was obtained from the cyclocondensation reaction between
4, 5a, and 6 for 12 h.
White solid; m.p.: 220–222 ◦C; Yield: 84%; 1H NMR (400 MHz, DMSO-d6,
δ
ppm): 9.49 (s, 1H, NH),
8.05–8.04 (m, 2H, Ar-H), 7.33–7.28 (m, 4H, Ar–H), 7.25–7.22 (m, 3H, Ar–H), 6.71 (s, 1H, S–CH–N),
5.88 (s, 1H, –C=CH), 3.76 (d, 1H, CH2, J = 12 Hz), 3.72 (d, 1H, CH2, J = 12 Hz) and 2.39 (s, 3H, –CH3);
13C NMR (100 MHz, DMSO-d6,
δ ppm): 179.27, 169.78, 152.98, 143.54, 140.31, 136.81, 132.99, 131.16,
131.08, 129.61, 127.78, 99.76, 68.44, 33.04 and 14.53; HRMS (ESI-qTOF): Calcd. for C19H18N3O4S2
[M + H]+, 416.2166: found: 416.2147.
3.3.2. N-(5-methylisoxazol-3-yl)-4-(4-oxo-2-(p-tolyl)thiazolidin-3-yl)benzenesulfonamide (7b)
Compound 7b was obtained from the cyclocondensation reaction between
4, 5b, and 6 for 12 h.
White solid; m.p.: 234–236 ◦C; Yield: 82%; 1H NMR (400 MHz, DMSO-d6,
δ
ppm): 9.68 (s, 1H, NH),
8.10–8.09 (m, 2H, Ar-H), 7.33–7.31 (m, 2H, Ar-H), 7.27–25 (m, 2H, Ar-H), 7.19–7.18 (m, 2H, Ar-H),
6.68 (s, 1H, S-CH-N), 5.88 (s, 1H, -C=CH), 3.81 (d, 1H, CH2, J = 12 Hz), 3.77 (d, 1H, CH2, J = 12 Hz),
2.43 (s, 3H, -CH3) and 2.37 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 173.14, 169.97, 152.76,
141.98, 137.28, 133.23, 130.01, 129.47, 128.55, 128.49, 128.23, 100.11, 66.62, 36.89, 24.97 and 12.16; HRMS
(ESI-qTOF): Calcd. for C20H20N3O4S2 [M + H]+, 430.0875: found: 430.0893.

Molecules 2020, 25, 3570
13 of 17
3.3.3. 4-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7c
)
Compound 7c was obtained from the cyclocondensation reaction between
4, 5c, and 6 for 12 h.
White solid; m.p.: 242–234 ◦C; Yield: 84%; 1H NMR (400 MHz, DMSO-d6,
δ
ppm): 9.42 (s, 1H, NH),
8.02–8.01 (m, 2H, Ar-H), 7.25–7.24 (m, 2H, Ar-H), 7.21–7.20 (m, 2H, Ar-H), 6.85–6.84 (m, 2H, Ar-H),
6.56 (s, 1H, S-CH-N), 5.80 (s, 1H, -C=CH), 3.79 (s, 1H, -OCH3), 3.72 (d, 1H, CH2, J = 12 Hz), 3.69 (d, 1H,
CH2, J = 12 Hz) and 2.35 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 178.60, 168.20, 157.10,
143.22, 139.70, 132.71, 130.85, 129.58, 129.37, 127.39, 125.19, 102.19, 66.07, 52.53, 32.06 and 13.08; HRMS
(ESI-qTOF): Calcd. for C20H20N3O5S2 [M + H]+, 446.0521: found: 446.0546.
3.3.4. 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7d
Compound 7d was obtained from the cyclocondensation reaction between 5d, and for 12 h.
Yellow solid; m.p.: 216–218 ◦C; Yield: 80%; 1H NMR (400 MHz, DMSO-d6,
ppm): 9.54 (s, 1H, NH),
)
4,
6
δ
8.02–8.01 (m, 2H, Ar-H), 7.33–7.32 (m, 2H, Ar-H), 7.27–7.25 (m, 2H, Ar-H), 7.07–7.04 (m, 2H, Ar-H),
6.60 (s, 1H, S-CH-N), 6.18 (s, 1H, -C=CH), 3.77 (d, 1H, CH2, J = 12 Hz), 3.73 (d, 1H, CH2, J = 12 Hz) and
2.39 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 176.31, 168.22, 161.79, 160.24, 154.29, 143.81,
143.36, 129.57, 129.52, 129.36, 127.42, 125.69, 115.63, 105.09, 68.12, 33.58 and 12.70; HRMS (ESI-qTOF):
Calcd. for C19H17FN3O4S2 [M + H]+, 434.0858: found: 434.0893.
3.3.5. 4-(2-(2-chlorophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7e
Compound 7e was obtained from the cyclocondensation reaction between 5e, and for 12 h.
White solid; m.p.: 240–242 ◦C; Yield: 84%; 1H NMR (400 MHz, DMSO-d6,
ppm): 9.62 (s, 1H, NH),
)
4
,
6
δ
8.27–8.26 (m, 2H, Ar-H), 7.48–7.46 (m, 3H, Ar-H), 7.37–7.31 (m, 3H, Ar-H), 6.87 (s, 1H, S-CH-N),
6.35 (s, 1H, -C=CH), 3.92 (d, 1H, CH2, J = 12 Hz), 3.90 (d, 1H, CH2, J = 12 Hz) and 2.23 (s, 3H, -CH3);
13C NMR (100 MHz, DMSO-d6,
δ ppm): 171.64, 167.47, 156.19, 143.33, 141.16, 138.58, 135.94, 132.27,
130.80, 129.46, 127.47, 125.43, 122.06, 101.90, 65.58, 35.18 and 14.01; HRMS (ESI-qTOF): Calcd. for
C19H17ClN3O4S2 [M + H]+, 450.0786: found: 450.0796.
3.3.6. 4-(2-(3-chlorophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7f
Compound 7f was obtained from the cyclocondensation reaction between 5f, and for 12 h.
White solid; m.p.: 228–230 ◦C; Yield: 78%; 1H NMR (400 MHz, DMSO-d6,
ppm): 9.56 (s, 1H, NH),
)
4,
6
δ
8.04–8.02 (m, 2H, Ar-H), 7.35 (s, 1H, Ar-H), 7.27–7.25 (m, 4H, Ar-H), 7.14–7.11 (m, 1H, Ar-H), 6.65 (s, 1H,
S-CH-N), 6.46 (s, 1H, -C=CH), 3.78 (d, 1H, CH2, J = 12 Hz), 3.74 (d, 1H, CH2, J = 12 Hz) and 2.40 (s, 3H,
-CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 179.77, 167.82, 156.82, 143.99, 143.52, 133.04, 131.60,
129.69, 129.53, 127.56, 125.86, 124.57, 122.12, 103.76, 68.63, 34.98 and 13.79; HRMS (ESI-qTOF): Calcd.
for C19H17ClN3O4S2 [M + H]+, 450.1372: found: 450.1396.
3.3.7. 4-(2-(4-chlorophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7g
Compound 7g was obtained from the cyclocondensation reaction between 5g, and for 12 h.
White solid; m.p.: 245–247 ◦C; Yield: 80%; 1H NMR (400 MHz, DMSO-d6,
ppm): 9.76 (s, 1H, NH),
)
4
,
6
δ
8.02–8.01 (m, 2H, Ar-H), 7.33–7.32 (m, 2H, Ar-H), 7.24–7.23 (m, 2H, Ar-H), 7.19–7.17 (m, 2H, Ar-H),
6.60 (s, 1H, S-CH-N), 6.43 (s, 1H, -C=CH), 3.76 (d, 1H, CH2, J = 12 Hz), 3.73 (d, 1H, CH2, J = 12 Hz)
and 2.38 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 182.76, 165.85, 157.74, 141.75, 139.99,
128.90, 128.41, 127.88, 124.50, 124.32, 124.19, 99.96, 66.56, 31.80 and 14.15; HRMS (ESI-qTOF): Calcd. for
C19H17ClN3O4S2 [M + H]+, 450.0042: found: 450.0025.
3.3.8. 4-(2-(4-bromophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7h
)
Compound 7h was obtained from the cyclocondensation reaction between
4
,
5h, and
6 for 12 h.
1
Red solid; m.p.: 234–236 ◦C; Yield: 80%; H NMR (400 MHz, DMSO-d6,
δ ppm): 9.64 (s, 1H, NH),
8.10–8.09 (m, 2H, Ar-H), 7.48–7.46 (m, 3H, Ar-H), 7.24–7.22 (m, 2H, Ar-H), 7.17–7.15 (m, 2H, Ar-H),

Molecules 2020, 25, 3570
14 of 17
6.63 (s, 1H, S-CH-N), 6.49 (s, 1H, -C=CH), 3.76 (d, 1H, CH2, J = 12 Hz), 3.72 (d, 1H, CH2, J = 12 Hz)
and 2.39 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
ppm): 175.95, 167.58, 156.57, 143.74, 143.29,
δ
135.76, 129.44, 129.19, 125.61, 124.31, 123.96, 97.85, 65.68, 34.06 and 12.32; HRMS (ESI-qTOF): Calcd. for
C19H17BrN3O4S2 [M + H]+, 495.1038: found: 495.1071.
3.3.9. N-(5-methylisoxazol-3-yl)-4-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)
benzenesulfonamide (7i)
Compound 7i was obtained from the cyclocondensation reaction between
4, 5i, and 6 for 12 h.
White solid; m.p.: 225–227 ◦C; Yield: 80%; 1H NMR (400 MHz, DMSO-d6,
δ
ppm): 9.33 (s, 1H, NH),
8.04–8.02 (m, 2H, Ar-H), 7.52–751 (m, 2H, Ar-H), 7.25–7.23 (m, 2H, Ar-H), 6.70 (s, 1H, S-CH-N),
6.06 (s, 1H, -C=CH), 3.75 (d, 1H, CH2, J = 12 Hz), 3.71 (d, 1H, CH2, J = 12 Hz) and 2.36 (s, 3H,
-CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 178.60, 165.55, 158.09, 142.35, 139.95, 135.99, 135.88,
131.22, 130.49, 130.23, 128.74, 128.05, 98.29, 66.37, 34.75 and 12.43; HRMS (ESI-qTOF): Calcd. for
C20H17F3N3O4S2 [M + H]+, 484.0728 found: 484.0756.
3.3.10. N-(5-methylisoxazol-3-yl)-4-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)benzenesulfonamide (7j
Compound 7j was obtained from the cyclocondensation reaction between 5j, and for 12 h.
Yellow solid; m.p.: 246–248 ◦C; Yield: 74%; 1H NMR (400 MHz, DMSO-d6,
ppm): 9.64 (s, 1H, NH),
)
4,
6
δ
8.23–8.21 (m, 2H, Ar-H), 8.03–8.01 (m, 2H, Ar-H), 7.55–7.53 (m, 2H, Ar-H), 7.35–7.34 (m, 2H, Ar-H),
6.71 (s, 1H, S-CH-N), 6.15 (s, 1H, -C=CH), 3.78 (d, 1H, CH2, J = 12 Hz), 3.75 (d, 1H, CH2, J = 12 Hz)
and 2.40 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 179.08, 165.76, 158.84, 141.54, 139.90,
136.65, 134.01, 133.96, 130.38, 128.27, 127.80, 99.96, 67.36, 34.90 and 14.60; HRMS (ESI-qTOF): Calcd. for
C19H17N4O6S2 [M + H]+, 461.0075: found: 461.0099.
3.3.11. 4-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)
benzenesulfonamide (7k)
Compound 7k was obtained from the cyclocondensation reaction between
4, 5k, and 6 for 12 h.
White solid; m.p.: 224–226 ◦C; Yield: 81%; 1H NMR (400 MHz, DMSO-d6,
δ
ppm): 9.50 (s, 1H, NH),
8.03–8.01 (m, 2H, Ar-H), 7.29–7.27 (m, 2H, Ar-H), 7.22.7.20 (m, 2H, Ar-H), 7.10–7.09 (m, 2H, Ar-H),
6.95 (s, 1H, S-CH-N), 6.45 (s, 1H, -C=CH), 3.85 (d, 1H, CH2, J = 12 Hz), 3.82 (d, 1H, CH2, J = 12 Hz)
and 2.38 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ ppm): 174.75, 166.33, 156.87, 141.55, 140.04,
128.82, 128.28, 126.03, 124.64, 123.90, 122.60, 99.67, 67.49, 36.45 and 12.62; HRMS (ESI-qTOF): Calcd. for
C19H16F2N3O4S2 [M + H]+, 452.1434: found: 452.1481
3.3.12. 4-(2-(2,6-dichlorophenyl)-4-oxothiazolidin-3-yl)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (7l
)
Compound 7l was obtained◦from the cyclocondensation reaction between
4
,
5l, and
6 for 12 h.
1
Yellow solid; m.p.: 218–220 C; Yield: 80%; H NMR (400 MHz, DMSO-d6,
δ ppm): 9.30 (s, 1H,
NH), 8.20 (s. 1H, Ar-H), 8.12–8.11 (m, 2H, Ar-H), 8.01–8.00 (m, 2H, Ar-H), 7.63–7.62 (m, 2H, Ar-H),
7.54–7.51 (m, 2H, Ar-H), 7.31–7.26 (m, 2H, Ar-H), 6.71 (s, 1H, S-CH-N), 6.06 (s, 1H, -C=CH), 3.75 (d, 1H,
CH2, J = 12 Hz), 3.71 (d, 1H, CH2, J = 12 Hz) and 2.39 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6,
δ
ppm): 174.10, 165.46, 155.58, 144.34, 139.34, 130.13, 129.91, 129.82, 127.96, 127.53, 123.76, 123.48, 123.11,
100.51, 65.04, 35.50 and 14.70; HRMS (ESI-qTOF): Calcd. for C19H16Cl2N3O4S2 [M + H]+, 485.2672:
found: 485.2649.
4. Conclusions
In conclusion, the synthesis of sulfamethaoxazole incorporated 4-thiazolidinone hybrids (7a
was carried out and their antitubercular activity against M. Bovis BCG and MTB H37Ra strains were
determined. Among all the tested compounds, 7d 7g 7i 7k, and 7l were identified as the most active
compounds with activity IC90 range 0.22–0.057 against M. bovis BCG strain and 0.43–5.31 g/mL against
–l)
,
,
,
µ

Molecules 2020, 25, 3570
15 of 17
MTB H37Ra strain. The most potent compounds displayed lower cytotoxicity against MCF-7, HCT 116
and A549 cell line using MTT assay, suggesting that these molecules possess highly pharmacodynamic
properties. The most active compounds 7d, 7g, 7i, 7k, and 7l exhibited a higher selectivity index >10
against MCF-7, HCT 116 and A549 which indicated that they act as prominent antitubercular agents.
Thus, this suggests that the compounds from the present series 7d, 7g, 7i, 7k, and 7l can be further
optimized and developed as lead molecules.
Supplementary Materials: Supplementary Materials are available online. Experimental section, biological assays,
1H NMR, 13C NMR and HRMS spectra of all synthesized compounds.
Author Contributions: M.A.B., M.A.A.-O., and A.A.K., conceived and designed the experiments; M.A.B. performed
chemical synthesis and purifications. A.M.N., performed biological assays (antimycobacterial, cytotoxicity and
antibacterial). M.A.B. wrote the paper. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the Deanship of Scientific Research at King Saud University (Research
group no. RG 1435-006).
Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for funding this research group no. (RG 1435-006).
Conflicts of Interest: The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
References
1.
2.
3.
Dye, C.; Williams, B.G. The Population Dynamics and Control of Tuberculosis. Science 2010, 328, 856–861.
[CrossRef] [PubMed]
Zumla, A.; Nahid, P.; Cole, S.T. Advances in the development of new tuberculosis drugs and treatment
regimens. Nat. Rev. Drug. Discov. 2013, 5, 388–404. [CrossRef] [PubMed]
Zumla, A.I.; Gillespie, S.H.; Hoelscher, M.; Philips, P.P.; Cole, S.T.; Abubakar, I.; McHugh, T.D.; Schito, M.;
Maeurer, M.; Nunn, A.J. New antituberculosis drugs, regimens, and adjunct therapies: Needs, advances,
and future prospects. Lancet Infect. Dis. 2014, 4, 327–340. [CrossRef]
4.
5.
6.
7.
8.
Global Tuberculosis Control: WHO Report. 2019. Available online: https://www.who.int/tb/publications/
global_report/en/ (accessed on 25 July 2020).
Lugosi, L. Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guerin
to molecular biology. A review. Tuber. Lung Dis. 1992, 73, 252–261. [CrossRef]
Udwadia, Z.F.; Amale, R.A.; Ajbani, K.K.; Rodrigues, C. Totally drug-resistant tuberculosis in India.
Clin. Infect. Dis. 2012, 54, 579–581. [CrossRef]
Butler, M.S.; Blaskovich, M.A.; Cooper, M.A. Antibiotics in the clinical pipeline in 2013. J. Antibiot (Tokyo)
2013, 66, 571–591. [CrossRef]
Diacon, A.H.; Donald, P.R.; Pym, A.; Grobusch, M.; Patientia, R.F.; Mahanyele, R.; Bantubani, N.;
Narasimooloo, R.; De Marez, T.; van Heeswijk, R.R. Andomized pilot trial of eight weeks of bedaquiline
(TMC207) treatment for multidrug-resistant tuberculosis: Long-term outcome, tolerability, and effect on
emergence of drug resistance. Antimicrob. Agents Chemother. 2012, 56, 3271–3276. [CrossRef]
Gouvea, F.A.; Vasconcellos, G.A.; Berwaldt, A.C.P.S.; Neto, G.; Fischer, R.P.; Sakata, W.P.; Almeida, W.P.; Cunico, W.
2-Aryl-3-(2-morpholinoethyl)thiazolidin-4-ones: Synthesis, anti-inflammatory in vivo, cytotoxicity in vitro
and molecular docking studies. Eur. J. Med. Chem. 2016, 118, 259–265. [CrossRef]
9.
10. Monte, C.D.; Carradori, S.; Bizzarri, B.; Bolasco, A.; Caprara, F.; Mollica, A.; Rivanera, D.; Mari, E.;
Zicari, A.; Akdemir, A. Anti-Candida activity and cytotoxicity of a large library of new N-substituted-
1,3-thiazolidin-4-onederivatives. Eur. J. Med. Chem. 2016, 107, 82–96. [CrossRef]
11. Rane, R.A.; Sahu, N.U.; Shah, C.P. Synthesis and antibiofilm activity of marine natural product-based
4-thiazolidinones derivatives. Bioorg. Med. Chem. Lett. 2012, 22, 7131–7134. [CrossRef]
12. Zhang, X.; Li, X.; Li, D.; Qua, G.; Wang, J.; Loiseau, P.M.; Fan, X. Ionic liquid mediated and promoted
eco-friendly preparation of thiazolidinone and pyrimidine nucleoside-thiazolidinone hybrids and their
antiparasitic activities. Bioorg. Med. Chem. Lett. 2009, 19, 6280–6283. [CrossRef] [PubMed]
13. Onen-Bayram, F.E.; Buran, K.; Durmaz, I.; Berk, B.; Cetin-Atalay, R. 3-Propionyl-thiazolidine-4-carboxylic
acid ethyl esters: A family of antiproliferative thiazolidines. Med. Chem. Commun. 2015, 6, 90–93. [CrossRef]

Molecules 2020, 25, 3570
16 of 17
14. Barrec, M.L.; Chimirri, A.; De Luca, L.; Monforte, A.M.; Monforte, P.; Rao, A.; Zappala, M.; Balzarini, J.;
De Clercq, E.; Pannecouque, C.; et al. Discovery of 2,3-diaryl-1,3-thiazolidin-4-ones as potentanti-HIV-1
agents. Bioorg. Med. Chem. Lett. 2001, 11, 1793–1796. [CrossRef]
15. Ottana, R.; Maccari, R.; Giglio, M.; Del Corso, A.; Cappiello, M.; Mura, U.; Cosconati, S.; Marinelli, L.;
Novellino, E.; Sartini, S.; et al. Identification of 5-arylidene-4 thiazolidinone derivatives endowed with dual
activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications.
Eur. J. Med. Chem. 2011, 46, 2797–2806. [CrossRef] [PubMed]
16. Panico, A.M.; Vicini, P.; Geronikaki, A.; Incerti, M.; Cardile, V.; Crasci, L.; Messina, R.; Ronsisvalle, S.
Heteroarylimino-4-thiazolidinones as inhibitors of cartilage degradation. Bioorg. Chem. 2011, 39, 48–52.
[CrossRef] [PubMed]
17. Wrobel, J.; Jette, J.; Kao, W.; Rogers, J.; Di, L.; Chi, J.; Perez, M.C.; Chen, G.C.; Shen, E.S. 5-Alkylated
thiazolidinones as follicle-stimulating hormone (FSH) receptor agonists. Bioorg. Med. Chem. 2006, 14, 5729–5741.
[CrossRef] [PubMed]
18. Cutshall, N.S.; O’Day, C.; Prezhdo, M. Rhodanine derivatives as inhibitors of JSP-1. Bioorg. Med. Chem. Lett.
2005, 15, 3374–3379. [CrossRef] [PubMed]
19. Joshi, P.; Anderson, C.; Binch, H.; Hadida, S.; Yoo, S.; Bergeron, D.; Decker, C.; terHaar, E.; Moore, J.;
Garcia-Guzman, M.; et al. Identification of potent CNS-penetrant thiazolidinones as novel CGRP receptor
antagonists. Bioorg. Med. Chem. Lett. 2014, 24, 845–849. [CrossRef] [PubMed]
20. Chen, S.; Chen, L.; Le, N.T.; Zhao, C.; Sidduri, A.; Lou, J.P.; Michoud, C.; Portland, L.; Jackson, N.; Liu, J.J.;
et al. Synthesis and activity of quinolinyl-methylene-thiazolinones as potent and selective cyclin-dependent
kinase 1 inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 2134–2138. [CrossRef]
21. Unsal-Tan, O.; Ozadali, K.; Piskin, K.; Balkan, A. Molecular modeling, synthesis and screening of some new
4-thiazolidinone derivatives with promising selective COX-2 inhibitory activity. Eur. J. Med. Chem. 2012
57, 59–64. [CrossRef]
,
22. Raza, S.; Srivastava, S.P.; Srivastava, D.S.; Srivastava, A.K.; Haq, W.; Katt, S.B. Thiazolidin-4-one and
thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic
agents. Eur. J. Med. Chem. 2013, 63, 611–620. [CrossRef] [PubMed]
23. Kucukguzel, S.G.; Oruc, E.E.; Rollas, S.; Sahin, F.; Ozbek, A. Synthesis, characterization and biological
activity of novel 4-thiazolidinones, 1,3,4-oxadiazoles and some related compounds. Eur. J. Med. Chem. 2002
,
37, 197–206. [CrossRef]
24. Jaju, S.; Palkar, M.; Maddi, V.; Ronad, P.K.; Mamledesai, S.; Satyanarayana, D.; Ghatole, M. Synthesis and
antimycobacterial activity of a novel series of isonicotinyl hydrazide derivatives. Arch. Pharm. Chem. Life Sci.
2009, 342, 723–731. [CrossRef] [PubMed]
25. Babaoglu, K.; Page, M.A.; Jones, V.C.; McNeil, M.R.; Dong, C.; Naismith, J.H.; Lee, R.E. Novel inhibitors of an
emerging target in Mycobacterium tuberculosis; substituted thiazolidinones as inhibitors of dTDP-rhamnose
synthesis. Bioorg. Med. Chem. Lett. 2003, 13, 3227–3230. [CrossRef]
26. Parekh, H.H.; Parikh, K.H.; Parikh, A.R. Synthesis of some 4-thiazolidinone derivatives as antitubercular
ragents. J. Sci. Islm. Rep. Iran. 2004, 15, 143–148.
27. Aridoss, G.; Amirthaganesan, S.; Kim, M.S.; Kim, J.T.; Jeong, Y.T. Synthesis, spectral and biological evaluation
of some new thiazolidinones and thiazoles base dont-3-alkyl-r-2,c-6-diarylpiperidin-4-ones. Eur. J. Med. Chem.
2009, 44, 4199–4210. [CrossRef]
28. Patel, A.B.; Chikhalia, K.H.; Kumari, P. Facile synthesis of benzonitrile/nicotinonitriles baseds-triazines as
new potential antimycobacterial agents. Eur. J. Med. Chem. 2014, 79, 57–65. [CrossRef]
29. Ramani, A.V.; Monika, A.; Indira, V.L.; Karyavardhi, G.; Venkatesh, J.; Jeankumar, V.U.; Manjashetty, T.H.;
Yogeeswari, P.; Sriram, D. Synthesis of highly potent novel anti-tubercular isoniazid analogues with
preliminary pharmacokinetic evaluation. Bioorg. Med. Chem. Lett. 2012, 22, 2764–2767. [CrossRef]
30. More, U.A.; Joshi, S.D.; Aminabhavi, T.M.; Gadad, A.K.; Nadagouda, M.N.; Kulkarni, V.H. Design, synthesis,
molecular docking and 3D-QSAR studies of potent inhibitors of enoyl-acyl carrier protein reductase as
potential antimycobacterial agents. Eur. J. Med. Chem. 2014, 71, 199–218. [CrossRef]
31. Zhao, J.; Xu, J.; Chen, J.; Wang, X.; He, M. Metal-free oxidative coupling of amines with sodium sulfinates:
A mild access to sulfonamides. RSC Adv. 2014, 4, 64698–64701. [CrossRef]
32. Pandya, R.; Murashima, T.; Tedeschi, L.; Barrett, A.G.M. Facile one-pot synthesis of aromatic and
heteroaromatic sulfonamides. J. Org. Chem. 2003, 68, 8274–8276. [CrossRef] [PubMed]

Molecules 2020, 25, 3570
17 of 17
33. El-Mossalamy, E.H. Potentiometric and Spectroscopic Studies of Sulfonamide Azo-Dye Complexes with
some Transition Metal Ions and Uranium Portu. Port. Electrochim. Acta 2009, 27, 143–152. [CrossRef]
34. Singhal, A.; Parumala, S.K.R.; Sharma, A.; Peddinti, R.K. Hypervalent iodine mediated synthesis of di-and
tri-substituted isoxazoles via [3+2] cycloaddition of nitrile oxides. Tetrahedron Lett. 2015, 57, 719–722. [CrossRef]
35. Murugesan, V.; Makwana, N.; Suryawanshi, R.; Saxena, R.; Tripathi, R.; Paranjape, R.; Kulkarni, S.; Katti, S.B.
Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase
inhibitors. Bioorg. Med. Chem. 2014, 22, 3159–3170. [CrossRef]
36. Bhat, M.A.; Al-Omar, M.A.; Naglah, A.M.; Khan, A.A. [Et3NH][HSO4]-mediated efficient synthesis of novel
xanthene derivatives and their biological evaluation. J. Saudi Chem. Soc. 2020, 24, 425–433. [CrossRef]
37. Bhat, M.A. Synthesis and anti-mycobacterial activity of new 4-thiazolidinone and 1,3,4-oxadiazole derivatives
of isoniazid. Acta Pol. Pharm. 2014, 71, 763–770.
38. Boyle, J.; Otty, S.; Sarojini, V. A Safer and Convenient Synthesis of Sulfathiazole for Undergraduate Organic
and Medicinal Chemistry Classes. J. Chem. Educ. 2012, 89, 141–143. [CrossRef]
39. Iona, E.; Pardini, M.; Gagliardi, M.C.; Colone, M.; Stringaro, A.R.; Teloni, R.; Brunori, L.; Nisini, R.; Fattorini, L.;
Giannoni, F. Infection of human THP-1 cells with dormant Mycobacterium tuberculosis. Microbes Infect.
2012, 14, 959–967. [CrossRef]
40. Van de Loosdrecht, A.A.; Beelen, R.H.; Ossenkoppele, G.J.; Broekhoven, M.G.; Langenhuijsen, M.M.
A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against
leukemic cells from cell lines and patients with acute myeloid. J. Immunol. Methods 1994, 174, 311–320. [CrossRef]
41. Hartkoorn, R.C.; Chandler, B.; Owen, A.; Ward, S.A.; Squire, S.B.; Back, D.J.; Khoo, S.H. Differential drug
susceptibility of intracellular and extracellular tuberculosis, and the impact of P-glycoprotein. Tuberculosis
2007, 87, 248–255. [CrossRef]
42. Lipinski, C.A.; Lombardo, L.; Dominy, B.W.; Freeney, P.J. Experimental and computational approaches to
estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.
2001, 46, 3–26. [CrossRef]
43. Molinspiration Chemoinformatics Brastislava, Slovak Republic. 2014. Available online: http://www.
molinspiration.com/cgi-bin/properties (accessed on 25 July 2020).
44. Zhao, Y.H.; Abraham, M.H.; Lee, J.; Hersey, A.; Luscombe, N.C.; Beck, G.; Sherborne, B.; Cooper, I.
Rate-Limited Steps of Human Oral Absorption and QSAR Studies. Pharm. Res. 2002, 19, 1446–1457.
[CrossRef] [PubMed]
45. Drug-Likeness and Molecular Property Prediction. Available online: http://www.molsoft.com/mprop/
(accessed on 25 July 2020).
46. Ertl, P.; Rohde, B.; Selzer, P. Fast Calculation of Molecular Polar Surface Area as a Sum of Fragment-Based
Contributions and Its Application to the Prediction of Drug Transport Properties. J. Med. Chem. 2000
43, 3714–3717. [CrossRef] [PubMed]
,
47. Bouz, G.; Juhas, M.; Otero, L.P.; Red, C.P.; Jandourek, O.; Konecna, K.; Paterova, P.; Kubicek, V.; Janousek, J.;
Dolezal, M.; et al. Substituted N-(Pyrazin-2-yl)benzenesulfonamides; Synthesis, Anti-Infective Evaluation,
Cytotoxicity, and In Silico Studies. Molecules 2020, 25, 138. [CrossRef] [PubMed]
48. Tauro, M.; Laghezza, A.; Loiodice, F.; Piemontese, L.; CaraDonna, A.; Capelli, D.; Montanari, R.; Pochetti, G.;
Di Pizio, A.; Agamennone, M. Catechol-based matrix metalloproteinase inhibitors with additional anti
oxidative activity. J. Enzym. Inhib. Med. Chem. 2016, 31, 25–37. [CrossRef]
49. Ogryzek, M.; Chylewska, A.; Turecka, K.; Lesiak, D.; Krolicka, A.; Banasiuk, R.; Nidzworski, D.; Makowski, M.
Coordination chemistry of pyrazine derivatives analogues of PZA: Design, synthesis, characterization and
biological activity. RSC Adv. 2016, 6, 52009–52025. [CrossRef]
50. Pedersen, K.S.; Perlepe, P.; Aubrey, M.L.; Woodruff, D.N.; Reyes-Lillo, S.E.; Reinholdt, A.; Voigt, L.;
Li, Z.; Borup, K.; Rouzieres, M. Formation of the layered conductive magnet CrCl2(pyrazine) (2) through
redox-active coordination chemistry. Nat. Chem. 2018, 10, 1056–1061. [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).