Synthesis and DNase I inhibitory properties of some 4-thiazolidinone derivatives

Article abstract of DOI:10.1002/jcb.27339

Twelve new thiazolidinones were synthesized and, together with 41 previously synthesized thiazolidinones,?evaluated for inhibitory activity against deoxyribonuclease I (DNase I) in vitro. Ten compounds inhibited commercial bovine pancreatic DNase I with a

Full text of DOI:10.1002/jcb.27339

Received: 3 March 2018
DOI: 10.1002/jcb.27339
Accepted: 27 June 2018
|
R E S E A R C H A R T I C L E
Synthesis and DNase I inhibitory properties of some
4
‐thiazolidinone derivatives
1
2
3
4
Ana Kolarević
|
Budimir S. Ilić
|
Gordana Kocić
|
Zdravko Džambaski
|
2
4
Andrija Šmelcerović
|
Bojan P. Bondžić
1
Department of Pharmacy, Faculty of
Abstract
Medicine, University of Niš, Niš, Serbia
2
Twelve new thiazolidinones were synthesized and, together with 41 previously
synthesized thiazolidinones, evaluated for inhibitory activity against deoxyr-
ibonuclease I (DNase I) in vitro. Ten compounds inhibited commercial bovine
pancreatic DNase I with an IC50 below 200 μM and showed to be more potent
DNase I inhibitors than crystal violet (IC50 = 365.90 ± 47.33 μM), used as a
positive control. Moreover, three compounds were active against DNase I in rat
liver homogenate, having an IC50 below 200 μM. (3‐Methyl‐1,4‐dioxothiazoli-
din‐2‐ylidene)‐N‐(2‐phenylethyl)ethanamide (41) exhibited the most potent
DNase I inhibition against both commercial and rat liver DNase I with IC50
values of 115.96 ± 11.70 and 151.36 ± 15.85 μM, respectively. Site Finder and
molecular docking defined the thiazolidinones interactions with the most
important catalytic residues of DNase I, including the H‐acceptor interaction
with residues His 134 and His 252 and/or H‐donor interaction with residues
Glu 39 and Asp 168. The three most active compounds against both commercial
and rat liver DNase I (31, 38, and 41) exhibited favorable physico‐chemical,
pharmacokinetic, and toxicological properties. These observations could be
utilized to guide the rational design and optimization of novel thiazolidinone
inhibitors. Thiazolidinones as novel DNase I inhibitors could have potential
therapeutic applications due to the significant involvement of DNase I in the
pathophysiology of many disease conditions.
Department of Chemistry, Faculty of
Medicine, University of Niš, Niš, Serbia
3
Department of Biochemistry, Faculty of
Medicine, University of Niš, Niš, Serbia
4
Center for Chemistry ICTM, University
of Belgrade, Belgrade, Serbia
Correspondence
Zdravko Džambaski and Bojan P.
Bondžić, Center for Chemistry ICTM,
University of Belgrade, P.O. Box 815,
Belgrade 11000, Serbia.
Email: zdzambas@chem.bg.ac.rs (ZD);
bbondzic@chem.bg.ac.rs (BPB)
Andrija Šmelcerović, Department of
Chemistry, Faculty of Medicine,
University of Niš, Bulevar Dr Zorana
Đinđića 81, Niš 18000, Serbia.
Email: a.smelcerovic@yahoo.com;
andrija.smelcerovic@medfak.ni.ac.rs
Funding information
Ministry of Education, Science and
Technological Development of the
Republic of Serbia, Grant/Award
Numbers: OI 171025, TR 31060, OI
1
72044, OI 172020; Faculty of Medicine of
the University of Nis, Grant/Award
Number: Internal project No. 4
K E Y W O R D S
DNase I inhibition, molecular docking, synthesis, thiazolidinones
1
|
INTRODUCTION
physiological and pathological. Apoptosis does not
occur at random in all cells of a tissue. It is considered
The term apoptosis refers to the mechanism of
controlled cell death, which plays a complementary
but opposite role to cell proliferation to maintain a
balanced cell population (homeostasis). Its morpholo-
gical features suggest that it is an active, inherently
programmed phenomenon that can be triggered
by a variety of extrinsic and intrinsic signals, both
a process whereby organisms eliminate “unwanted”
(old, damaged, precancerous, excessively produced,
improperly developed, or genetically damaged) cells.
Such selectivity of apoptosis would provide the basis
1
-3
for a protective role against disease.
According to
4
-7
several reports,
deoxyribonuclease I (DNase I) is
considered one of the main nucleases involved in DNA
|
J Cell Biochem. 2018;1-11.
wileyonlinelibrary.com/journal/jcb
© 2018 Wiley Periodicals, Inc.
1

2
KOLAREVIĆ ET AL.
|
TABLE 1 Chemical structures and DNase I inhibition of 2‐alkylidene‐4‐oxothiazolidines 1‐35
Group A
Reference on
DNase I inhibition
Compd.
R
1
R
2
R
3
R
3
′
synthesis
IC50 ± SD (µM)
2
5
1
2
3
4
5
6
7
8
9
H
CO
CONH(CH
CO Et
2
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Stojanović et al
>200
24
H
2
)
2
Ph
H
Marković et al
>200
2
2
2
2
5
7
7
7
7
Me
Me
Me
Me
H
2
H
Džambaski et al
Džambaski et al
Džambaski et al
Džambaski et al
>200
COPh
H
191.30 ± 18.13
>200
CONHPh
CONH(CH
H
2
)
2
2
Ph
Ph
H
>200
2
CO
2
Et
Me
Me
Me
CH
CH
CH
CH
CH
Me
Me
H
Stojanović et al
>200
2
2
2
2
2
2
2
4
H
COPh
Marković et al
Marković et al
Marković et al
Marković et al
Marković et al
Marković et al
Marković et al
>200
4
3
3
3
3
3
H
CONH(CH
2
)
>200
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
H
CO
2
Et
2
2
2
2
2
CO
CO
CO
CO
CO
2
2
2
2
2
Et
Et
Et
Et
Et
>200
H
COPh
191.84 ± 16.04
>200
H
CONHPh
CONH(CH
CN
H
)
2 2
Ph
190.59 ± 22.35
>200
H
2
2
2
2
2
7
7
7
7
7
Me
Me
Bn
Bn
Bn
(CH
(CH
(CH
(CH
(CH
(CH
(CH
H
CO
2
Et
Džambaski et al
Džambaski et al
Džambaski et al
Džambaski et al
Džambaski et al
>200
CONHPh
COPh
>200
>200
COPh
CH
CH
H
2
CO
2
2
Et
Et
162.87 ± 25.05
>200
CONHPh
2
CO
2
6
2
2
2
2
2
2
2
)
)
)
)
)
)
)
3
3
2
3
3
3
3
Br
Br
Br
Br
Br
Br
Br
CO
2
Et
Bondžić et al
Bondžić et al
>200
26
COPh
H
>200
25
CO
CO
CO
2
2
2
Et
Et
Et
Me
Me
CH
CH
Me
H
Stojanović et al
>200
2
2
2
2
6
6
6
6
Bondžić et al
Bondžić et al
Bondžić et al
Bondžić et al
>200
2
CO
2
2
Et
Et
>200
COPh
2
CO
>200
CN
(CH
H
2
)
2
CHO
>200
COPh
New compound
New compound
New compound
New compound
New compound
New compound
New compound
New compound
New compound
167.90 ± 32.49
>200
H
CONHPh
CN
H
H
H
H
H
193.77 ± 20.66
>200
H
CONHPh
COPh
Me
H
Me
Me
OH
OH
H
H
120.04 ± 19.14
>200
CONH(CH
)
2 2
Ph
H
o‐Br‐Bn
CO
COPh
CO Et
2
Et
H
>200
(CH
(CH
)
2 4
Br
Br
Me
Me
H
>200
)
2 4
2
(CH
)
2 2
CHO
>200
Abbreviation: DNase I, deoxyribonuclease I.
degradation during apoptosis. Elevated levels of
DNase I and excessive apoptosis have been observed
in various pathological conditions, including AIDS,
neurodegenerative disorders (Alzheimer’s disease,
Parkinson’s disease, Huntington’s disease, amyo-
trophic lateral sclerosis, cerebellar degeneration,
8

KOLAREVIĆ ET AL.
3
|
TABLE 2 Chemical structures and DNase I inhibition of 2,5‐dialkylidene‐4‐oxothiazolidines 36 and 37
Group B
Compd.
R
1
R
2
R
3
Reference on synthesis
DNase I inhibition IC50 ± SD (µM)
3
6
7
Me
Me
COPh
N(CH
3
3
)
2
2
New compound
New compound
>200
>200
3
2 2
CONH(CH ) Ph
N(CH
)
Abbreviation: DNase I, deoxyribonuclease I.
2
3-27
retinitis pigmentosa, and spinal muscular atro-
2‐alkylidene‐4‐oxothiazolidines (group A, 1‐26)
3
,8-10
4
phy),
graft‐versus‐host disease, ischemic injuries
(Table 1), four 2‐alkylidene‐4‐oxothiazolidine S‐oxides
3
,11,12
27
(
myocardial infarction and stroke),
acute fatty
(group C, 38‐41) (Table 3), seven 6,7‐dihydro‐2H‐
1
3
14
26
liver, idiopathic dilated cardiomyopathy, type 2
thiazolo[3,2‐a]pyridin‐3(5H)‐ones (group D, 42‐48)
1
5
16-18
diabetes, cisplatin‐induced nephrotoxicity,
aminophen‐induced hepatocellular necrosis,
gamma radiation–induced injuries.
acet-
and
(Table 4), two 2‐alkylidene‐7a‐methylhexahydro‐
1
9
26
2H‐pyrano[2,3‐d]thiazoles (group E, 49 and 50)
2
0
Therefore,
(Table 5), and two 4a‐methyl‐2,3,4,4a,7,8,9,10a‐octahy-
dropyrano[2′,3′:4,5]thiazolo[3,2‐a]pyridines (group F,
DNase I inhibitors may be useful in the treatment of
such diseases. However, the number of known organic
DNase I inhibitors, either natural or synthetic, is
2
6
52 and 53)
(Table 6), together with 12 newly
synthesized thiazolidinone derivatives, including
nine 2‐alkylidene‐4‐oxothiazolidines (group A, 27‐35)
(Table 1), two 2,5‐dialkylidene‐4‐oxothiazolidines
(group B, 36 and 37) (Table 2), and one 2‐alkylidene‐
7a‐methylhexahydro‐2H‐pyrano[2,3‐d]thiazole (group
E, 51) (Table 5) were evaluated for inhibitory activity
against bovine pancreatic DNase I in vitro. Those
inhibiting the commercial DNase I with IC50 values
below 200 µM were further evaluated for inhibitory
activity against DNase I in rat liver homogenate. Site
Finder and molecular docking are in silico drug design
methods used to better understand the drug‐target
interactions that hypothesize the designing of potential
2
1
relatively small, and the discovery of novel organic
DNase I inhibitors, especially those with potential
therapeutic applications, would be of great interest.
Both natural and synthetic thiazolidinones represent
compounds of great interest due to their broad range of
biological activities, including antibacterial, antifungal,
antitubercular, anticancer, analgesic, anti‐inflamma-
tory, anticonvulsant, antidepressant, antiviral/anti‐
HIV, antidiabetic, antiarrhythmic, and trypanocidal
(
antiepimastigote) activities. They also act as follicle‐
stimulating hormone receptor agonists and muscarinic
2
2
receptor 1 agonists. To find novel organic DNase I
inhibitors, in the current study 41 previously synthe-
sized thiazolidinone derivatives, including twenty‐six
2
8,29
drug candidates.
As a result of missing X‐Ray
diffraction/nuclear magnetic resonance (XRD/NMR)
TABLE 3 Chemical structures and DNase I inhibition of 2‐alkylidene‐4‐oxothiazolidine S‐oxides 38‐41
Group C
Compd.
R
1
R
2
R
3
R
3
′
Reference on synthesis
DNase I inhibition IC50 ± SD (µM)
2
2
2
2
7
7
7
7
38
39
40
41
Me
Me
Me
Me
CO
2
Et
H
H
H
H
H
H
H
H
Džambaski et al
Džambaski et al
Džambaski et al
Džambaski et al
141.53 ± 11.66
>200
COPh
CONHPh
2 2
CONH(CH ) Ph
173.66 ± 17.86
115.96 ± 11.70
Abbreviation: DNase I, deoxyribonuclease I.

4
KOLAREVIĆ ET AL.
|
TABLE 4 Chemical structures and DNase I inhibition of 6,7‐dihydro‐2H‐thiazolo[3,2‐a]pyridin‐3(5H)‐ones 42‐48
Group D
Compd.
R
1
R
2
Reference on synthesis
DNase I inhibition IC50 ± SD (µM)
2
2
2
2
2
2
2
6
6
6
6
6
6
6
42
43
44
45
46
47
48
H
COPh
CO Et
Bondžić et al
Bondžić et al
Bondžić et al
Bondžić et al
Bondžić et al
Bondžić et al
Bondžić et al
>200
>200
>200
>200
>200
>200
>200
Me
Me
Me
Me
CH
CH
2
COPh
CONHPh
2 2
CONH(CH ) Ph
2
2
CO
2
Et
Et
CO
2
Et
CO
2
COPh
Abbreviation: DNase I, deoxyribonuclease I.
TABLE 5 Chemical structures and DNase I inhibition of 2‐alkylidene‐7a‐methylhexahydro‐2H‐pyrano[2,3‐d]thiazoles 49‐51
Group E
Compd.
R
1
R
2
Reference on synthesis
DNase I inhibition IC50 ± SD (µM)
2
6
49
50
51
(CH
(CH
(CH
2
2
2
3
) Br
3
) Br
4
) Br
COPh
Bondžić et al
Bondžić et al
>200
>200
>200
26
CONHPh
CO
2
Et
New compound
Abbreviation: DNase I, deoxyribonuclease I.
TABLE 6 Chemical structures and DNase I inhibition of 4a‐methyl‐2,3,4,4a,7,8,9,10a‐octahydropyrano[2′,3′:4,5]thiazolo[3,2‐a]pyridines
52 and 53
Group F
Compd.
R
Reference on synthesis
DNase I inhibition IC50 ± SD (µM)
2
6
5
2
3
COPh
CN
Bondžić et al
Bondžić et al
>200
>200
26
5
Abbreviation: DNase I, deoxyribonuclease I.
atomic‐level details between a small organic inhibitor
properties of thiazolidinones at the molecular level
using the molecular docking. Finally, an in silico study
of the physico‐chemical, pharmacokinetic, and toxico-
logical properties of the compounds most active against
3
0
and bovine pancreatic DNase I, the Site Finder was
used to calculate possible active sites in DNase I. In
addition, we wanted to clarify DNase I inhibitory

KOLAREVIĆ ET AL.
5
|
2
6,27
both commercial and rat liver DNase I was done. To the
best of our knowledge, this is the first report on DNase I
inhibition by thiazolidinone derivatives.
published procedure.
Desired N,N‐dimethyl
enamines 36 and 37 were prepared by the regioselec-
tive C‐5 functionalization of 2‐alkylidene‐4‐oxothia-
zolidines in a reaction with Bredereck’s reagent.
‐Hydroxy thiazolidine derivatives 31 and 32 were
prepared from corresponding vinyl‐chlorides
dimethyl sulfoxide (DMSO) initiated chloride transfer
from the exocyclic C=C bond to the C(5) position of
the ring and subsequent formation and hydrolysis of
5
31
2
|
MATERIALS AND METHODS
by
Experimental part referring to the synthesis and character-
ization of compounds 1‐53, evaluation of DNase I inhibition,
and in silico studies is available as Supporting Information.
3
2
alkoxydimethylsulfonium salt. Compound 35 was
prepared by regioselective Michael addition of thia-
zolidinone substrate to acrolein, according to the
3
3
|
RESULTS AND DISCUSSION
Synthesis of the studied
2
6
published procedure.
Reduction of aldehyde 35
yields the hydroxypropyl group at C‐5 as an internal
nucleophile. Next, lactam reduction and acid pro-
moted imine formation followed by subsequent
intramolecular addition of hydroxyethyl group to
imine takes place to close the tetrahydropyran ring
.1
|
thiazolidinones
Synthesis of 41 thiazolidinones, including compounds
2
5
24
27
25
24
23
27
26
1
2
,
2, 3‐6, 7, 8, 9, 10‐14, 15‐19, 20, 21,
25 26 27 26 26
26
2, 23‐26, 38‐41, 42‐50, 52, and 53, have
and gave compound 51 (Scheme 1).
already been published. In the current study, 12 new
thiazolidinones (compounds 27‐37 and 51) were
synthesized. Compounds 27‐30 were prepared by the
base catalyzed reaction of α‐mercapto esters and
α‐substituted nitriles according to the published
3
.2
|
DNase I inhibition
Among 53 investigated thiazolidinones, 10 compounds,
including seven 2‐alkylidene‐4‐oxothiazolidines (4, 11,
13, 18, 27, 29, and 31) (Table 1), and three 2‐alkylidene‐
4‐oxothiazolidine S‐oxides (38, 40, and 41) (Table 3),
inhibited bovine pancreatic DNase I with IC50 values
2
3
procedure
(Scheme 1). Compounds 33 and 34
were prepared by the regioselective N‐alkylation
of 2‐alkylidene‐4‐oxothiazolidines according to the
SCHEME 1 Reagents and conditions: (i) K
2
CO
(1.5 equiv), toluene, 110°C; (iv) (a) m‐CPBA (1.2‐2 equiv), CH
CO (0.1 equiv), acroleine (1.2 equiv), DMF, rt; (vii) (a) NaBH
4
3
cat, EtOH, reflux; (ii) MeI, o‐BrC
6
H
4
CH
2
Br, or Br(CH
Cl , 0°C; (b) SOCl
(10 equiv), EtOH, 0°C, HCl cat;
2
)
4
Br (1.1‐1.5 equiv), K
2
CO
3
(1‐1.2
t
equiv), DMF, rt; (iii) BuOCH(NMe
10°C → rt; (v) DMSO, 70°C; (vi) K
b) conc HCl
2
)
2
2
2
2
(1.1 equiv), CH
2
Cl
2
,
−
2
3
(

6
KOLAREVIĆ ET AL.
|
below 200 μM. All 10 compounds showed to be more
potent DNase I inhibitors as compared with crystal
violet (IC50 = 365.90 ± 47.33 μM), used as a positive
control. Compounds 41 and 31 exhibited the most
potent DNase
I inhibition with IC50 values of
1
15.96 ± 11.70 and 120.04 ± 19.14 μM, respectively. On
the other hand, studied 2,5‐dialkylidene‐4‐oxothiazoli-
dines (Table 2), 6,7‐dihydro‐2H‐thiazolo[3,2‐a]pyridin‐3
(
5H)‐ones (Table 4), 2‐alkylidene‐7a‐methylhexahydro‐
2
4
H‐pyrano[2,3‐d]thiazoles (Table 5), as well as
a‐methyl‐2,3,4,4a,7,8,9,10a‐octahydropyrano[2′,3′:4,5]
FIGURE 1 The top‐ranked DNase I binding site, represented
by a gray‐red surface map
thiazolo[3,2‐a]pyridines (Table 6) did not show DNase I
inhibition within the investigated concentration
3
0
(
IC50 > 200 μM).
mechanism of DNase I has been already highlighted.
To obtain a more complete picture of the tested
compounds as DNase I inhibitors, 10 compounds that
inhibited commercial bovine pancreatic DNase I
It was confirmed that catalytic residues His 134 and
His 252 are a part of the ion binding site IV, which is
implicated in the cleavage of scissile phosphate.
Furthermore, several site‐directed mutagenesis experi-
ments on residues surrounding His 134 and His 252
demonstrated that single mutations of Glu 39 or Asp
168 resulted in very low activities on DNA mole-
(
Tables 1 and 3) were further investigated on their
ability to inhibit DNase I in rat liver homogenate. As a
result, three compounds, 31, 38, and 41, inhibited rat
liver DNase I with IC50 values of 164.74 ± 16.12,
3
3,34
1
90.34 ± 14.49, and 151.36 ± 15.85 μM, respectively.
cule.
The effects of these mutations also confirmed
The other seven compounds did not inhibit rat liver
DNase I with an IC50 below 200 μM.
the active role of Glu 39 and Asp 168 in the IV catalytic
2
+
site. In addition, the importance of Ca coordination
sites (sites I and II) for the structural integrity and
3
0
3.3
|
In silico studies
activity of DNase I is well known.
The interaction profiles of thiazolidinones with
DNase I domain are shown in Figures 2-4 and
Supporting Information Table S2. Compound 41, which
corresponds to one of the most promising inhibitors
reported in this series, showed dominant hydrogen bond
interactions with two catalytic histidines, His 134 and
His 252 (Figure 4F). Furthermore, identical interactions
with His 134 or His 252 were also observed for
compounds 4, 13, 18, 27, 31, and 38 (Figures 2-4;
Supporting Information Table S2). In addition, com-
pounds 4 and 27 showed H‐donor interactions with
residues Asp 168 and Glu 39 (Supporting Information
Table S2), which are also implicated in the cleavage of
3
.3.1
|
Molecular docking
The binding site residues in DNase I have been
identified using the Site Finder implemented in the
Molecular Operating Environment (MOE) software.
The results from the analysis highlighted that amino
acid residues like Asn 7, Arg 9, Glu 39, Tyr 76, Glu 78,
Arg 111, His 134, Ala 136, Pro 137, Asp 168, Asn 170,
Thr 203, Thr 205, Thr 207, Tyr 211, Asp 251, and His
2
52 constituted the binding pocket of the DNase I
structure (Supporting Information Table S1). Our
results are consistent with a recent study highlighting
the conservation of the amino acids involved in the
identified cation‐binding sites across DNase I and
DNase I‐like protein. It is worth mentioning that
inhibitor‐binding pocket, represented by a gray‐red
surface map, is within the region that interacts with
3
3
scissile phosphate.
The results from Supporting
3
0
Information Table S2 indicate that thiazolidinones 11,
29, and 40 were not found to possess any similar
interactions as previously discussed compounds. How-
ever, these compounds were observed to interact with
Tyr 211, Thr 203, or Arg 111 respectively, which
DNA octamer d(GGTATACC) (Figure 1).
2
The intermolecular contacts between thiazolidi-
nones and DNase I were analyzed using the ligand
interaction diagram of MOE suite. It illustrates the
existence of hydrogen bond, pi‐H, and H‐pi interactions
2
+
30
constitute the Ca
coordination sites I and II.
Compounds 11, 29, and 40 showed decreased DNase I
inhibition compared with other thiazolidinones (Tables
1,3), presumably because of their interaction with
(
Supporting Information Table S2). In addition, the
3
4
bond distances, bond energy, and binding free energy
between the inhibitor and receptor atoms were also
examined. Of note, the importance of Glu 39, His 134,
Asp 168, and His 252 residues in the catalytic
residues distal from the catalytic histidines. Conse-
quently, the presence of interactions with the most
important catalytic residues of DNase I binding site is
expected to enhance the efficiency of thiazolidinones.

KOLAREVIĆ ET AL.
7
|
FIGURE 2 Three‐/two‐dimensional view of compounds 4 (A,B), 11 (C,D), 13 (E,F), and 18 (G,H) bound in the active site of DNase I.
The polar part of the active site is shown as a pink surface, hydrophobic part as a green surface, and the solvent‐exposed part is shown as a
red surface

8
KOLAREVIĆ ET AL.
|
FIGURE 3 Three‐/two‐dimensional view of compounds 27 (A,B), 29 (C,D), and 31 (E,F) bound in the active site of DNase I. The polar
part of the active site is shown as a pink surface, hydrophobic part as a green surface, and the solvent‐exposed part is shown as a red surface
3
.3.2
|
In silico study of the
silico study of the physico‐chemical, pharmacokinetic, and
toxicological properties was performed. These three com-
pounds fulfilled Lipinski’s rule of five indicating their good
oral bioavailability (Supporting Information Table S3). They
were predicted as compounds capable of being absorbed by
the intestine. Compound 41 might be able to pass through
the blood‐brain barrier, and compound 31 was predicted as
physico‐chemical, pharmacokinetic,
and toxicological properties
To obtain a complete picture of compounds 31, 38, and 41,
as the most active compounds against both commercial
bovine pancreatic DNase I and DNase I in rat liver
homogenate, and their potential therapeutic application, in

KOLAREVIĆ ET AL.
9
|
FIGURE 4 Three‐/two‐dimensional view of compounds 38 (A,B), 40 (C,D), and 41 (E,F) bound in the active site of DNase I. The polar part of
the active site is shown as a pink surface and hydrophobic part as a green surface, whereas the solvent‐exposed part is shown as a red surface
permeable across Caco‐2 cells. None of the three compounds
was predicted as a P‐glycoprotein inhibitor, an inhibitor
of renal organic cation transporter, or as an inhibitor of
CYP450 isoenzymes, whereas compound 38 might act as
CYP450 3A4 substrate (Supporting Information Table S4).
Compounds 31, 38, and 41 were predicted as weak
inhibitors of human Ether‐à‐go‐go‐Related Gene, non‐
AMES toxic, and ready biodegradable. According to the
median lethal dose (LD ), compounds 31, 38, and 41 were
predicted as slightly toxic compounds and according to the
median toxic dose (TD ) as noncarcinogenic compounds
(Supporting Information Table S4).
50
4
|
CONCLUSION
A series of 53 thiazolidinones, including 12 newly synthe-
sized thiazolidinones, was used in the DNase I inhibition
50

10
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ACKNOWLEDGMENTS
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The financial support of this work by Ministry of
Education, Science and Technological Development of
the Republic of Serbia (Grants No. OI 172020, OI 172044,
OI 171025, and TR 31060) and Faculty of Medicine of the
University of Nis (Internal project No. 4) is gratefully
acknowledged. The authors would like to thank Chemi-
cal Computing Group and Schrödinger LLC., for provid-
ing us the academic licenses free of cost for this study.
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CONFLICTS OF INTEREST
The authors declare that there are no conflicts of interest.
ORCID
Andrija Šmelcerović
724-0967
http://orcid.org/0000-0001-
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How to cite this article: Kolarević A, Ilić BS,
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