Design and synthesis of new 4-methylthiazole derivatives: In vitro and in silico studies of antimicrobial activity

Article abstract of DOI:10.1016/j.molstruc.2021.130692

The development of resistance against antimicrobial drugs has become a world-wide issue. It is predicted that some or perhaps all the antimicrobial drugs used in clinics will be out of the treatment protocols soon. Therefore, researchers pay more attention to the development of new antimicrobial drugs. For this purpose, we designed and synthesized new 4-methylthiazole-(benz)azole derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR, HSQC, NOESY, HMBC and LC/MS-IT-TOF spectral and elemental analyses. Then, their antimicrobial activity against bacteria and fungi strains was tested. The antibacterial effect of the compounds was found valuable as compared with their anticandidal activity. By combining the findings with molecular docking results, structure-activity relationship (SAR) was explained. Thus, in the development of new antimicrobial agents which can be used as DNA gyrase inhibitors, SAR showed that the products might be used in the discovery of new antimicrobials where their activity is owed to the allosteric effect. Although the effect of compound 3f was modest compared to the reference compound, it was better than the other synthesized compounds. Also, compound 3f has a better allosteric effect and might be a good lead candidate to synthesize new and better active hits. In addition, it was observed that all the synthesized compounds showed half potency against P. aeruginosa compared to the reference drug. On the other hand, no significant difference was seen between compounds against gram-positive or gram-negative bacteria. Briefly, meaningful data to correlate the SAR with thiazole-(benz)azole hybridized compounds were presented in this study. In future projects, the mentioned ideas can be used to synthesize new compounds having better antibacterial activity, particularly against resistant organisms.

Full text of DOI:10.1016/j.molstruc.2021.130692

Journal of Molecular Structure 1241 (2021) 130692
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Design and synthesis of new 4-methylthiazole derivatives: In vitro and
in silico studies of antimicrobial activity
a,b,∗
f
, Sam DAWBAA , Demokrat NUHAa,d, S¸ ule Aybüke YAVUZe,
a,c
Asaf Evrim EVREN
a
Ülküye Dudu GÜL , Leyla YURTTAS¸
a
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, 26470 Eski s¸ ehir, Turkey
b
Vocational School of Health Services, Pharmacy Services, Bilecik Seyh Edebali University, Bilecik, Turkey
c
Department of Pharmacy, Faculty of Medicine and Health Sciences, Thamar University, Dhamar, Yemen
d
Faculty of Science, Department of Chemistry, Eskisehir Technical University, 26555 Eski s¸ ehir, Turkey
e
Department of Biotechnology, Faculty of Arts and Science, Mersin University, 33343 Mersin, Turkey
f
Vocational School of Health Services, Biotechnology Application and Research Center, Bilecik Seyh Edebali University, Bilecik, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of resistance against antimicrobial drugs has become a world-wide issue. It is predicted
that some or perhaps all the antimicrobial drugs used in clinics will be out of the treatment protocols
soon. Therefore, researchers pay more attention to the development of new antimicrobial drugs. For this
purpose, we designed and synthesized new 4-methylthiazole-(benz)azole derivatives. The structural elu-
cidation of the compounds was performed by 1H-NMR, 13 C-NMR, HSQC, NOESY, HMBC and LC/MS-IT-TOF
spectral and elemental analyses. Then, their antimicrobial activity against bacteria and fungi strains was
tested. The antibacterial effect of the compounds was found valuable as compared with their antican-
didal activity. By combining the findings with molecular docking results, structure-activity relationship
Received 18 March 2021
Revised 2 May 2021
Accepted 9 May 2021
Available online 18 May 2021
Keywords:
Antimicrobial activity
Benzazole
DNA gyrase
(
SAR) was explained. Thus, in the development of new antimicrobial agents which can be used as DNA
Molecular docking
Thiazole
gyrase inhibitors, SAR showed that the products might be used in the discovery of new antimicrobials
where their activity is owed to the allosteric effect. Although the effect of compound 3f was modest
compared to the reference compound, it was better than the other synthesized compounds. Also, com-
pound 3f has a better allosteric effect and might be a good lead candidate to synthesize new and better
active hits. In addition, it was observed that all the synthesized compounds showed half potency against
P. aeruginosa compared to the reference drug. On the other hand, no significant difference was seen be-
tween compounds against gram-positive or gram-negative bacteria. Briefly, meaningful data to correlate
the SAR with thiazole-(benz)azole hybridized compounds were presented in this study. In future projects,
the mentioned ideas can be used to synthesize new compounds having better antibacterial activity, par-
ticularly against resistant organisms.
Allosteric effect
©
2021 Elsevier B.V. All rights reserved.
1
. Introduction
thiamine [4] and various natural bioactive compounds [5]. Thi-
azole containing natural antibiotics (bleomycins etc.) are pro-
duced mainly from secondary metabolites sourced from Actino-
mycetes and gram-positive mycelial sporulating bacteria, pretty
much the genus Streptomyces [6]. Many synthetic drugs in use
today such as abafungin, aminitrozole, amiphenazole, aztreonam,
dasatinib, febuxostat, fentiazac, fanetizole, lurasidone, meloxicam,
nitazoxanide, nizatidine, pramipexazole, ritonavir, ruvaconazole,
sudoxicam, sulfathiazole, tenonitrozole, tiazofurin, thiabendazole,
voreloxin, zopolrestat carry thiazole ring [7-11]. Additionally, sub-
stituted thiazole derivatives and analogous rings are also widely
involved as building blocks in the structure of numerous newly de-
signed molecules due to their diverse bioactivity reported in many
Thiazole ring is a five-membered aromatic heterocycle contain-
ing sulfur and nitrogen atoms at 1st and 3rd positions. This liq-
uid substance is slightly soluble in water and possesses moder-
ately basic chemical character with a pKa value of 2.5 [1] Thiazole
and their derivatives exist as part of the structure of molecules
of great importance such as penicillines [2], cephalosporines [3],
∗
Corresponding author at: Faculty of Pharmacy, Department of Pharmaceutical
Chemistry, Anadolu University, 26470 Eski s¸ ehir, Turkey.
E-mail addresses: asafevrim.evren@bilecik.edu.tr, asafevrimevren@anadolu.edu.tr
(A.E. EVREN).
https://doi.org/10.1016/j.molstruc.2021.130692
022-2860/© 2021 Elsevier B.V. All rights reserved.
0

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
2
.1.2. Synthesis of 2-chloro-N-(4-methylthiazole-2-yl) propanamide
(
2)
Compound 1 was solved in tetrahydrofuran (THF), triethylamine
was used as a catalyst. The final mixture was cooled in an ice
bed, then 2-chloropropionyl chloride diluted in tetrahydrofuran
was cautiously added dropwise to the solution. The mixture was
stirred at room temperature for further 1h after the addition of 2-
chloropropionyl chloride. The reaction was controlled by TLC. After
completion of the reaction, the solvent was evaporated, and the
solid product was washed with water and filtered. Subsequently,
the crude product was recrystallized from ethanol.
Fig. 1. The main structure of penicillins.
studies including antibacterial, anticancer, anticonvulsant, antifilar-
ial, antifungal, anthelmintic, anti-inflammatory, antiulcer, antiviral,
immunosuppressant action [12-19].
2
.1.3. General synthesis of N-(4-methylthiazol-2-yl)-2-(substituted
mercapto)propanamide (3a-3i)
Among thiazole compounds, 2,4-disubstituted thiazole deriva-
tives have been included in numerous studies regarding their an-
timicrobial activities [20]. In particular, 2-amino-1,3-thiazole phar-
macophore presents as a privileged structure due to its prevalence
of antibacterial activity [21]. On the other hand, aryl sulfide func-
tion is an important moiety that provides diverse biological activ-
ity to the compounds it is part of [22]. In fact, the core structure of
the penicillin group antibiotics includes 5,5-dimethyl thiazolidine-
Mercapto derivatives (1.14 mmol) was dissolved in acetone (25
mL) and K CO3 (0.23g, 1.71 mmol) was added to the solution fol-
2
lowed by 2-chloro-N-(4-methylthiazole-2-yl)propanamide (2) (0.3
g, 1.14 mmol). The mixture was stirred at room temperature. The
reaction was monitored with TLC. After the reaction was com-
pleted, acetone was evaporated, and the residue was washed with
water.
4
-carboxylic acid (as shown Fig. 1). Therefore, we designed our
2
.1.4. 2-((1-Methyl-1H-tetrazol-5-yl)thio)-N-(4-methylthiazol-2-yl)
compounds to base the penicillin structure.
propanamide (3a)
m. p. 188-190°C, yield 79 %, 1HNMR (300 MHz, DMSO-d , ppm)
Today, resistance against antimicrobial drugs is a major concern.
It is predicted that the drugs currently used in clinics cannot be
used in the future. In fact, lists have been even created for some
bacteria [23]. Despite the procedures applied clinically to reduce
the resistance i.e. rational drug use and decreased antibiotic mis-
use, it is important to fight the resistance using different mecha-
nisms including the development of new active molecules [24,25].
In the way of the above literature and based on the need
to develop new and effective antimicrobial agents, novel 2,4-
disubstituted thiazole derivatives were synthesized and evaluated
for their antibacterial and antifungal activity.
6
δ 1.60 (d, J = 7.05 Hz, 3H, -CH -C-S), 2.34 (s, 3H, thiazole-CH ),
3
3
3
.95 (s, 3H, tetrazole-CH ), 4.55 (q, J = 7.02 Hz, 1H, H-C-S), 7.16
3
(
s, 1H, Ar-H), 12.33 (brs, 1H, -NH). 13C-NMR (75 MHz, DMSO-d ,
6
ppm) δ 11.59 (thiazole-CH ), 18.90 (-CH -C-S), 34.33 (tetrazole-
3
3
CH ), 46.44 (H-C-S), 127.27, 135.27, 152.02, 156.58, 169.12. For
3
C9H N OS calculated: Elemental Analysis: %C, 38.01; %H, 4.25;
12
6
2
%
N, 29.55; found: %C, 38.03; %H, 4.24; %N, 29.56. HRMS (m/z):
[
M+H]+ calculated 285.0587; found 285.0589.
2
.1.5. 2-((1-Methyl-1H-imidazol-2-yl)thio)-N-(4-methylthiazol-2-yl)
propanamide (3b)
m. p. 109–111 °C, yield 85 %, 1HNMR (300 MHz, DMSO-d , ppm)
2. Experimental
6
δ 1.41 (d, J = 7.02 Hz, 3H, -CH -C-S), 2.34 (s, 3H, thiazole-CH ),
3
3
2
.1. Chemistry
3
.56 (s, 3H, imidazol-CH ), 4.11 (q, J = 6.99 Hz, 1H, H-C-S), 7.01
3
(
s, 1H, Ar-H), 7.13 (d, J = 1.23 Hz, 1H, Ar-H), 7.32 (d, J = 1.14
All chemicals used in the syntheses were purchased either from
13
Hz, 1H, Ar-H), 12.29 (brs, 1H, -NH). C-NMR (75 MHz, DMSO-d ,
6
Merck Chemicals (Merck KGaA, Darmstadt, Germany) or Sigma-
Aldrich Chemicals (Sigma-Aldrich Corp., St. Louis, MO, USA). The
reactions and the purities of the compounds were observed by
thin-layer chromatography (TLC) on silica gel 60 F254 aluminum
sheets obtained from Merck (Darmstadt, Germany). Melting points
of the synthesized compounds were recorded by the MP90 digi-
tal melting point apparatus (Mettler Toledo, Ohio, USA) and were
presented as uncorrected. 1H NMR and 13C NMR spectral anal-
yses were achieved using a Bruker 300 MHz and 75 MHz digi-
tal FT-NMR spectrometer (Bruker Bioscience, Billerica, MA, USA) in
ppm) δ 11.55 (thiazole-CH ), 17.68 (-CH -C-S), 33.67 (imidazole-
3
3
CH ), 45.44 (H-C-S), 124.75, 127.04, 129.48, 135.37, 137.79, 156.34,
3
1
70.00. For C11 H14 N OS calculated: Elemental Analysis: %C, 46.79;
4
2
%
H, 5.00; %N, 19.84; found: %C, 46.81; %H, 4.98; %N, 19.85. HRMS
m/z): [M+H]+ calculated 283.0682; found 283.0691.
(
2
.1.6. 2-((4,5-Dihydrothiazol-2-yl)thio)-N-(4-methylthiazol-2-yl)
propanamide (3c)
m. p. 181–183 °C, yield 82 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.51 (d, J = 7.11 Hz, 3H, -CH -C-S), 2.34 (s, 3H, thiazole-
3
DMSO-d . In the NMR spectra, splitting patterns were designated
6
CH ), 3.46 (t, J = 7.62, 2H, dihydrothiazol), 4.14 (t, J = 8.25, 2H,
3
as follows: s: singlet; d: doublet; t: triplet; m: multiplet. Coupling
constants (J) were reported as Hertz. High resolution mass spectro-
metric (HRMS) analyses were performed using a LC/MS-IT-TOF sys-
tem (Shimadzu, Kyoto, Japan). Elemental analyses were performed
on a Leco 932 CHNS analyzer (Leco, Michigan, USA).
dihydrothiazol), 4.66 (q, J = 7.11 Hz, 1H, H-C-S), 7.15 (s, 1H, Ar-
H), 12.16 (brs, 1H, -NH). 13C-NMR (75 MHz, DMSO-d , ppm) δ
6
1
1.57 (thiazole-CH ), 18.63 (-CH -C-S), 35.81 (dihydrothiazol -CH ),
3
3
3
4
5.35 (H-C-S), 64.51 (dihydrothiazol -CH ), 127.22, 135.37, 162.72,
3
1
69.46. For C10H13N OS calculated: Elemental Analysis: %C, 41.79;
3
3
%
H, 4.56; %N, 14.62; found: %C, 41.77; %H, 4.59; %N, 14.60. HRMS
(
m/z): [M+H]+ calculated 288.0294; found 288.0301.
2.1.1. Synthesis of 4-methylthiazole-2-amine (1)
Chloroacetone (39.77 mmol, 3.20 mL) and its equivalent
thiourea (39.77 mmol, 3.028 g) were dissolved in ethanol and
stirred at room temperature 4h. The reaction control was checked
by thin-layer chromatography (TLC). After the completion of the
reaction, the crude product was obtained by filtration and then re-
crystallized from ethanol.
2.1.7. 2-((5-Methyl-1,3,4-thiadiazol-2-yl)thio)-N-(4-methylthiazol-
2-yl)propanamide (3d)
m. p. 187–189 °C, yield 79 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.57 (d, J = 7.05 Hz, 3H, -CH -C-S), 2.34 (s, 3H, thiazole-
3
CH ), 2.69 (s, 3H, thiadiazole-CH ), 4.65 (q, J = 7.02 Hz, 1H, H-C-S),
3
3
2

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
7
.16 (s, 1H, Ar-H), 12.32 (brs, 1H, -NH). 13C-NMR (75 MHz, DMSO-
d , ppm) δ 11.57 (thiazole-CH ), 15.71 (thiadiazole-CH ), 18.50
7.41 (m, 1H, Ar-H), 7.45 – 7.51 (m, 2H, Ar-H), 7.84 (d, J = 7.62
Hz, 1H, Ar-H), 8.04 (d, J = 7.95 Hz, 1H, Ar-H), 12.38 (brs, 1H, -
NH). 13C-NMR (75 MHz, DMSO-d6, ppm) δ 11.60 (thiazole-CH3),
18.94 (-CH3-C-S), 46.45 (H-C-S), 121.80, 122.43, 125.30, 126.97,
127.31, 135.38, 152.94, 156.35, 164.75, 169.26. For C14 H13N3OS3 cal-
culated: Elemental Analysis: %C, 50.12; %H, 3.91; %N, 12.53; found:
6
3
3
(
-CH -C-S), 46.44 (H-C-S),127.26, 135.30, 156.37, 162.48, 167.36,
3
169.21. For C10H12N OS calculated: Elemental Analysis: %C, 39.98;
4
3
%
H, 4.03; %N, 18.65; found: %C, 39.95; %H, 4.06; %N, 18.62. HRMS
(
m/z): [M+H]+ calculated 301.0246; found 301.0246.
%
C, 50.09; %H, 3.93; %N, 12.51. HRMS (m/z): [M+H]+ calculated
2
.1.8. N-(4-methylthiazol-2-yl)-2-((5-nitro-1H-benzimidazol-2-yl)
336.0294; found 336.0296. Solubility: practically insoluble in wa-
ter and anhydrous ethanol, soluble in hot ethanol, freely soluble in
DMSO.
thio)propanamide (3e)
m. p. 199–201 °C, yield 80 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.64 (d, J = 7.08 Hz, 3H, -CH -C-S), 2.33 (s, 3H, thiazole-
3
CH ), 4.88 (q, J = 7.11 Hz, 1H, H-C-S), 7.14 (s, 1H, Ar-H), 7.58
3
2.2. Antimicrobial activity
(
d, J = 8.85 Hz, 1H, Ar-H) 8.03 (dd, J = 2.28Hz, J = 6.57 Hz,
1
2
13
1
H, Ar-H), 8.29 (s, 1H, Ar-H). C-NMR (75 MHz, DMSO-d , ppm)
6
The antimicrobial activity of final compounds (3a-3i) com-
pounds was screened on eight bacterial and three fungal strains
according to the standard procedure of CLSI [26,27] as described
in the previous study [28]. The antibacterial activities of the syn-
thesized compounds were tested against Escherichia coli (ATCC
δ 11.57 (thiazole-CH ), 18.75 (-CH -C-S), 44.47 (H-C-S), 110.91,
3
3
114.10, 117.54, 127.14, 135.32, 142.14, 156.38, 156.92, 169.91. For
C14 H13N O S calculated: Elemental Analysis: %C, 46.27; %H, 3.61;
5
3 2
%
N, 19.27; found: %C, 46.25; %H, 3.64; %N, 19.29. HRMS (m/z):
[
M+H]+ calculated 364.0533; found 364.0534.
2
5922), Serratia marcescens (ATCC 8100), Klebsiella pneumoniae
(
ATCC 13883), Pseudomonas aeruginosa (ATCC 27853), Enterococcus
2
.1.9. 2-((5-Methoxy-1H-benzimidazol-2-yl)thio)-N-(4-methylthiazol-
-yl)propanamide (3f)
faecalis (ATCC 2942), Bacillus subtilis (ATCC 6633), Staphylococcus
aureus (ATCC 29213), and Staphylococcus epidermidis (ATCC 12228).
Candida albicans (ATCC 24433), Candida krusei (ATCC 6258), and
Candida parapsilopsis (ATCC 22019) were used to test the antifun-
gal activity of the same compounds. Tetracycline (against bacte-
rial strains) and fluconazole (against candida strains) were used as
standard reference drugs.
2
m. p. 167–169 °C, yield 86 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.59 (d, J = 7.08 Hz, 3H, -CH -C-S), 2.33 (s, 3H, thiazole-
3
CH ), 3.77 (s, 3H, -OCH ), 4.68 (q, J = 7.02 Hz, 1H, H-C-S), 6.77 (dd,
3
3
J = 2.46Hz, J = 6.27 Hz, 1H, Ar-H), 6.97 (s, 1H, Ar-H), 7.13 (s, 1H,
1
2
13
Ar-H), 7.35 (d, J = 8.73 Hz, 1H, Ar-H). C-NMR (75 MHz, DMSO-
d , ppm) δ 11.65 (thiazole-CH ), 18.78 (-CH -C-S), 44.85 (H-C-S),
6
3
3
5
5.91 (-OCH ), 97.36 (4 of benzimidazole), 111.23 (6 of benzimida-
3
2
.3. ADME parameters
zole), 115.52 (7 of benzimidazole), 126.85 (4 of thiazole), 135.28 (5
of thiazole), 148.07 (2 of benzimidazole), 155.89 (5 of benzimida-
zole), 157.01 (2 of thiazole), 170.23 (C=O). For C15H16 N O S cal-
The prediction of the physicochemical parameters of com-
4
2 2
pounds (3a-3i) was calculated using the SwissADME web-based
culated: Elemental Analysis: %C, 51.70; %H, 4.63; %N, 16.08; found:
program [29-31].
%
C, 51.73; %H, 4.60; %N, 16.11. HRMS (m/z): [M+H]+ calculated
349.0787; found 349.0794. Solubility: practically insoluble in wa-
2
.4. Docking study
ter and anhydrous ethanol, soluble in hot ethanol, freely soluble in
DMSO.
The crystal structure of the DNA gyrase enzyme was retrieved
from the Protein Data Bank server (PDB code: 5NPK). The protein
preparation process, ligand preparation process, grid generation,
docking, and visualization studies were worked on Schrodinger’s
Maestro molecular modeling package [32].
2
2
.1.10. 2-((5-Methyl-4H-1,2,4-triazol-3-yl)thio)-N-(4-methylthiazol-
-yl)propanamide (3g)
m. p. 100–102 °C, yield 78 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.48 (d, J = 7.02 Hz, 3H, -CH -C-S), 2.34 (s, 3H, thiazole-
3
The water molecules were removed from the crystal structure.
Ligands were set to the physiological pH (pH = 7.4± 1.0) at the pro-
tonation step. In molecular docking simulations: Glide/SP docking
protocols were applied for the prediction of topologies of 3f and 3i
at the allosteric pocket of the target structure [33], after the prepa-
ration steps, the molecules were docked to the allosteric pocket of
5NPK. The docking study was used here to predict the relationship
between structure and inhibition of DNA gyrase enzyme. After de-
termination of the best poses, strain energy calculation and rescor-
ing function [34] was performed for the ligands with more than
4 kcal/mol energy difference between the docked and free confor-
mations received to eliminate the calculation errors.
CH ), 3.55 (s, 3H, triazol-CH ), 4.27 (q, J = 6.99 Hz, 1H, H-C-S),
3
3
.15 (s, 1H, Ar-H), 8.62 (s, 1H, Ar-H), 12.20 (brs, 1H, -NH). 1 C-NMR
3
7
(
75 MHz, DMSO-d , ppm) δ 11.58 (thiazole-CH ), 18.17 (-CH -C-
6 3 3
S), 31.47 (triazol-CH ), 45.32 (H-C-S), 127.23, 135.44, 147.06, 147.15,
3
156.15, 169.50. For C10H13N OS calculated: Elemental Analysis: %C,
5 2
4
2.38; %H, 4.62; %N, 24.71; found: %C, 42.38; %H, 4.62; %N, 24.71.
HRMS (m/z): [M+H]+ calculated 284.0634; found 284.0637.
2
.1.11. 2-((1H-benzimidazol-2-yl)thio)-N-(4-methylthiazol-2-yl)
propanamide (3h)
m. p. 181–183 °C, yield 82 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.62 (d, J = 7.08 Hz, 3H, -CH -C-S), 2.33 (s, 3H, thiazole-
3
CH ), 4.82 (q, J = 7.08 Hz, 1H, H-C-S), 7.13 – 7.18 (m, 3H, Ar-H),
3
7
.45 – 7.48 (m, 2H, Ar-H), 12.60 (brs, 1H, -NH). 13C-NMR (75 MHz,
3. Results and discussion
DMSO-d , ppm) δ 11.57 (thiazole-CH ), 18.85 (-CH -C-S), 44.65
6
3
3
3
.1. Chemistry
(
H-C-S), 114.51, 122.20, 127.16, 135.33, 149.03, 156.35, 169.93. For
C14 H14 N OS calculated: Elemental Analysis: %C, 52.81; %H, 4.43;
4
2
The compounds 3a-3i were synthesized as summarized in
%N, 17.60; found: %C, 52.84; %H, 4.40; %N, 17.63. HRMS (m/z):
M+H]+ calculated 319.0682; found 319.0691.
Scheme 1. Initially, the 4-methylthiazole-2-amine (1) resulted
from the reaction of thiourea with 1-chloropropan-2-one. Then,
the obtained compound 1 was acylated to gain 2-chloro-N-(4-
methylthiazol-2-yl)propanamide (2). Lastly, the mercapto deriva-
tives and compound 2 were reacted in acetone to obtain N-(4-
methylthiazol-2-yl)propanamide derivatives as the core structure.
The structures of synthesized compounds (3a-3i) were confirmed
[
2
.1.12. 2-(Benzothiazol-2-ylthio)-N-(4-methylthiazol-2-yl)
propanamide (3i)
m. p. 194–196 °C, yield 82 %, 1HNMR (300 MHz, DMSO-d6,
ppm) δ 1.67 (d, J = 7.05 Hz, 3H, -CH -C-S), 2.34 (s, 3H, thiazole-
3
CH ), 4.91 (q, J = 7.05 Hz, 1H, H-C-S), 7.16 (s, 1H, Ar-H), 7.36 –
3
3

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
Scheme 1. The synthesis diagram of the compounds 3a–3i. Reagents and conditions: (a) EtOH, r.t., 24 h; (b) TEA, THF, ClCOCH2Cl, 0–5 °C, then r.t 3 h; (c) Acetone, K2CO3, r.t.
by 1H-NMR, 13C-NMR, 2D-NMR (HSQC, NOESY, HMBC) and high-
resolution mass spectroscopy (HRMS).
3.1.1. NMR spectrum
In the 1H-NMR and 13C-NMR spectra, the peaks were seen at
estimated aromatic and aliphatic regions. The mass peaks [M+1] of
the compounds were in agreement with their predicted molecular
formula (3a-3i).
Scheme 2. As numbered the molecular structure of compound 3f.
The 1H-NMR spectra showed signals at δ 2.33–2.34 ppm
(
CH ) for 4-methylthiazole protons which were singlet peaks.
3
carbons and also found new two peaks that we could not observe
in the C13-NMR spectrum. These were belonging to 3a and 7a of
the benzimidazole carbons observed at δ 135.10 and δ 139.8 ppm,
respectively.
Propanamide protons were observed at δ 1.41–1.67 ppm (CH ) as
3
doublet and δ 4.11–4.91 ppm (CH) as quartet peaks. A broad sin-
glet peak seen at δ 12.16–12.60 ppm indicated the propanamide
N–H proton. The appearance of a pair of singlets, doublets, triplets,
and/or multiplets δ 6.77–8.62 ppm were due to the aromatic pro-
tons of the aromatic rings. The 13C-NMR spectra showed signals
3.2. ADME parameters
at δ 11.55–11.65 ppm for 4-methyl thiazole carbon (CH ), while
3
those at δ 17.68–18.94 ppm were for propanamide (CH ), δ 44.47–
The computational results were shown in Table 1. According to
these results, there was no violation of Lipinski’s rule of five [35].
Even if there is no exact finding in practice, these scores are in
harmony with the activity potential of the compounds and these
approximations would inspire drug design. In fact, it may be sug-
gested that synthesized compounds may have a good pharmacoki-
netic profile. Thus, the drug-likeness issue of the compounds was
tipped to positive.
3
4
6.45 ppm for propanamide (CH), δ 97.36–167.36 ppm for aromatic
carbon and δ 169.12–170.23 ppm for carbonyl (C=O) carbon. M+1
peaks in LC-MS/MS spectra were in agreement with the calculated
molecular weight of the target compounds (3a–3i). Elemental anal-
ysis results for C, H, and N elements agreed to the calculated val-
ues for the synthesized compounds.
3
.1.2. Evaluation of 2D-NMR spectra
D advanced NMR studies (HSQC, NOESY, HMBC) were carried
2
3.3. Antimicrobial activity
out by taking compound 3f (Scheme 2), which has the highest ac-
tivity among the synthesized compounds. Firstly, the obtained data
from the H -NMR and C13-NMR spectrum was analyzed. Then, the
HSQC spectrum was merged with H1 and C13-NMR spectrums to
match the carbons that had hydrogen(s). Then, using the HMBC
data, all carbons were marked. As a result, we exactly matched all
Although there are numerous antimicrobial studies about sub-
stituted thiazoles from different positions, 2,4-disubstituted thia-
zoles are more attractive to eliminate the invasive microbes and
have generally fewer side effects than other derivatives [11,36-39].
As a result, in this study, the core structure of the final compounds
1
4

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
Table 1
Physicochemical, pharmacokinetic and medicinal chemistry properties of the final compounds (by Swis-
sAdme) 3a-3i.
Physicochemical Properties
Pharmacokinetics
Medicinal Chemistry
HBA
HBD
TPSA
Log Po/w
Log S
GIA
Log Kp
RoF (V)
SA
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
5
3
3
4
5
4
4
3
3
9
7
1
1
1
1
2
2
1
2
1
6
1
139.13
113.35
133.19
149.55
170.03
133.44
126.24
124.21
136.66
181.62
81.65
1.26
1.81
2.13
2.22
2.06
2.68
1.38
2.80
3.53
-0.40
0.88
-4.01
-3.93
-4.79
-5.47
-6.47
-5.85
-4.59
-5.69
-6.87
-3.64
-1.63
High
High
High
Low
Low
Low
High
High
Low
Low
High
-6.98
-6.65
-6.38
-6.23
-6.22
-6.03
-7.08
-5.83
-5.30
-8.83
-7.92
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (0)
Yes (1)
Yes (0)
3.26
3.15
3.64
3.42
3.39
3.27
3.27
3.17
3.32
5.17
2.91
g
h
i
RF- 1
RF- 2
HBA: H-bond acceptor, HBD: H-bond acceptor, TPSA: Topologic polar surface area ( A˚ ²) Log Po/w: Consensus
Log Po/w (Average of all five predictions), Log S: Water Solubility, GIA: Gastrointestinal absorption, Log Kp:
skin permeation (cm/s) RoF (V): Rule of Five (violation number), SA: Synthetic accessibility from 1 (very
easy) to 10 (very difficult). RF- 1: Tetracycline, RF-2: Fluconazole
Table 2
According to the results of in vitro study, the final compounds
showed modest potency. In general, the MIC values of the tested
compounds were approximately 125.00 μg/mL. However, com-
pound 3f against E. coli (ATCC 25922) and S. marcescens (ATCC
8100) and compound 3i against S. marcescens (ATCC 8100) and E.
faecalis (ATCC 2942) were found active at 62.50 μg/mL. Also, the
inhibition activity of compound 3f (MIC:15.63 μg/mL) has an 8-
fold or 16-fold higher potency than other compounds against S. au-
reus (ATCC 29213). It was found that all synthetic compounds show
half-effect activity against P. aeruginosa compared to the reference
drug.
Antifungal activity of the compounds 3a-3i as
MIC values (μg/mL)
A
B
C
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
125.00
125.00
>250.00
125.00
125.00
250.00
125.00
125.00
>250.00
7.81
125.00
125.00
>250.00
125.00
125.00
250.00
125.00
125.00
125.00
7.81
62.50
62.50
62.50
15.63
125.00
250.00
125.00
125.00
>250.00
3.91
g
h
i
The most active compound against E. coli was 3f; against S.
marcescens were 3f and 3i; against E. faecalis was 3i. Also, against
the rest of the strains, all compounds showed the same potency.
There were no differences in potency between the tested com-
pounds against gram-positive (+) and gram-negative(-) strains.
As a simple assertion about antimicrobial results, the final com-
pounds, 2,4-disubstituted thiazole derivatives, showed modest ac-
tivity at most against the invasive bacteria and fungus. According
to previous studies by different groups [40-42] they used chal-
cone moiety, hydrazide, and several bulky groups at the 4th po-
sition, then they viewed the docking performance at the DNA gy-
rase active site. In those studies, although a significant antimi-
crobial activity was observed, DNA gyrase interactions were found
just enough. However, 2,4-disubstituted thiazole moiety is an im-
portant motif to observe the antimicrobial activity. Alternatively,
since the thiazole ring system allows for substitution diversity and
also can be easily synthesized, it is important to make recommen-
dations for future studies, namely structure-activity relationship
S. D.
A: C. albicans (ATCC 24433), B: C. krusei (ATCC
258), C: C. parapsilopsis (ATCC 22019). S.D:
6
Standard Drug= Fluconazole.
was synthesized according to this superiority and inspired also by
ß-lactams.
3
.3.1. Anticandidal activity
The final compounds (3a-3i) were tested against Candida albi-
cans (ATCC 24433), Candida krusei (ATCC 6258), and Candida para-
psilopsis (ATCC 22019). The results were showed in Table 2.
Based on the results, there was no compound worthy of note
as an antifungal drug except 3d (MIC: 15.63 μg/mL against C.
parapsilopsis). The standard drug, fluconazole, was found 4-fold
more active than compound 3d. Therefore, the activity poten-
tial as anticandidal was found modest, yet it may be useful as
a base to develop anticandidal drugs. 5-Methylthiadiazole moi-
ety showed better activity than (benz)azoles, therefore our future
studies for the development of anticandidal drugs would be in de-
signing a linkage of thiazole-thiadiazole and modification of the
substitutes.
(
SAR).
Based on the above information, the focus was upon those two
compounds to determine the mechanism of action. Since there
was no enough concentration for effective inhibition to occur, ei-
ther the binding energy between the compounds and the active
pocket was low or the compounds could not fit well inside the
pocket. But it is more logical to determine the shapes of interac-
tions at the binding site and then discuss the structure-activity re-
lationship (SAR) for developing new antimicrobial agents. There-
fore, the common features of the compounds and bacteria strains
were determined. First, the common feature of the gram (+) and
the gram (-) strains, both have a DNA gyrase enzyme. S. aureus and
E. coli are commonly used for the isolation of DNA gyrase [43,44].
Secondly, the active compounds have the thiazole-benzazole moi-
eties, and designing with the bioisosteric replacement is fashion-
3
.3.2. Antibacterial activity
The final compounds (3a-3i) were tested against Escherichia
coli (ATCC 25922), Serratia marcescens (ATCC 8100), Klebsiella
pneumoniae (ATCC 13883), Pseudomonas aeruginosa (ATCC 27853),
Enterococcus faecalis (ATCC 2942), Bacillus subtilis (ATCC 6633),
Staphylococcus aureus (ATCC 29213). The results were shown in
Table 3.
5

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
Table 3
Antibacterial activity of the compounds 3a-3i as MIC values (μg/mL).
A
B
C
D
E
F
G
H
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
125.00
125.00
>250.00
125.00
125.00
62.50
125.00
125.00
125.00
125.00
125.00
62.50
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
7.81
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
62.50
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
62.50
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
7.81
250.00
250.00
250.00
250.00
250.00
15.63
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
125.00
g
h
i
125.00
125.00
>250.00
7.81
125.00
125.00
62.50
250.00
250.00
125.00
<0.98
S. D.
3.91
15.63
A: E. coli (ATCC 25922), B: S. marcescens (ATCC 8100), C: K. pneumoniae (ATCC 13883), D: P. aerug-
inosa (ATCC 27853), E: E. faecalis (ATCC 2942), F: B. subtilis (ATCC), G: S. aureus (ATCC 29213), H:
S. epidermidis (ATCC 12228) A-D: Gram negative bacteria, E-H: Gram positive bacteria. S.D: Stan-
dard Drug=Tetracycline
Fig. 2. Compounds 3f (green carbons) and 3i (turquoise carbons), and reference compound (maroon carbons) in DNA gyrase allosteric pocket (PDBID: 5NPK). The active site
residues were draw in stick form (black carbons). If there is an interaction between ligand and residue, these residues were represented in a ball-stick form (plum carbons).
Red line represents the DNA chain.
able to obtain active compounds since time immemorial. A pre-
vious study [33] has reported that compound 1 (reference com-
pound: RF, include thiophene and pyrrolopyridine moieties as
bioisosteres of thiazole and benzazoles, respectively) showed mod-
est activity against DNA gyrase enzyme. Because of these reasons,
we built up the docking study on DNA gyrase considering this
work.
According to docking results, collected poses of 3f and 3i
have not shown the strain penalty, therefore the results should
be in harmony with the experimental study. Also, compound 3f
showed three H-bonds with Arg630, Glu634, and Arg1342. On
the other hand, compound 3i displayed two H-bond with Arg630
and Pro1343, and one π- π stacking with Arg1342. Glutamic acid
(634) and arginine (630) amino acids were described as impor-
tant residues to obtain the inhibitor activity on the enzyme. Thus,
the in-silico study supports the in vitro study due to differences
in the interactions. The thiazole moiety of compound 3f and thio-
phene moiety of the reference drug (RF) were in the same direc-
tion in the pocket which facilitates the interaction with signifi-
cant residues. In spite of that compound 3i was docked around
the same coordinates as those of the reference compound, the thi-
azole moiety was unable to fit into the thiophene cavity, there-
fore, its inhibition activity against DNA gyrase was lower than
3
.3.3. Molecular docking study
The aim of the DNA gyrase poisoning is simply based on the
settling of the compound between the DNA and enzyme [45,46],
however it was reported the discovering of a new pocket for
thiophene analogs in 2017 [33]. It was observed that the com-
pounds have no interaction with nucleotides in this pocket, albeit
it showed modest activity by an allosteric mechanism. Accordingly,
the products in our study were simulated in the allosteric pocket.
The collected best poses were shown in Figs. 2–6, and the results
of strain rescore was displayed in Table 4.
3f.
Despite the bicyclics, pyrrolizidine (RF) and benzimidazole
3f), located in different areas, interacted with the same residue
(
6

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
Fig. 3. 2D interaction diagram of 3f in active site. (PDBID: 5NPK).
Fig. 4. Compound 3f in active site as 3D pose. Red line represents the DNA chain. (PDBID: 5NPK).
(
Arg1342) by approaching from a different side causing benzimida-
mended for designing new antibacterial molecules with better ac-
zole N1 atom to form H-bond with this residue. Thus, it is thought
that the benzimidazole ring was a better choice than benzothia-
zole ring for this activity. Additionally, each final compound can be
useful according to its potential sites (N, O, S) for ligand-complex
studies in the future, like one of the known antimicrobial elements,
silver. Due to the silver(I) complexes for antimicrobial applications
tivity:
• 4-Methyl substituent can be replaced with small polar moieties
such as chlorine, hydroxy, oxo, fluorine, and trifluoromethyl
which may enable the interaction with Arg1342.
[
47-49], the combination of the silver(I) and the compounds can
• The Propionamide chain can be enlarged between two-four car-
improve the antimicrobial activity.
bons to reach the hydrophobic cavity.
Briefly, because of the simple, cheap, and no time-consuming
synthesis of 2,4-disubstituted thiazoles and their high poten-
tial chemotherapeutic effects, the following modifications recom-
• More than one substitution on benzimidazole, especially 5,6-
disubstituted derivatives may be convenient to increase the ac-
tivity allosterically.
7

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
Fig. 5. 2D interaction diagram of compound 3i in active site. (PDBID: 5NPK).
Fig. 6. Compound 3i in active site as 3D pose. Red line represents the DNA chain.
Table 4
Strain rescore results.
Compound
Strain_Penalty
Strain_Energy
Bound_Energy
Unbound_Energy
Energy_Offset
3
3
i
0.00
0.00
3.45
4.02
10.39
12.27
6.94
8.26
4.00
4.00
f
strain penalty was calculated by the following calculation (=[(E{bound}-E{free}) - energy_offset] ∗ scale_factor,
if [E{bound}-E{free} - energy_offset] > 0).
8

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
4. Conclusion
Reference
[
1] A. Ayati, S. Emami, A. Asadipour, A. Shafiee, A. Foroumadi, Recent applications
of 1,3-thiazole core structure in the identification of new lead compounds and
drug discovery, Eur. J. Med. Chem. 97 (2015) 699–718, doi:10.1016/j.ejmech.
2015.04.015.
In this study, novel (benz)azole derivatives including 4-
methylthiazole were synthesized and investigated for their
antimicrobial activity. The final compounds showed antibacterial
activity between modest and good activity against gram(+) and
gram-(-) strains. Compound 3f had more attractive values against
different strains. On the other hand, the results of the docking
study gave the hope to fight against the development of antibac-
terial resistance, as well as the design of new compounds. But
above all, since the antimicrobial agents used in clinics usually
are applied through oral or semi-solid forms, ADME parameters
should be considered at the beginning of the designing of new
compounds. Briefly, meaningful data to correlate the SAR with
thiazole-(benz)azole hybridized compounds were presented in this
study. As a future project, the mentioned ideas will be used to
synthesize new compounds having better antibacterial activity,
particularly against resistant organisms.
[
2] P.L. Lobo, B. Poojary, M. Kumsi, V. Chandra, N.S. Kumari, K.R. Chandrashekar,
Synthesis, antimicrobial and antioxidant activities of 2-[1-{3,5-diaryl-4,5-
dihydro-1H-pyrazolenyl}]-4-(4-nitrophenyl)-[1,3]-thiazoles, Med. Chem. Res.
22 (2012) 1689–1699, doi:10.1007/s00044-012-0154-3.
[3] H.I. El-Subbagh, A.M. Al-Obaid, 2,4-Disubstituted thiazoles II. A novel class of
antitumor agents, synthesis and biological evaluation, Eur. J. Med. Chem. 31
(1996) 1017–1021, doi:10.1016/s0223-5234(97)86181-8.
[4] F. Azam, S. Singh, S.L. Khokhra, O. Prakash, Synthesis of Schiff
ꢀ
bases of naphtha[1,2-d]thiazol-2-amine and metal complexes of 2-(2 -
hydroxy)benzylideneaminonaphthothiazole as potential antimicrobial agents,
J. Zhejiang Univ. Sci. B 8 (2007) 446–452, doi:10.1631/jzus.2007.B0446.
5] A. Rouf, C. Tanyeli, Bioactive thiazole and benzothiazole derivatives, Eur. J. Med.
Chem. 97 (2015) 911–927, doi:10.1016/j.ejmech.2014.10.058.
[
[
6] D.J. Newman, G.M. Cragg, K.M. Snader, Natural products as sources of new
drugs over the period 1981-2002, J. Nat. Prod. 66 (2003) 1022–1037, doi:10.
1021/np030096l.
[7] R.M. Borde, M.A. Gaikwad, R.A. Waghmare, A.S. Munde, Design, synthesis
and in-vitro anti-inflammatory, antimicrobial activities of some novel 2, 3-
disubstituted -1,3-thiazolidin-4-one derivatives containing thiazole moiety, J.
Ultra Chem. 14 (2018) 104–114, doi:10.22147/juc/140303.
5
. Ethics approval and consent to participate
[
8] P. Arora, R. Narang, S. Bhatia, S. Nayak, S. Singh, B. Narasimhan, Synthesis,
molecular docking and QSAR studies of 2, 4-disubstituted thiazoles as antimi-
crobial agents, J. Appl. Pharmaceut. Sci. (2015) 028–042, doi:10.7324/japs.2015.
Not applicable.
50206.
[
9] S.K. Bharti, G. Nath, R. Tilak, S.K. Singh, Synthesis, anti-bacterial and anti-
fungal activities of some novel Schiff bases containing 2,4-disubstituted thi-
azole ring, Eur. J. Med. Chem. 45 (2010) 651–660, doi:10.1016/j.ejmech.2009.
6. Human and animal rights
11.008.
Not applicable.
[
10] M.T. Chhabria, S. Patel, P. Modi, P.S. Brahmkshatriya, Thiazole: A review on
chemistry, synthesis and therapeutic importance of its derivatives, Curr. Top.
Med. Chem. 16 (2016) 2841–2862.
7
. Consent for Publication
[
11] M.M. Masood, M. Irfan, S. Alam, P. Hasan, A. Queen, S. Shahid, M. Zahid,
A. Azam, M. Abid, Synthesis, Antimicrobial Evaluation and In silico Studies
of Novel 2,4- disubstituted-1,3-thiazole Derivatives, Lett. Drug Des. Discov. 16
Not applicable.
(2018) 160–173, doi:10.2174/1570180815666180502120042.
[
12] H. Mohammad, Antimicrobial Characterization and Therapeutic Applications
of Novel Synthetic Thiazole Compounds against Multidrug-Resistant Staphylo-
cocci and Enterococci, in, 2016.
8. Availability of DATA AND MATERIALS
[
13] N. Vukovic, S. Sukdolak, S. Solujic, T. Milosevic, Synthesis and antimicro-
bial evaluation of some novel 2-aminothiazole derivatives of 4-hydroxy-
chromene-2-one, Arch. Pharm. (Weinheim) 341 (2008) 491–496, doi:10.1002/
ardp.200700215.
The authors confirm that the data supporting the findings of
this research are available along with the manuscript.
[
14] A. Biernasiuk, M. Kawczy n´ ska, A. Berecka-Rycerz, B. Rosada, A. Gu-
mieniczek, A. Malm, K. Dzitko, K.Z. Ła˛czkowski, Synthesis, antimicro-
bial activity, and determination of the lipophilicity of ((cyclohex-3-
enylmethylene)hydrazinyl)thiazole derivatives, Med. Chem. Res. 28 (2019)
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or
2023–2036, doi:10.1007/s00044-019-02433-2.
[15] P. Yogi, M. Ashid, N. Hussain, S. Khan, A. Joshi, One-pot synthesis of thiazoles
via hantzsch thiazole reaction and their antimicrobial activity, Asian J. Chem.
28 (2016) 927–932, doi:10.14233/ajchem.2016.19603.
Not-for-profit sectors
[16] B.S. Holla, K.V. Malini, B.S. Rao, B.K. Sarojini, N.S. Kumari, Synthesis of
some new 2,4-disubstituted thiazoles as possible antibacterial and anti-
inflammatory agents, Eur. J. Med. Chem. 38 (2003) 313–318, doi:10.1016/
s0223-5234(02)01447-2.
[17] N.P. Prajapati, K.D. Patel, R.H. Vekariya, H.D. Patel, D.P. Rajani, Thiazole fused
thiosemicarbazones: Microwave-assisted synthesis, biological evaluation and
molecular docking study, J. Mol. Struct. 1179 (2019) 401–410, doi:10.1016/j.
molstruc.2018.11.025.
Conceptualization: LY, AEE; Methodology: AEE, SD, DN, S¸ AY;
Software: AEE; Validation: AEE, SD; Formal analysis: SD, DN, S¸ AY;
Investigation: AEE, SD, DN, S¸ AY, ÜDG; Writing-Original Draft, Re-
view & Editing: AEE, DN, SD; Visualization: LY, ÜDG, AEE; Supervi-
sion: LY, ÜDG
[18] S. Wagle, A.V. Adhikari, N.S. Kumari, Synthesis of Some Novel 2,4-Disubstituted
Thiazoles as Possible Antimicrobial Agents, Phosphorus Sulfur Silicon Relat
Elem, 183 (2008) 1285-1300, 10.1080/10426500701641049.
Declaration of Competing Interest
[19] A.F.M.H. Rahman, M.H. Bhuiyan, Synthesis and antimicrobial evaluation of
some thiazole derivatives, J. Sci. Res. 3 (2010), doi:10.3329/jsr.v3i1.5419.
[
20] A.K. Jain, R. Singla, B. Shrivastava, Thiazole: a remarkable antimicrobial and
antioxidant agents, Pharmacologyonline 2 (2011) 1072–1084.
The author confirms that this article content has no conflict of
interest.
[21] J. Stefanska, G. Nowicka, M. Struga, D. Szulczyk, A.E. Koziol, E. Augustynowicz-
Kopec, A. Napiorkowska, A. Bielenica, W. Filipowski, A. Filipowska,
A. Drzewiecka, G. Giliberti, S. Madeddu, S. Boi, P.La Colla, G. Sanna, An-
timicrobial and anti-biofilm activity of thiourea derivatives incorporating a
Acknowledgments
2
-aminothiazole scaffold, Chem. Pharm. Bull. (Tokyo) 63 (2015) 225–236,
doi:10.1248/cpb.c14-00837.
We gratefully thank Anadolu University DOPNA Laboratory for
analyzing the synthesized compounds.
[
22] A. Hussein, A. El-Adasy, I.S. Hafi, E.A. Ishak, E.H. Gawish, M.S. El-Gaby, Biolog-
ical evaluation of some novel thiazole, thiazolo [3, 2-a] pyridine and thiazolo
ꢀ
ꢀ
[
3 , 2 : 1, 6] pyridine rerivatives containing diphenyl moiety as antimicrobial
agents, J. App. Pharm. 6 (2014) 296–307.
Supplementary materials
[23] C. Willyard, The drug-resistant bacteria that pose the greatest health threats,
Nature 15 (2017) 543, doi:10.1038/nature.2017.21550.
[
24] M.M. Canuto, F. Gutierrez, Antifungal drug resistance to azoles and polyenes,
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130692.
Lancet Infect. Dis.
7.
2 (2002) 550–563, doi:10.1016/S1473-3099(02)00371-
9

A.E. EVREN, S. DAWBAA, D. NUHA et al.
Journal of Molecular Structure 1241 (2021) 130692
[
25] H.C. Neu, General concepts on the chemotherapy of infectious diseases, Med.
Clin. North Am. 71 (1987) 1051–1064, doi:10.1016/s0025-7125(16)30796-9.
26] CLSIMethods for Dilution Antimicrobial Susceptibility Tests For Bacteria That
Grow Aerobically; Approved Standard—Ninth Edition. CLSI document M07-A9.,
Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, USA, 2012.
[39] R. Gondru, S. Kanugala, S. Raj, C. Ganesh Kumar, M. Pasupuleti, J. Banothu,
R. Bavantula, 1,2,3-triazole-thiazole hybrids: Synthesis, in vitro antimicrobial
activity and antibiofilm studies, Bioorg. Med. Chem. Lett. 33 (2021) 127746,
doi:10.1016/j.bmcl.2020.127746.
[
[40] M.H. Muluk, P.S. Patil, S.L. Kasare, R.S. Kulkarni, P.P. Dixit, P.B. Choudhary,
K.P. Haval, Synthesis and molecular docking studies of novel pyridine-thiazole-
hydrazone conjugates as antimicrobial and antioxidant agents, Eur. Chem. Bull.
9 (2020), doi:10.17628/ecb.2020.9.184-192.
[
27] A. Espinel-Ingroff, E. Cantón, Antifungal susceptibility testing of filamentous
fungi, in: Antimicrobial Susceptibility Testing Protocols, CLSI, Wayne, PA, USA,
2007, pp. 209–241.
[
28] A.E. Evren, L. Yurttas, M. Yılmaz-Cankilic, Synthesis of novel N-(naphthalen-1-
yl)propanamide derivatives and evaluation their antimicrobial activity, Phos-
phorus Sulfur Silicon Relat. Elem. 195 (2019) 158–164, doi:10.1080/10426507.
[41] R.E. Khidre, I.A.M. Radini, Design, synthesis and docking studies of novel
thiazole derivatives incorporating pyridine moiety and assessment as an-
timicrobial agents, Sci. Rep. 11 (2021) 7846, doi:10.1038/s41598- 021-86424-
7.
2019.1657428.
[
[
29] A. Daina, O. Michielin, V. Zoete, SwissADME:
a
free web tool to evaluate
[42] P.S. Patil, S.L. Kasare, A.D. Badar, R.S. Kulkarni, P.P. Dixit, J.A. Kulkarni,
P.B. Choudhari, K.P. Haval, Synthesis, antimicrobial evaluation, and molecular
docking study of new thiazole-5-phenylpropenone derivatives, Russian J. Gen-
eral Chem. 90 (2020) 1523–1528, doi:10.1134/s1070363220080216.
[43] A.Y. Saiki, L.L. Shen, C.M. Chen, J. Baranowski, C.G. Lerner, DNA cleavage ac-
tivities of Staphylococcus aureus gyrase and topoisomerase IV stimulated by
quinolones and 2-pyridones, Antimicrob. Agents Chemother. 43 (1999) 1574–
1577, doi:10.1128/AAC.43.7.1574.
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules, Sci. Rep. 7 (2017) 42717, doi:10.1038/srep42717.
30] A. Daina, O. Michielin, V. Zoete, iLOGP: a simple, robust, and efficient descrip-
tion of n-octanol/water partition coefficient for drug design using the GB/SA
approach, J. Chem. Inf. Model 54 (2014) 3284–3301, doi:10.1021/ci500467k.
[
31] A. Daina, V. Zoete, A boiled-egg to predict gastrointestinal absorption and brain
penetration of small molecules, ChemMedChem 11 (2016) 1117–1121, doi:10.
1
002/cmdc.201600182.
[44] J.C. Bronstein, S.L. Olson, K. LeVier, M. Tomilo, P.C. Weber, Purification and
characterization of recombinant Staphylococcus haemolyticus DNA gyrase and
topoisomerase IV expressed in Escherichia coli, Antimicrob. Agents Chemother.
48 (2004) 2708–2711, doi:10.1128/AAC.48.7.2708-2711.2004.
[45] K. Lal, N. Poonia, P. Rani, A. Kumar, A. Kumar, Design, synthesis, antimicrobial
evaluation and docking studies of urea-triazole-amide hybrids, J. Mol. Struct.
(2020) 1215, doi:10.1016/j.molstruc.2020.128234.
[
32] S. Maestro, Version 10.6, LLC, New York, 2016.
[
33] P.F. Chan, T. Germe, B.D. Bax, J. Huang, R.K. Thalji, E. Bacque, A. Checchia,
D. Chen, H. Cui, X. Ding, K. Ingraham, L. McCloskey, K. Raha, V. Srikannathasan,
A. Maxwell, R.A. Stavenger, Thiophene antibacterials that allosterically stabi-
lize DNA-cleavage complexes with DNA gyrase, Proc. Natl. Acad. Sci. U S A, 114
(2017) E4492-E4500, doi:10.1073/pnas.1700721114.
[
[
34] MacroModelversion 4.8, Schrödinger, LLC, New York, NY, 2016 in.
35] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and compu-
tational approaches to estimate solubility and permeability in drug discovery
and development settings, Adv. Drug Deliv. Rev. 23 (1997) 3–25, doi:10.1016/
S0169-409x(96)00423-1.
[46] M. Erol, I. Celik, G. Kuyucuklu, Synthesis, Molecular docking, molecular
dynamics, DFT and Antimicrobial Activity Studies of 5-substituted-2-(p-
methylphenyl)benzoxazole Derivatives, J. Mol. Struct. 1234 (2021), doi:10.1016/
j.molstruc.2021.130151.
[47] S.W. Jaros, M.F. Guedes da Silva, M. Florek, P. Smolenski, A.J. Pombeiro,
A.M. Kirillov, Silver(I) 1,3,5-Triaza-7-phosphaadamantane coordination poly-
mers driven by substituted glutarate and malonate building blocks: self-
assembly synthesis, structural features, and antimicrobial properties, Inorg.
Chem. 55 (2016) 5886–5894 10.1021/acs.inorgchem.6b00186.
[48] S.W. Jaros, P. Smole n´ ski, M.F.C. Guedes da Silva, M. Florek, J. Król,
Z. Staroniewicz, A.J.L. Pombeiro, A.M. Kirillov, New silver BioMOFs driven
by 1,3,5-triaza-7-phosphaadamantane-7-sulfide (PTA-S): synthesis, topologi-
cal analysis and antimicrobial activity, CrystEngComm (2013) 15, doi:10.1039/
c3ce40913a.
[
36] R. Sadashiva, D. Naral, J. Kudva, S.Madan Kumar, K. Byrappa,
R.Mohammed Shafeeulla, M. Kumsi, Synthesis, structure characterization,
in vitro and in silico biological evaluation of a new series of thiazole nu-
cleus integrated with pyrazoline scaffolds, J. Mol. Struct. 1145 (2017) 18–31,
doi:10.1016/j.molstruc.2017.05.066.
[
37] P. Gobala Krishnan, K. Gnanaprakash, K.B. Chandrasekhar, Design, synthesis,
characterization and antitubercular activity of some nov-el 2, 4-disubstituted
thiazole derivatives, Int. J. Res. Pharmaceut. Sci. 10 (2019) 1504–1509, doi:10.
26452/ijrps.v10i2.729.
[
38] A.I. Pricopie, M. Focsan, I. Ionut, G. Marc, L. Vlase, L.I. Gaina, D.C. Vodnar, S. El-
emer, G. Barta, A. Pirnau, O. Oniga, Novel 2,4-disubstituted-1,3-thiazole deriva-
tives: synthesis, anti-candida activity evaluation and interaction with bovine
serum albumine, Molecules 25 (2020), doi:10.3390/molecules25051079.
[49] T.A. Fernandes, I.F.M. Costa, P. Jorge, A.C. Sousa, V. Andre, N. Cerca, A.M. Kir-
illov, Silver(I) coordination polymers immobilized into biopolymer films for an-
timicrobial applications, ACS Appl. Mater. Interfaces 13 (2021) 12836–12844,
doi:10.1021/acsami.0c19446.
10