Derivatives of pyridine and thiazole hybrid: Synthesis, DFT, biological evaluation via antimicrobial and DNA cleavage activity

Article abstract of DOI:10.1016/j.bioorg.2019.103476

A novel series of the 2-pyridine substituted 3a-e and 4-pyridine substituted 4a-e thiazole derivatives were synthesized, characterized, and evaluated for the biological activity. Crystallographic parameters and inter- and intramolecular interactions of 3a

Full text of DOI:10.1016/j.bioorg.2019.103476

Journal Pre-proofs
Derivatives of Pyridine and Thiazole Hybrid: Synthesis, DFT, Biological
Evaluation via Antimicrobial and DNA Cleavage Activity
Serpil Eryılmaz, Emine Türk Çelikoğlu, Önder İdil, Ersin İnkaya, Zehra
Kozak, Ender Mısır, Melek Gül
PII:
S0045-2068(19)31293-3
DOI:
https://doi.org/10.1016/j.bioorg.2019.103476
YBIOO 103476
Reference:
To appear in:
Bioorganic Chemistry
Received Date:
Revised Date:
Accepted Date:
7 August 2019
3 November 2019
24 November 2019
Please cite this article as: S. Eryılmaz, E. Türk Çelikoğlu, O. İdil, E. İnkaya, Z. Kozak, E. Mısır, M. Gül,
Derivatives of Pyridine and Thiazole Hybrid: Synthesis, DFT, Biological Evaluation via Antimicrobial and DNA
Cleavage Activity, Bioorganic Chemistry (2019), doi: https://doi.org/10.1016/j.bioorg.2019.103476
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Derivatives of Pyridine and Thiazole Hybrid: Synthesis, DFT, Biological Evaluation via
Antimicrobial and DNA Cleavage Activity
Serpil Eryılmaza*, Emine Türk Çelikoğlub, Önder İdilc, Ersin İnkayad, Zehra Kozake, Ender Mısıra,
Melek Güle
aDepartment of Physics, Faculty of Arts and Sciences, Amasya University, 05100, Amasya, Turkey
bDepartment of Biology, Faculty of Arts and Sciences, Amasya University, 05100, Amasya, Turkey
cDepartment of Pre-School Education, Faculty of Education, Amasya University, 05100, Amasya, Turkey
dDepartment of Machinery and Metal Technologies, Merzifon Vocational School, 05300, Amasya University, Turkey
eDepartment of Chemistry, Faculty of Arts and Sciences, Amasya University, 05100, Amasya, Turkey
Abstract
A novel series of the 2-pyridine substituted 3a-e and 4-pyridine substituted 4a-e thiazole
derivatives were synthesized, characterized, and evaluated for the biological activity.
Crystallographic parameters and inter- and intramolecular interactions of 3a and 3c single crystals
were examined through XRD analysis. The chemical reactivity potentials of the compounds were
evaluated, by comparing with a theoretical approach based on DFT. The biological activity properties
of synthesized compounds were determined by antimicrobial activity with Gram positive, Gram
negative, Yeast via minimal inhibitory concentration (MIC) method and DNA cleavage activity
studies. The most obvious findings to emerge from this study are that on the basis of both biological
activity and chemical reactivity 4-pyridine thiazole hybrid compounds 4a-e showed more potent
activity than 3a-e. In general, the antimicrobial activity of synthesized compounds follows the
Bacillus cereus>Staphylococcus aureus>Candida albicans>Escherichia coli>Pseudomonas
aeruginosa. The most potent compound 4c (MIC values 0.02 mM) exhibited antimicrobial activity
against Staphylococcus aureus and Bacillus cereus. Furthermore, this compound has a good
electrophilicity index value (4.56 eV).
Keywords
Pyridine, Thiazole, DFT, Chemical reactivity, Antimicrobial activity, DNA cleavage activity
1. Introduction
In the late 19th century, a series of successful works by Hofmann [1] and Hantzsch [2]
pioneered the development of thiazole synthesis chemistry. Afterwards, synthesis processes having
different mechanisms called as Gabriel, Cook-Heilborn and Tcherniac contributed to the obtained of

new thiazole derivative compounds [3]. Thiazole ring having a strong S-C-N fragment which is a
member of the family of five-membered heterocyclic compounds; has been the subject of many
different types of research to date. Determining that the cyanine dyes contain a thiazole derivative
skeleton as a photographic sensitizer [4]; it is considered as one of the first step of its use in different
commercial industry branches with its dyestuff feature [5-7]. In 1967, Stoll et al. reported that the
strong nut-like odour of cocoa extract originated from thiazole derivative compound [8]. This
potential that attracted the attention of the researchers has supported by studies showing that thiazole
groups have as a strong flavour component in today's food industry [9-11]. On the other hand, natural
compounds such as thiamine (known as vitamin B1), thiamine pyrophosphate (TPP), epothilone,
bacitracin, penicillin antibiotics and a wide range of synthetic drug groups contain thiazole moiety.
Previous research has shown that it is an undeniable fact that thiazole based-compounds had effective
pharmacological importance with antimicrobial [12-15], antitumor [16-18], anti-diabetic [19-21],
anticonvulsant [22,23], anti-inflammatory [24-26], antioxidant [27,28], anti-HIV [29,30] and more
activity properties.
Another important member of the heterocyclic compounds family is the pyridine skeleton,
which is the building block of many natural products such as vitamins, coenzymes, and alkaloids. In
the industrial chemistry; it is used as a solvent and reagent, or as a starting or intermediate material in
the synthesis processes of high effect insecticide, bactericide and herbicide products [31]. Pyridine
moiety plays an active role in the design of many pharmaceutically active compounds with its
specific basic structure, water solubility, stability, and the ability to make hydrogen bond [32].
Variety of biological activity studies such as antimicrobial, antiviral, antioxidant, analgesic,
anticonvulsant, antidiabetic, anticancer, antimalarial, which are reported at a broad scale prove
pyridine derivatives pharmacologic importance [33-39].
Due to the pharmacological properties of the pyridine substituted thiazole compounds were
synthesized newly compounds via Hantzsch synthesis [40]. We report herein the synthesis of the
thiazole possessing pyridine group and application of the biologically activity. The most important
finding of this study is easily generated hybrid molecules thiazole containing pyridine group, which
is an important precursor of biologically active synthetic and natural compounds, via single step. As
examples, mycothiazole, the natural thiazole compound, shows a selective activity against lung
cancer which is isolated from sponge Spongia mycofijiensis [41]. Other natural compounds WS75624
A and B, which are similar to the hybrid structure of the synthesized compounds in this work, have
hypertensive agents [42]. Also, single crystal forms of compounds 3a and 3c were examined X-ray
diffraction (XRD) technique. Frontier molecular orbital (HOMO-LUMO) energies, some reactivity

parameters (ionization potential, electron affinity, chemical hardness-softness, etc.) and their
potential to be non-linear optical (NLO) material of novel series of pyridine substituted thiazole
derivative compounds 3a-e and 4a-e were investigated comparatively by theoretical an approach at
DFT/B3LYP/6-311G(d, p) level.
2. Material and Methods
2.1. General Methods
All chemicals and reagents were procured from Merck, Alfa-Aesar, Acros and used without
further purification. Reactions were monitored by thin-layer chromatography (TLC) SiO2-precoated
(0.2 mm layer) Al sheets (Merck). Products were purified on glass column chromatography (CC)
using silica gel (SiO2) 60 (230-400 mesh) with a solvent gradient of 2:1 (ethyl acetate/ n-hexane). By
using Thermo Scientific Barnstead/Electrothermal Apparatus melting points were determined. IR
Spectra were conducted Perkin-Elmer FT-IR spectrometer; KBr pellets; in cm-1. NMR spectra were
recorded with Bruker AC-400 MHz and Varian Inova (500 MHz) NMR spectrometer. The coupling
constants are reported J (Hertz) and chemical shift, δ (parts per million). Mass spectra was measured
with Agilent 7890-GCMS and the mass spectra showed the expected molecular ion peaks. UV-Vis
absorption measurements were performed by Perkin-Elmer LAMBDA 650 UV/Vis spectrometer.
Photoluminescence excitation and emission were characterized using a Cary Eclipse G9800A
Fluorescence Spectrophotometer (Varian, USA).
General procedure for synthesis of aryl substituted 2-(pyridin-2-yl)thiazole 3a-e and 2-(pyridin-4-
yl)thiazole 4a-e compounds:
A solution 1 or 2 (1.2 mmol) of in dry EtOH (25 mL) was stirred under N2 and refluxed. Then, the
appropriate bromo substituted aromatic ketone (1.5 mmol) in (15 mL) dry EtOH was added directly. After
cooling to room temperature, the solvent was poured into water, and the insoluble thiazole derivatives were
allowed to settle. The residual solid was washed by decantation with water. The solid was solved ethyl acetate,
evaporated, and the residue purified by column chromotography
4-([1,1'-biphenyl]-4-yl)-2-(pyridin-2-yl)thiazole, 3a: Yield: 72%; mp: 185-187 ºC; FTIR (ATR): ν
3110-3002 (Caro-H stretching) 1581 (C-N stretching, pyridine ring), 1556-1453 (thiazole ring
1
skeletal vibration), 852 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ 8.67 (d, J =
4.2 Hz, 1H, H10), 8.34 – 8.21 (m, 2H, H7, H5), 8.16 (d, J = 8.0 Hz, 2H, H13, H17), 8.01 (m, 1H,
H8), 7.79 (d, J = 8.1 Hz, 2H, H14, H16), 7.74 (d, J = 7.6 Hz, 2H, H19, H23), 7.50 (m, 3H, H20, H21,
H22), 7.40 (d, J = 7.0 Hz, 1H, H9); 13C NMR (101 MHz, DMSO-d6, ppm) δ 168.85(C2),
155.70(C6), 150.85(C4), 150.22(C10), 140.27(C12), 140.01(C15), 138.27(C8), 133.52(C18),

129.45(C22-C20),
128.08(C21),
127.52(C14-C16),
127.11(C13-C17),
127.05(C23,C29),
125.74(C9), 119.81(C7), 117.51(C5); GC-MSD: m/z 314.0 (C20H14N2S, M+); 284 (C20H16N2)+; 207
(C15H13N)+; 177 (C14H10)+ ; Anal. Calcd for C20H14N2S: C, 76.40; H, 4.49; N, 8.91; S, 10.20; Found:
C, 76.28; H, 4.98; N, 8.75%.
4-(benzofuran-2-yl)-2-(pyridin-2-yl)thiazole, 3b: Yield: 65%; mp: 178-179 ºC; FTIR (ATR): ν
3121-3029 (Caro-H stretching), 1583 (C-N stretching pyridine ring), 1567-1437(thiazole ring skeletal
vibration), 787 (C-S stretching) cm-1; 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.68 (dd, J = 2.8, 1.9
Hz, 1H, H10), 8.25 (m, 2H, H5, H7), 8.08 – 7.98 (m, 1H, H8), 7.72 (d, J = 7.6 Hz, 1H, H18), 7.66 (d,
J = 8.0 Hz, 1H, H15), 7.55 (ddd, J = 6.6, 3.1, 1.5 Hz, 1H, H16), 7.41 – 7.26 (m, 3H, H9, H17, H20);
13C NMR (101 MHz, DMSO-d6, ppm) δ 169.99(C2), 154.75(C6), 151.63(C14), 150.43(C12),
150.30(C10), 147.27(C4), 138.38(C8), 128.82(C19), 126.05(C16), 125.48(C17), 123.89(C7),
122.10(C18), 119.86(C9), 119.28(C5), 111.66(C15), 103.97(C20); GC-MSD:
278.1(C16H10N2OS, M+); 249 (C16H12N2O)+; 145 (C10H8O)+.
m/z
4-(4-bromophenyl)-2-(pyridin-2-yl)thiazole, 3c: Yield: 75%; mp: 162-164 ºC; FTIR (ATR): ν 3063-
2957 (Caro-H stretching), 1603(C-N stretching pyridine ring), 1502-1417(thiazole ring skeletal
1
vibration), 787 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ 8.65 (d, J = 4.6 Hz,
1H, H10), 8.32 (s, 1H, H5), 8.24 (d, J = 7.9 Hz, 1H, H7), 8.07 – 7.92 (m, 3H, H13, H17, H8), 7.67 (d,
J = 8.5 Hz, 2H, H14, H16), 7.57 – 7.46 (m, 1H, H9); 13C NMR (101 MHz, DMSO-d6, ppm) δ
168.97(C2), 154.79(C6), 150.70(C4), 150.17(C10), 138.20(C8), 133.60(C12), 132.20(C14-C16),
128.49 (C13-C17), 125.73(C9), 121.87(C15), 119.78(C7), 118.08(C5); GC-MSD: m/z 318.0
(C14H9BrN2S, (M+1)+); 242 (C14H10N2S-1)+; Anal. Calcd for C14H9BrN2S: C, 53.01; H, 2.86; Br,
25.19; N, 8.83; S, 10.11 Found: C, 52.91; H, 3.01; N, 8.81 %.
4-(2-(pyridin-2-yl)thiazol-4-yl)benzonitrile, 3d: Yield: 60%; mp: 175-178 ºC; FTIR (ATR): ν 3094-
2991(Caro-H stretching), 2212 (CN, nitrile stretching), 1595(C-N stretching pyridine ring), 1475
1
(thiazole ring skeletal vibration), 813 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ
8.66 (d, J = 4.6 Hz, 1H, H10), 8.52 (s, 1H, H5), 8.30 – 8.21 (m, 3H, H7, H13, H17), 8.01 (td, J = 7.8,
13
1.4 Hz, 1H, H8), 7.95 (d, J = 8.3 Hz, 2H,H14,H16), 7.54 (dd, J = 7.3, 5.0 Hz, 1H, H9); C NMR
(101 MHz, DMSO-d6, ppm) δ 169.37(C2), 154.10(C6), 150.51(C4), 150.25(C10), 138.46(C12),
138.35(C8), 133.37(C14-C16), 127.16(C13-C17), 125.97(C9), 120.69(C7), 119.90(C5),
119.31(C15), 110.90(C18); GC-MSD: m/z 263.1(C15H9N3S, M+); 234.8 (C15H11N3+1)+; 206.9
(C14H12N2-1)+; 159.1 (C11H11N +1)+.

4-(3-bromophenyl)-2-(pyridin-2-yl)thiazole, 3e: Yield: 65%; mp: 168-169 ºC; FTIR (ATR): ν 3080-
2995 (Caro-H stretching), 1585 (C-N stretching pyridine ring), 1557-1508 (thiazole ring skeletal
1
vibration), 778 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ 8.67 (d, J = 4.8 Hz,
1H, H10), 8.30 (d, J = 0.8 Hz, 1H, H7), 8.28 (s, 1H, H5), 8.09 (dd, J = 7.8, 0.9 Hz, 1H, H8), 8.02 (td,
13
J = 7.8, 1.5 Hz, 1H, H17), 7.63 – 7.50 (m, 3H, H13, H15, H16), 7.46 (m, 1H, H9); C NMR (101
MHz, DMSO-d6, ppm) δ 168.93(C2), 154.27(C6), 150.57(C4),
150.16(C10), 138.44(C8),
136.63(C12), 131.52(C13), 131.41(C7), 129.02(C15), 125.90(C9), 125.49(C16), 122.81(C14),
119.99(C17), 118.89(C5); GC-MSD: m/z 318.0 (C14H9BrN2S, (M+1)+); 242 (C14H10N2S-1)+.
4-([1,1'-biphenyl]-4-yl)-2-(pyridin-4-yl)thiazole, 4a: Yield: 69%; mp: 189-191 ºC; FTIR (ATR): ν
3098-2987(Caro-H stretching), 1579 (C-N stretching pyridine ring), 1521-1468(thiazole ring skeletal
1
vibration), 792 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ 8.98 (d, J = 5.7 Hz,
2H, H8, H10), 8.65 (s, 1H, H5), 8.47 (d, J = 5.8 Hz, 2H, H7, H11), 8.21 (d, J = 8.2 Hz, 2H, H17,
H13), 7.84 (d, J = 8.1 Hz, 2H,H16, H14); 7.77 (d, J = 8.2 Hz, 2H, H19, H23), 7.51 (t, J = 7.6 Hz,
1H), 7.44 – 7.35 (m, 3H, H22, H20, H21); 13C NMR (101 MHz, DMSO-d6, ppm) δ 162.53 (C2),
156.85(C4), 145.78(C8, C10), 145.34(C6), 140.86(C15), 139.86(C18), 132.73(C12), 129.49(C20-
C22), 128.24(C21), 127.67(C17-C13), 127.40(C23-C19), 127.12(C16-C14), 122.70(C7-C11),
120.33(C5); GC-MSD: m/z 314.0 (C20H14N2S, M+); 284 (C20H16N2)+ ; 207 (C15H13N)+;177
(C14H10)+ ; Anal. Calcd for C20H14N2S: C, 76.40; H, 4.49; N, 8.91; S, 10.20 Found: C, 76.30; H, 5.09;
N, 8.69 %.
4-(benzofuran-2-yl)-2-(pyridin-4-yl)thiazole, 4b: Yield: 60%; mp: 183-184 ºC; FTIR (ATR): ν 3109-
3045 (Caro-H stretching), 1586 (C-N stretching pyridine ring), 1568-1436 (thiazole ring skeletal
vibration), 789(C-S stretching) cm-1; 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 6.4 Hz, 2H,
H8, H10), 8.56 (s, 1H, H5), 8.48 (d, J = 6.4 Hz, 2H, H7, H11), 7.75 (d, J = 7.6 Hz, 1H, H18), 7.69 (d,
J = 8.2 Hz, 1H, H15), 7.50 (s, 1H, H20), 7.44 – 7.36 (m, 1H, H16), 7.32 (t, J = 7.5 Hz, 1H, H17); 13C
NMR (101 MHz, DMSO-d6, ppm) δ 163.64(C2), 154.85(C4), 150.85(C14), 148.20(C12),
145.66(C8-C10), 145.11(C6), 128.64(C19), 125.88(C16), 124.06(C17), 122.94(C7-C11),
122.31(C18), 121.92(C5), 111.78(C15), 104.94(C20); GC-MSD: m/z 278.1(C16H10N2OS, M+); 249
(C16H12N2O)+; 145 (C10H8O)+.
4-(4-bromophenyl)-2-(pyridin-4-yl)thiazole, 4c: Yield: 72%; mp: 164-168 ºC; FTIR (ATR): ν 3050-
3028 (Caro-H stretching), 1602 (C-N stretching pyridine ring), 1520-1495 (thiazole ring skeletal
1
vibration), 784 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 5.0 Hz,
2H, H8, H10 ), 8.72 (s, 1H, H5), 8.47 (d, J = 2.6 Hz, 2H, H7, H11), 8.32 (s, 1H, H13), 8.12 (d, J =
7.7 Hz, 1H, H17), 7.63 (d, J = 7.8 Hz, 1H, H15), 7.49 (t, J = 7.9 Hz, 1H, H16); 13C NMR (101 MHz,

DMSO-d6, ppm) δ 162.32(C2) , 155.47(C4), 145.97(C6), 144.89(C8, C10), 135.78(C12),
132.02(C16), 131.64(C13), 129.30(C15), 125.78(C17), 123.12(C7,C11), 122.91(C14), 121.96(C5);
GC-MSD: m/z 318.0 (C14H9BrN2S, (M+1)+); 242 (C14H10N2S-1)+.
4-(2-(pyridin-4-yl)thiazol-4-yl)benzonitrile, 4d: Yield: 55%; mp: 182-184 ºC; FTIR (ATR): ν 3102-
3058 (Caro-H stretching), 2221 (CN, nitrile stretching), 1583 (C-N stretching pyridine ring), 1540-
1
1486 (thiazole ring skeletal vibration), 802 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6,
ppm) δ 8.96 (d, J = 4.8 Hz, 2H, H8,H10 ), 8.83 (s, 1H, H5), 8.59-8.54 (m, 3H, H7, H10, H11), 8.19
13
(d, J = 7.6 Hz, 1H, H17), 7.82 (d, J = 7.7 Hz, 1H, H15), 7.65-7.59 (m, 1H, H16); C NMR (101
MHz, DMSO-d6, ppm) δ 163.41(C2), 156.16(C4), 150.09(C8-C10), 147.27(C6), 138.92(C12),
136.15(C16-C14), 132.48 (C13-C17), 126.24 (C7-C11), 124.32(C18), 120.49(C15), 117.61(C5); GC-
MSD: m/z 263.1(C15H9N3S, M+); 234.8 (C15H11N3+1)+; 206.9 (C14H12N2-1)+; 159.1 (C11H11N +1)+.
4-(3-bromophenyl)-2-(pyridin-4-yl)thiazole, 4e: Yield: 61%; mp: 172-174 ºC; FTIR (ATR): ν 3078-
3019 (Caro-H stretching), 1574 (C-N stretching pyridine ring), 1524-1498 (thiazole ring skeletal
1
vibration), 795 (C-S stretching) cm-1; H NMR (400 MHz, DMSO-d6, ppm) δ 8.99 (d, J = 6.3 Hz,
2H, H8, H10), 8.67 (s, 1H, H5), 8.47 (d, J = 6.1 Hz, 2H, H7, H11), 8.07 (d, J = 8.5 Hz, 2H, H13,
H17), 7.73 (d, J = 8.5 Hz, 2H, H14, H16); 13C NMR (101 MHz, DMSO-d6, ppm) δ 162.45(C2),
156.01(C4), 145.72(C6), 145.24(C8-C10), 132.82(C12), 132.42(C14-C16), 128.83(C13-C17),
122.92(C7-C11), 122.61(C15), 121.22(C5); GC-MSD: m/z 318.0 (C14H9BrN2S, (M+1)+); 242
(C14H10N2S-1)+.
2.3. Single crystal XRD analysis
The single-crystal X-ray data were collected on a Bruker D8 QUEST (Bruker, USA)
diffractometer. X-ray diffraction study and all diffraction measurements were performed at room
temperature 296 K. Data collection with XAREA [43], cell refinement with X-AREA, data reduction
with XRED32 [43]. The hybrid structures were solved by direct methods using SHELXS-2013 [44]
and refined with full-matrix least-squares calculations on F2 using SHELXL-2014 [44] implemented
in Win-GX [45] program suite. All carbon bound H atoms were placed geometrically and treated
using a riding model, fixing the bond length at 0.93 Å.
2.4. Theoretical details
Theoretical approaches for pyridine substituted thiazole compounds 3a-e and 4a-e were
performed with the Gaussian 09W package [46] and GaussView 5.0 [47] molecular visualization
programmes. The geometric optimization process of the compounds was fulfilled with Density

Functional Theory (DFT) [48], Becke’s Three-Parameter Hybrid Functional using the Lee, Yang and
Parr correlation (B3LYP) [49] method with 6-311G(d,p) basis set in the ground state and gas phase.
The highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital
(LUMO) energy values of the groups of compounds were calculated by at a level of time dependent
(TD)-DFT in order to specify the intramolecular charge transfer interactions. Some chemical activity
parameters such as I; ionization potential (I=-EHOMO), A;electron affinity (A=-ELUMO),
χ;electronegativity (χ=(I+A)/2), η;chemical hardness (η=(I-A)/2), Ѕ;chemical softness (Ѕ=1/2η),
μ;chemical potential (μ=-( I+A)/2) and ω;electrophilicity index (ω=μ2/2η) of the molecular groups
were calculated by using HOMO-LUMO energy values [50-52]. To determine the potentials of
compounds to be non-linear optical material (NLO); parameters of total electric dipole moment (μtot)
mean polarizability (<α>) and total first-order hyperpolarizability (βtot) with x, y, z components were
calculated as theoretical by using the following equations given [53-55].
2
2
μtot=(μx +μy +μz2)1/2
(1)
(2)
(3)
<α>=(α xx+α yy+α zz)/3
βtot=[(βxxx+βxyy+βxzz)2+(βyyy+βyzz+βyxx)2+(βzzz+βzxx+βzyy)2]1/2
2.5. Minimal Inhibitory Concentration (MIC) Method
In this study according to MIC method, Gram positive Staphylococcus aureus ATCC 6538P,
Bacillus cereus ATCC 7064, Gram negative Escherichia coli W3110, Pseudomonas aeruginosa
ATCC 27853 and yeast Candida albicans ATCC 10231 were used as microorganisms. Stock
solutions of all synthesized complexes were prepared in DMSO-d6 and used in experiments. All
cultures were incubated in nutrient broth in 37°C for 24 hours. Bacterial and yeast cells were
suspended and used in 50 ml of nutrient medium. The turbidity of bacterial and yeasts suspensions
was adjusted at a concentration of approximately 106 cells/ml by matching with 0.5 McFarland
turbidity standards. The microorganisms grown were transferred to test tubes with 1 ml and then
complexes were added. After serial dilutions, hybrid compounds were incubated at 37°C degrees for
1 night in the incubator. The minimum inhibitor concentration, at which no growth was observed,
was taken as the MIC value (mM). For control purposes, vancomycin and cefepime were used as
antibacterial and fluconazole was used as antifungal. For control purposes, amikacin and cefepime
were used as antibacterial and fluconazole was used as an antifungal.

2.6. DNA cleavage activity
DNA cleavage activity of pyridine substituted thiazole compounds was carried out on double-
stranded pBR322 circular plasmid DNA by using gel electrophoresis. 10 mM concentration of
complexes were prepared in DMSO-d6 (Dimethyl sulfoxide) and treated with 0.25 ppm pBR322
plasmid DNA at 37 °C for 2 hours in pH 8 Tris Buffer. The reactions were carried out in the presence
and absence of 30 mM H2O2 as an activator. Control experiments were done in the presence of
DMSO-d6. After incubation, 1 µl 6X gel loading buffer was added then this mixture was loaded on
1% agarose gel for 90 min at 80V in TBE buffer (pH 8). Gels were stained with ethidium bromide for
15 min and washed deionized water for 15 min. Then gels were photographed under UV
transilluminator.
3. Results and Discussion
3.1. Chemistry
The derivatives of the pyridine substituted thiazole were depicted as a synthesis from
acetophenone, thioamide and synthesis process was presented in Scheme 1. The pyridine-2-
carbothioamide 1 was condensed with acetophenone derivatives followed by cyclization to give aryl
substituted 2-(pyridin-2-yl)thiazole 3a-e and pyridine-4-carbothioamide 2 afforded aryl substituted
2-(pyridin-4-yl)thiazole 4a-e compounds. In this reaction; 1-([1,1'-biphenyl]-4-yl)-2-bromoethan-1-
one (a), 1-(benzofuran-2-yl)-2-bromoethan-1-one (b), 2-bromo-1-(4-bromophenyl)ethan-1-one (c), 4-
(2-bromoacetyl)benzonitrile (d), 2-bromo-1-(3-bromophenyl)ethan-1-one (e) were subjected to
Hantzsch reaction with thioamides to give thiazole ring.
For comparison, we synthesized the aryl substituted 2-(pyridin-2-yl)thiazole and 2-(pyridin-4-
yl)thiazole derivatives. Not surprisingly, increase of the reaction yield was more the replacement
pyridine-2-carbothioamide than pyridine-4-carbothioamide.
The reactions employing α-bromoketone provided high yields of 2-pyridyl substituted
thiazoles compounds 3a-e. However the reaction with 4-(2-bromoacetyl)benzonitrile gave a low
yield of the appropriate products 4a-e under different reaction conditions.
The variation of 1-([1,1'-biphenyl]-4-yl)-2-bromoethan-1-one, and 2-bromo-1-(4-
bromophenyl)ethan-1-one gave high yields of 2,4-disubstituted thiazoles. Other α-bromoketones
were allowed moderated yield of 1,3-thiazole ring. On the other hand, the performance control in the
reactions was found to be related to the ratio of ketone compound as using 1.5 equivalents of α-
bromoketones. After the purification with column chromatography, all products were obtained good

yield range from 55% to 75%. The chemical structure and yield values of the synthesized groups of
compounds are shown in Scheme 1.
Scheme 1 is here
The NMR spectral data show the evidence of the products. The thiazole ring proton was
determined at δ= 8.25 – 8.72 ppm singlet around. The 3a-e compounds of the thiazole ring proton
shifted upfield than 4a-e. The NMR spectrum of structure 3b revealed at 8.25 ppm while benzonitrile
derivatives, 3d, of thiazole ring proton was 8.52 ppm shifted due to the electron donating and
electron withdrawing substituents. 13C NMR spectrum of compounds 3 and 4 derivatives showed
signals the range of 162-169 ppm at the pyridine substituted carbon in thiazole ring. Although
analogously 4 were chemical shift closed 162 ppm, 3a-e compounds closed 169 ppm downfield
shifts. The synthesized hybrid thiazole-pyridines display characteristics stretching frequency of
thiazole ring C=N around 1540-1450 cm-1 and C-S-C vibration 840-740 cm-1, which these values
results correlated similar compounds in literature [56]. Moreover, 1H NMR and 13C NMR values are
1
13
in accordance with the chemical structure of title compounds as similar literature [57]. H and C
NMR spectrums of the 3a-e and 4a-e compounds are given in the section of Supplementary Materials
with Figure S1-S10.
The TG/DTA curves were obtained using Hitachi / SII 7300. 3.5 mg samples were run in
ceramic sample pans under nitrogen atmosphere. The TG curves of the 3b and 4b are given in Figure
1 and thiazole compounds showed similar thermal behaviour with only the first stage.
Figure 1 is here
Comparing the emission spectrum of all compounds with the excitation and absorption, there
is a significant Stokes shift in the range of 1093-2393 cm-1. To determine the emission of the 3c, the
excitation spectra of the samples at 332 nm monitored at 352ꢀnm in Figure 2. The excitation,
emission, and absorption values and Stokes shift are summarized in Table 1.
Figure 2 is here

Table 1 is here
3.2. Crystal structure of compound 3a and 3c
Since the single crystal form of pyridine substituted thiazole compounds 3a and 3c can be
obtained, the findings from the single crystal XRD analysis of these compounds are given in this
section.
The crystal structure of 3a consists of biphenyl, pyridine and thiazole groups. The molecule
crystallized the orthorhombic structure and Pca21 space group. There are four molecules in the unit
cell. In the thiazole ring, C1-S1 and C2-S1 bond lengths are 1.706 (7) Å and 1.726 (8) Å,
respectively. Similarly, the C2-N1 and C3-N1 bond length values are 1.296 (8) Å and 1.373 (8) Å,
respectively. These values are consistent with the C-S and C-N values in the thiazole ring in the
literature [58]. The C-N values in the pyridine ring, C5-N1 and C1-N1 bond lengths are 1.45 (2) Å
and 1.359 (2) Å.
Details of the data collection conditions and the parameters of the refinement process of 3a
crystal are given in Table 2 and molecular structure with the atomic numbering scheme ORTEP view
for the compound is shown in Figure 3.
Table 2 is here
Figure 3 is here
The crystal structure of 3a has an intramolecular C—H···N type hydrogen bond and details
are given in Table 4. Also, C8—H8···Cg3 type intermolecular interaction holds the crystal structure
together and packing diagram of the 3a is given with Figure S.11 in the Supplementary Material.
The 3c formed by the combination of three important groups such as 4-bromophenyl, pyridine
and thiazole crystallized in monoclinic structure and P21 space group. There are two molecules in the
unit cell. As can be seen from Table 3, the unit cell parameters a, b, c; 4.0396 (10) (Å), 10.504 (3)
(Å), 14.839 (4) (Å) and α, β, γ; 90 (°), 91.642 (8) (°), 90 (°). Molecular structure with the atomic
numbering scheme ORTEP view for the 3c is shown in Figure 3.

Thiazole ring C7-S1 and C6-S1 bond lengths for 3c are 1.698 (18) Å and 1.74 (2) Å,
respectively. Similarly, the C6-N2 and C8-N2 bond length values are 1.292 (18) Å and 1.377 (18) Å,
respectively. These values are consistent with the C-S and C-N values in the thiazole ring in the
literature [58]. The C-N values in the pyridine ring, we see that C5-N1 and C1-N1 bond lengths are
1.29 (2) Å and 1.34 (2) Å. The Br1-C12 bond length value in the bromophenyl ring is 1.905(13) Å,
and this value is 1.909 (3) Å in the literature, and the Br-C value in the molecule is not very different
from the literature [59].
The dihedral angle between the thiazole ring and the bromophenyl group is 14.93°. Similarly,
the dihedral angle value between the thiazole ring and the pyridine ring is 4.83o. The 3c crystal has
only one intramolecular C—H ··· N type hydrogen bond and details are given in Table 3.
Table 3 is here
3.3. Theoretical
Optimized molecular structures with total energy values of pyridine substituted thiazole
derivative 3a-e and 4a-e compounds with DFT/B3LYP/6-311G(d,p) are given in Figure 4. According
to the calculated total energy values of molecular structures; in view of that compounds of the group
3a-e having 2-pyridine position have lower energy values than those of group 4a-e, they can be said
to exhibit a more stable structure.
Figure 4 is here
Frontier molecular orbital energies namely HOMO-LUMO energy values play an important
role in determining some reactivity properties of structures, especially in modelling studies involving
molecular groups derived from different substituents. Considering that the high HOMO energy value
is related to the ability of the molecular structure to donate electrons and the low LUMO energy
value is associated with the ability to accept electrons [60-62]; it will be possible to identify those
which tend to exhibit nucleophilic or electrophilic character within the molecular groups. Besides, the
HOMO-LUMO (ΔE) energy gap value contains clues about the stability or reactivity of molecular
systems; it can be said that structures with a narrow energy gap can be less stable and more reactive.
The calculated HOMO and LUMO, (ΔE) energy gap values of the 3a-e and 4a-e compounds are
given in Table 4.
It can be seen from Table 4 that the 3a-e group was higher HOMO and LUMO energy values
than the 4a-e group. In other words, compounds having 2-pyridine position (with high HOMO

values) exhibit electron donor character, while those at 4-pyridine position (with low LUMO values)
exhibit electron acceptor character. Compound 4b with a value of 3.70 eV has the smallest energy
gap (ΔE), while compound 4d with a value of 4.19 eV has the largest energy gap (ΔE), so 4b is
considered to be more reactive and less stable than others. HOMO-LUMO orbital diagrams of 4b and
4d compounds represent in Figure 5 and others in Figure S.12 (see Supplementary Material).
Table 4 is here
By calculated the values of some parameters, also known as global reactivity descriptors,
tabulated in Table 4; the hybrid compounds whose properties are prominent within the groups have
been identified. According to the ionization potential (I) and electron affinity (A) values associated
with HOMO and LUMO energy, 3b with low I value and 4d with high A value come into
prominence for given compounds. Hence 3b compound has displayed a nucleophilic character while
4d has better electrophilic character compared to others. The 4-pyridine substituted compound group
has high χ with decreasing order of 4d>4e>4c>4a>4b and high ω values with decreasing order of
4d>4c>4e>4b>4a as regards 3a-e group, and the compound 4d with 4.56 and 4.97 eV values has a
higher electronegativity and good electrophilic character than the others. According to the chemical
hardness-softness (η, S) values which are effective in determining the intramolecular charge transfer
of the molecular structures that the compound having the high S and low η value is 4b has been
observed.
Figure 5 is here
The delocalized π-electron charge density or donor-acceptor groups which connected through
the π-conjugation bridge (D-π-A) are the factors that affect the potential of being nonlinear optical
materials of the molecular structures [63-65]. It is known that the thiazole derivative compounds have
a strong π-conjugation effect and the conjugate systems formed by with different electron-donating
groups with their character of electron-attracting exhibit high NLO properties, and this potential
keeps the interest in these compounds for the researchers [66-69].
In order to determine the potential in NLO applications of synthesized 3a-e and 4a-e
compounds; total dipole moment, mean polarizability, first-order hyperpolarizability parameters were
calculated at DFT/B3LYP/6-311G(d,p) level using Equations (1-3) and results are presented in Table

5. (The detailed version of all the components of the parameters is given with Table S.13-15 in the
Supplementary Material).
Table 5 is here
As can be seen from the table, the total electric dipole moment (μtot) values and mean
polarizability (<α>) values were obtained as 3d>4d>4e>4b>4a>3c>4c>3e>3a and
4a>3a>3b>4b>3d>3c>4d>4c>3e>4e in decreasing order. The comparison of compound groups
according to βtot values, which is another determinant parameter for molecular structures exhibiting
NLO properties, is 4b>4c> 3b>3c>3d>4a>4d>3a>4e>3e. Further, these parameters were calculated
at the same theoretical level for the urea molecule which is considered a threshold value in such
analyses and obtained values are 3.8872 Debye for μtot, 5.0098x10-24 esu for <α>, 621.3132x10-33 esu
for βtot. Comparing the results, compound 4b functionalized with benzofuran and position 4 of the
pyridine moiety, characterized by a high βtot value (10584.11x10-33 esu), are seen to be 17 times
higher than the urea molecule, so it is a good candidate for NLO material. The compound 4b also had
higher potential for intramolecular charge transfer as expected due to its narrow energy gap (3.70 eV)
and high chemical softness value (0.27 eV-1) and the higher βtot value supported this result.
3.4. Antimicrobial activity
In the study, it was determined that MIC values of positive control DMSO-d6 for the thiazole
derivates were prepared more than 5 mM. New synthesized thiazole hybrid compounds have
different effects on microorganisms. As shown in the Table 6, it can be stated that thiazole
derivatives have moderate effect on gram negatives.
Table 6 is here
In addition, only 3c and 4c derivatives have more effect on E. coli than other gram negative
ones. When the effects of thiazole derivatives on Gram positives are examined, it is seen that this
effect is more than gram negatives. When the gram positive bacteria S. aureus were examined, the
MIC values for 3c and 4a were found to be 1.2 mM. Furthermore, the MIC values for 4e and 4b are
0.15 mM, it can be stated that this value has a value of 0.02 mM for 4c. MIC values for B. cereus, the

other gram positive bacteria, were 1.2 and 1.4 mM for 3c and 4d respectively, 0.6 mM for 4a, 0.3
mM for 3b, 0.15 mM for 4b, 0.04 mM for 4e and 0.02 mM for 4c. The effect of thiazole compounds
is quite high on gram positives. According to the findings, it would be correct to make a
3c<4b<4e<4c order on the gram positives. As shown the results, 4c was found to be the most
effective compound on gram positives with a value of 0.02 mM. It has been reported that new
thiazole derivatives have antimicrobial effects [70].
In this study with C. albicans, an important pathogen for humans and also yeast, derivatives
were generally found to be effective. As a matter of fact, when the MIC values were examined, we
found that these values were 1.2 mM for 3a and 4b, 0.6 mM for 3e, 3b, 4a and 4e, and 0.15 mM for
3c and 4c. The result of the study with C. albicans, 3c and 4c were found to be more effective than
the others.
For the standard antibiotics MIC values ranging from 0.01- 8.65 mM. Compound 4c has a
lower mic value than the reference antibiotic cefepime against Bacillus cereus ATCC 7064 strain.
This value reinforces the possibility that compound 4c may be a new and more effective
antimicrobial agent for gram positive microorganisms.
CN and Br groups can capture radical groups and accellerate the antimicrobial activity of
compounds. When compared antimicrobial activity of CN and Br groups, thiazole derivates
containing Br have more potent atimicrobial activity against test microorganisms.
Increased antibiotic resistance made it necessary to obtain new chemicals as shown
antimicrobials behaviours. In recent years, it has been shown that rapid bactericidal activity is
important in the treatment of diseases caused by staphylococci such as endocarditis, meningitis and
osteomyelitis, and diseases caused by E. coli such as digestion and urogenital [71,72].
It has been earlier shown that one of the most important heterocyclic units is a thiazole moiety
in several known antimicrobial agents which penicillin, abafungin, amoxicillin etc. [73]. Oniga et al.
reported 12 different pyridine-thiazole derivatives that were active against S. aureus, B. cereus,
C.albicans [74]. In our study to the present, we have found the activity of 4c including against S.
aureus, B. cereus.
Also, the thiazole group compounds may have an advantage in that they are used in the
treatment of more severe clinical diseases than bacteriostatic agents. Therefore, antimicrobial use of
thiazole derivatives with high antimicrobial activity may be possible.

3.5. DNA cleavage activity
DNA cleavage study revealed Tris-HCl buffer (50 mM, pH:8) and H2O2 (30mM) conditions.
H2O2 induces the formation of hydroxyl radicals which attack the DNA bounds and cause DNA
cleavage. These cause different mobility properties of pBR 322 plasmid DNA on agarose gel
electrophoresis. The DNA cleavage was controlled by the relaxation of the supercoiled circular form
of pBR322 DNA into the nicked and linear form. The supercoiled form is the fastest migration form
on the agarose gel. If one strand is cleaved, the supercoils will relax to produce a slower moving open
circular form (Form II). If both strands are cleaved, a linear form (Form III) will be generated that
migrates in between Form I and Form II.
In this study, 4d (Figure 6 A11 and B11) and 4e (Figure 6 A10 and B10) compounds have
been caused cleavage activity both buffer and H2O2 conditions. Other compounds haven't been
caused effective cleavage of pBR 322 DNA but in the presence of H2O2 increased cleavage activity
were observed. 3d (Figure 6 B5), 4a (Figure 6 B8), 4c (Figure 6 B9), 4e (Figure 6 B10) and 4d
(Figure 6 B11) caused cleavage of DNA in the presence of H2O2. DMSO-d6 scavenging activity was
observed compared with H2O2 control (Figure 6 B1 and B2). 3a (Figure 6 B3), 3e (Figure 6 B4), 3c
(Figure 6 B6), 3b (Figure 6 B7) and 4b (Figure 6 B12) showed DMSO-d6 like activity.
Figure 6 is here
DNA cleavage activity was observed in CN group when Br and CN groups were compared.
This may be due to the radical capture and hydrolysis of the CN group. No effect of Br and CN
groups in buffer conditions at the 2 pyridine positions (Figure 6 A5 and A6), while the CN group
showed DNA cleavage activity under hydrogen peroxide conditions (Figure 6 B5). Furthermore, 4-
pyridines are more effective than 2-pyridines relative to the position of the pyridine ring (Figure 6 A
and B). The groups 3a, 4a and 3b, 4b, unlike other substances, do not contain electron attractive
groups. Although π-conjugation increased, no effect was seen in both.
Conclusion:
Based on the extensive analyses, this paper consists to (i) obtain an effective synthesis of all
the ten types of pyridine skeleton thiazole, (ii) conduct structural features based-DFT as theoretical
approach, (iii) characterize the antimicrobial and DNA cleavage activity. The most stable in terms of

total energy values 3a-e derivative compounds showed the highest yield. Furthermore, we confirmed
that 3a-e compounds were exhibited highest HOMO value based on the comparison result of with the
4a-e compounds via DFT. Compound 4b was identified not only by having the potential to be the
highest NLO material, but also by the lowest energy gap. We found that the pyridine substituted
thiazole compounds effective antimicrobial activity on the Gram (+) bacteria. Also, it can be
emphasized 4c, 4e, 4b have an effect on Bacillus cereus. However, 3a-e groups haven’t effect on
Gram (+), Gram (-) and Yeast as compared with 4a-e. In addition, compounds 4d and 4e exhibited
strong cleavage activity both buffer and H2O2 conditions. The findings of this study will be
undoubtedly important for the systematic analysis and thus facilitate biological activity evaluations of
thiazole derivatives in the literature, and we believe that may serve to design antimicrobial drugs.
Acknowledgements
This work was supported by the Amasya University Scientific Research Foundation (Grant
No:FMB-BAP 17-0255). The authors acknowledge to Scientific and Technological Research
Application and Research Center, Sinop University, Turkey, for the use of the Bruker D8 QUEST
diffractometer. At the same time, we would like to thank Amasya Central Research Laboratory for
their contribution to the analysis process of the compound groups.
Supplementary Material
Supplementary material includes spectral characterization of pyridine substituted thiazole
compounds, frontier molecular orbital diagrams, the components of the dipole moment,
polarizability, first-order hyperpolarizability, packing diagram of the 3a. CCDC 1935341 for 3a and
CCDC 1825209 for 3c contain supplementary crystallographic data (excluding structure factors) for
the structures reported in this article. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_request@ccdc.cam.ac.uk or by
contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax:+44 1223336033.
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Figure Captions
Scheme 1. Synthesis of thiazole compouds 3a-e and 4a-e. Reaction condition: (i) ethanol, reflux, under N2
atm, 18h.
Figure 1. The TG/DTA curves of the compounds 3b and 4b.
Figure 2. The excitation emission, absorption spectra of the 3c
Figure 3. ORTEP views of the a) 3a and b) 3c compounds with showing the atom-numbering scheme.
Figure 4. Optimized molecular structures and total energy values of the compounds 3a-e and 4a-e by
DFT/B3LYP/6-311G(d,p).
Figure 5. HOMO-LUMO molecular orbital diagrams of the compounds 4b and 4d (TD-DFT/B3LYP/6-311G(d,p).
Figure 6. A. DNA Cleavage activity of the compounds 3a-e and 4a-e in buffer conditions. 1. pBR322 control. 2.
DMSO control. 3. 3a + pBR322 DNA 4. 3e + pBR322 DNA 5. 3d+ pBR322 DNA 6. 3c + pBR322 DNA 7. 3b +
pBR322 DNA 8. 4a + pBR322 DNA 9. 4c + pBR322 DNA 10. 4e + pBR322 DNA 11. 4d + pBR322 DNA 12. 4b +
pBR322 DNA B. DNA Cleavage activity of compounds in H2O2 conditions. 1. pBR322 + H2O2. 2. DMSO + H2O2.
3. 3a +H2O2 + pBR322 DNA 4. 3e + H2O2 + pBR322 DNA 5. 3d + H2O2 + pBR322 DNA 6. 3c + H2O2 + pBR322 DNA
7. 3b + H2O2 + pBR322 DNA 8. 4a + H2O2 + pBR322 DNA 9. 4c + H2O2 + pBR322 DNA 10. 4e + H2O2 + pBR322
DNA 11. 4d + H2O2 + pBR322 DNA 12. 4b + H2O2 + pBR322 DNA.

Scheme 1. Synthesis of thiazole compouds 3a-e and 4a-e. Reaction condition: (i) ethanol, reflux, under N2
atm, 18h.
3b
4b

Figure 1. The TG/DTA curves of compounds 3b and 4b

3c
1
300
250
200
150
100
50
Emission
0.8
0.6
0.4
0.2
0
Excitation
Absorption
0
290
340
390
Wavelength (nm)
440
Figure 2. The excitation emission, absorption spectra of the compound 3c