Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents

Article abstract of DOI:10.1080/10426507.2018.1550642

New N-(5-methyl-4-phenylthiazol-2-yl)-2-(substituted thio)acetamides were synthesized and studied for their anticancer activity. The title compounds were procured by reacting 2-chloro-N-(5-methyl-4-phenylthiazol-2-yl)acetamide with some mercapto derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR and LC-MS/MS spectral data and elemental analyses. The synthesized compounds were investigated for their antitumor activities against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell line for determining their selective cytotoxicity. 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenylthiazol-2-yl)acetamide (4c) showed high selectivity, and whose IC₅₀ value was determined as 23.30 ± 0.35 μM and >1000 μM against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell lines, respectively. 2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4a) and 2-[(1-Methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4c) exhibited the highest apoptosis percentage among those tested, but not as high as the standard, cisplatin.

Full text of DOI:10.1080/10426507.2018.1550642

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis and biological evaluation of 5-methyl-4-
phenyl thiazole derivatives as anticancer agents
Asaf E. Evren, Leyla Yurttas, Büşra Ekselli & Gülşen Akalin-Ciftci
To cite this article: Asaf E. Evren, Leyla Yurttas, Büşra Ekselli & Gülşen Akalin-Ciftci (2019):
Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents,
Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2018.1550642
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1550642
Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives
as anticancer agents
a
b
b
Asaf E. Evrena , Leyla Yurttas , Bus¸ra Ekselli , and Guls¸en Akalin-Ciftci
€
€
b
aFaculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University, Eskis¸ehir, Turkey; Faculty of Pharmacy, Department of
Biochemistry, Anadolu University, Eskis¸ehir, Turkey
ABSTRACT
ARTICLE HISTORY
Received 12 June 2018
Accepted 17 November 2018
New N-(5-methyl-4-phenylthiazol-2-yl)-2-(substituted thio)acetamides were synthesized and studied
for their anticancer activity. The title compounds were procured by reacting 2-chloro-N-(5-methyl-
4-phenylthiazol-2-yl)acetamide with some mercapto derivatives. The structural elucidation of the
1
compounds was performed by H-NMR, 13C-NMR and LC-MS/MS spectral data and elemental anal-
KEYWORDS
Azoles; anticancer activity;
thiazole; apoptosis
yses. The synthesized compounds were investigated for their antitumor activities against A549
human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell line for determining their
selective cytotoxicity. 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenylthiazol-2-yl)acetamide
(4c) showed high selectivity, and whose IC50 value was determined as 23.30 0.35 mM and
>1000 mM against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell
lines, respectively. 2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide
(4a) and 2-[(1-Methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4c) exhib-
ited the highest apoptosis percentage among those tested, but not as high as the stand-
ard, cisplatin.
GRAPHICAL ABSTRACT
Introduction
misdiagnosis or the misapplicaiton of treatments makes the
patient’s condition worse in many cases. Therefore, the con-
trol of malignancies is a massive concern.[4–8] About 12.7 mil-
lion cancer cases and 7.6 million cancer deaths were reported
worldwide in 2008. Generally, 56% of the cancer cases and
64% of the deaths due to cancer were in economically devel-
oping countries. Lung cancer in males is one of the commonly
diagnosed cancer. Also, lung cancer is the leading cause of the
death for each sex in both economically developed and devel-
oping countries. In 2035, the estimated death number due to
lung cancer may be about 2.9 million cases, and the estimated
Cancer has been described as a complex disease which
includes over 100 various diseases caused by the uncon-
trolled mitosis of the body’s cells and that evolves in time.[1]
Even though cancer can progress in virtually any of the
body’s tissues, and each type of cancer has its unique fea-
tures, the essential processes that produce cancer are fairly
similar in all forms of the disease.[2,3]
In recent years, anticancer therapies have made extraordin-
ary progress after the approval of some small molecule inhibi-
tors. But the incidence of cancer continuously rises, and the
CONTACT Asaf E. Evren
asafevrimevren@anadolu.edu.tr
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Anadolu University,
Eskis¸ehir, Turkey.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/10426507.2018.1550642.
ß 2019 Taylor & Francis Group, LLC

2
A. E. EVREN ET AL.
Scheme 1. The synthesis diagram of the compounds 4a–4i. Reagents and conditions: (a) Bromine, CH3COOH, HBr (b) EtOH, r.t., 24 h; (c) TEA, THF, ClCOCH2Cl,
0–5 ꢀC, then r.t 3 h; (d) Acetone, Potassium carbonate, rt.
new lung cancer cases is expected to be over 3.3 million with tiazofurin and BMS-354825;[41,42] antidiabetic drug troglita-
zone[43] possess a thiazole nucleus. Moreover, the anticancer
activity of some synthesized thiazole derivatives was accrued
in vitro against A549 human lung adenocarcinoma cells in
previous studies.[44–46]
Also, azole derivatives like imidazole, triazole, tetrazole,
thiadiazole, benzimidazole and benzothiazole have been
utilized for their high anticancer activities in earlier stud-
ies.[47–54] In these study, the anticancer activity of the 1,5-
disubstituted tetrazole moiety has been reported. Here, the
researchers have found a way that breaking the resistance of
some cancer cell lines, such as A549-T12 which is a cell line
with an a-tubulin mutation with increased resistance
to Taxol.[55–58]
Based on the above information, we synthesized some
new 5-methyl-4-phenyl thiazole derivatives in this work.
There are nine compounds (4a–4i), and we investigated
their anticancer activity against A549 human lung adenocar-
cinoma cells and NIH/3T3 mouse embryoblast cell line for
determining their selective cytotoxicity. Also, apoptotic cell
deaths caused by the most cytotoxic compounds
were determined.
reference to cancer data of 2012.[9–11]
Cytotoxic chemotherapy agents have powerful anticancer
activity and they are used in many treatments. Although
there are several active agents used clinically against tumors,
most chemotherapy protocols do not effectively increase the
patient survival. Even though many patients respond to
treatment well at the beginning, they go on to develop
resistance against the chemotherapeutic which can cause the
treatment to fail with a poorer prognosis. These issues are
announced by several reports that stated the resistance
developing against the therapeutic agents.[12–18] Thus, a goal
of researchers is to execute the selective inactivation of the
DNA in tumor cells with the agents which have small
structure.[19–21]
Among various heterocyclic rings, the thiazole ring repre-
sents a leading molecule in medicinal chemistry and its
derivatives have been used in different studies. Recently
activity studies of thiazole ring and derivatives have focused
on various biological properties such as antifungal,[22–24]
antibacterial,[25] antiviral,[26–28] analgesic,[29] anticancer,[30]
antihypertensive,[31] and antiproliferative[32,33] activities.
Additionally, the thiazole ring plays an important role in
many anticancer pathways such as inhibition of tyrosine
kinase,[34] peroxisome proliferator activated receptor gamma
(PPARy),[35,36] tumor necrosis factor (TNF-a),[37] inhibition
of phosphatidylinositol 3-kinase (PI3K),[38,39] and inhibition
of c-Jun N-terminal kinase stimulatory phosphatase-1 (JSP-
Results and discussion
Chemistry
In this study, we synthesized nine new compounds which
included the N-(5-methyl-4-phenylthiazol-2-yl)acetamide
1).[40] Furthermore, recent clinically used anticancer drugs nucleus in their core structures. The synthesis reaction was

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
performed via four steps. In the first step, propiophenone concentrations was close, but still the required IC50 value
and bromine were reacted in acetic acid to get 2-bromo-1- for A549 cells is smaller than the required IC50 value for
phenylpropanone (1).[59] Then compound 1 and thiourea NIH/3T3. It means that the required cytotoxic doses were
was reacted at room temperature for ring closure to obtain found to be nontoxic against NIH/3T3 cells. On the con-
2-amino-4-phenyl-5-methylthiazole (2).[60] Compound (2) trary, compound 4g was determined with nonselective pro-
was acetylated with chloroacetyl chloride pursuant to file which displayed cytotoxicity against both of the tumor
method.[61] Finally, the obtained product 2-chloro-N-(5- and normal cell lines (IC50=353.22 12.18 lM against A549
methyl-4-phenylthiazol-2-yl)acetamide (3) was reacted with and IC50=77.15 9.84 lM against NIH/3T3), which indicates
2-mercapto azole derivatives to gain the final products N-(5- that the required therapeutic dose was found to be cytotoxic
methyl-4-phenylthiazol-2-yl)-2-(substituted mercapto)aceta- against NIH/3T3 cells.
After determination of the most cytotoxic compounds,
their apoptotic effect was investigated. The apoptotic effects
of compounds 4a–4f were analyzed for A549 human lung
mide (4a–4i) as shown in Scheme 1. All the synthesized
compounds were characterized by analytical and spec-
tral data.
1
The H-NMR spectra of compounds showed signals at d adenocarcinoma based on Annexin V-PI binding capacities
2.45–2.47 ppm (CH3) for 5-methyl thiazole protons which in flow cytometry as to their IC50 values. Early and late
were singlet peaks. Acetyl protons were observed at d apoptotic rates of compounds were given in Table S2
3.95–4.48 ppm (CH2) as a singlet and a broad singlet peak (Supplemental Materials) as percentages. Also, early and late
seen at d 12.38–12.78 ppm indicated the acetamide N–H apoptotic rates by flow cytometric analysis against both cell
proton. The appearance of a pair of singlet, doublets, triplets lines portrait were shown in Figure S28. Especially, com-
and/or multiplets at d 6.75–8.57 ppm was due to the aro- pounds 4b, 4e and 4f killed a high percentage of A549 cells
matic protons of the aromatic rings. The 13C-NMR spectra by the way of necrosis. On the contrary, compounds 4a and
of compounds showed signals at d 35.20–37.41 ppm for 4c have killed A549 cells by the way of apoptosis.
methylene carbon (CH2), at d 12.32–12.34 ppm for 5-methyl
thiazole carbon (CH3), at d 94.89–165.93 ppm for aromatic
Results of ADME parameters and rule of five
carbon and at d 165.88–170.00 for carbonyl (C ¼ O) carbon.
M þ 1 peaks in LC-MS/MS spectra were in agreement with
Log P values were found between 1.99-5.30. Drug-likeness
the calculated molecular weight of the target compounds
model scores (DLMS) were found between ꢁ0.30 and 1.05.
(4a–4i). Elemental analysis results for C, H and N elements
were in agreement to the calculated values for the synthe-
sized compounds.
Especially, the DLM score for the most active compounds
4a, 4b, 4c, 4d, 4e and 4f were found 0.86, 1.05, 0.69, 0.55,
0.54 and 0.73. The number of hydrogen bond donor (HBD)
was stated for 4g, 4h and 4i as 2 and for the rest of them as
1. Also, the number of hydrogen bond acceptor (HBA) was
determined as maximal 7 for all compounds. Molecular vol-
Anticancer activity
The cytotoxicity assays and determination of IC50 doses of ume was calculated between 285.75 and 346.66 A3. All find-
cisplatin and all compounds against A549 and NIH/3T3 cell ings are in accord with the range according to Lipinski’s
were performed by MTT assay (as shown in Table S1 rule of five. Even if there is no exact finding in practice,
Supplemental Materials). The formazan formation was quan- these results are in agreement with the active compounds.
tified spectrophotometrically at 540 nm using a microplate Additionally, these findings are making them oral anticancer
reader. Relating to the assay results, all compounds have agents. Thus, it may be said that synthesized compounds
showed high anticancer activity. Additionally, compounds may have a good pharmacokinetic profile. All findings were
4a–4f displayed stronger activity than cisplatin against A549 shown in Table S3.
These results point out that 2-substituted-N-(5-methyl-4-
cell line.
Compounds 4a, 4b, 4c, 4d, 4e and 4f were significantly phenylthiazol-2-yl)acetamide nucleus showed good anti-
more active than the reference drug (cisplatin). Among cancer activity. The highest activity by the way of apoptosis
them, compounds 4a, 4c and 4e were determined to be 7 was observed when the functional group substitutions are
times more active than cisplatin whereas compound 4b was smaller such as in compounds 4a–4d. The compounds bear-
found to be 5 times more active than cisplatin. At most ing a benzothiazole nucleus were found to be more effective
compounds 4d and 4f were found 15 times more active than the compounds bearing a benzimidazole nucleus.
than cisplatin. whereas compounds 4g and 4h exhibited Besides, the presence of an electron withdrawing group sub-
lower activity than cisplatin. The IC50 values of synthesized stitution on the benzothiazole or the absence of any substi-
compounds and reference drug were given in Table S 1.
When evaluated according to the toxicity of the com-
pounds, compound 4c showed highly cytotoxic effect against
A549 cells (IC50= 23.30 0.35 lM) and it did not show cyto-
tution on the benzimidazole increased the activity. But their
selective apoptotic anticancer activity was established to be
inadequate compared to the five-membered ring systems.
In general, compounds 4a (1-methyl-1H-imidazol-2-yl)
toxic activity against NIH/3T3 cells (IC50>1000 lM). and 4c (1-methyl-tetrazol-2-yl) were found to be more
Similarly, compounds 4b, 4d and 4f showed selective cyto- suited as chemotherapeutic agents against A549 human lung
toxicity against A549 cells. On the other hand, for com- adenocarcinoma cells. Most particularly, compound 4c was
pounds 4a, 4e and 4h, the difference between the superior to 4a due to apoptosis rates and can be considered

4
A. E. EVREN ET AL.
for several reasons. Firstly, compound 4c has smaller Synthesis of 2-chloro-N-(5-methyl-4-phenylthiazol-2-yl)
molecular volume than the others, and it has low molecular acetamide (3)[61]
weight. Also, it has low partition constant (Log P ¼ 1.99).
In an ice bath, 2-amino-4-phenyl-5-methylthiazole
All these parameters can positively affect the solubility. In
(40 mmol) was dissolved in tetrahydrofuran (THF) and trie-
fact, one of the major influences may be breaking the devel-
thylamine (48 mmol) was added into the flask. 2-
oped resistance by 1,5-disubstituted tetrazole moiety.[55]
Chloroacetylchloride (48 mmol) was dissolved in THF and
Therefore compound 4c showed a potent anti-lung cancer
the solution was added to the dropping funnel. This solution
activity as it may increase the chance of breaking a drug
was added dropwise gradually to the flask. After the drop-
resistance development.
ping is over the mixture was stirred at room temperature
for 3 h. The completion of the reaction was monitored with
the help of TLC. The reaction solvent was evaporated, and
the crude product was washed with water and filtered.
Experimental
Chemistry
All chemicals were purchased from Sigma-Aldrich Chemical
Co (Sigma-Aldrich Corp., St. Louis, MO, USA) and Merck
Chemicals (Merck KGaA, Darmstadt, Germany). All melting
Synthesis of N-(5-methyl-4-phenylthiazol-2-yl)-2-
(substituted thio) acetamide derivatives (4a–i)
2-Chloro-N-(5-methyl-4-phenylthiazol-2-yl)acetamide
and
points (m.p.) were determined by MP90 digital melting
point apparatus (Mettler Toledo, Ohio, USA) and were
uncorrected. All reactions were monitored by thin-layer
chromatography (TLC) using Silica Gel 60 F254 TLC plates
(Merck KGaA, Darmstadt, Germany). Spectroscopic data
were recorded with the following instruments: 1H NMR
(nuclear magnetic resonance) Bruker DPX 300 FT-NMR
spectrometer, 13C NMR, Bruker DPX 75 MHz spectrometer
(Bruker Bioscience, Billerica, MA, USA) M þ 1 peaks were
determined by Shimadzu 8040 LC/MS/MS system
(Shimadzu, Tokyo, Japan). Elemental analyses were per-
formed on a Leco 932 CHNS analyzer (Leco, Michigan,
equal mole 2-mercapto aryl derivatives were reacted in the
presence of potassium carbonate in acetone. The completion
of the reaction was monitored with the help of TLC. From
the reaction mixture, the solution was evaporated and
treated with water to yield the final products. The final
products (4a–4i) were recrystallized from ethanol.
2 -[(1-Methyl-1H-imidazol-2-yl)thio]-N-(5-methyl-4-
phenylthiazol-2-yl)acetamide (4a)
1
m. p. 157-159 ꢀC, Yield: 73%, light-brown powder, H-NMR
1
(300 MHz, DMSO-d6, ppm) d 2.46 (s, 3H, CH3), 3.60 (s, 3H,
imidazole-CH3), 3.95 (s, 2H, CH2), 6.95 (d, J ¼ 1.20 Hz, H,
Ar-H), 7.27 (d, J ¼ 1.20 Hz, H, Ar-H), 7.31–7.38 (m, H, Ar-
H), 7.42–7.47 (m, 2 H, Ar-H), 7.61-7.62 (m, H, Ar-H), 7.65
(d, J ¼ 1.45 Hz, H, Ar-H), 12.39 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 12.32 (C-8), 33.47 (C-d), 37.41
(C-10), 121.78 (C-6), 124.16 (C-b), 127.74 (C-2),
128.42(C-4), 128.84 (C-3), 129.13 (C-c), 135.27 (C-1), 144.66
(C-5), 144.81 (C-a), 154.12 (C-7), 167.28 (C-9). For
C16H16N4OS2 calculated: Elem. Anal.: 55.79% C, 4.68% H,
16.27% N, found: 55.78% C, 4.67% H, 16.28% N. HRMS
(m/z): [M þ 1]þ calculated 345.0838; found 345.0830.
USA). The Supplemental Materials file contains sample H
and 13C NMR Spectra for products 4 (Figures S1–S27).
Materials and methods
General synthesis of 2-bromo-1-phenylpropane (1)[59]
In a flask, propiophenone (9.39 g, 0.07 mol) was dissolved in
acetic acid and hydrobromic acid was added as a catalyst.
The bromine (13.42 g, 0.084 mol) was dissolved in acetic
acid. Reaction temperature was set to 0–5 ꢀC. The bromine
solution from the dropping funnel was carefully added drop-
wise, considering the color change. The mixture was stirred
at room temperature until the reaction is finished which was
checked by TLC. After the reaction was completed, the mix-
ture was poured into ice-water and the reaction mixture was
neutralized with saturated NaHCO3 solution. Extraction was
performed with dichloromethane (DCM) (3 ꢂ 100 mL).
Combined organics was dried over Na2SO4 and evaporated
in vacuo to give the title product.
N-(5-Methyl-4-phenylthiazol-2-yl)-2-[(4-methyl-4H-1,2,4-
triazol-3-yl)thio]acetamide (4b)
1
m. p. 193–195 ꢀC, Yield: 80%, off-white powder, H-NMR
(300 MHz, DMSO-d6, ppm) d 2.46 (s, 3H, CH3), 3.60 (s, 3H,
triazole-CH3), 4.12 (s, 2H, CH2), 7.32–7.37 (m, H, Ar-H),
7.43–7.47 (m, 2H, Ar-H), 7.62–7.65 (m, 2H, Ar-H), 8.57 (s,
H, Ar-H), 12.38 (brs, H, NH). 13C-NMR (75 MHz, DMSO-
d6, ppm) d 12.32 (C-8), 31.32 (C-c), 36.69 (C-10), 121.84
(C-6), 127.76 (C-2), 128.42 (C-4), 128.85 (C-3), 135.25 (C-
Synthesis of 2-amino-4-phenyl-5-methylthiazole (2)[60]
2-Bromo-1-phenylpropanone (12.78 g, 0.06 mol) and thio- 1), 144.70 (C-5), 146.81 (C-b), 148.77 (C-a), 154.09 (C-7),
urea (4.57 g, 0.06 mol) were dissolved in ethanol and mixed 166.63 (C-9). For C15H15N5OS2 calculated: Elem. Anal.:
at room temperature for 24 h. The completion of the reac- 52.16% C; 4.38% H, 20.27% N. found: 52.17% C, 4.39% H,
tion was controlled by the TLC. The mixture was filtered 20.26% N. HRMS (m/z): [M þ 1]þ calculated 346.0783;
and obtained the raw product.
found 346.0780.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
2 -[(1-Methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-
phenylthiazol-2-yl)acetamide (4c)
131.72 (C-e), 134.10 (C-b), 135.23 (C-1), 144.75 (C-5),
153.83 (C-g), 154.11 (C-7), 165.93 (C-a), 169.09 (C-9). For
C19H14ClN3OS3 calculated: Elem. Anal.: 52.83% C, 3.27% H,
9.73% N, found: 52.84% C, 3.28% H, 9.74% N. HRMS
(m/z): [M þ 1]þ calculated 432.0060; found 432.0059.
m. p. 196-168 ꢀC, Yield: 82%, brown solid, 1H-NMR
(300 MHz, DMSO-d6, ppm) d 2.47 (s, 3H, CH3), 3.99 (s, 3H,
CH3), 4.35 (s, 2H, CH2), 7.36 (brs, H, Ar-H), 7.46 (brd,
J ¼ 4.05 Hz, 2H, Ar-H), 7.64 (brs, 2H, Ar-H), 12.48 (H,
NH). 13C-NMR (75 MHz, DMSO-d6, ppm) d 12.33 (C-8),
34.20 (C-b), 36.61 (C-10), 121.95 (C-6), 127.89 (C-2),
128.43(C-4), 128.86 (C-3), 135.22 (C-1), 144.75 (C-5), 153.55
(C-a), 154.03 (C-7), 165.88 (C-9). For C14H14N6OS2 calcu-
lated: Elem. Anal.: 48.54% C, 4.07% H, 24.26% N, found:
48.53% C, 4.08% H, 24.27% N. HRMS (m/z): [M þ 1]þ cal-
culated 347.0743; found 347.0730.
2 -[(5-Methoxy-1H-benzimidazol-2-yl)thio]-N-(5-methyl-
4-phenylthiazol-2-yl)acetamide (4g)
m. p. 94-96 ꢀC, Yield: 73%, brown powder, 1H-NMR
(300 MHz, DMSO-d6, ppm) d 2.45 (s, 3H, CH3), 3.75 (s, 3H,
O-CH3), 4.31 (s, 2H, CH2), 6.75 (dd, J1=2.45 Hz, J2=8.72 Hz,
H, Ar-H), 6.96 (d, J ¼ 2.35 Hz, H, Ar-H), 7.32-7.37 (m, 2H,
Ar-H), 7.43-7.48 (2H, Ar-H), 7.63-7.66 (m, 2H, Ar-H), 11.31
(brs, H, benzimidazole-NH), 12.41 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 12.33 (C-8), 35.43 (C-10),
55.92 (C-h), 94.89 (C-f), 110.31 (C-c or C-d), 111.01 (C-c or
C-d), 121.72 (C-6), 127.73 (C-2), 128.42 (C-4), 128.57 (C-b),
128.84 (C-3), 133.52 (C-g), 135.31 (C-1), 144.65 (C-5),
148.73 (C-a), 154.33 (C-7), 155.80 (C-e), 167.03 (C-9). For
C20H18N4O2S2 calculated: Elem. Anal.: 58.52% C, 4.42% H,
13.65% N, found: 58.53% C, 4.41% H, 13.66% N. HRMS
(m/z): [M þ 1]þ calculated 411.0944; found 411.0928.
2 -[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]-N-(5-methyl-4-
phenylthiazol-2-yl)acetamide (4d)
m. p. 204-206 ꢀC, Yield: 76%, off-white solid, 1H-NMR
(300 MHz, DMSO-d6, ppm) d 2.47 (s, 3H, CH3), 2.67 (s, 3H,
thiadiazole-CH3), 4.35 (s, 2H, CH2), 7.32–7.38 (m, H, Ar-
H), 7.43–7.48 (m, 2H, Ar-H), 7.63–7.66 (m, 2H, Ar-H),
12.47 (brs, H, NH). 13C-NMR (75 MHz, DMSO-d6, ppm) d
12.33 (C-8), 15.66 (C-c), 37.08 (C-10), 121.90 (C-6), 127.78
(C-2), 128.43 (C-4), 128.86 (C-3), 135.24 (C-1), 144.73 (C-
5), 154.09 (C-7), 164.36 (C-b), 166.11 (C-a), 166.38 (C-9).
For C15H14N4OS3 calculated: Elem. Anal.: 49.70% C, 3.89%
H, 15.46% N, found: 49.71% C, 3.88% H, 15.45% N. HRMS
(m/z): [M þ 1]þ calculated 363.0403; found 363.0403.
N-(5-Methyl-4-phenylthiazol-2-yl)-2-[(5-nitro-1H-
benzimidazol-2-yl)thio]acetamide (4h)
1
m. p. 191-193 ꢀC, Yield: 72%, deep brown powder, H-NMR
(300 MHz, DMSO-d6, ppm) d 2.45 (s, 3H, CH3), 4.40 (s, 2H,
CH2), 7.13–7.37 (m, H, Ar-H), 7.43–7.48 (m, 2H, Ar-H),
7.57 (d, J ¼ 8.86 Hz, H, Ar-H), 7.63–7.66 (m, 2H, Ar-H),
8.02 (dd, J1=2.29, J2=8.86, H, Ar-H), 8.29 (d, J ¼ 2.19, H,
Ar-H), 11.88 (brs, H, benzimidazole-NH), 12.78 (brs, H,
NH). 13C-NMR (75 MHz, DMSO-d6, ppm) d 12.33 (C-8),
35.20 (C-10), 110.77 (C-f), 113.98 (C-c), 117.59 (C-d),
121.79 (C-6), 127.75 (C-2), 128.42 (C-4), 128.84 (C-3),
135.27 (C-1), 140.67 (C-g), 142.21 (C-e), 144.68 (C-5),
145.37 (C-b), 154.19 (C-7), 157.23 (C-a), 166.75 (C-9). For
C19H15N5O3S2 calculated: Elem. Anal.: 53.64% C, 3.55% H,
16.46% N, found: 53.65% C, 3.56% H, 16.45% N. HRMS
(m/z): [M þ 1]þ calculated 426.0689; found 426.0673.
2 -(Benzothiazol-2-ylthio)-N-(5-methyl-4-phenylthiazol-2-
yl)acetamide (4e)
m. p. 139-141 ꢀC, Yield: 78%, brown powder, 1H-NMR
(300 MHz, DMSO-d6, ppm) d 2.46 (s, 3H, CH3), 4.48 (s, 2H,
CH2), 7.34-7.39 (m, 2H, Ar-H), 7.43-7.49 (m, 3H, Ar-H),
7.64-7.67 (m, 2 H, Ar-H), 7.81 (d, J ¼ 7.57 Hz, H, Ar-H),
8.01-8.04 (m, H, Ar-H), 12.54 (brs, H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 12.33 (C-8), 36.69 (C-10),
121.62 (C-c or C-f), 121.92 (C-6), 122.39 (C-c or C-f),
125.07 (C-d or C-e), 126.91 (C-d or C-e), 127.78 (C-2),
128.44 (C-4), 128.87 (C-3), 135.25 (C-1), 135.30 (C-b),
144.73 (C-5), 152.94 (C-g), 154.13 (C-7), 166.10 (C-a) and
(C-9). For C19H15N3OS3 calculated: Elem. Anal.: 57.41% C,
3.80% H, 10.57% N, found: 57.40% C, 3.81% H, 10.58% N.
HRMS (m/z): [M þ 1]þ calculated 398.0450; found 398.0440.
2 -[(1H-benzimidazol-2-yl)thio]-N-(5-methyl-4-
phenylthiazol-2-yl)acetamide (4i)
1
m. p. 122-124 ꢀC, Yield: 70%, light brown powder, H-NMR
2 -[(5-Chlorobenzothiazol-2-yl)thio]-N-(5-methyl-4-
phenylthiazol-2-yl)acetamide (4f)
(300 MHz, DMSO-d6, ppm) d 2.45 (s, 3H, CH3), 4.36 (s, 2H,
CH2), 7.10–7.13 (m, 3H, Ar-H), 7.43–7.48 (m, 4H, Ar-H),
7.63-7.66 (m, 2H, Ar-H), 12.64 (brs, 2H, NH). 13C-NMR
(75 MHz, DMSO-d6, ppm) d 12.34 (C-8), 35.29 (C-10),
109.93 (C-c), 121.94 (C-6), 122.75 (C-d), 127.73 (C-2),
128.42 (C-4), 128.84 (C-3), 132.72 (C-b), 135.32 (C-1),
144.66 (C-5), 149.92 (C-a), 154.35 (C-7), 170.00 (C-9). For
C19H16N4OS2 calculated: Elem. Anal.: 59.98% C, 4.24% H,
14.73% N, found: 59.99% C, 4.25% H, 14.72% N. HRMS
1
m. p. 165-166 ꢀC, Yield: 79%, light brown powder, H-NMR
(300 MHz, DMSO-d6, ppm) d 2.46 (s, 3H, CH3), 4.48 (s, 2H,
CH2), 7.33–7.38 (m, H, Ar-H), 7.41–7.49 (m, 3H, Ar-H),
7.63–7.67 (m, 2H, Ar-H), 7.88 (d, J ¼ 2.00 Hz, H, Ar-H),
8.07 (d, J ¼ 8.59 Hz, H, Ar-H), 12.55 (brs, H, NH). 13C-
NMR (75 MHz, DMSO-d6, ppm) d 12.34 (C-8), 36.79 (C-
10), 121.05 (C-c or C-f),121.95 (C-6), 123.85 (C-c or C-f),
125.07 (C-d), 127.79 (C-2), 128.43 (C-4), 128.87(C-3), (m/z): [M þ 1]þ calculated 381.0838; found 381.0838.

6
A. E. EVREN ET AL.
Biochemistry
of the compounds. Particularly, several preliminary tests
such as state the ADME (absorption, distribution, metabol-
ism, excretion) properties are becoming more important due
to the occur of many new compounds which are resulting
from the original compounds synthesis studies that acceler-
ated at the end of the 1990s. We want to learn these proper-
ties of the new compounds; thus, we can work up a
connection relationship between molecular structure and
their properties.[64,65]
Cell viability analysis
MTT method was performed to measure the cytotoxicity of
the tested compounds against NIH/3T3 and A549 cell lines
according to the reported data.[62] The A549 and NIH/3T3
cells were cultured at a density of 5 ꢂ 103 cells per well in
flat bottomed 96-well plates with various concentrations (50-
1000 lM) at the same time cisplatin was used as control
drug and they incubated 24 h. After incubation, MTT pow-
der (5 mg/mL) dissolved in phosphate-buffered saline (PBS)
was added to each well (20 lL). 2-4 h later, the medium was
removed from the plate and 100 lL of DMSO was added to
each well to dissolve the dye and kept for 10 min. The cells
were measured at 540 nm using microtiter plate reader
(BioTek Instruments ELx808IU, USA). Cell viability was cal-
culated as a percentage and compared with the control cells.
Each concentration was repeated in three wells and half-
maximal inhibitory concentration 50 (IC50) values were
defined as the drug concentrations that reduced absorbance
to 50% of control values.
Predictions of ADME properties of the obtained com-
pounds 4a–4i were calculated by the online Molinspiration
property program[66] and the Molsoft software.[67]
Conclusions
In summary, we have synthesized novel 2-[substituted thio]-
N-(5-methyl-4-phenylthiazol-2-yl) acetamide derivatives
(4a–4i) and evaluated their anticancer activity against A549
lung adenocarcinoma cells in this study. In general, all com-
pounds (4a–4i) have shown to possess an anticancer activity.
Mainly, compounds 4a–4f have acted against A549 lung
adenocarcinoma cells in low concentrations. According to
apoptosis rates and IC50 values, we indicate that compound
4c (1-methyl-1H-tetrazol-5-yl) has been stated both selective
and the most active compound against A549 lung adenocar-
cinoma cells.
The determination of early/late apoptosis by
flow cytometry
The A549 and 3T3 cells were seeded at 105 cells/mL per
well in six well plates at 37 ꢀC in a humidified atmosphere
containing 5% CO2 in air. Then, cells were treated with cis-
platin and active compounds at IC50 doses for 24 h. The
A549 and 3T3 cells were harvested and washed twice with
ice-cold PBS and resuspended in 100 lL of binding buffer. A
volume of 5 lL (5 lg/mL) of Annexin V-FITC and PI were
added to the cells and incubated for 15 min in the dark at
room temperature (20–25 ꢀC). Then, 400 lL of binding buf-
fer was added to the mixture samples and analyzed with a
flow cytometer (BD FACS Aria Cell Sorter flow cytometry,
BD Biosciences).[63]
Acknowledgments
This study was supported by the Anadolu University Scientific
Research Project, Eskisehir, Turkey (Project no. 1705S311). Anadolu
€
Universitesi.
Disclosure statement
The authors confirm that this article content has no conflict of interest.
Data sources
ORCID
GLOBOCAN extrapolates incidence, mortality, and preva-
lence of cancer globally. Incidence data are acquired from
population-based cancer registries (PBCR). Although the
quality of information from less developed countries is often
considered limited compared with that from more developed
countries, PBCR are a key source of information on the
local scale and profile of cancer and are critical in develop-
ing and evaluating cancer control programs.[10] Statistical
data obtained from GLOBOCAN 2012, developed by the
IARC, were used.[11] Furthermore, the incidence and mortal-
ity rates were calculated by using the simple percent-
age method.
Asaf E. Evren
http://orcid.org/0000-0002-8651-826X
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