Synthesis and characterization of a new series of thiadiazole derivatives as potential anticancer agents

Article abstract of DOI:10.1515/hc-2020-0002

Cancer is one of the most common causes of death in the world. Despite the importance of combating cancer in healthcare systems and research centers, toxicity in normal tissues and the low efficiency of anticancer drugs are major problems in chemotherapy. Nowadays the aim of many medical research projects is to discover new safer and more effective anticancer agents. 1,3,4-Thiadiazole compounds are important fragments in medicinal chemistry because of their wide range of biological activities, including anticancer activities. The aim of this study was to determine the capacity of newly synthesized 1,3,4-thiadiazole compounds as chemotherapeutic agents. The structures of the obtained compounds were elucidated using ¹H-NMR, ¹³C-NMR and mass spectrometry. Although the thiadiazole derivatives did not prove to be significantly cytotoxic to the tumour tissue cultures, compound 4i showed activity against the C6 rat brain cancer cell line (IC₅₀ 0.097 mM) at the tested concentrations.

Full text of DOI:10.1515/hc-2020-0002

Heterocycl. Commun. 2020; 26: 6–13
Research Article
Open Access
Ulviye Acar Çevik, Derya Osmaniye*, Serkan Levent, Begüm Nurpelin Sağlik,
BSeytülnKatyha Çeasvuişsoğlau,nYudsufcÖzhkaay ranadcZatfeerrAisızmaKatpiloannciklof a new
series of thiadiazole derivatives as potential
anticancer agents
https://doi.org/10.1515/hc-2020-0002
Received July 31, 2019; accepted January 22, 2020.
Introduction
Abstract: Cancer is one of the most common causes of Cancer is a disease caused by a group of cells (usually
death in the world. Despite the importance of combating coming from a single cell) that have uncontrolled growth [1].
cancer in healthcare systems and research centers, toxi- Cancer has become one of the most feared diseases world-
city in normal tissues and the low efficiency of anticancer wide. Cancer is the second leading cause of death after
drugs are major problems in chemotherapy. Nowadays cardiovascular disease. Every year, 9.6 million people die
the aim of many medical research projects is to discover of this disease worldwide [2,3].
new safer and more effective anticancer agents. 1,3,4-
Many cancers can be cured if detected early and
Thiadiazole compounds are important fragments in medi- treated promptly by surgery, radiation, chemotherapy,
cinal chemistry because of their wide range of biological or immunotherapy [4]. Chemotherapy (CTX), which is a
activities, including anticancer activities. The aim of this very common and standardized therapy, uses antican-
study was to determine the capacity of newly synthesized cer drugs (or chemotherapeutical agents) to treat cancer.
1,3,4-thiadiazole compounds as chemotherapeutic agents. But chemotherapy has its limitations: one is the lack of
The structures of the obtained compounds were eluci- selectivity which leads to severe side effects and limited
1
dated using H-NMR, 13C-NMR and mass spectrometry. efficacy; the other is the emergence of drug resistance
Although the thiadiazole derivatives did not prove to be [5]. Therefore, there is an urgent need to design and syn-
significantly cytotoxic to the tumour tissue cultures, com- thesize potent and highly selective molecules to improve
pound 4i showed activity against the C6 rat brain cancer current anticancer therapy with lower or no toxicity to
cell line (IC50 0.097 mM) at the tested concentrations.
normal cells [6].
Sulfur-containing organic molecules have acqui-
Keywords: 1,3,4-Thiadiazole, Anticancer, MTT assay, red special attention in the field of medicinal chemistry.
1H-NMR, 13C-NMR.
Heterocyclic compounds with nitrogen and sulfur in their
structures are often employed in medicinal chemistry
drug design [7]. The five-membered thiadiazole ring is
an important pharmacophore which contains one sulfur
and two nitrogen atoms [8]. The sulfur atom of 1,3,4-
thiadiazole imparts the improved mesoionic nature and
liposolubility which give this class of compounds good
tissue permeability [9]. The potential anticancer activity
of this structure is one the most interesting areas that
have encouraged researchers to focus on it. Hence, a large
number of 1,3,4-thiadiazole derivatives have been synthe-
sized and their molecular mechanism of anticancer acti-
vity has been investigated [10-15].
* Corresponding author: Derya Osmaniy, Anadolu University, Faculty
of Pharmacy, Department of Pharmaceutical Chemistry, 26470,
Eskişehir, Turkey; Anadolu University, Faculty of Pharmacy, Doping
and Narcotic Compounds Analysis Laboratory, 26470, Eskişehir,
Turkey, E-Mail: dosmaniye@anadolu.edu.tr
Tel.: +90-222-335-0780 (ext. 3777); Fax: +90-222-335-0750.
Ulviye Acar Çevik, Serkan Levent, Begüm Nurpelin Sağlik,
Betül Kaya Çavuşoğlu, Yusuf Özkay and Zafer Asım Kaplancik,
Anadolu University, Faculty of Pharmacy, Department of
Pharmaceutical Chemistry, 26470, Eskişehir, Turkey; Anadolu
University, Faculty of Pharmacy, Doping and Narcotic Compounds
Analysis Laboratory, 26470, Eskişehir, Turkey.
In the present study, aiming to identify new chemical
entities, 1,3,4-thiadiazole derivatives were synthesized
Open Access. © 2020 Ulviye Acar Çevik et al., published by De Gruyter.ꢀ
Attribution alone 4.0 License.
ꢀThis work is licensed under the Creative Commons

U.A. Çevik et al.: Thiadiazole derivatives as new anticancer agentsꢁ
ꢁ7
and their anticancer activity was evaluated against human (0.07 mol, 5.8 mL) was added dropwise with stirring. After
breast and lung cancer cell lines.
addition of chloroacetyl chloride was completed, the
reaction mixture was stirred for an additional 1h at room
temperature. The solvent was evaporated under reduced
pressure and the product was washed with water, dried
and recrystallized from ethanol.
Experimental
Chemistry
Preparation of N-(5-trifluoromethyl-1,3,4-thiadiazol-2-
yl)-2-[(5-(substitutedamino)-1,3,4-thiadiazol-2-yl)thio]
All chemicals were obtained either from Merck (Merck acetamides (4a-4j)
KGaA, Darmstadt, Germany) or Sigma-Aldrich (Sigma- Compounds 2a-2j (2 mmol) and compound 3a (2 mmol,
Aldrich Corp., St. Louis, MO, USA) and used without 0.489 g) were stirred at room temperature in acetone
further chemical purification. Chemical purities of the (40 mL) for 6 h. After TLC screening, the solvent was eva-
compounds were checked by classical TLC applications porated under reduced pressure. The product was washed
performed on silica gel 60 F254 (Merck KGaA, Darmstadt, with water, dried, and recrystallized from ethanol.
Germany). Melting points of the compounds were mea-
sured using an automatic melting point determination N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-2-((5-
instrument (MP90, Mettler-Toledo, OH, USA) and were (methylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide (4a):
1
1
presented as uncorrected. H and 13C NMR spectra were Yield: 80 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz,
recorded in DMSO-d6 using a Bruker digital FT-NMR spec- DMSO-d6): 2.84 (3H, d, J=4.5 Hz, -CH3), 4.13 (2H, s, -CH2-),
trometer (Bruker Bioscience, MA, USA) at 300 MHz and 7.74 (1H, br.s., -NH), 13C-NMR (75 MHz, DMSO-d6): δ = 31.49,
75 MHz, respectively. M+1 peaks were determined using 38.86, 120.79 (J1=269.8 Hz), 149.30, 149.72 (J2=36.7 Hz),
a Shimadzu LC/MS IT-TOF system (Shimadzu, Tokyo, 164.63, 169.72, 170.98. HRMS (m/z): [M+H]+ calcd for C8H7
Japan).
F3N6OS3: 356.9868; found: 356.9855.
2-((5-(Ethylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(5-
Materials and methods
trifluoromethyl-1,3,4-thiadiazol-2-yl)acetamide (4b):
1
Yield: 79 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz,
Preparation of N-substitutedhydrazinecarbothioamides
(1a-1j)
DMSO-d6): 1.13 (3H, t, J=7.2 Hz, -CH3), 3.24 (2H, q, J=5.3 Hz,
-CH2-), 4.17 (2H, s, -CH2-), 7.81 (1H, br.s., -NH). 13C-NMR
A suitable isothiocyanate derivative (0.01 mol) and hyd- (75 MHz, DMSO-d6): δ = 14.62, 38.10, 39.83, 120.56 (J1=270.2
razine hydrate (0.02 mol) were stirred in ethanol (100 mL) Hz), 148.64, 150.53 (J2=37.1 Hz), 163.09, 168.93, 170.15. HRMS
at room temperature. After completion of the reaction, the (m/z): [M+H]+ calcd for C9H9F3N6OS3: 371.0025; found:
precipitated product was filtered and recrystallized from 371.0005.
ethanol.
2-((5-((2-Methoxyethyl)amino)-1,3,4-thiadiazol-2-yl)thio)-
Preparation of 5-(substitutedamino)-1,3,4-thiadiazole-2-
thiols (2a-2j)
N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acetamide (4c):
1
Yield: 81 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz,
Compounds 1a-1j (0.009 mol) were dissolved in ethanol DMSO-d6): 3.25 (3H, s, -CH3), 3.41 (2H, t, J=4.5 Hz, -CH2-),
(100 mL) and a solution of NaOH (0.01 mol, 0.4 g) in ethanol 3.47 (2H, t, J=4.6 Hz, -CH2-), 4.03 (2H, s, -CH2-), 7.88 (1H,
was added. Carbon disulfide (0.01 mol, 0.6 mL) was added br.s., -NH), 12.67 (1H, s, -NH). 13C-NMR (75 MHz, DMSO-
and the mixture was refluxed for 8 h. After this period, the d6): δ = 40.41, 44.35, 58.40, 70.39, 121.32 (J1=269.3 Hz),
solution was cooled and acidified to pH 4–5 with hydro- 147.90 (J2=38.2 Hz), 150.63, 168.12, 169.81, 171.52. HRMS
chloric acid solution and recrystallized from ethanol.
(m/z): [M+H]+ calcd for C10H11F3N6O2S3: 401.00130; found:
401.0108.
Preparation of 2-chloro-N-(5-trifluoromethyl -1,
3,4-thiadiazol-2-yl)acetamide (3a)
N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-2-((5-
2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (0.06 mol, (propylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide (4d):
1
10.1 g) was dissolved in tetrahydrofuran (150 mL) and Yield: 80 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz,
triethylamine (0.07 mol, 10.2 mL) was added. The mixture DMSO-d6): 0.88 (3H, t, J=7.4 Hz, -CH3), 1.54 (2H, q, J=7.11 Hz,
was cooled in an ice bath and chloroacetyl chloride -CH2-), 3.18 (2H, q, J=5.55 Hz, -CH2-), 4.00 (2H, s, -CH2-),

ꢁ
8ꢁ
U.A. Çevik et al.: Thiadiazole derivatives as new anticancer agents
7.76 (1H, br.s., -NH). 13C-NMR (75 MHz, DMSO-d6): δ = 11.81, 10.33 (1H, s, -NH). 13C-NMR (75 MHz, DMSO-d6): δ = 41.38,
22.22, 40.83, 46.79, 121.43 (J1=269.3 Hz), 147.53 (J2=35.8 Hz), 117.75, 121.82 (J1=268.8 Hz), 122.24, 129.52, 140.98, 146.25
150.30, 168.81, 170.05, 171.86. HRMS (m/z): [M+H]+ calcd (J2=35.2 Hz), 152.21, 154.59, 165.06, 173.05. HRMS (m/z):
for C10H11F3N6OS3: 385.0181; found: 385.0149.
[M+H]+ calcd for C13H9F3N6OS3: 419.0025; found: 419.0017.
2-((5-(Isopropylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(5-
N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-((5-(p-tolylamino)-
trifluoromethyl-1,3,4-thiadiazol-2-yl)acetamide (4e):
1,3,4-thiadiazol-2-yl)thio)acetamide (4j):
1
1
Yield: 78 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz, Yield: 83 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz,
DMSO-d6): 1.15 (6H, d, J=6.5 Hz, -CH3), 3.72-3.78 (1H, m, DMSO-d6): 2.24 (3H, s, -CH3), 2.60 (3H, s, -CH3), 4.21
-CH-), 4.01 (2H, s, -CH2-), 7.68 (1H, br.s., -NH). 13C-NMR (2H, s, -CH2-), 7.13 (2H, d, J=8.3 Hz, -phenyl), 7.43 (2H, d,
(75 MHz, DMSO-d6): δ = 22.58, 40.61, 46.91, 121.37 J=8.5 Hz, -phenyl), 10.31 (1H, s, -NH), 12.68 (1H, s, -NH).
(J1=269.3 Hz), 147.70 (J2=35.7 Hz), 150.17, 168.48, 169.05, 13C-NMR (75 MHz, DMSO-d6): δ = 18.95, 20.76, 117.88, 123.57
171.71. HRMS (m/z): [M+H]+ calcd for C10H11F3N6OS3: (J1=268.8 Hz), 129.87, 131.22, 138.60, 146.35 (J2=35.2 Hz),
385.0181; found: 385.0158.
154.01, 165.32, 171.47, 173.08. HRMS (m/z): [M+H]+ calcd for
C14H11F3N6OS3: 433.0181; found: 433.0171.
2-((5-(Allylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(5-
trifluoromethyl-1,3,4-thiadiazol-2-yl)acetamide (4f):
1
Yield: 85 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz, Cytotoxicity test
DMSO-d6): 3.87 (2H, t, J=5.1 Hz, -CH2-), 4.19 (2H, s, -CH2-),
5.15 (2H, qd, J1=1.7 Hz, J2=15.5 Hz, -CH2-), 5.80-5.93 (1H, m, Metabolic activity of viable cells was measured by MTT
-CH-), 7.99 (1H, br.s., -NH). 13C-NMR (75 MHz, DMSO-d6): assay based on the reduction of 3-(4,5-dimethylthiazol-
δ = 37.89, 47.09, 116.69, 120.50 (J1=270.2 Hz), 134.67, 149.11, 2-yl)-2,5-diphenyltetrazolium salt to formazan product,
150.72 (J2=37.1 Hz), 162.73, 168.73, 170.17. HRMS (m/z): which can be quantified spectrophotometrically to deter-
[M+H]+ calcd for C10H9F3N6OS3: 383.0025; found: 383.0010. mine the percentage of viable cells. The anticancer acti-
vity of compounds 4a-4j were screened according to the
2-((5-(butylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(5-
MTT assay. The MTT assay was performed as previously
described [16-18]. A459, MCF-7, HepG2 and C6 cancer cell
trifluoromethyl-1,3,4-thiadiazol-2-yl)acetamide (4g):
1
Yield: 82 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz, lines were used in the MTT assay. Cisplatin was used as a
DMSO-d6): 0.87 (3H, t, J=7.3 Hz, -CH3), 1.31 (2H, q, reference drug.
J=7.6 Hz, -CH2-), 1.49 (2H, q, J=7.4 Hz, -CH2-), 3.21 (2H, q,
Prediction of ADME (Absorption, Distribution, Meta-
J=5.4 Hz, -CH2-), 4.20 (2H, s, -CH2-), 7.83 (1H, br.s., -NH), bolism, and Excretion) parameters and BBB (Blood–
13.57 (1H, s, -NH). 13C-NMR (75 MHz, DMSO-d6): δ = 14.05, brain barrier) permeability
19.96, 30.95, 37.54, 44.70, 120.38 (J1=270.2 Hz), 148.11, 151.16
Online Molinspiration property calculation program
(J2=37.6 Hz), 161.89, 168.32, 170.42. HRMS (m/z): [M+H]+ was used to predict absorption, distribution, metabolism
calcd for C11H13F3N6OS3: 399.0338; found: 399.0335.
and excretion (ADME) parameters of compounds 3a-3j [19].
The blood brain barrier (BBB) permeability of the com-
pounds was evaluated using an online BBB Predictor [20].
2-((5-(Isobutylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(5-
trifluoromethyl-1,3,4-thiadiazol-2-yl)acetamide (4h):
1
Yield: 80 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz,
DMSO-d6): 0.88 (6H, d, J=6.7 Hz, -CH3), 1.81-1.89 (1H, m,
-CH-), 3.05 (2H, dd, J1=5.7 Hz, J2=6.7 Hz, -CH2-), 3.91 (2H, s, Results and discussion
-CH2-), 7.75 (1H, br.s., -NH). 13C-NMR (75 MHz, DMSO-d6):
δ = 20.52, 27.95, 42.21, 52.60, 121.88 (J1=268.9 Hz), 145.95 Chemistry
(J2=35.1 Hz), 151.20, 170.04, 171.92, 173.49. HRMS (m/z):
[M+H]+ calcd for C11H13F3N6OS3: 399.0338; found: 399.0324. The compounds 4a-4j were synthesized as summarized
in Scheme 1. For the synthesis of the compounds 1a-1j,
N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-2-((5-
a suitable isothiocyanate and an excess of hydrazine
hydrate were reacted. Secondly, thiadiazole derivatives
(phenylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide (4i):
1
Yield: 86 %, M.P. = 247.6 – 249.9 °C, H-NMR (300 MHz, (2a-2j) were obtained by means of the reaction of thiourea
DMSO-d6): 4.04 (2H, s, -CH2-), 6.98 (1H, t, J=7.3 Hz, -phenyl), derivatives (1a-1j) and carbon disulfide in the presence of
7.32 (2H, t, J=7.4 Hz, -phenyl), 7.56 (2H, d, J=7.7 Hz, -phenyl), NaOH. 2-Chloro-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)

U.A. Çevik et al.: Thiadiazole derivatives as new anticancer agentsꢁ
ꢁ9
Compounds
R
4a
Methyl
4b
4c
4d
4e
4f
Ethyl
Methoxyethyl
Propyl
Isopropyl
Allyl
4g
4h
4i
Butyl
Isobutyl
Phenyl
4j
4-Methylphenyl
Scheme 1ꢂSynthesis route for the target compounds (4a-4j).
acetamide (3a) was prepared via the acetylation reaction 10.31 ppm and 10.33 ppm. Compound 4f bearing an allyl
between 2-amino-5-trifluoromethyl-1,3,4-thiadiazole and moiety gave a double quartet peak at 5.15 ppm. Additio-
chloroacetyl chloride. In the last step, the reaction nally, 4f had a triplet peak at 3.87 and multiplet peak
of compounds 2a-2j and compound 3a afforded the target between 5.80 ppm and 5.93 ppm. In the 13C NMR spectrum,
compounds (4a-4j).
aliphatic peaks belonging to substituents were observed
The final compounds were purified, and their structu- between 11.81 ppm and 70.39 ppm. Aromatic carbons
res were characterized by spectroscopic methods (1H-NMR, were observed between 116.69 ppm and 173.49 ppm. The
13C-NMR, and LC-MS/MS). In the 1H NMR spectrum, mono- trifluoromethyl carbon gave a peak between 120.38 ppm
substituted benzene protons had triplet and doublet peaks and 123.57 ppm as a quartet. The thiadiazole carbon to
between 6.98 ppm and 7.56 ppm. 1,4-disubstituted benzene which the trifluoromethyl group was attached gave a peak
protons had doublet peaks between 7.13 ppm and 7.43 ppm. between 146.25 ppm and 150.72 ppm. All masses were in
Methylene protons had singlet peaks between 3.91 ppm accordance with the estimated M+H values.
and 4.21 ppm. The thiadiazole NH gave broad singlet peaks
In addition to structure elucidations using routine
1
13
between 7.68 ppm and 7.99 ppm if it had an aliphatic subs- spectroscopic methods, 2D NMR studies including H- C
1
13
tituent. The thiadiazole NH of compounds 4i and 4j, with HMBC and H- C HSQC were performed for compound
aromatic substituents, gave broad singlet peaks between 4a, as seen in Figure 1 and Figure 2. According to the

ꢁ
10ꢁ
U.A. Çevik et al.: Thiadiazole derivatives as new anticancer agents
Figure 1ꢂHSQC spectrum of compound 4a.
Figure 2ꢂHMBC spectrum of compound 4a.

U.A. Çevik et al.: Thiadiazole derivatives as new anticancer agentsꢁ
ꢁ11
information obtained in the HSQC, the peak at 31.49 ppm However, when the non-substituted state of this aromatic
belongs to the methyl carbon and the peak at 38.86 ppm ring was compared to the methyl-bearing state at position
belongs to the methylene carbon. HMBC shows interac- 4, it was found that the methyl group reduced activity.
tions between hydrogen and carbon at a distance of 2 to
4 bonds. Using the HMBC spectrum presented in Figure 2,
it was determined that the peak at 149.30 ppm belongs to Prediction of ADME parameters and BBB permeability
the thiadiazole carbon to which the sulphur is attached,
the peak at 169.72 ppm belongs to the carbonyl carbon As an important drug discovery approach it is beneficial to
and the peak at 170.98 ppm belongs to the methylamino- evaluate the pharmacokinetic profiles of drug candidates
bound carbon of the thiadiazole ring.
during the early developmental phases. In recent years,
with the help of combinatorial chemistry, the number of
drug candidates for which early data on absorption, dis-
tribution, metabolism and excretion (ADME) are needed
has significantly increased [21]. Thus, predictions of the
Biological Evaluations
All new synthesized thiadiazole compounds (4a-4j) ADME properties of the obtained compounds (4a-4j) were
were tested for cytotoxicity against A549 (lung) and calculated using online Molinspiration chemical property
MCF-7 (breast) human cancer lines. The IC50 values of software [19]. This program is based on Lipinski’s rule of
the compounds are presented in Table 1. Anticancer acti- five, which predicts the ADME properties of drug-like com-
vities were tested using an MTT assay against human pounds, and is very important to optimize a biologically
lung (A549), breast (MCF-7) liver (HepG2) and rat brain active compound. According to Lipinski’s rule, an orally
(C6) cancer cells; the assay is used to measure cell via- active drug should not possess more than one violation of the
bility (the activity of living cells) via the mitochondrial criteria. The theoretical calculations of ADME parameters
dehydrogenase catalyzed conversion of tetrazolium MTT (topological polar surface area (TPSA), molecular volume
salt (3-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MV), number of hydrogen acceptors (nOHNH), number of
bromide) to formazan. These structures of thiadiazole hydrogen donors (nON), partition coefficient (log P), and
derivatives did not prove to be significantly cytotoxic to molecular weight (MW)) are accessible in Table 2 along with
the A549, MCF-7 and C6 cell lines at tested concentra- the violations of Lipinski’s rule. In regard to these data,
tions. Compound 4i (phenyl-substituted) was determined the obtained compounds (4a-4j) suited Lipinski’s rule by
to have an IC50 value of 0.097 mM against C6 cell line. In displaying no violation. As a result, it can be suggested that
contrast, the p-tolyl-containing derivative (4j) showed no the synthesized compounds may have a good pharmacoki-
promising activity. Based on the activity results obtained netic profile, increasing their pharmacological significance.
on the C6 cell line, it can be assumed that incorporation of
The activity of the compounds against brain cancer
an aromatic ring into the structure increases the activity. (C6) has prompted curiosity as to whether they can cross
Table 1ꢂIC50 of compounds 4a–4j and cisplatin against MCF-7 and A549 cell lines.
IC50 (mM)
Compound
MCF-7
A549
HepG2
C6
4a
4b
4c
4d
4e
4f
≥1
≥1
≥1
≥1
≥1
≥1
0.358 0.142
≥1
≥1
≥1
0.217 0.135
0.487 0.089
0.728 0.075
0.626 0.081
≥1
≥1
≥1
≥1
≥1
0.756 0.095
0.341 0.026
≥1
0.867 0.206
0.417 0.276
4g
4h
≥1
0.365 0.028
0.385 0.088
0.541 0.043
0.885 0.068
≥1
0.647 0.330
0.587 0.048
4i
0.472 0.251
≥1
0.353 0.091
0.097 0.021
4j
cis
0.264 0.030
0.019 0.009
0.332 0.024
0.013 0.003
0.258 0.022
0.06 0.004
0.256 0.055
0.03 0.004

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U.A. Çevik et al.: Thiadiazole derivatives as new anticancer agents
Table 2ꢂSome physicochemical parameters of the compounds 4a-4j in prediction of ADME profiles.
Comp.
MW (g/mol)
logP
TPSA (ANG2)
HBA
HBD
Vol (ANG3)
Vio
BBB
4a
4b
4c
4d
4e
4f
4g
4h
4i
356.38
370.41
400.43
384.43
384.43
382.42
398.46
398.46
418.45
432.48
1.38
1.76
1.36
2.26
2.05
2.02
2.82
2.50
3.51
3.96
92.69
92.69
101.93
92.69
92.69
92.69
92.69
92.69
92.69
92.96
7
7
8
7
7
7
7
7
7
7
2
2
2
2
2
2
2
2
2
2
246.83
263.63
289.42
280.43
280.22
274.80
297.23
297.02
301.68
318.24
0
0
0
0
0
0
0
0
0
0
+
+
+
+
+
+
+
+
+
+
4j
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Conflicts of Interest: The authors declare no conflict of
interest.
Acknowledgements: This study was financially supported
by Anadolu University Scientific Projects Fund, Project
No: 1903S016.

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