Synthesis of novel thiazolylpyrazoline derivatives and evaluation of their antimicrobial activities and cytotoxicities

Turk J Chem

Turkish Journal of Chemistry

(2016) 40: 641 – 654

¨

http://journals.tubitak.gov.tr/chem/

˙

c

⃝ TUBITAK

doi:10.3906/kim-1512-12

Research Article

Synthesis of novel thiazolylpyrazoline derivatives and evaluation of their

antimicrobial activities and cytotoxicities

Aouatef TABBI¹, Zafer Asım KAPLANCIKLI^2,∗, Dahmane TEBBANI¹,

2

3

4

¨

Leyla YURTTAS¸ , Zerrin CANTURK , Ozlem ATLI , Merve BAYSAL ,

Gu¨lhan TURAN-ZITOUNI²

¹Department of Chemistry, Faculty of Sciences, Mentouri University, Constantin, Algeria

²Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey

³Department of Microbiology, Faculty of Pharmacy, Anadolu University, Eski¸sehir, Turkey

⁴Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey

Received: 04.12.2015

•

Accepted/Published Online: 03.02.2016

•

Final Version: 21.06.2016

Abstract: Several novel thiazolylpyrazoline derivatives were synthesized by reacting substituted 3,5-diaryl-1-thiocarba-

moyl-2-pyrazolines with phenacylbromides. The structures of the synthesized compounds were conﬁrmed by IR, ¹H

NMR, ¹³C NMR, and MS spectral data. Their antimicrobial activities against Staphylococcus aureus (ATCC-25923), En-

terococcus faecalis (ATCC-29212), Enterococcus faecalis (ATCC-51922), Listeria monocytogenes (ATCC-1911), Klebsiella

pneumoniae (ATCC-700603), Pseudomonas aeruginosa (ATCC-27853), Escherichia coli (ATCC-35218), Escherichia coli

(ATCC-25922), Candida albicans (ATCC-90028), Candida glabrata (ATCC-90030), Candida krusei (ATCC-6258), and

Candida parapsilosis (ATCC-22019) were investigated. The compounds were also studied for their cytotoxic eﬀects using

a MTT assay. Compound 7c showed the highest antimicrobial activity, possessing the same potential as chloramphenicol

against K. pneumonia, P. aeruginosa, and E. coli (ATCC-25923).

Key words: 2-Pyrazoline, thiazole, thiazolylpyrazoline, antimicrobial activity, cytotoxicity

1. Introduction

It has been reported that the morbidity, mortality, and costs related to the treatment of infectious diseases

have been increased by antimicrobial resistance. The threat from resistance (particularly multiple resistance in

bacterial strains that have disseminated widely) has never been so great. The main dynamics driving this threat

are increased antibiotic use, bigger movement of people, and increased industrial and economic development.¹

The need for novel antibacterial and antifungal agents is greater than ever because of the emergence of multidrug

resistance in common pathogens, the quick emergence of new infections, and the potential for use of multidrug-

resistant agents in bioweapons.²

Every antimicrobial development candidate is considered “novel” by those who make it, but the multiple

approaches to developing new compounds neither carry equal potential to overcome preexisting resistance

mechanisms nor are they associated with equal development risk. There is a spectrum of innovation that ranges

from developments within established classes, to completely new microbial pharmacophores and molecular

targets.³

^∗Correspondence: zakaplan@anadolu.edu.tr

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TABBI et al./Turk J Chem

General sources for novel antimicrobial agents include biological sources as well as large collections of

diﬀerent compounds collected from various laboratories. The recent advance of synthetic libraries represents a

major advancement in the discovery of new lead compounds for antimicrobial drug development.⁴

Compounds having heterocyclic ring systems continue to attract considerable interest due to their wide

range of biological activities. Amongst them, ﬁve-membered heterocyclic compounds, particularly azoles, occupy

a unique place in the realm of natural and synthetic organic chemistry.⁵

Pyrazolines constitute a remarkable class of heterocycles due to their actual biological activities such as

anticancer, antioxidant, antibacterial, antifungal, antidepressant, anti-inﬂammatory, anticonvulsant, antitumor,

and analgesic properties.^6,7

In addition, a thiazole ring is found in many potent biologically active compounds, such as sulfathiazole

(antimicrobial drug), ritonavir (antiretroviral drug), abafungin (antifungal drug), bleomycine, and tiazofurin

(antineoplastic drug). It has been observed over the years that thiazole derivatives have several biological

activities such as antihypertensive, anti-inﬂammatory, antischizophrenia, antibacterial, anti-HIV, hypnotics,

antiallergic, analgesic, antithrombotic, ﬁbrinogen receptor antagonist, bacterial DNA gyrase B inhibitor, anti-

tumor, and cytotoxic activities.⁸

Thus, the synthesis and biological activities of novel thiazolylpyrazoline derivatives activated a great

deal of research. Remarkably, thiazolylpyrazoline derivatives were reported to display a variety of signiﬁcant

biological importance such as antimicrobial, antiviral, anti-inﬂammatory, antiamebic, and anticancer activities

and β -ketoacyl-acyl carrier protein synthase III (FabH), epidermal growth factor receptor tyrosine kinase

(EGFR TK) inhibitors, superoxidase inhibitors, and free radical scavengers.⁹⁻¹⁶

In a recent study, in silico molecular docking simulation was performed to position thiazolylpyrazoline

derivatives in the DNA topoisomerase IV receptor structure active site to determine the probable binding

model.¹⁷This study revealed that all the molecules showed good binding energy toward the target receptor

DNA topoisomerase IV. Thiazolylpyrazoline derivatives have been tested for antimicrobial activity and some

compounds showed good activity proﬁles against tested microbes. In another study, some thiazolylpyrazoline

derivatives were synthesized and evaluated for their antifungal activity. According to the in silico molecular

docking study, the compounds possessed the required binding energy to dock themselves with the binding

pocket of Cytochrome P₄₅₀14α-sterol demethylase (CYP51). The synthesized compounds showed signiﬁcant

antifungal activity, which has been fully supported by an in silico molecular docking study.¹⁸

Keeping in view the therapeutic importance of thiazolylpyrazoline derivatives and in continuation of our

work on the synthesis of biologically active thiazolylpyrazoline compounds, herein we describe the synthesis and

evaluation of the antimicrobial and cytotoxic activities of novel molecules.¹⁹⁻²⁴

2. Results and discussion

2.1. Chemistry

The synthesis of thiazolylpyrazoline derivatives (7a–7j, 8a, 8b, 9a, 9b) was carried out according to the steps

outlined in Schemes 1 and 2. The intermediate products, 1-(4’-methoxyphenyl)-3-(5,6,7,8,-tetrahydronaphthalen-

2-yl)-2-propen-1-one (1) and 1-(4’-methoxyphenyl)-3-phenylprop-2-en-1-one (2), were synthesized via the base-

catalyzed Claisen–Schmidt condensation of 4-methoxyacetophenone with 5,6,7,8-tetrahydronaphthalene-2-car-

baldehyde and benzaldehyde, respectively. Likewise 3-phenyl-1-(5,6,7,8-tetrahydronaphthalene-2-yl)prop-2-en-

1-one (3) was obtained by the condensation of 1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone with benzalde-

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TABBI et al./Turk J Chem

hyde. Secondly, the cyclization of chalcones (1–3) with thiosemicarbazide in the presence of sodium hy-

droxide led to 3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1-thiocarbamoyl-2-pyrazoline (4), 3-

(4’-methoxyphenyl)-5-phenyl-1-thiocarbamoyl-2-pyrazoline (5), and 5-phenyl-3-(5,6,7,8-tetrahydronaphthalen-

2-yl)-1-thiocarbamoyl-2-pyrazoline (6), respectively. Finally, reactions of 4, 5, and 6 with phenacylbromide

derivatives gave compounds 7a–7j, 8a, 8b, 9a, and 9b (Table 1).

O

1

a

b

N

O

H₂N

S

4

O

2

c

b

N

O

H₂N

S

O

5

O

N

O

c

b

3

N

H₂N

S

6

a: 5,6,7,8-Tetrahydronaphthalene-2-carbaldehyde / NaOH, b: Thiosemicarbazide / NaOH,

c: Benzaldehyde / NaOH

Scheme 1. Synthesis of intermediate compounds.

The structures of the compounds were elucidated by IR, ¹H NMR, ¹³C NMR, and MS spectral data.

The spectral analysis for intermediate original compound 4 was given, but the spectral analysis for compounds

5 and 6, which were examined in previous studies, was not given.^19,25In the IR spectra of the ﬁnal compounds

7a–7j, 8a, 8b, 9a, and 9b, C=N and C=C stretching vibrations were observed in the region 1630–1450 cm⁻¹

The aromatic C–H stretching vibrations gave rise to bands at 3117–3015 cm⁻¹

.

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TABBI et al./Turk J Chem

R₁

O

R₂

Br

R₃

R₄

4

5

6

O

N

R₁

S

N

S

R₂

R₃

R₄

7a-j

8a-b

9a-b

Scheme 2. Synthesis of title compounds.

Table 1. Some properties of the compounds.

Compounds R₁

R₂

H

Cl

O–CH₂–O

NO₂

H

R₃

F

Cl

R₄

H

Molecular formula Yield (%) Mp (^◦C)

7a

7b

7c

7d

7e

7f

7g

7h

7i

H

C₂₉H₂₆FN₃OS

C₂₉H₂₆ClN₃OS

C₂₉H₂₆BrN₃OS

C₃₀H₂₉N₃OS

89

91

87

82

80

91

80

85

84

88

82

80

78

192

193

187

178

172

221

171

194

170

164

213

212

176

185

Br

CH₃

OCH₃

NO₂

Cl

C₃₀H₂₉N₃O₂S

C₂₉H₂₆N₄O₃S

C₂₉H₂₅Cl₂N₃OS

C₃₀H₂₇N₃O₃S

C₂₉H₂₆N₄O₃S

H

Cl

CH₃

7j

OCH₃

H

OH

H

OCH₃C₃₁H₃₁N₃O₃S

8a

8b

9a

9b

H

C₂₅H₂₁N₃OS

C₂₅H₂₁N₃O₂S

C₂₈H₂₆ClN₃S

C₂₉H₂₇N₃S

H

In the ¹H NMR spectra, C₆and C₇protons resonated as multiplets at δ 1.77–1.83 ppm and C₅and

C₈protons at 2.70–2.80 ppm, corresponding to tetrahydronaphthalenes; the methylene of the pyrazoline ring

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TABBI et al./Turk J Chem

resonated as a pair of doublets of doublets at δ 3.30–3.40 ppm (H_A) and 3.85–3.92 ppm (H_B). The CH proton

(H_X) at position 5 of the pyrazoline ring appeared as a doublet of doublets or a broad signal at δ 5.60–5.68 ppm

due to vicinal coupling with the two magnetically nonequivalent protons of the methylene group at position 4

of pyrazoline (Figure). All the other aromatic and aliphatic protons were observed at expected regions.

H_A

Ar

H_B

N

H_X

N

Ar

S

Ar

Figure. ABX system of pyrazoline ring.

¹³C NMR chemical shift values of the carbon atoms at 43.61–44.62 ppm (pyrazoline C₄), 64.42–64.88

ppm (pyrazoline C₅), and about 148.20–161.10 ppm (pyrazoline C₃) corroborate the 2-pyrazoline character

deduced from the ¹H NMR data. All the other aromatic and aliphatic carbon atoms were observed at expected

regions.

The mass spectra (EIMS) of the compounds (7a–7j, 8a, 8b, 9a, and 9b) are also in agreement with

their molecular formula.

2.2. Biology

MICs were recorded as the minimum concentration of a compound that inhibits the growth of tested microor-

ganisms. All of the compounds tested illustrated signiﬁcant antibacterial and antifungal activity when compared

with reference drugs. When compared with chloramphenicol (MIC = 200 µg/mL), all of the compounds and

chloramphenicol showed the same level of activity against K. pneumoniae (ATCC-700603) and P. aeruginosa

(ATCC-27853) (Table 2). A similar result was obtained from E. coli (ATCC-25923): compound 7c showed the

same level of activity when compared with chloramphenicol. When compared with ketoconazole (MIC = 2 and

3.125 µg/mL), all of the compounds showed low activity against the tested fungi.

The necessity when generating a chemotherapeutic agent is to show minimal or no side-eﬀects on healthy

cells in patients receiving chemotherapy. The cytotoxic activities of these compounds were evaluated against a

normal mouse embryonic ﬁbroblast cell line, NIH/3T3, for determining the selectivity of potential antimicrobial

agents.

When we evaluated the eﬀects of the synthesized compounds against the NIH/3T3 cell line (healthy),

most of the compounds were found to have higher IC₅₀values (Table 2) than their eﬀective doses (MIC = 200

µg/mL), which were also the same as the positive control, chloramphenicol, against K. pneumoniae and P.

aeruginosa. Thus, they may be regarded as nontoxic at their eﬀective antibacterial doses. Only compounds 8a

and 8b exhibited antimicrobial activity with MIC values lower than their IC₅₀values against K. pneumonia

and P. aeruginosa as a result of cytotoxicity.

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Table 2. Antimicrobial activity and cytotoxicity of the compounds (µg/mL).

A

B

C

D

E

F

G

H

I

J

K

L

Cyt.

7a

7b

7c

7d

7e

7f

7g

7h

7i

400 400 400 400 200 200 400 400 200 200 100

400 400 400 400 200 200 400 200 200 200 100

400 400 400 400 200 200 400 400 200 200 100

100

-

> 500

301.63

371.60

> 500

-

7j

8a

8b

9a

9b

Ref.1 6.25 25

Ref.2

200 25

-

200 200 200 200

-

2

-

2

-

3.125 3.125

-

A: S. aureus, B: E. faecalis (ATCC-29212), C: E. faecalis (ATCC-51922), D: L. monocytogenes, E: K. pneumonia,

F: P. aeruginosa, G: E. coli (ATCC-35218), H: E. coli (ATCC-25923), I: C. albicans, J: C. glabrata, K: C. krusei,

L: C. parapsilopsis,

Ref.1: Chloramphenicol, Ref.2: Ketoconazole, Cyt (Cytotoxicity): IC₅₀values for cell lines (NIH3T3)

3. Conclusion

All the synthesized compounds showed antibacterial activity against K. pneumoniae and P. aeruginosa, with a

MIC value of 200 µg/mL. They did not show any cytotoxicity against ﬁbroblasts. The results mentioned above

suggest that thiazolylpyrazolines have potential as antibacterial compounds that are worth being investigated

further for the development of new drugs to treat infectious diseases.

4. Experimental

4.1. General remarks

All chemicals were purchased from commercial suppliers and used without puriﬁcation. Melting point (mp)

was determined on an Electrothermal 9100 melting point apparatus (Weiss-Gallenkamp, Loughborough, UK)

and are uncorrected. Spectroscopic data were recorded with the following instruments: IR, Shimadzu 8400S

spectrophotometer (Shimadzu, Tokyo, Japan); NMR, Bruker 500 MHz spectrometer in CDCl₃using TMS

internal standard; and MS, LC/MS/MS Mass Spectrometer (3200 Q TRAP, AB Sciex Instruments, USA).

4.2. Chemistry

Chalcones (1, 2, 3): All chalcone derivatives were synthesized according to the literature.^19,25

4.2.1. General procedure for the synthesis of the intermediate compounds (4, 5, 6)

A mixture of chalcone (0.01 mol), thiosemicarbazide (0.012 mol), and sodium hydroxide (0.01 mol) was reﬂuxed

in ethanol (30 mL) for 8 h. The solution was poured into crushed ice. The precipitated solid was ﬁltered,

washed with water, and dried. The product was crystallized from ethanol.

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TABBI et al./Turk J Chem

4.2.1.1 3-(4’-Methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1-thiocarbamoyl-2-pyrazoline

(4)

Yield: 87%, mp 230 ^◦C. IR ν_max(cm⁻¹): 3470.7, 3375.2 (N–H stretching), 1560.9, 1510.4, 1467.5 (C=N and

C=C stretching), 1210.2, 1168.0, 1095.5, 1010.0 (C–N stretching and aromatic C–H bending). ¹H NMR (500

MHz, CDCl₃)δ (ppm): 1.72–1.83 (4H, m, tetrahydronaphthalene C_6,7–H), 2.70–2.78 (4H, m, tetrahydronaph-

thalene C_5,8–H), 3.20 (1H, dd, J = 17.5 Hz, J = 3.4 Hz, pyrazoline C₄–H), 3.74 (1H, dd, J = 17.41 Hz, J =

11.31 Hz, pyrazoline C₄–H), 3.88 (3H, s, OCH₃), 5.99 (1H, dd, J = 11.12 Hz, J = 2.68 Hz, pyrazoline C₅–H),

6.91 (1H, s, Ar–H), 6.95 (3H, d, J = 8.86 Hz, Ar–H), 7.03 (1H, d, J = 7.86 Hz, Ar–H), 7.70 (2H, d, J = 8.82

Hz, Ar–H).

4.2.2. General procedure for compounds 7a–7j

A mixture of 3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1-thiocarbamoyl-2-pyrazoline (4) (0.001

mol) and appropriate 2-bromoacetophenone derivative (0.001 mol) was reﬂuxed in ethanol (20 mL) for 4 h. The

reaction mixture was cooled and ﬁltered.

4.2.2.1. 4-(4’-Fluorophenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-

pyrazolin-1-yl]thiazole (7a)

IR ν_max(cm⁻¹): 3125.7, 3045.3 (aromatic C–H), 1620.9, 1500.3 (C=N and C=C stretching), 1220.4, 1170.1,

1055.2 (C–N stretching and aromatic C–H bending). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.75–1.86 (4H, m,

tetrahydronaphthalene C_6,7–H), 2.73–2.81 (4H, m, tetrahydronaphthalene C_5,8–H), 3.35 (1H , dd, J = 17.37

Hz, J = 6.42 Hz, pyrazoline C₄–H), 3.89 (1H, dd, J = 16.75 Hz, J = 12.90 Hz, pyrazoline C₄–H), 3.90 (3H, s,

OCH₃), 5.62–5.73 (1H, br, pyrazoline C₅–H), 6.73 (1H, s, thiazole–H), 6.97 (2H, d, J = 8.83 Hz, Ar–H), 7.02

(2H, d, J = 8.71 Hz, Ar–H), 7.08 (2H, d, J = 8.37 Hz, Ar–H), 7.17 (1H, d, J = 6.52 Hz, Ar–H), 7.70–7.74

(2H, m, Ar–H), 7.75 (2H, d, J = 8.71 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.16 (2CH₂), 29.15 (CH₂), 29.48 (CH₂), 43.71 (pyrazoline

C₄), 55.41 (OCH₃), 64.43 (pyrazoline C₅), 102.46 (thiazole C₅), 114.17, 115.32, 128.09, 129.44 (2CH, Ar–C),

124.14, 130.89, 136.79, 137.40, 138.65 (Ar–C), 123.80 127.61, 127.72 (Ar–CH), 157.37 (thiazole C₂), 161.10

(pyrazoline C₃), 161.39 (C–OCH₃), 163.35 (C–F), 165.27 (S–C=N).

For C₂₉H₂₆FN₃OS calculated: (%) C 72.03, H 5.42, N 8.69; found: (%) C 72.08, H 5.38, N 8.56.

MS [M+1]⁺: m/z 484

4.2.2.2. 4-(4’-Chlorophenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-

pyrazolin-1-yl]thiazole (7b)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.75–1.86 (4H, m, tetrahydronaphthalene C_6,7–H), 2.73–2.81 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.35 (1H, dd, J = 17.37 Hz, J = 6.42 Hz, pyrazoline C₄–H), 3.72–3.76 (1H,

dd, J = 16.75 Hz, J = 12.90 Hz, pyrazoline C₄–H), 3.90 (3H, s, OCH₃), 5.62–5.73 (1H, br, pyrazoline C₅–H),

6.79 (1H, s, thiazole–H), 6.97 (2H, d, J = 8.83 Hz, Ar–H), 7.07 (1H, d, J = 8.38 Hz, Ar–H), 7.18 (2H, br,

Ar–H), 7.32 (2H, d, J = 8.55 Hz, Ar–H), 7.68 (2H, d, J = 8.54 Hz, Ar–H), 7.74 (2H, d, J = 8.89 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.16 (2CH₂), 29.16 (CH₂), 29.49 (CH₂), 43.67 (pyrazoline

C₄), 55.41 (OCH₃), 64.43 (pyrazoline C₅), 103.35 (thiazole C₅), 114.17, 127.26, 128.07, 128.52 (2CH, Ar–C),

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TABBI et al./Turk J Chem

123.82, 127.68, 129.28 (Ar–CH), 124.16, 133.07, 136.79, 137.38, 138.69 (Ar–C), 149.94 (thiazole C₂), 152.15

(pyrazoline C₃), 161.08 (C-OCH₃), 165.27 (S–C=N).

MS [M+1]⁺: m/z 500

4.2.2.3. 4-(4’-Bromophenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-

pyrazolin-1-yl]thiazole (7c)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.76–1.85 (4H, m, tetrahydronaphthalene C_6,7–H), 2.73–2.82 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.36 (1H, dd, J = 17.39 Hz, J = 6.57 Hz, pyrazoline C₄–H), 3.87 (1H, dd, J

= 17.39 Hz, J = 11.89 Hz, pyrazoline C₄–H), 3.88 (3H, s, OCH₃), 5.58–5.67 (1H, br, pyrazoline C₅–H), 6.80

(1H, s, thiazole–H), 6.97 (2H, d, J = 8.91 Hz, Ar–H), 7.06 (1H, d, J = 8.39 Hz, Ar–H), 7.17 (2H, m, Ar–H),

7.47 (2H, d, J = 8.60 Hz, Ar–H), 7.62 (2H, d, J = 8.54 Hz, Ar–H), 7.74 (2H, d, J = 8.87 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.16 (2CH₂), 29.16 (CH₂), 29.49 (CH₂), 43.67 (pyrazoline

C₄), 55.41 (OCH₃), 64.44 (pyrazoline C₅), 103.48 (thiazole C₅), 114.17, 127.57, 128.07, 131.46 (2CH, Ar-C),

121.29, 133.76, 136.79, 137.38, 138.66 (Ar–C), 123.82,127.68, 129.45 (Ar–CH), 149.90 (thiazole C₂), 152.23

(pyrazoline C₃), 161.08 (C–OCH₃), 165.27 (S–C=N).

MS [M+1]⁺: m/z 546

4.2.2.4. 4-(4’-Methylphenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-

pyrazolin-1-yl]thiazole (7d)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.75–1.85 (4H, m, tetrahydronaphthalene C_6,7–H), 2.38 (3H, s, CH₃),

2.72–2.84 (4H, m, tetrahydronaphthalene C_5,8–H), 3.35 (1H, dd, J = 17.36 Hz, J = 6.55 Hz, pyrazoline C₄–H),

3.86 (1H, dd, J = 17.35 Hz, i=11.91 Hz, pyrazoline C₄–H), 3.88 (3H, s, OCH₃), 5.59–5.68 (1H, br, pyrazoline

C₅–H), 6.76 (1H, s, thiazole–H), 6.97 (2H, d, J = 8.91 Hz, Ar–H), 7.06 (1H, d, J = 8.45 Hz, Ar–H), 7.17 (2H,

d, J = 8.14 Hz, Ar–H), 7.18 (1H, s, Ar–H), 7.19 (1H, d, J = 6.52 Hz, Ar–H), 7.65 (2H, d, J = 8.11 Hz, Ar–H),

7.74 (2H, d, J = 8.88 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 21.25 (CH₃), 23.18 (2CH₂), 29.47 (CH₂), 29.73 (CH₂), 43.61

(pyrazoline C₄), 55.40 (OCH₃), 64.42 (pyrazoline C₅), 102.19 (thiazole C₅), 114.15, 123.86, 125.93, 129.41

(2CH, Ar–C), 124.27, 132.06, 136.69, 137.33, 138.76 (Ar–C), 127.72, 128.04, 129.41 (Ar–CH), 151.05 (thiazole

C₂), 152.02 (pyrazoline C₃), 161.01 (C-OCH₃), 165.14 (S–C=N).

MS [M+1]⁺: m/z 480

4.2.2.5. 4-(4’-Methoxyphenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-

pyrazolin-1-yl]thiazole (7e)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.74–1.85 (4H, m, tetrahydronaphthalene C_6,7–H), 2.70–2.84 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.35 (1H, dd, J = 17.37 Hz, J = 6.36 Hz, pyrazoline C₄–H), 3.84 (3H, s,

OCH₃), 3.87 (1H, dd, J = 17.50 Hz, J = 10.00 Hz, pyrazoline C₄–H), 3.8 (3H, s, OCH₃), 5.60–5.83 (1H, br,

pyrazoline C₅–H), 6.67 (1H, s, thiazole–H), 6.90 (2H, d, J = 8.80 Hz, Ar–H), 6.97 (2H, d,J = 8.84 Hz, Ar–H),

7.06 (1H, d, J = 8.20 Hz, Ar–H), 7.18 (1H, s, Ar–H), 7.19 (1H, d, J = 7.00 Hz, Ar–H), 7.70 (2H, d, J = 8.79

Hz, Ar–H), 7.74 (2H, d, J = 8.84 Hz, Ar–H).

648

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¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.15 (2CH₂), 29.16 (CH₂), 29.47 (CH₂), 43.76 (pyrazoline

C₄), 55.30 (OCH₃), 55.41 (OCH₃), 64.43 (pyrazoline C₅), 101.00 (thiazole C₅), 113.84, 114.18, 123.84, 129.45

(2CH, Ar–C), 127.41, 127.57, 128.18 (Ar–CH), 124.06, 129.36, 136.81, 137.44, 138.55 (Ar–C), 156.41 (thiazole

C₂), 159.32 (pyrazoline C₃), 161.08 (C–OCH₃), 161.18 (C–OCH₃), 165.09 (S–C=N).

MS [M+1]⁺: m/z 496

4.2.2.6. 4-(4’-Nitrophenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyra-

zolin-1-yl]thiazole (7f)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.77–1.84 (4H, m, tetrahydronaphthalene C_6,7–H), 2.74–2.82 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.40 (1H, dd, J = 17.43 Hz, J = 6.15 Hz, pyrazoline C₄–H), 3.89 (3H, s,

OCH₃), 3.93 (1H, dd, J = 17.43 Hz, J = 11.76 Hz, pyrazoline C₄–H), 5.76–5.85 (1H, br, pyrazoline C₅–H),

6.98 (2H, d, J = 8.87 Hz, Ar–H), 7.01 (1H, s, thiazole–H), 7.08 (1H, d, J = 8.35 Hz, Ar–H), 7.18 (1H, s,

Ar–H), 7.19 (1H, d, J = 6.86 Hz, Ar–H), 7.76 (2H, d, J = 8.88 Hz, Ar–H), 7.89 (2H, d, J = 8.91 Hz, Ar–H),

8.22 (2H, d, J = 8.95 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.11 (2CH₂), 29.15 (CH₂), 29.50 (CH₂), 43.90 (pyrazoline

C₄), 55.44 (OCH₃), 64.47 (pyrazoline C₅), 106.91 (thiazole C₅), 114.25, 123.93, 126.55, 128.27 (2CH, Ar–C),

123.76, 127.55, 129.56 (Ar–CH), 123.40, 137.09, 137.57, 138.12, 140.04 (Ar–C), 146.86 (thiazole C₂), 148.20

(pyrazoline C₃), 161.38 (C–OCH₃), 165.37 (S–C=N).

MS [M+1]⁺: m/z 511

4.2.2.7. 4-(3’,4’-Dichlorophenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-

2-pyrazolin-1-yl]thiazole (7g)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.75–1.86 (4H, m, tetrahydronaphthalene C_6,7–H), 2.70–2.80 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.36 (1H, dd, J = 17.44 Hz, J = 6.77 Hz, pyrazoline C₄–H), 3.87 (1H, dd, J

= 17.50 Hz, J = 10.00 Hz, pyrazoline C₄–H), 3.88 (3H, s, OCH₃), 5.19–5.36 (1H, br, pyrazoline C₅–H), 6.79

(1H, s, thiazole–H), 6.97 (2H, d, J = 8.84 Hz, Ar–H), 7.07 (1H, d, J = 8.00 Hz, Ar–H), 7.15 (1H, dd, J = 9.5

Hz, J = 1.62 Hz, Ar–H), 7.19 (1H, s, Ar–H), 7.38 (1H, d, J = 8.40 Hz, Ar–H), 7.52 (1H, dd, J = 8.38 Hz, J

= 2.02 Hz, Ar–H), 7.73 (2H, d, J = 8.85 Hz, Ar–H), 7.81 (1H, d, J = 1.98 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.14 (2CH₂), 29.15 (CH₂), 29.45 (CH₂), 43.67 (pyrazoline

C₄), 55.40 (OCH₃), 64.54 (pyrazoline C₅), 104.31 (thiazole C₅), 114.18, 128.08 (2CH, Ar–C), 123.73, 124.96,

127.89, 128.04, 129.53, 130.24 (Ar–CH), 124.06, 129.57, 131.01, 132.46, 136.89, 137.41, 138.47 (Ar–C), 148.66

(thiazole C₂), 152.47 (pyrazoline C₃), 161.13 (C–OCH₃), 165.28 (S–C=N).

MS [M+1]⁺: m/z 534

4.2.2.8. 4-(Benzo[1,3]dioxol-5-yl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-

2-pyrazolin-1-yl]thiazole (7h)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.71–1.81 (4H, m, tetrahydronaphthalene C_6,7–H), 2.68–2.80 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.45 (1H, dd, J = 17.55 Hz, J = 3.55 Hz, pyrazoline C₄–H), 3.90 (3H, s,

OCH₃), 4.01 (1H, dd, J = 17.57 Hz, J = 6.45 Hz, pyrazoline C₄–H), 5.95–6.02 (1H, br, pyrazoline C₅–H),

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TABBI et al./Turk J Chem

6.00 (2H, s, dioxolane), 6.53 (1H, s, thiazole–H), 6.87 (1H, d, J = 8.15 Hz, Ar–H), 7.00 (2H, d, J = 8.85 Hz,

Ar–H), 7.05 (1H, d, J = 7.93 Hz, Ar–H), 7.22 (1H, s, Ar–H), 7.25 (1H, s, Ar–H), 7.41 (1H, d, J = 8.12 Hz,

Ar–H), 7.67 (1H, d, J = 8.81 Hz, Ar–H), 7.78 (2H, d, J = 9.23 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 22.99 (2CH₂), 29.17 (CH₂), 29.43 (CH₂), 44.62 (pyrazoline

C₄), 55.51 (OCH₃), 64.57 (pyrazoline C₅), 101.43 (thiazole C₅), 107.16 (CH₂–dioxolane), 114.42, 123.74

(2CH, Ar–C), 108.62, 113.99, 123.64, 127.22, 129.18, 129.88 (Ar–CH), 121.64, 128.46, 134.37, 136.91, 138.07

(Ar–C), 144.34 (thiazole C₂), 147.98, 148.73 (2C–dioxolane), 149.84 (pyrazoline C₃), 162.37 (C–OCH₃), 164.64

(S–C=N).

MS [M+1]⁺: m/z 510

4.2.2.9. 4-(3’-Nitrophenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyra-

zolin-1-yl]thiazole (7i)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.75–1.85 (4H, m, tetrahydronaphthalene C_6,7–H), 2.73–2.89 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.39 (1H, dd, J = 17.43 Hz, J = 6.69 Hz, pyrazoline C₄–H), 3.90 (1H, dd, J

= 17.37 Hz, J = 11.94 Hz, pyrazoline C₄–H), 3.89 (3H, s, OCH₃), 5.57–5.67 (1H, br, pyrazoline C₅–H), 6.94

(1H, s, thiazole–H), 6.99 (2H, d, J = 8.94 Hz, Ar–H), 7.10 (1H, d, J = 8.37 Hz, Ar–H), 7.21 (1H, d, J = 6.76

Hz, Ar–H), 7.22 (1H, s, Ar–H), 7.50 (1H, t, J = 7.97 Hz, Ar–H), 7.75 (2H, d, J = 8.84 Hz, Ar–H), 8.03 (1H,

d, J = 7.82 Hz, Ar–H), 7.74 (1H, dd, J = 8.15 Hz, J = 1.4 Hz, Ar–H), 8.59 (1H, s, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.14 (2CH₂), 29.17 (CH₂), 29.43 (CH₂), 43.75 (pyrazoline

C₄), 55.42 (OCH₃), 64.56 (pyrazoline C₅), 105.13 (thiazole C₅), 114.20, 128.10 (2CH, Ar–C), 121.05, 121.92,

123.93, 127.71, 129.21, 129.57, 131.43 (Ar–CH), 124.04, 136.49, 136.96, 137.57, 138.52 (Ar–C), 148.59 (C–NO₂),

148.72 (thiazole C₂), 152.53 (pyrazoline C₃), 161.17 (C–OCH₃), 165.44 (S–C=N).

MS [M+1]⁺: m/z 511

4.2.2.10. 4-(2’,5’-Dimethoxyphenyl)-2-[3-(4’-methoxyphenyl)-5-(5,6,7,8-tetrahydronaphthalen-2-

yl)-2-pyrazolin-1-yl]thiazole (7j)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.74–1.85 (4H, m, tetrahydronaphthalene C_6,7–H), 2.69–2.82 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.33 (1H, dd, J = 17.43 Hz, J = 7.06 Hz, pyrazoline C₄–H), 3.80 (3H, s,

OCH₃), 3.87 (3H, s, OCH₃), 3.88 (1H, dd, J = 15.00 Hz, J = 10.00 Hz, pyrazoline C₄–H), 3.89 (3H, s,

OCH₃), 5.57–5.81 (1H, br, pyrazoline C₅–H), 6.79 (1H, dd, J = 8.87 Hz, J = 3.03 Hz, Ar–H), 6.85 (1H, s,

thiazole–H), 6.97 (2H, d, J = 8.94 Hz, Ar–H), 7.04 (1H, d, J = 7.83 Hz, Ar–H), 7.19 (1H, s, Ar–H), 7.21 (1H,

d, J = 8.00 Hz, Ar–H), 7.35 (1H, m, Ar–H), 7.58 (1H, d, J = 3.03 Hz, Ar–H), 7.74 (2H, d, J = 8.60 Hz,

Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.16 (2CH₂), 29.17 (CH₂), 29.42 (CH₂), 43.92 (pyrazoline

C₄), 55.41 (OCH₃), 55.69 (OCH₃), 56.03 (OCH₃), 64.83 (pyrazoline C₅), 108.21 (thiazole C₅), 114.16, 129.35

(2CH, Ar–C), 112.42, 114.44, 123.92, 127.33, 128.06 (Ar–CH), 124.20, 136.61, 137.44, 138.95 (Ar–C), 151.33

(thiazole C₂), 153.53 (pyrazoline C₃), 161.06 (C–OCH₃), 163.53 (S–C=N).

MS [M+1]⁺: m/z 526

650

TABBI et al./Turk J Chem

4.2.3. General procedure for compounds 8a, 8b

A mixture of 3-(4’-methoxyphenyl)-5-phenyl-2-pyrazolin-1-carbothioamide (5) (0.001 mol) and 2-bromoacetophe-

none (0.001 mol) in ethanol (20 mL) was reﬂuxed for 4 h. The reaction mixture was cooled and ﬁltered.

4.2.3.1. 2-[3-(4’-Methoxyphenyl)-5-phenyl-2-pyrazolin-1-yl]-4-phenylthiazole (8a)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.36 (1H, dd, J = 17.34 Hz, J = 6.36 Hz, pyrazoline C₄–H), 3.89 (3H,

s, OCH₃), 3.93 (1H, dd, J = 17.34 Hz, J = 11.87 Hz, pyrazoline C₄–H), 5.78–5.89 (1H, br, pyrazoline C₅–H),

6.81 (1H, s, thiazole–H), 6.98 (2H, d, J = 8.91 Hz, Ar–H), 7.27–7.42 (6H, m, Ar–H), 7.48 (2H, d, J = 8.37 Hz,

Ar–H), 7.71 (2H, d, J = 8.47 Hz, Ar–H), 7.75 (2H, d, J = 8.89 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 43.80 (pyrazoline C₄), 55.42 (OCH₃), 64.62 (pyrazoline C₅),

103.02 (thiazole C₅), 114.20, 126.01, 126.67, 128.13, 128.43, 128.73 (2CH, Ar–C), 126.55, 127.78 (CH), 124.00,

127.66, 141.54 (C), 145 (thiazole C₂), 150.05 (pyrazoline C₃), 161.18 (C–OCH₃), 165.12 (S–C=N).

MS [M+1]⁺: m/z 412

4.2.3.2. 2-[2-(3-(4’-Methoxyphenyl)-5-phenyl-2-pyrazolin-1-yl]thiazol-4-yl]phenol (8b)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 3.33 (1H, dd, J = 17.47 Hz, J = 7.06 Hz, pyrazoline C₄–H), 3.88 (3H,

s, OCH₃), 3.94 (1H, dd, J = 17.47 Hz, J = 11.83 Hz, pyrazoline C₄–H), 5.56 (1H, dd, J = 11.79 Hz, J =

7.00 Hz, pyrazoline C₅–H), 6.80 (1H, two d, J = 7.10 Hz, J = 1.18 Hz, Ar–H), 6.81 (1H, s, thiazole–H), 6.91

(1H, d, J = 8.17 Hz, Ar–H), 6.98 (2H, d, J = 8.89 Hz, Ar–H), 7.15 (1H, two d, J = 7.23 Hz, J = 1.61 Hz,

Ar–H), 7.33 (2H, d, J = 8.88 Hz, Ar–H), 7.35 (1H, m, Ar–H), 7.42 (4H, m, Ar–H), 7.49 (1H, dd, J = 7.84 Hz,

J = 1.56 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 44.44 (pyrazoline C₄), 55.43 (OCH₃), 64.88 (pyrazoline C₅),

101.66 (thiazole C₅), 114.27, 126.10, 128.24, 129.31 (2CH, Ar–C), 117.71, 119.12, 125.80, 128.32, 129.54 (CH),

123.59, 125.93, 140.67 (C), 148.78 (thiazole C₂), 153.19 (pyrazoline C₃), 155.73 (C–OH), 161.40 (C–OCH₃),

164.82 (S–C=N).

MS [M+1]⁺: m/z 428

4.2.4. General procedure for compounds 9a, 9b

A mixture 5-phenyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyrazolin-1-carbothioamide (6) and 2-bromoacetophe-

none (0.001 mol) in ethanol (20 mL) was reﬂuxed for 4 h. The reaction mixture was cooled and ﬁltered.

4.2.4.1. 2-[5-Phenyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyrazolin-1-yl]-4-(4’-chlorophenyl)]

thiazole (9a)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.80–1.91 (4H, m, tetrahydronaphthalene C_6,7–H), 2.79–2.90 (4H, m,

tetrahydronaphthalene C_5,8–H), 3.36 (1H, dd, J = 17.42 Hz, J = 6.42 Hz, pyrazoline C₄–H), 3.92 (1H, dd, J

= 17.42 Hz, J = 11.92 Hz, pyrazoline C₄–H), 5.72–5.84 (1H, br, pyrazoline C₅–H), 6.80 (1H, s, thiazole–H),

7.15 (1H, d, J = 7.97 Hz, Ar–H), 7.29 (1H, m, Ar–H), 7.30 (2H, d, J = 8.59 Hz, Ar–H), 7.38 (2H, t, J = 7.36

Hz, Ar–H), 7.45 (2H, d, J = 7.32 Hz, Ar–H), 7.48 (1H, s, Ar–H), 7.53 (1H, dd, J = 7.85 Hz, J = 1.18 Hz,

Ar–H), 7.62 (2H, d, J = 8.52 Hz, Ar–H).

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¹³C NMR (500 MHz, CDCl₃) δ (ppm): 23.02–23.07 (2CH₂– tetrahydronaphthalene), 29.43–29.49

(2CH₂–tetrahydronaphthalene), 43.76 (pyrazoline C₄), 64.59 (pyrazoline C₅), 103.47 (thiazole C₅), 126.60,

127.22, 128.56, 128.72 (2CH, Ar–C), 123.67, 127.18, 127.78, 129.54 (CH), 128.47, 129.23, 133.18, 137.61, 139.77,

141.61 (C), 149.81 (thiazole C₂), 152.81 (pyrazoline C₃), 165.14 (S–C=N).

MS [M+1]⁺: m/z 470

4.2.4.2. 2-[5-Phenyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-2-pyrazolin-1-yl]-4-(4’-methylphenyl)]

thiazole (9b)

¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.80–1.89 (4H, m, tetrahydronaphthalene C_6,7–H), 2.36 (3H, s, CH₃),

2.79–2.88 (4H, m, tetrahydronaphthalene C_5,8–H), 3.36 (1H, dd, J = 17.42 Hz, J = 6.27 Hz, pyrazoline C₄–H),

3.92 (1H, dd, J = 17.40 Hz, J = 11.91 Hz, pyrazoline C₄–H), 5.76–5.92 (1H, br, pyrazoline C₅–H), 6.75 (1H,

s, thiazole–H), 7.13 (1H, s, Ar–H) 7.15 (2H, d, J = 8.00 Hz, Ar–H), 7.29 (1H, m, Ar–H), 7.37 (2H, t, J = 7.83

Hz, Ar–H), 7.47 (2H, dd, J = 8.50 Hz, J = 1.15 Hz, Ar–H), 7.48 (1H, s, Ar–H), 7.54 (1H, dd, J = 7.91 Hz,

J = 1.6 Hz, Ar–H), 7.60 (2H, d,J = 8.12 Hz, Ar–H).

¹³C NMR (500 MHz, CDCl₃) δ (ppm): 21.24 (1H, s, CH₃), 23.03–23.07 (2CH₂– tetrahydronaphthalene),

29.42–29.49 (2CH₂–tetrahydronaphthalene), 43.71 (pyrazoline C₄), 64.58 (pyrazoline C₅), 102.25 (thiazole C₅),

125.92, 126.67, 128.69, 129.11 (2CH, Ar–C), 123.68, 127.19, 127.73, 129.52 (CH), 128.53, 137.39, 137.59, 139.73,

141,70 (C), 149.65 (thiazole C₂), 152.65 (pyrazoline C₃), 164.98 (S–C=N).

MS [M+1]⁺: m/z 450

4.3. Microbiology

The microbiological assay was carried out according to the CLSI reference M7-A7 broth microdilution method.²⁶

Chloramphenicol and ketoconazole were used as reference drugs. In the current work, thiazolylpyrazoline deriva-

tives (7a–7j, 8a, 8b, 9a, and 9b) were tested for their in vitro antimicrobial activity against Staphylococcus

aureus (ATCC-25923), E. faecalis (ATCC-29212), E. faecalis (ATCC-51922), L. monocytogenes (ATCC-1911),

K. pneumoniae (ATCC-700603), P. aeruginosa (ATCC-27853), E. coli (ATCC-35218), E. coli (ATCC-25922),

C. albicans (ATCC-90028), C. glabrata (ATCC-90030), C. krusei (ATCC-6258), and C. parapsilosis (ATCC-

22019) (Table 2).

4.4. Cytotoxicity

Cytotoxicity tests were performed using the MTT assay. The tetrazolium salt MTT [3-(4,5-dimethylthiazol-

2-yl)-2,5-diphenyltetrazolium bromide] is used to measure the metabolic activity of viable cells. Tetrazolium

salts are reduced to formazan by mitochondrial succinate dehydrogenase, an enzyme that is only active in cells

with an intact metabolism. The formazan can be quantiﬁed photometrically and it is in correlation with the

number of viable cells.²⁷Cytotoxicity was tested using NIH3T3 (mouse embryonic ﬁbroblast cell line) cells.

NIH3T3 cells were incubated in RPMI medium (Hyclone, Thermo Scientiﬁc, USA) supplemented with fetal

calf serum (Hyclone, Thermo Scientiﬁc, USA), 100 IU/mL penicillin and 100 mg/mL streptomycin (Hyclone,

Thermo Scientiﬁc, USA) at 37 ^◦C in a humidiﬁed atmosphere of 95% air and 5% CO₂. NIH3T3 cells were

seeded at 10,000 cells into each well of 96-well plates. After 24 h of incubation, the culture media were removed

and compounds were added to culture medium in the range between 3.9 and 500 µg mL⁻¹concentrations

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TABBI et al./Turk J Chem

with a dilution factor of 2. After 24 h of incubation, 20 µL of MTT solution (5 mg mL⁻¹MTT powder in

PBS) was added to each well. After 3 h of incubation at 37 ^◦C, 5% CO₂, contents of the wells were removed

and 100 µL of dimethyl sulfoxide (DMSO) was added to each well. Then OD of the plate was read at 540

nm. Inhibition% was calculated for each concentration of the compounds and IC₅₀values were estimated by

nonlinear regression analysis. Stock solutions of compounds were prepared in dimethyl sulfoxide (DMSO) and

further dilutions were made with fresh culture medium. The ﬁnal DMSO concentration was under 0.1%. All

experiments were performed in triplicate (Table 2).²⁷

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Article Doi

Synthesis of novel thiazolylpyrazoline derivatives and evaluation of their antimicrobial activities and cytotoxicities

DOI: 10.3906/kim-1512-12

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Article abstract of DOI:10.3906/kim-1512-12

Full text of DOI:10.3906/kim-1512-12

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